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Entry
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- #312750 - RETT SYNDROME; RTT
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- OMIM
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<p>
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<span class="h4">#312750</span>
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<br />
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<strong>Table of Contents</strong>
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</p>
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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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<li role="presentation">
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<a href="/clinicalSynopsis/312750"><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="#mapping">Mapping</a>
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<a href="#molecularGenetics">Molecular Genetics</a>
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<a href="#genotypePhenotypeCorrelations">Genotype/Phenotype Correlations</a>
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<a href="#pathogenesis">Pathogenesis</a>
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<a href="#populationGenetics">Population Genetics</a>
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<a href="#history">History</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#animalModel">Animal Model</a>
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<li role="presentation">
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<a href="#seeAlso"><strong>See Also</strong></a>
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<li role="presentation">
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<a href="#references"><strong>References</strong></a>
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<li role="presentation">
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<a href="#contributors"><strong>Contributors</strong></a>
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<li role="presentation">
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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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</ul>
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<div style="display: table-cell;">External Links</div>
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</div>
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</a>
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</h4>
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</div>
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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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</a>
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<div id="mimClinicalResourcesLinksFold" class="panel-collapse collapse in mimLinksFold" role="tabpanel" aria-labelledby="clinicalResources">
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<div><a href="https://clinicaltrials.gov/search?cond=RETT SYNDROME" 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=3164&Typ=Pat" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'EuroGentest', 'domain': 'orpha.net'})">Atypical Rett syndrome </a></div><div style="margin-left: 0.5em;"><a href="https://www.orpha.net/consor/cgi-bin/ClinicalLabs_Search_Simple.php?lng=EN&LnkId=91&Typ=Pat" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'EuroGentest', 'domain': 'orpha.net'})">Rett syndrome </a></div>
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</div>
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<div><a href="https://www.ncbi.nlm.nih.gov/books/NBK1497/" 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/rett-syndrome" 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=312750[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=3095" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'OrphaNet', 'domain': 'orpha.net'})">Atypical Rett syndrome</a></div><div style="margin-left: 0.5em;"><a href="https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=778" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'OrphaNet', 'domain': 'orpha.net'})">Rett syndrome</a></div>
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</div>
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<div><a href="https://www.possumcore.com/nuxeo/nxdoc/default/987b8b45-1591-477e-8332-fbb496b7382f/view_documents?source=omim" class="mim-tip-hint" title="A dysmorphology database of multiple malformations; metabolic, teratogenic, chromosomal, and skeletal syndromes; and their images." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'POSSUM', 'domain': 'possum.net.au'})">POSSUM</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimAnimalModels">
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<span class="panel-title">
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<span class="small">
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<a href="#mimAnimalModelsLinksFold" id="mimAnimalModelsLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimAnimalModelsLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Animal Models</div>
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</div>
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</a>
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</span>
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<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:1206" 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/312750" 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/OMIA002406/" 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 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:312750" class="definition" title="Coriell Cell Repositories; cell cultures and DNA derived from cell cultures." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'CCR', 'domain': 'ccr.coriell.org'})">Coriell</a></div>
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<span>
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<span class="mim-tip-bottom" qtip_title="<strong>Looking for this gene or this phenotype in other resources?</strong>" qtip_text="Select a related resource from the dropdown menu and click for a targeted link to information directly relevant.">
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<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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<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> 68618008<br />
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<strong>ICD10CM:</strong> F84.2<br />
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<strong>ORPHA:</strong> 3095, 778<br />
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<strong>DO:</strong> 1206<br />
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">ICD+</a>
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</div>
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<div>
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<span class="h3">
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<span class="mim-font mim-tip-hint" title="Phenotype description, molecular basis known">
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<span class="text-danger"><strong>#</strong></span>
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312750
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</span>
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</span>
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<div>
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<a id="preferredTitle" class="mim-anchor"></a>
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<h3>
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RETT SYNDROME; RTT
|
|
|
|
</span>
|
|
</h3>
|
|
</div>
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<a id="alternativeTitles" class="mim-anchor"></a>
|
|
<div>
|
|
<p>
|
|
<span class="mim-font">
|
|
<em>Alternative titles; symbols</em>
|
|
</span>
|
|
</p>
|
|
</div>
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
RTS<br />
|
|
AUTISM, DEMENTIA, ATAXIA, AND LOSS OF PURPOSEFUL HAND USE
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
</div>
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<a id="includedTitles" class="mim-anchor"></a>
|
|
<div>
|
|
<p>
|
|
<span class="mim-font">
|
|
Other entities represented in this entry:
|
|
</span>
|
|
</p>
|
|
</div>
|
|
<div>
|
|
<span class="h3 mim-font">
|
|
RETT SYNDROME, ZAPPELLA VARIANT, INCLUDED
|
|
</span>
|
|
</div>
|
|
|
|
<div>
|
|
<span class="h4 mim-font">
|
|
|
|
RETT SYNDROME, PRESERVED SPEECH VARIANT, INCLUDED<br />
|
|
RETT SYNDROME, ATYPICAL, INCLUDED
|
|
</span>
|
|
</div>
|
|
|
|
</div>
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<a id="phenotypeMap" class="mim-anchor"></a>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>Phenotype-Gene Relationships</strong>
|
|
</span>
|
|
</h4>
|
|
<div>
|
|
<table class="table table-bordered table-condensed table-hover small mim-table-padding">
|
|
<thead>
|
|
<tr class="active">
|
|
<th>
|
|
Location
|
|
</th>
|
|
<th>
|
|
Phenotype
|
|
</th>
|
|
<th>
|
|
Phenotype <br /> MIM number
|
|
</th>
|
|
<th>
|
|
Inheritance
|
|
</th>
|
|
<th>
|
|
Phenotype <br /> mapping key
|
|
</th>
|
|
<th>
|
|
Gene/Locus
|
|
</th>
|
|
<th>
|
|
Gene/Locus <br /> MIM number
|
|
</th>
|
|
</tr>
|
|
</thead>
|
|
<tbody>
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/geneMap/X/851?start=-3&limit=10&highlight=851">
|
|
Xq28
|
|
</a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
Rett syndrome
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/312750"> 312750 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="X-linked dominant">XLD</abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
MECP2
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/300005"> 300005 </a>
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/geneMap/X/851?start=-3&limit=10&highlight=851">
|
|
Xq28
|
|
</a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
Rett syndrome, atypical
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/312750"> 312750 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="X-linked dominant">XLD</abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
MECP2
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/300005"> 300005 </a>
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/geneMap/X/851?start=-3&limit=10&highlight=851">
|
|
Xq28
|
|
</a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
Rett syndrome, preserved speech variant
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/312750"> 312750 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="X-linked dominant">XLD</abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
MECP2
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/300005"> 300005 </a>
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
</tbody>
|
|
</table>
|
|
</div>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
|
|
|
|
<div class="btn-group ">
|
|
<a href="/clinicalSynopsis/312750" class="btn btn-warning" role="button"> Clinical Synopsis </a>
|
|
<button type="button" id="mimPhenotypicSeriesToggle" class="btn btn-warning dropdown-toggle mimSingletonFoldToggle" data-toggle="collapse" href="#mimClinicalSynopsisFold" onclick="ga('send', 'event', 'Unfurl', 'ClinicalSynopsis', 'omim.org')">
|
|
<span class="caret"></span>
|
|
<span class="sr-only">Toggle Dropdown</span>
|
|
</button>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
<div class="btn-group">
|
|
<button type="button" class="btn btn-success dropdown-toggle" data-toggle="dropdown" aria-haspopup="true" aria-expanded="false">
|
|
PheneGene Graphics <span class="caret"></span>
|
|
</button>
|
|
<ul class="dropdown-menu" style="width: 17em;">
|
|
<li><a href="/graph/linear/312750" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Linear'})"> Linear </a></li>
|
|
<li><a href="/graph/radial/312750" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Radial'})"> Radial </a></li>
|
|
</ul>
|
|
</div>
|
|
<span class="glyphicon glyphicon-question-sign mim-tip-hint" title="OMIM PheneGene graphics depict relationships between phenotypes, groups of related phenotypes (Phenotypic Series), and genes.<br /><a href='/static/omim/pdf/OMIM_Graphics.pdf' target='_blank'>A quick reference overview and guide (PDF)</a>"></span>
|
|
|
|
|
|
|
|
<div>
|
|
<p />
|
|
</div>
|
|
|
|
|
|
<div id="mimClinicalSynopsisFold" class="well well-sm collapse mimSingletonToggleFold">
|
|
<div class="small" style="margin: 5px">
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<strong> INHERITANCE </strong>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
|
|
<div>
|
|
<span class="mim-font">
|
|
|
|
- X-linked dominant <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1847879&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1847879</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001423" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001423</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001423" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001423</a>]</span><br />
|
|
|
|
</span>
|
|
</div>
|
|
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<strong> GROWTH </strong>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
|
|
|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<em> Height </em>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
<span class="mim-font">
|
|
|
|
- Short stature <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/422065006" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">422065006</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/237836003" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">237836003</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/237837007" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">237837007</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/E34.31" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">E34.31</a>, <a href="https://purl.bioontology.org/ontology/ICD10CM/R62.52" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">R62.52</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/783.43" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">783.43</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0349588&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0349588</a>, <a href="https://bioportal.bioontology.org/search?q=C0013336&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0013336</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003510" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003510</a>, <a href="https://hpo.jax.org/app/browse/term/HP:0004322" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0004322</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0004322" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0004322</a>]</span><br />
|
|
|
|
</span>
|
|
</div>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<em> Weight </em>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
<span class="mim-font">
|
|
|
|
- Cachexia <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/238108007" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">238108007</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/285384003" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">285384003</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/R64" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">R64</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/799.4" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">799.4</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0006625&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0006625</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0004326" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0004326</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0004326" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0004326</a>]</span><br />
|
|
|
|
</span>
|
|
</div>
|
|
</div>
|
|
|
|
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<strong> HEAD & NECK </strong>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
|
|
|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<em> Head </em>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
<span class="mim-font">
|
|
|
|
- Normal birth head circumference <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1839339&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1839339</a>]</span><br /> -
|
|
Deceleration of head growth <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/253130001" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">253130001</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0431352&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0431352</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0005484" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0005484</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0005484" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0005484</a>]</span><br /> -
|
|
Microcephaly <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/1148757008" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">1148757008</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/Q02" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">Q02</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/742.1" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">742.1</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C4551563&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C4551563</a>, <a href="https://bioportal.bioontology.org/search?q=C0025958&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0025958</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000252" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000252</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000252" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000252</a>]</span> <a href="https://elementsofmorphology.nih.gov/index.cgi?tid=0584d323b99dcd7001cc50e224947aca" target="_blank" class="small mim-tip-eom" title="<img src="https://elementsofmorphology.nih.gov/images/terms/Microcephaly-small.jpg"> <br/>Further Information: <a href="https://elementsofmorphology.nih.gov/index.cgi?tid=0584d323b99dcd7001cc50e224947aca" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'EOM\', \'domain\': \'elementsofmorphology.nih.gov\'})">Elements of Morphology</a>"><span class="glyphicon glyphicon-user" aria-hidden="true"></span></a><br />
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</span>
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</div>
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</div>
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<div>
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<div>
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<span class="h5 mim-font">
|
|
<em> Teeth </em>
|
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</span>
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</div>
|
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<div style="margin-left: 2em;">
|
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<span class="mim-font">
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|
- Bruxism <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/90207007" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">90207007</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/191983006" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">191983006</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/F45.8" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">F45.8</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0006325&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0006325</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003763" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003763</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003763" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003763</a>]</span><br />
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</span>
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</div>
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</div>
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</div>
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</div>
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<div>
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<div>
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<span class="h5 mim-font">
|
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<strong> CARDIOVASCULAR </strong>
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</span>
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</div>
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<div style="margin-left: 2em;">
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<div>
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<div>
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<span class="h5 mim-font">
|
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<em> Heart </em>
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</span>
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</div>
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<div style="margin-left: 2em;">
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<span class="mim-font">
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|
- Prolonged QTc interval <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1560305&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1560305</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0005184" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0005184</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0005184" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0005184</a>]</span><br /> -
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|
T-wave abnormalities <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1839341&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1839341</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0005135" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0005135</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0005135" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0005135</a>]</span><br />
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</span>
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</div>
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</div>
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</div>
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</div>
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<div>
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<div>
|
|
<span class="h5 mim-font">
|
|
<strong> RESPIRATORY </strong>
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|
</span>
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</div>
|
|
<div style="margin-left: 2em;">
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<div>
|
|
<span class="mim-font">
|
|
|
|
- Periodic apnea while awake <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C3806822&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C3806822</a>]</span><br /> -
|
|
Intermittent hyperventilation <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/423427003" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">423427003</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1828017&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1828017</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0004879" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0004879</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0004879" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0004879</a>]</span><br /> -
|
|
Breath holding <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/90480005" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">90480005</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/713013008" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">713013008</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/R06.89" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">R06.89</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0476287&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0476287</a>, <a href="https://bioportal.bioontology.org/search?q=C0235744&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0235744</a>]</span><br />
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</span>
|
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</div>
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</div>
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</div>
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<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<strong> ABDOMEN </strong>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
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<div>
|
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<div>
|
|
<span class="h5 mim-font">
|
|
<em> Gastrointestinal </em>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
<span class="mim-font">
|
|
|
|
- Constipation <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/14760008" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">14760008</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/K59.0" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">K59.0</a>, <a href="https://purl.bioontology.org/ontology/ICD10CM/K59.00" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">K59.00</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/564.00" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">564.00</a>, <a href="https://purl.bioontology.org/ontology/ICD9CM/564.0" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">564.0</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0009806&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0009806</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002019" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002019</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002019" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002019</a>]</span><br /> -
|
|
Gastroesophageal reflux <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/235595009" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">235595009</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/722884003" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">722884003</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/698065002" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">698065002</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/K21" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">K21</a>, <a href="https://purl.bioontology.org/ontology/ICD10CM/K21.9" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">K21.9</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/530.81" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">530.81</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C3813607&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C3813607</a>, <a href="https://bioportal.bioontology.org/search?q=C4317146&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C4317146</a>, <a href="https://bioportal.bioontology.org/search?q=C0017168&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0017168</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002020" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002020</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002020" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002020</a>]</span><br />
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|
|
|
</span>
|
|
</div>
|
|
</div>
|
|
|
|
</div>
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|
</div>
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|
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|
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<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<strong> SKELETAL </strong>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
|
|
|
|
|
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<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<em> Spine </em>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
<span class="mim-font">
|
|
|
|
- Scoliosis <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/298382003" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">298382003</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/20944008" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">20944008</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/111266001" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">111266001</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/M41.9" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">M41.9</a>, <a href="https://purl.bioontology.org/ontology/ICD10CM/M41" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">M41</a>, <a href="https://purl.bioontology.org/ontology/ICD10CM/Q67.5" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">Q67.5</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0559260&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0559260</a>, <a href="https://bioportal.bioontology.org/search?q=C0036439&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0036439</a>, <a href="https://bioportal.bioontology.org/search?q=C0700208&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0700208</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002650" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002650</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002650" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002650</a>]</span><br /> -
|
|
Kyphosis <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/71311003" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">71311003</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/414564002" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">414564002</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/413428007" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">413428007</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/M40.20" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">M40.20</a>, <a href="https://purl.bioontology.org/ontology/ICD10CM/Q76.41" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">Q76.41</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/737.1" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">737.1</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0265673&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0265673</a>, <a href="https://bioportal.bioontology.org/search?q=C0022821&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0022821</a>, <a href="https://bioportal.bioontology.org/search?q=C2115817&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C2115817</a>, <a href="https://bioportal.bioontology.org/search?q=C0022822&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0022822</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002808" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002808</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002808" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002808</a>]</span><br />
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</span>
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</div>
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</div>
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<div>
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<div>
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<span class="h5 mim-font">
|
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<em> Feet </em>
|
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</span>
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</div>
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<div style="margin-left: 2em;">
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<span class="mim-font">
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|
- Small feet <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/299461003" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">299461003</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1848673&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1848673</a>, <a href="https://bioportal.bioontology.org/search?q=C0576224&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0576224</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001773" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001773</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001773" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001773</a>]</span><br /> -
|
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Cold feet <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/271585001" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">271585001</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0424741&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0424741</a>]</span><br /> -
|
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Vasomotor disturbance <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1411888&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1411888</a>]</span><br />
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</span>
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</div>
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</div>
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</div>
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</div>
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<div>
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<div>
|
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<span class="h5 mim-font">
|
|
<strong> MUSCLE, SOFT TISSUES </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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- Muscle wasting <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/88092000" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">88092000</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0541794&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0541794</a>, <a href="https://bioportal.bioontology.org/search?q=C0026846&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0026846</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003202" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003202</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003202" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003202</a>]</span><br />
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</span>
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</div>
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</div>
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</div>
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<div>
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<div>
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<span class="h5 mim-font">
|
|
<strong> NEUROLOGIC </strong>
|
|
</span>
|
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</div>
|
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<div style="margin-left: 2em;">
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<div>
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<div>
|
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<span class="h5 mim-font">
|
|
<em> Central Nervous System </em>
|
|
</span>
|
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</div>
|
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<div style="margin-left: 2em;">
|
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<span class="mim-font">
|
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|
- Normal development until 6-18 months <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1839334&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1839334</a>]</span><br /> -
|
|
Mental retardation, profound <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/31216003" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">31216003</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/F73" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">F73</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0020796&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0020796</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002187" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002187</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002187" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002187</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/317-319.99" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">317-319.99</a>]</span><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 /> -
|
|
EEG abnormalities - slow waking background, intermittent rhythmical slowing (3-5Hz), epileptiform discharges <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1839335&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1839335</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 /> -
|
|
Reduction or loss of acquired skills (e.g., purposeful hand use, speech) <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1839336&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1839336</a>]</span><br /> -
|
|
Gait ataxia <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/25136009" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">25136009</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/R26.0" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">R26.0</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0751837&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0751837</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002066" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002066</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002066" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002066</a>]</span><br /> -
|
|
Gait apraxia <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/30767006" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">30767006</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1510417&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1510417</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0010521" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0010521</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0010521" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0010521</a>]</span><br /> -
|
|
Truncal ataxia <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/250067008" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">250067008</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0427190&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0427190</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002078" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002078</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002078" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002078</a>]</span><br /> -
|
|
Dystonia <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/15802004" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">15802004</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/G24.9" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">G24.9</a>, <a href="https://purl.bioontology.org/ontology/ICD10CM/G24" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">G24</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0013421&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0013421</a>, <a href="https://bioportal.bioontology.org/search?q=C0393593&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0393593</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001332" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001332</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001332" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001332</a>]</span><br /> -
|
|
Cortical atrophy (frontal area) <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1839337&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1839337</a>]</span> <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/278849000" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">278849000</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002120" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002120</a>]</span><br />
|
|
|
|
</span>
|
|
</div>
|
|
</div>
|
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|
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<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<em> Behavioral Psychiatric Manifestations </em>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
<span class="mim-font">
|
|
|
|
- Autistic behaviors <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0856975&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0856975</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000729" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000729</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000729" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000729</a>]</span><br /> -
|
|
Hand stereotypies (e.g., hand wringing) <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1839338&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1839338</a>]</span><br /> -
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Sleep disturbance <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/53888004" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">53888004</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/39898005" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">39898005</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/44186003" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">44186003</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/G47" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">G47</a>, <a href="https://purl.bioontology.org/ontology/ICD10CM/G47.9" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">G47.9</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/780.5" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">780.5</a>, <a href="https://purl.bioontology.org/ontology/ICD9CM/780.50" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">780.50</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0700201&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0700201</a>, <a href="https://bioportal.bioontology.org/search?q=C0037317&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0037317</a>, <a href="https://bioportal.bioontology.org/search?q=C0851578&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0851578</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002360" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002360</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002360" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002360</a>]</span><br /> -
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Bruxism <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/90207007" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">90207007</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/191983006" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">191983006</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/F45.8" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">F45.8</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0006325&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0006325</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003763" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003763</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003763" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003763</a>]</span><br /> -
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Breath holding <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/90480005" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">90480005</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/713013008" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">713013008</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/R06.89" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">R06.89</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0476287&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0476287</a>, <a href="https://bioportal.bioontology.org/search?q=C0235744&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0235744</a>]</span><br />
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<span class="h5 mim-font">
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<strong> MISCELLANEOUS </strong>
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- Prevalence 1/10,000-1/15,000 female births<br /> -
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Initially normal for first 6-18 months which is then followed by withdrawal and regression<br /> -
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Four clinical stages - Stage I, early onset stagnation (onset 6 months-1.5 year)<br /> -
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Stage II, rapid developmental regression (onset 1-4 years)<br /> -
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Stage III, pseudostationary period (onset 2-10 years)<br /> -
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Stage IV, late motor deterioration (when ambulation ceases)<br /> -
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Most cases are sporadic<br /> -
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De novo mutations occur almost exclusively on the paternally derived X chromosome<br />
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<strong> MOLECULAR BASIS </strong>
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- Caused by mutation in the methyl-CpG-binding protein-2 gene (MECP2, <a href="/entry/300005#0001">300005.0001</a>)<br />
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<span class="mim-tip-floating" qtip_title="<strong>Looking For More References?</strong>" qtip_text="Click the 'reference plus' icon <span class='glyphicon glyphicon-plus-sign'></span> at the end of each OMIM text paragraph to see more references related to the content of the preceding paragraph.">
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<p>A number sign (#) is used with this entry because Rett syndrome (RTT) is caused by mutation in the gene encoding methyl-CpG-binding protein-2 (MECP2; <a href="/entry/300005">300005</a>) on chromosome Xq28.</p><p>See also the congenital variant of Rett syndrome (<a href="/entry/613454">613454</a>), which is caused by mutation in the FOXG1 gene (<a href="/entry/164874">164874</a>) on chromosome 14q13.</p>
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<p>Rett syndrome is a neurodevelopmental disorder that occurs almost exclusively in females. It is characterized by arrested development between 6 and 18 months of age, regression of acquired skills, loss of speech, stereotypic movements (classically of the hands), microcephaly, seizures, and mental retardation. Rarely, classically affected males with somatic mosaicism or an extra X chromosome have been described (<a href="#65" class="mim-tip-reference" title="Moog, U., Smeets, E. E. J., van Roozendaal, K. E. P., Schoenmakers, S., Herbergs, J., Schoonbrood-Lenssen, A. M. J., Schrander-Stumpel, C. T. R. M. <strong>Neurodevelopmental disorders in males related to the gene causing Rett syndrome in females (MECP2).</strong> Europ. J. Paediat. Neurol. 7: 5-12, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12615169/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12615169</a>] [<a href="https://doi.org/10.1016/s1090-3798(02)00134-4" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12615169">Moog et al., 2003</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12615169" 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>Rett (<a href="#80" class="mim-tip-reference" title="Rett, A. <strong>Ueber ein eigenartiges hirnatrophisches Syndrom bei Hyperammoniamie in Kindesalter.</strong> Wien. Med. Wschr. 116: 723-738, 1966.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/5300597/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">5300597</a>]" pmid="5300597">1966</a>, <a href="#81" class="mim-tip-reference" title="Rett, A. <strong>Cerebral atrophy associated with hyperammonaemia. In: Vinken, P. J.; Bruyn, G. W. (eds.): Handbook of Clinical Neurology. Vol. 29.</strong> Amsterdam: North Holland (pub.) 1977. Pp. 305-329."None>1977</a>), a Viennese pediatrician, first described Rett syndrome after observing 2 girls who exhibited the same unusual behavior who happened to be seated next to each other in the waiting room. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=5300597" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#36" class="mim-tip-reference" title="Hagberg, B., Aicardi, J., Dias, K., Ramos, O. <strong>A progressive syndrome of autism, dementia, ataxia, and loss of purposeful hand use in girls: Rett's syndrome: report of 35 cases.</strong> Ann. Neurol. 14: 471-479, 1983.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/6638958/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">6638958</a>] [<a href="https://doi.org/10.1002/ana.410140412" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="6638958">Hagberg et al. (1983)</a> described 35 patients, all girls from 3 countries (France, Portugal, and Sweden), with a uniform and striking, progressive encephalopathy. After normal development up to the age of 7 to 18 months, developmental stagnation occurred, followed by rapid deterioration of high brain functions. Within 1.5 years, this deterioration progressed to severe dementia, autism, loss of purposeful use of the hands, jerky truncal ataxia, and 'acquired' microcephaly. Thereafter, a period of apparent stability lasted for decades. Additional neurologic abnormalities intervened insidiously, mainly spastic paraparesis, vasomotor disturbances of the lower limbs, and epilepsy. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=6638958" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#16" class="mim-tip-reference" title="Bruck, I., Philippart, M., Giraldi, D., Antoniuk, S. <strong>Difference in early development of presumed monozygotic twins with Rett syndrome.</strong> Am. J. Med. Genet. 39: 415-417, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1715129/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1715129</a>] [<a href="https://doi.org/10.1002/ajmg.1320390411" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1715129">Bruck et al. (1991)</a> described a set of monozygotic female twins with Rett syndrome. The authors noted that normal early development has generally been insisted on as an essential criterion for the diagnosis; however, twin 1 was considered to be abnormal from birth, while delay was not suspected in twin 2 until she was about 1 year old. Some regression occurred during the second year in both twins, who at age 4 years were clinically indistinguishable. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1715129" 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 striking deceleration of growth has been found across all measurements in 85 to 94% of girls with Rett syndrome and may provide the earliest clinical indication of this disorder. <a href="#67" class="mim-tip-reference" title="Motil, K. J., Schultz, R., Brown, B., Glaze, D. G., Percy, A. K. <strong>Altered energy balance may account for growth failure in Rett syndrome.</strong> J. Child Neurol. 9: 315-319, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7930413/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7930413</a>] [<a href="https://doi.org/10.1177/088307389400900319" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7930413">Motil et al. (1994)</a> studied dietary intake and energy production in 9 Rett syndrome girls, comparing them to 7 healthy controls. Metabolic rate while sleeping was 23% lower in Rett syndrome girls than in controls, while metabolic rates during waking hours did not differ between the 2 groups. Dietary intake and fecal fat loss were also the same. The energy balance in girls with Rett syndrome was 55 +/- 43 kcal/kg lean body mass daily; in controls, the balance was 58 +/- 22 kcal/kg lean body mass per day. <a href="#67" class="mim-tip-reference" title="Motil, K. J., Schultz, R., Brown, B., Glaze, D. G., Percy, A. K. <strong>Altered energy balance may account for growth failure in Rett syndrome.</strong> J. Child Neurol. 9: 315-319, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7930413/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7930413</a>] [<a href="https://doi.org/10.1177/088307389400900319" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7930413">Motil et al. (1994)</a> speculated that a small difference in energy balance would be sufficient to account for the growth failure in Rett syndrome girls and may explain the greater time that the Rett syndrome girls spent in involuntary motor activity. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7930413" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#40" class="mim-tip-reference" title="Hagberg, B. <strong>Rett syndrome: clinical peculiarities and biological mysteries.</strong> Acta Paediat. 84: 971-976, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8652969/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8652969</a>] [<a href="https://doi.org/10.1111/j.1651-2227.1995.tb13809.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8652969">Hagberg (1995)</a> reviewed a Swedish series of 170 affected females, aged 2 to 52 years. The well-recognized classic phenotype was found in 75% of cases. Atypical variant forms, mainly more mildly affected mentally retarded girls and adolescent women, were still in a minority, but constituted an expanding cohort. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8652969" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>The presence of metatarsal and metacarpal abnormalities in some patients with Rett syndrome prompted <a href="#57" class="mim-tip-reference" title="Leonard, H., Thomson, M., Bower, C., Fyfe, S., Constantinou, J. <strong>Skeletal abnormalities in Rett syndrome: increasing evidence for dysmorphogenetic defects.</strong> Am. J. Med. Genet. 58: 282-285, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8533832/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8533832</a>] [<a href="https://doi.org/10.1002/ajmg.1320580316" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8533832">Leonard et al. (1995)</a> to conduct radiologic studies of 17 cases. Short fourth and/or fifth metatarsals were identified in 11 (65%), short fourth and/or fifth metacarpals in 8 of 14 (57%), and reduced bone density in the hands was found in 12 of 14 cases (86%). <a href="#58" class="mim-tip-reference" title="Leonard, H., Thomson, M., Glasson, E., Fyfe, S., Leonard, S., Ellaway, C., Christodoulou, J., Bower, C. <strong>Metacarpophalangeal pattern profile and bone age in Rett syndrome: further radiological clues to the diagnosis.</strong> Am. J. Med. Genet. 83: 88-95, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10190478/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10190478</a>] [<a href="https://doi.org/10.1002/(sici)1096-8628(19990312)83:2<88::aid-ajmg3>3.0.co;2-7" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10190478">Leonard et al. (1999)</a> examined hand radiographs of 100 girls with Rett syndrome, representing 73% of the known Australian population of girls with Rett syndrome, aged 20 and under. A metacarpophalangeal pattern profile was established, revealing that the shortest bone was the second metacarpal. Short distal phalanx of the thumb was seen in all age groups and in classic and atypical cases. In girls less than 15 years old, bone age was more advanced in Rett syndrome patients compared with controls (left hand p = 0.03, right hand p = 0.004), but was most advanced in the younger group. Bone age normalized with chronological age. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=8533832+10190478" 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="#63" class="mim-tip-reference" title="Miyamoto, A., Yamamoto, M., Takahashi, S., Oki, J. <strong>Classical Rett syndrome in sisters: variability of clinical expression.</strong> Brain Dev. 19: 492-494, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9408598/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9408598</a>] [<a href="https://doi.org/10.1016/s0387-7604(97)00052-1" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9408598">Miyamoto et al. (1997)</a> described 2 Japanese sisters with classic RTT. The youngest sister, aged 6 years and 6 months, never stood or walked alone, showed severe spasticity, growth retardation, and microcephaly, developed sleep-wake rhythm disturbance from age 4, and seizures from age 5 years. The elder, 7 years and 9 months old at the time of report, walked alone and had mild spasticity, no growth retardation, normal sleep-wakefulness rhythm, and no seizures. The variability in the sisters stood in contrast to that in monozygotic twins with RTT who usually show little clinical difference. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9408598" 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="#92" class="mim-tip-reference" title="Sirianni, N., Naidu, S., Pereira, J., Pillotto, R. F., Hoffman, E. P. <strong>Rett syndrome: confirmation of X-linked dominant inheritance, and localization of the gene to Xq28. (Letter)</strong> Am. J. Hum. Genet. 63: 1552-1558, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9792883/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9792883</a>] [<a href="https://doi.org/10.1086/302105" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9792883">Sirianni et al. (1998)</a> reported 3 affected sisters of a Brazilian family who showed rapid deceleration of head growth with subsequent progressive mental deterioration. Two surviving affected daughters, examined at ages 9 and 5.5 years, showed no purposeful hand movements, but had persistent hand stereotypes and rubbing of the torso. They had significant muscle wasting and inability to walk, and showed spontaneous episodes of hyperventilation while awake. They had a severe attention deficit and no language development, with intellectual and adaptive behavior at the 1- to 6-month level. Although the younger daughter was still able to reach for food, she was without other purposeful hand use. <a href="#56" class="mim-tip-reference" title="Leonard, H., Bower, C. <strong>Is the girl with Rett syndrome normal at birth?</strong> Dev. Med. Child Neurol. 40: 115-121, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9489500/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9489500</a>]" pmid="9489500">Leonard and Bower (1998)</a> retrospectively studied the neonatal characteristics and early development of Australian girls with Rett syndrome. The mean weight and head circumference of newborn girls later identified as Rett patients was lower than that of the reference Australian population. Girls who had learned to walk had larger heads at birth than those who had not; girls who had never been ambulant had the smallest heads at birth. In 46.5% of girls, parents reported unusual development or behavior in the first 6 months. The authors stated that these results provided evidence that girls with Rett syndrome may not be normal at birth. They further suggested that using normal development in the first 6 months and normal neonatal head circumference as diagnostic criteria may cause missed or delayed diagnoses. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=9489500+9792883" 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>Neuropathologic Findings</em></strong></p><p>
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<a href="#74" class="mim-tip-reference" title="Papadimitriou, J. M., Hockey, A., Tan, N., Masters, C. L. <strong>Rett syndrome: abnormal membrane-bound lamellated inclusions in neurons and oligodendroglia.</strong> Am. J. Med. Genet. 29: 365-368, 1988.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3354608/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3354608</a>] [<a href="https://doi.org/10.1002/ajmg.1320290216" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3354608">Papadimitriou et al. (1988)</a> reported light-microscopic evidence of white matter disease in the brain biopsy of a patient with Rett syndrome. Ultrastructurally, many neurons and oligodendroglia contained membrane-bound electron-dense inclusions with a distinct lamellar and granular substructure. <a href="#10" class="mim-tip-reference" title="Armstrong, D., Dunn, J. K., Antalffy, B., Trivedi, R. <strong>Selective dendritic alterations in the cortex of Rett syndrome.</strong> J. Neuropath. Exp. Neurol. 54: 195-201, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7876888/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7876888</a>] [<a href="https://doi.org/10.1097/00005072-199503000-00006" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7876888">Armstrong et al. (1995)</a> systematically studied brains of 16 girls with Rett syndrome who ranged in age from 2 to 35 years. They found no evidence that the pyramidal neurons in Rett syndrome degenerate progressively with increasing age. Instead, they found a striking decrease in the dendritic trees of selected cortical areas, chiefly projection neurons of the motor, association, and limbic cortices. They suggested that this may result in abnormalities of trophic factors. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=3354608+7876888" 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>Neuroradiographic Findings</em></strong></p><p>
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<a href="#47" class="mim-tip-reference" title="Horska, A., Farage, L., Bibat, G., Nagae, L. M., Kaufmann, W. E., Barker, P. B., Naidu, S. <strong>Brain metabolism in Rett syndrome: age, clinical, and genotype correlations.</strong> Ann. Neurol. 65: 90-97, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19194883/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19194883</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19194883[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/10.1002/ana.21562" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19194883">Horska et al. (2009)</a> performed proton magnetic resonance spectroscopy (MRS) on 40 girls with Rett syndrome with a mean age of 6.1 years. Compared to 12 controls, Rett syndrome patients had a decreased N-acetylaspartate (NAA)/creatine (Cr) ratio and increased myoinositol/Cr ratio with age (p = 0.03), suggestive of progressive axonal damage and astrocytosis. The mean NAA/Cr ratio was 12.6% lower in RTT patients with seizures compared with those without seizures (p = 0.017), and NAA/Cr ratios decreased with increasing clinical severity score (p = 0.031). The mean glutamate and glutamine/Cr ratio was 36% greater in RTT patients than in controls (p = 0.043), which may have been secondary to increasing glutamate/glutamine cycling at the synaptic level. The findings indicated that Rett syndrome is associated with mild white matter pathology, and suggested that MRS can provide a noninvasive measure of cerebral involvement in RTT. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19194883" 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>Cardiac Abnormalities</em></strong></p><p>
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<a href="#53" class="mim-tip-reference" title="Kerr, A. M., Armstrong, D. D., Prescott, R. J., Doyle, D., Kearney, D. L. <strong>Rett syndrome: analysis of deaths in the British survey.</strong> Europ. Child Adolesc. Psychiat. 6 (suppl. 1): 71-74, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9452925/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9452925</a>]" pmid="9452925">Kerr et al. (1997)</a> found an annual mortality rate in Rett syndrome of 1.2%; a high proportion (26%) of these deaths were sudden and unexplained. <a href="#90" class="mim-tip-reference" title="Sekul, E. A., Moak, J. P., Schultz, R. J., Glaze, D. G., Dunn, J. K., Percy, A. K. <strong>Electrocardiographic findings in Rett syndrome: an explanation for sudden death?</strong> J. Pediat. 125: 80-82, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8021793/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8021793</a>] [<a href="https://doi.org/10.1016/s0022-3476(94)70128-8" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8021793">Sekul et al. (1994)</a> reported prolonged QT interval in patients with Rett syndrome. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=8021793+9452925" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#34" class="mim-tip-reference" title="Guideri, F., Acampa, M., Hayek, G., Zappella, M., Di Perri, T. <strong>Reduced heart rate variability in patients affected with Rett syndrome: a possible explanation for sudden death.</strong> Neuropediatrics 30: 146-148, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10480210/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10480210</a>] [<a href="https://doi.org/10.1055/s-2007-973480" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10480210">Guideri et al. (1999)</a> studied the heart rate variability and corrected QT interval in 54 females (mean age, 10 +/- 5.5 years) in various clinical stages of Rett syndrome, using continuous 12-lead ECG monitoring for 10 minutes in the supine position. The total power spectrum of heart rate variability (from 0.03 to 0.4 Hz), mainly its low frequency (LF) and high frequency (HF) components, was significantly lower in children with Rett syndrome compared with that in controls. The sympathovagal balance, expressed by the ratio LF/HF, was significantly higher in patients, reflecting the prevalence of sympathetic activity. The RR interval was significantly shorter and the corrected QT interval longer in the patient group than in the control group. The authors suggested that in children with Rett syndrome, loss of physiologic heart rate variability associated with an increase of adrenergic tone, represents the electrophysiologic basis of cardiac instability and sudden death. <a href="#28" class="mim-tip-reference" title="Ellaway, C. J., Sholler, G., Leonard, H., Christodoulou, J. <strong>Prolonged QT interval in Rett syndrome.</strong> Arch. Dis. Child. 80: 470-472, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10208957/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10208957</a>] [<a href="https://doi.org/10.1136/adc.80.5.470" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10208957">Ellaway et al. (1999)</a> determined the prevalence of QT prolongation in a cohort of 34 Australian patients. Nine patients had significantly longer corrected QT values than a group of healthy, age-matched controls. There was no apparent correlation between the presence of QT prolongation and phenotypic severity. The authors concluded that QT prolongation should be considered in all patients with Rett syndrome. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=10208957+10480210" 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>Zappella Variant</em></strong></p><p>
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<a href="#25" class="mim-tip-reference" title="De Bona, C., Zappella, M., Hayek, G., Meloni, I., Vitelli, F., Bruttini, M., Cusano, R., Loffredo, P., Longo, I., Renieri, A. <strong>Preserved speech variant is allelic of classic Rett syndrome.</strong> Europ. J. Hum. Genet. 8: 325-330, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10854091/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10854091</a>] [<a href="https://doi.org/10.1038/sj.ejhg.5200473" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10854091">De Bona et al. (2000)</a> stated that preserved speech variant (PSV) Rett syndrome shares with classic Rett syndrome the same course and the stereotypic hand-washing activities, but differs in that patients typically recover some degree of speech and hand use, and usually do not show growth failure. Progressive scoliosis, epilepsy, and other minor handicaps, usually present in Rett syndrome, are rare in the preserved speech variant. The authors reported mutations in the MECP2 gene in both classic and PSV Rett syndrome (see <a href="/entry/300005#0012">300005.0012</a>), establishing that the 2 forms are allelic disorders. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10854091" 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="#112" class="mim-tip-reference" title="Zappella, M., Meloni, I., Longo, I., Hayek, G., Renieri, A. <strong>Preserved speech variants of the Rett syndrome: molecular and clinical analysis.</strong> Am. J. Med. Genet. 104: 14-22, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11746022/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11746022</a>] [<a href="https://doi.org/10.1002/ajmg.10005" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11746022">Zappella et al. (2001)</a> reported clinical and mutation analysis findings in 18 patients with preserved speech variant Rett syndrome. Ten (55%) had an MECP2 mutation. All had slow recovery of verbal and praxic abilities, evident autistic behavior, and normal head circumference. Six were overweight, often obese, had kyphosis, coarse face, and mental age of 2 to 3 years, and were able to speak in sentences; 4 had normal weight, mental age not beyond 1 to 2 years, and spoke in single words and 2-word phrases. The course of the disorder was in stages as in classic Rett syndrome. Hand washing was present in the first years of life but often subsequently disappeared. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11746022" 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="#79" class="mim-tip-reference" title="Renieri, A., Mari, F., Mencarelli, M. A., Scala, E., Ariani, F., Longo, I., Meloni, I., Cevenini, G., Pini, G., Hayek, G., Zappella, M. <strong>Diagnostic criteria for the Zappella variant of Rett syndrome (the preserved speech variant).</strong> Brain Dev. 31: 208-216, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18562141/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18562141</a>] [<a href="https://doi.org/10.1016/j.braindev.2008.04.007" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18562141">Renieri et al. (2009)</a> presented a detailed evaluation of 29 patients with Zappella variant, also known as preserved speech variant, Rett syndrome. All 29 patients had mutation in the MECP2 gene, of which 28 were missense (see, e.g., R133C; <a href="#0001">312750.0001</a>) or late truncating mutations. There was great variability with respect to language, manual abilities, and somatic features, allowing for further statistical subdivision into low, intermediate, and high functioning. In general, patients with Zappella variant Rett syndrome had less microcephaly, later onset of regression, a tendency to be overweight, better hand use, and better speech acquisition compared to patients with classic Rett syndrome. The majority (76%) of patients with Zappella variant had autistic features. Diagnostic criteria was presented. <a href="#79" class="mim-tip-reference" title="Renieri, A., Mari, F., Mencarelli, M. A., Scala, E., Ariani, F., Longo, I., Meloni, I., Cevenini, G., Pini, G., Hayek, G., Zappella, M. <strong>Diagnostic criteria for the Zappella variant of Rett syndrome (the preserved speech variant).</strong> Brain Dev. 31: 208-216, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18562141/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18562141</a>] [<a href="https://doi.org/10.1016/j.braindev.2008.04.007" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18562141">Renieri et al. (2009)</a> proposed the term 'Zappella variant' rather than 'preserved speech variant' to described milder forms of Rett syndrome because other aspects besides speech are involved. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18562141" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#1" class="mim-tip-reference" title="Adegbola, A. A., Gonzales, M. L., Chess, A., LaSalle, J. M., Cox, G. F. <strong>A novel hypomorphic MECP2 point mutation is associated with a neuropsychiatric phenotype.</strong> Hum. Genet. 124: 615-623, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18989701/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18989701</a>] [<a href="https://doi.org/10.1007/s00439-008-0585-6" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18989701">Adegbola et al. (2009)</a> reported a 10-year-old girl who had slowing of motor skills and hypotonia at age 12 months. She had purposeful hand movements with occasional hand-wringing stereotypes, was morbidly obese, was prone to aggressive outbursts, and had mild autistic features. EEG showed multifocal spike and wave discharges without overt seizures. Full-scale IQ was 70 at age 6 years and 58 at age 8 years. Her father had an IQ of 85, had special schooling, and showed behavioral dyscontrol and hyperactivity in childhood and adolescence. His behavioral difficulties improved with age. Both father and daughter were found to have a mutation in the MECP2 gene (<a href="/entry/300005#0036">300005.0036</a>), that resulted in decreased, but not absent MECP2 function. The findings were consistent with a hypomorphic MECP2 allele contributing to a neuropsychiatric phenotype in this family. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18989701" 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>Affected Males</em></strong></p><p>
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<a href="#22" class="mim-tip-reference" title="Coleman, M. <strong>Is classical Rett syndrome ever present in males?</strong> Brain Dev. 12: 31-32, 1990.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2344021/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2344021</a>] [<a href="https://doi.org/10.1016/s0387-7604(12)80171-9" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2344021">Coleman (1990)</a> reported a possible case of Rett syndrome in a male, and <a href="#77" class="mim-tip-reference" title="Philippart, M. <strong>The Rett syndrome in males.</strong> Brain Dev. 12: 33-36, 1990.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2344022/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2344022</a>] [<a href="https://doi.org/10.1016/s0387-7604(12)80172-0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2344022">Philippart (1990)</a> reported 2 such cases. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=2344022+2344021" 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="#89" class="mim-tip-reference" title="Schwartzman, J. S., Zatz, M., Vasquez, L. R., Gomes, R. R., Koiffmann, C. P., Fridman, C., Otto, P. G. <strong>Rett syndrome in a boy with a 47,XXY karyotype. (Letter)</strong> Am. J. Hum. Genet. 64: 1781-1785, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10330367/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10330367</a>] [<a href="https://doi.org/10.1086/302424" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10330367">Schwartzman et al. (1999)</a> described a male patient with Rett syndrome and the 47,XXY karyotype of Klinefelter syndrome. The propositus showed normal development until age 8 months. At that time, he sat without support, played normally, and was able to grasp objects and to put food into his mouth. He had started to say some words comprehensibly. At age 11 months, it was noted that he had lost purposeful hand movements and language skills. He also began to show regression in social contact. At age 1 year, he began to show stereotypic hand movements, bruxism, and constipation. At age 28 months, he presented severe global retardation and slight diffuse hypotonia. At the time of the last observation, at age 37 months, loss of purposeful hand movements, manual apraxia, and slight global hypotonia were persistent. The clinical and laboratory findings did not overlap with any described for Klinefelter syndrome. DNA studies indicated that the additional sex chromosome was paternal in origin, i.e., that the nondisjunction occurred in the paternal first meiotic division. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10330367" 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="Clayton-Smith, J., Watson, P., Ramsden, S., Black, G. C. M. <strong>Somatic mutation in MECP2 as a non-fatal neurodevelopmental disorder in males.</strong> Lancet 356: 830-832, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11022934/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11022934</a>] [<a href="https://doi.org/10.1016/s0140-6736(00)02661-1" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11022934">Clayton-Smith et al. (2000)</a> presented a male with somatic mosaicism for an MECP2 mutation (<a href="/entry/300005#0010">300005.0010</a>) leading to a progressive but nonfatal neurodevelopmental disorder. The patient was a normal-sized product of a full-term gestation. He was a placid baby who never crawled, but walked at 15 months and learned to say some single words in the second year of life. At around 2 years of age, he lost interest in his surroundings and lost his speech. At age 3 years, he began to have generalized seizures, and magnetic resonance imaging (MRI) revealed atrophy of the brainstem and frontal and temporal lobes. Electroencephalography (EEG) showed excessive slow-wave activity during sleep and a relative poverty of rhythmic activity while awake. At 6 years of age, he had a thoracic scoliosis and poor lower-limb musculature, and he walked with an ataxic gait. He had abnormal muscle tone with rigidity of the limbs and truncal hypotonia. His feet were small, blue, and puffy. His hand use was very limited, but there were no obvious hand-wringing movements. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11022934" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#60" class="mim-tip-reference" title="Maiwald, R., Bonte, A., Jung, H., Bitter, P., Storm, Z., Laccone, F., Herkenrath, P. <strong>De novo MECP2 mutation in a 46,XX male patient with Rett syndrome. (Letter)</strong> Neurogenetics 4: 107-108, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12481990/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12481990</a>] [<a href="https://doi.org/10.1007/s10048-002-0137-5" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12481990">Maiwald et al. (2002)</a> reported a 46,XX male with Rett syndrome caused by mutation in the MECP2 gene (<a href="/entry/300005#0026">300005.0026</a>). Upon amniocentesis performed because of advanced maternal age, a female karyotype was detected in a sonographically male fetus. Both the phenotype and the karyotype were confirmed after birth, and the absence of mullerian structures was demonstrated by ultrasonography. Motor development was delayed; he was able to sit only at 14 months of age. He was still not able to walk and there was no speech at the age of 24 months. At the age of 2 years, he showed truncal muscular hypotonia, microcephaly, spasticity, and convergent strabismus of the left eye. There was a loss of purposeful hand skills at approximately 6 months of age, and a deceleration of head growth at approximately 7 months. The clinical appearance of the boy resembled female Rett cases, which was explained by the karyotype. In addition, preferential expression of the normal allele may have contributed to the rather mild phenotype. The authors noted that similar features had been described in male patients with MECP2 mutations and a Klinefelter karyotype (46,XXY). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12481990" 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="#98" class="mim-tip-reference" title="Topcu, M., Akyerli, C., Sayi, A., Toruner, G. A., Kocoglu, S. R., Cimbis, M., Ozcelik, T. <strong>Somatic mosaicism for a MECP2 mutation associated with classic Rett syndrome in a boy.</strong> Europ. J. Hum. Genet. 10: 77-81, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11896459/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11896459</a>] [<a href="https://doi.org/10.1038/sj.ejhg.5200745" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11896459">Topcu et al. (2002)</a> reported a boy with features of classic Rett syndrome who was a somatic mosaic for a mutation in the MECP2 gene (<a href="/entry/300005#0005">300005.0005</a>). He had normal psychomotor development through the first 6 months. Loss of acquired purposeful hand skills began around 11 months, and stereotypic hand movements became apparent at 15 months. He never crawled or walked and had never spoken. On examination at 12 years of age he was microcephalic with stereotypic hand movements, tremors, and apraxia. He had a thoracic scoliosis and poor lower limb musculature, small and cold hands and feet, hypospadias, and cryptorchidism. Electroencephalography showed an excess of slow wave activity and paroxysmal sharp theta wave activity prominent on wake recordings of frontal regions. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11896459" 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>Atypical Rett Syndrome</em></strong></p><p>
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Molecular analysis has allowed the broadening of the phenotype of MECP2 mutations beyond RTT to include girls who have mild mental retardation, autism, and a phenotype resembling Angelman syndrome (<a href="/entry/105830">105830</a>), as well as males with severe encephalopathy. <a href="#45" class="mim-tip-reference" title="Heilstedt, H. A., Shahbazian, M. D., Lee, B. <strong>Infantile hypotonia as a presentation of Rett syndrome.</strong> Am. J. Med. Genet. 111: 238-242, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12210319/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12210319</a>] [<a href="https://doi.org/10.1002/ajmg.10633" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12210319">Heilstedt et al. (2002)</a> reported a girl with a phenotype of atypical RTT who had a heterozygous mutation in the MECP2 gene (<a href="/entry/300005#0016">300005.0016</a>). She presented with hypotonia and developmental delay in infancy without a clear period of normal development. As part of her evaluation for hypotonia, muscle biopsy and respiratory chain enzyme analysis showed a slight decrease in respiratory chain enzyme activity consistent with previous reports of RTT. The mother did not carry an MECP2 mutation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12210319" 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="#105" class="mim-tip-reference" title="Watson, P., Black, G., Ramsden, S., Barrow, M., Super, M., Kerr, B., Clayton-Smith, J. <strong>Angelman syndrome phenotype associated with mutations in MECP2, a gene encoding a methyl CpG binding protein.</strong> J. Med. Genet. 38: 224-228, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11283202/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11283202</a>] [<a href="https://doi.org/10.1136/jmg.38.4.224" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11283202">Watson et al. (2001)</a> identified MECP2 mutations in 5 of 47 patients with a clinical diagnosis of Angelman-like phenotype and no cytogenetic or molecular abnormality of chromosome 15q11-q13. Four of these patients were female and 1 male. By the time of diagnosis, 3 of the patients were showing signs of regression and had features suggestive of Rett syndrome; in the remaining 2, the clinical phenotype was still considered to be Angelman-like. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11283202" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#49" class="mim-tip-reference" title="Imessaoudene, B., Bonnefont, J.-P., Royer, G., Cormier-Daire, V., Lyonnet, S., Lyon, G., Munnich, A., Amiel, J. <strong>MECP2 mutation in non-fatal, non-progressive encephalopathy in a male.</strong> J. Med. Genet. 38: 171-174, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11238684/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11238684</a>] [<a href="https://doi.org/10.1136/jmg.38.3.171" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11238684">Imessaoudene et al. (2001)</a> identified MECP2 mutations in 6 of 78 patients with possible Angelman syndrome but with normal methylation pattern at the UBE3A locus (<a href="/entry/601623">601623</a>). Of these, 4 were females with a phenotype consistent with Rett syndrome, one was a female with progressive encephalopathy of neonatal onset, and one was a male with a nonprogressive encephalopathy of neonatal onset. This boy had a gly428-to-ser mutation (<a href="/entry/300005#0023">300005.0023</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11238684" 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="#35" class="mim-tip-reference" title="Hagberg, B. A., Skjeldal, O. H. <strong>Rett variants: a suggested model for inclusion criteria.</strong> Pediat. Neurol. 11: 5-11, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7986294/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7986294</a>] [<a href="https://doi.org/10.1016/0887-8994(94)90082-5" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7986294">Hagberg and Skjeldal (1994)</a> suggested a model of inclusion and exclusion criteria for the diagnosis of Rett syndrome that relaxed the international criteria originally drawn up in Vienna in September 1984. The new model permitted the diagnosis of forme frustes, cases with late regression, and congenital variants. <a href="#38" class="mim-tip-reference" title="Hagberg, B., Hanefeld, F., Percy, A., Skjeldal, O. <strong>An update on clinically applicable diagnostic criteria in Rett syndrome: comments to Rett syndrome clinical criteria consensus panel satellite to European Paediatric Neurology Society Meeting, Baden Baden, Germany, 11 September 2001.</strong> Europ. J. Paediat. Neurol. 6: 293-297, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12378695/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12378695</a>] [<a href="https://doi.org/10.1053/ejpn.2002.0612" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12378695">Hagberg et al. (2002)</a> provided an updated diagnostic criteria. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=7986294+12378695" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#71" class="mim-tip-reference" title="Neul, J. L., Kaufmann, W. E., Glaze, D. G., Christodoulou, J., Clarke, A. J., Bahi-Buisson, N., Leonard, H., Bailey, M. E. S., Schanen, N. C., Zappella, M., Renieri, A., Huppke, P., Percy, A. K. <strong>Rett syndrome: revised diagnostic criteria and nomenclature.</strong> Ann. Neurol. 68: 944-950, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21154482/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21154482</a>] [<a href="https://doi.org/10.1002/ana.22124" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21154482">Neul et al. (2010)</a> provided revised diagnostic criteria for Rett syndrome and emphasized that it remains a clinical diagnosis, since not all Rett patients have MECP2 mutations and not all patients with MECP2 mutations have Rett syndrome. The most important feature for classic Rett syndrome is a period of clear developmental regression followed by limited recovery or stabilization. Other main criteria include loss of purposeful hand skills, loss of spoken language, gait abnormalities, and stereotypic hand movements. Although deceleration of head growth is a supportive feature, it is no longer necessary for diagnosis. Exclusion criteria include other primary causes of neurologic dysfunction and abnormal psychomotor development in the first 6 months of life. Criteria for variant or atypical forms of Rett syndrome were also presented. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21154482" 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="#76" class="mim-tip-reference" title="Percy, A. K., Neul, J. L., Glaze, D. G., Motil, K. J., Skinner, S. A., Khwaja, O., Lee, H.-S., Lane, J. B., Barrish, J. O., Annese, F., McNair, L., Graham, J., Barnes, K. <strong>Rett syndrome diagnostic criteria: lessons from the Natural History Study.</strong> Ann. Neurol. 68: 951-955, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21104896/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21104896</a>] [<a href="https://doi.org/10.1002/ana.22154" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21104896">Percy et al. (2010)</a> validated the revised diagnostic criteria provided by <a href="#71" class="mim-tip-reference" title="Neul, J. L., Kaufmann, W. E., Glaze, D. G., Christodoulou, J., Clarke, A. J., Bahi-Buisson, N., Leonard, H., Bailey, M. E. S., Schanen, N. C., Zappella, M., Renieri, A., Huppke, P., Percy, A. K. <strong>Rett syndrome: revised diagnostic criteria and nomenclature.</strong> Ann. Neurol. 68: 944-950, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21154482/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21154482</a>] [<a href="https://doi.org/10.1002/ana.22124" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21154482">Neul et al. (2010)</a> in an analysis of 819 patients enrolled in a natural history study of Rett syndrome. Of the 819 patients, 765 females fulfilled 2002 criteria (<a href="#38" class="mim-tip-reference" title="Hagberg, B., Hanefeld, F., Percy, A., Skjeldal, O. <strong>An update on clinically applicable diagnostic criteria in Rett syndrome: comments to Rett syndrome clinical criteria consensus panel satellite to European Paediatric Neurology Society Meeting, Baden Baden, Germany, 11 September 2001.</strong> Europ. J. Paediat. Neurol. 6: 293-297, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12378695/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12378695</a>] [<a href="https://doi.org/10.1053/ejpn.2002.0612" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12378695">Hagberg et al., 2002</a>) for classic (85.4%) or variant (14.6%) Rett syndrome. All those classified as having classic Rett syndrome fulfilled the revised main criteria, and all those with variant Rett syndrome met 3 of 6 main criteria in the 2002 classification, 2 or 4 main criteria in the revised system, and 5 of 11 supportive criteria in both. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=21154482+12378695+21104896" 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>See developmental and epileptic encephalopathy-2 (DEE2; <a href="/entry/300672">300672</a>) for discussion of a Rett syndrome-like phenotype caused by mutation in the CDKL5 gene (<a href="/entry/300203">300203</a>).</p><p><strong><em>Prenatal Diagnosis</em></strong></p><p>
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As pointed out by <a href="#5" class="mim-tip-reference" title="Amir, R. E., Van den Veyver, I. B., Wan, M., Tran, C. Q., Francke, U., Zoghbi, H. Y. <strong>Rett syndrome is caused by mutations in X-linked MECP2, encoding methyl-CpG-binding protein 2.</strong> Nature Genet. 23: 185-188, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10508514/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10508514</a>] [<a href="https://doi.org/10.1038/13810" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10508514">Amir et al. (1999)</a>, the discovery of MECP2 as the gene responsible for Rett syndrome enabled testing for early diagnosis and prenatal detection. In addition, the finding that epigenetic regulation has a role in the pathogenesis of RTT opened possible opportunities for therapy. <a href="#5" class="mim-tip-reference" title="Amir, R. E., Van den Veyver, I. B., Wan, M., Tran, C. Q., Francke, U., Zoghbi, H. Y. <strong>Rett syndrome is caused by mutations in X-linked MECP2, encoding methyl-CpG-binding protein 2.</strong> Nature Genet. 23: 185-188, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10508514/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10508514</a>] [<a href="https://doi.org/10.1038/13810" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10508514">Amir et al. (1999)</a> suggested that partial loss of function of MECP2 may decrease transcriptional repression of some genes. The relatively normal development during the first 6 to 18 months of life may allow for presymptomatic therapeutic intervention, especially if newborn screening programs can identify affected females. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10508514" 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="#88" class="mim-tip-reference" title="Schanen, N. C., Dahle, E. J. R., Capozzoli, F., Holm, V. A., Zoghbi, H. Y., Francke, U. <strong>A new Rett syndrome family consistent with X-linked inheritance expands the X chromosome exclusion map.</strong> Am. J. Hum. Genet. 61: 634-641, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9326329/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9326329</a>] [<a href="https://doi.org/10.1086/515525" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9326329">Schanen et al. (1997)</a> stated that familial recurrences of Rett syndrome comprise only approximately 1% of the total reported cases; the vast majority of cases are sporadic. However, it is the familial cases that are key for understanding the genetic basis of the disorder. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9326329" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#36" class="mim-tip-reference" title="Hagberg, B., Aicardi, J., Dias, K., Ramos, O. <strong>A progressive syndrome of autism, dementia, ataxia, and loss of purposeful hand use in girls: Rett's syndrome: report of 35 cases.</strong> Ann. Neurol. 14: 471-479, 1983.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/6638958/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">6638958</a>] [<a href="https://doi.org/10.1002/ana.410140412" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="6638958">Hagberg et al. (1983)</a> suggested that the exclusive involvement of females is best explained by X-linked dominant inheritance with lethality in the hemizygous males. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=6638958" 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="#95" class="mim-tip-reference" title="Tariverdian, G., Kantner, G., Vogel, F. <strong>A monozygotic twin pair with Rett syndrome.</strong> Hum. Genet. 75: 88-90, 1987.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3804336/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3804336</a>] [<a href="https://doi.org/10.1007/BF00273849" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3804336">Tariverdian et al. (1987)</a> and <a href="#96" class="mim-tip-reference" title="Tariverdian, G. <strong>Follow-up of monozygotic twins concordant for the Rett syndrome.</strong> Brain Dev. 12: 125-127, 1990.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2344007/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2344007</a>] [<a href="https://doi.org/10.1016/s0387-7604(12)80192-6" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2344007">Tariverdian (1990)</a> reported 5-year-old monozygotic Turkish female twins concordant for Rett syndrome, suggesting a genetic cause of RTT. <a href="#75" class="mim-tip-reference" title="Partington, M. W. <strong>Rett syndrome in monozygotic twins.</strong> Am. J. Med. Genet. 29: 633-637, 1988.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3377006/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3377006</a>] [<a href="https://doi.org/10.1002/ajmg.1320290322" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3377006">Partington (1988)</a> described affected monozygotic twin sisters. <a href="#17" class="mim-tip-reference" title="Buhler, E. M., Malik, N. J., Alkan, M. <strong>Another model for the inheritance of Rett syndrome.</strong> Am. J. Med. Genet. 36: 126-131, 1990.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2333902/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2333902</a>] [<a href="https://doi.org/10.1002/ajmg.1320360125" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2333902">Buhler et al. (1990)</a> pointed to the existence of about 10 familial cases of Rett syndrome and to an elevated parental consanguinity rate of 2.4%. They suggested a model involving autosomal modifying genes that function as a suppressor in relation to an X-chromosomal mutation causing Rett syndrome. <a href="#116" class="mim-tip-reference" title="Zoghbi, H. Y., Percy, A. K., Schultz, R. J., Fill, C. <strong>Patterns of X chromosome inactivation in the Rett syndrome.</strong> Brain Dev. 12: 131-135, 1990.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2344009/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2344009</a>] [<a href="https://doi.org/10.1016/s0387-7604(12)80194-x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2344009">Zoghbi et al. (1990)</a> reviewed familial instances including 6 pairs of concordantly affected monozygotic twins; 4 families with 2 affected sisters; and 2 families with 2 affected half sisters. The affected half sisters had the same mother. <a href="#6" class="mim-tip-reference" title="Anvret, M., Wahlstrom, J., Skogsberg, P., Hagberg, B. <strong>Segregation analysis of the X-chromosome in a family with Rett syndrome in two generations.</strong> Am. J. Med. Genet. 37: 31-35, 1990.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2240040/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2240040</a>] [<a href="https://doi.org/10.1002/ajmg.1320370109" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2240040">Anvret et al. (1990)</a> described Rett syndrome in 2 generations of a family. The index case was a 12-year-old girl with classic Rett syndrome; her maternal aunt, aged 44 years, had mild Rett syndrome. Studies with X-linked DNA markers detected no deletions. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=2344009+3804336+2333902+2240040+3377006+2344007" 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="#62" class="mim-tip-reference" title="Martinho, P. S., Otto, P. G., Kok, F., Diament, A., Marques-Dias, M. J., Gonzalez, C. H. <strong>In search of a genetic basis for the Rett syndrome.</strong> Hum. Genet. 86: 131-134, 1990.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2265825/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2265825</a>] [<a href="https://doi.org/10.1007/BF00197693" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2265825">Martinho et al. (1990)</a>, in agreement with others, found no increase in parental age or in spontaneous abortion rates among the mothers of affected children and found a normal sex ratio among sibs. They found no chromosome rearrangements and no correlation between the fragile site at Xp22 and Rett syndrome. In 2 isolated cases of RTT, <a href="#12" class="mim-tip-reference" title="Benedetti, L., Munnich, A., Melki, J., Tardieu, M., Turleau, C. <strong>Parental origin of the X chromosomes in Rett syndrome. (Letter)</strong> Am. J. Med. Genet. 44: 121-122, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1355631/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1355631</a>] [<a href="https://doi.org/10.1002/ajmg.1320440131" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1355631">Benedetti et al. (1992)</a> excluded both maternal uniparental heterodisomy and isodisomy. <a href="#108" class="mim-tip-reference" title="Webb, T., Watkiss, E., Woods, C. G. <strong>Neither uniparental disomy nor skewed X-inactivation explains Rett syndrome.</strong> Clin. Genet. 44: 236-240, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7906210/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7906210</a>] [<a href="https://doi.org/10.1111/j.1399-0004.1993.tb03889.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7906210">Webb et al. (1993)</a> likewise excluded unilateral parental disomy through study of the locus DXS255 using the probe M27-beta; all informative probands had inherited an allele from each of their parents. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=1355631+7906210+2265825" 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="Akesson, H. O., Hagberg, B., Wahlstrom, J., Witt Engerstrom, I. <strong>Rett syndrome: a search for gene sources.</strong> Am. J. Med. Genet. 42: 104-108, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1308347/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1308347</a>] [<a href="https://doi.org/10.1002/ajmg.1320420121" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1308347">Akesson et al. (1992)</a> presented genealogic data on 77 Swedish females with Rett syndrome suggesting that there is a genetic component in transmission of the disorder. In most cases, ancestry was traced back to 1720-1750. Common ancestry was seen in 2 pairs of females with Rett syndrome. In 39 of the 77 cases, it was possible to trace ancestry to 9 small and separate rural areas, and 17 pairs even originated from the same farm or small group of dwellings. The common origin was found equally often among descendants of the father as of the mother, and there was a raised rate of consanguineous marriages. In what they referred to as 'an a priori test of the first study,' <a href="#4" class="mim-tip-reference" title="Akesson, H. O., Wahlstrom, J., Witt Engerstrom, I., Hagberg, B. <strong>Rett syndrome: potential gene sources: phenotypical variability.</strong> Clin. Genet. 48: 169-172, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8591665/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8591665</a>] [<a href="https://doi.org/10.1111/j.1399-0004.1995.tb04082.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8591665">Akesson et al. (1995)</a> examined an additional 20 Rett syndrome females who were consecutively traced. Of these, 10 of 19 (53%) originated from the earlier defined 'Rett areas,' and 11 of 19 (58%) could be traced to the same homestead. In 2 clusters, each consisting of 3 Rett syndrome females, all 6 subjects were descendants of the same 2 couples several generations ago. Consanguineous marriages among grandparents on both sides were found to have occurred in 11% (4 of 37), compared to 1% in the general Swedish population. The authors considered the findings a confirmation of the first study, and postulated that transmission starting with a premutation may result in a full mutation over generations, most likely if the parents have the premutation in homozygous form. A genealogic study of 32 Swedish patients with atypical Rett syndrome led <a href="#3" class="mim-tip-reference" title="Akesson, H. O., Hagberg, B., Wahlstrom, J. <strong>Rett syndrome, classical and atypical: genealogical support for common origin.</strong> J. Med. Genet. 33: 764-766, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8880578/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8880578</a>] [<a href="https://doi.org/10.1136/jmg.33.9.764" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8880578">Akesson et al. (1996)</a> to conclude that most atypical cases are variants of classic Rett syndrome. Eleven persons (34%) were traced to a small number of parishes in areas in which classic patients had been found. In 4 cases, typical and atypical Rett syndrome patients were found in the same pedigree. The authors proposed a 2-gene model, including one autosomal and one X-linked gene, to explain the genetics of this disorder. In a follow-up study looking for mutations of the MECP2 gene in 3 clusters and 2 pedigrees chosen at random in Sweden, <a href="#109" class="mim-tip-reference" title="Xiang, F., Stenbom, Y., Anvret, M. <strong>MECP2 mutations in Swedish Rett syndrome clusters. (Letter)</strong> Clin. Genet. 61: 384-385, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12081725/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12081725</a>] [<a href="https://doi.org/10.1034/j.1399-0004.2002.610512.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12081725">Xiang et al. (2002)</a> could not demonstrate that patients with Rett syndrome from the same cluster area share a common genetic defect. All of the identified mutations in the MECP2 gene were de novo and not premutations such as trinucleotide expansion. Recurrence of cases with the syndrome present in Rett clusters appeared to be the result of independent mutational events. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=12081725+1308347+8591665+8880578" 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="#97" class="mim-tip-reference" title="Thomas, G. H. <strong>High male:female ratio of germ-line mutations: an alternative explanation for postulated gestational lethality in males in X-linked dominant disorders.</strong> Am. J. Hum. Genet. 58: 1364-1368, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8651313/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8651313</a>]" pmid="8651313">Thomas (1996)</a> suggested that the exclusive occurrence of RTT in females, without evidence of male lethality, can be explained by de novo X-linked mutations occurring exclusively in male germ cells that result in affected daughters. Thus, he suggested that it is the high male:female de novo germline mutation rate that explains the absence of affected males in Rett syndrome. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8651313" 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="#102" class="mim-tip-reference" title="Villard, L., Levy, N., Xiang, F., Kpebe, A., Labelle, V., Chevillard, C., Zhang, Z., Schwartz, C. E., Tardieu, M., Chelly, J., Anvret, M., Fontes, M. <strong>Segregation of a totally skewed pattern of X chromosome inactivation in four familial cases of Rett syndrome without MECP2 mutation: implications for the disease.</strong> J. Med. Genet. 38: 435-442, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11432961/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11432961</a>] [<a href="https://doi.org/10.1136/jmg.38.7.435" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11432961">Villard et al. (2001)</a> identified a mutation in the MECP2 gene in only 1 of 5 families with RTT, suggesting an alternative molecular basis for the phenotype in the other 4 familial cases. X-chromosome inactivation studies showed that all the mothers and 6 of 8 affected girls had a totally skewed pattern of X inactivation, whereas only 9% of 43 sporadic RTT females had a skewed pattern of X inactivation, and all of their mothers had random X inactivation. In the familial cases, it was the paternal X chromosome that was active. Genotype analysis suggested that the skewed X-inactivation phenotype was due to a locus in the region between markers at DXS1068 and DXS1024, although the lod score for this analysis was not significant. The results suggested that the 2 traits, completely skewed X inactivation and RTT, are not linked. <a href="#102" class="mim-tip-reference" title="Villard, L., Levy, N., Xiang, F., Kpebe, A., Labelle, V., Chevillard, C., Zhang, Z., Schwartz, C. E., Tardieu, M., Chelly, J., Anvret, M., Fontes, M. <strong>Segregation of a totally skewed pattern of X chromosome inactivation in four familial cases of Rett syndrome without MECP2 mutation: implications for the disease.</strong> J. Med. Genet. 38: 435-442, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11432961/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11432961</a>] [<a href="https://doi.org/10.1136/jmg.38.7.435" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11432961">Villard et al. (2001)</a> proposed that familial Rett syndrome transmission is due to 2 traits being inherited: an X-linked locus abnormally escaping X inactivation, and the presence of a skewed X inactivation in carrier women. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11432961" 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="#84" class="mim-tip-reference" title="Rosenberg, C., Wouters, C. H., Szuhai, K., Dorland, R., Pearson, P., Poll-The, B. T., Colombijn, R. M., Breuning, M., Lindhout, D. <strong>A Rett syndrome patient with a ring X chromosome: further evidence for skewing of X inactivation and heterogeneity in the aetiology of the disease.</strong> Europ. J. Hum. Genet. 9: 171-177, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11313755/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11313755</a>] [<a href="https://doi.org/10.1038/sj.ejhg.5200604" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11313755">Rosenberg et al. (2001)</a> reported a female patient with Rett syndrome and 46,X,r(X) karyotype. The X-derived marker was about one-tenth the size of a normal X chromosome, with FISH analysis showing that the breakpoint on Xq was proximal to the MECP2 gene. X-inactivation studies demonstrated that the normal X chromosome was active and the ring X chromosome inactive in all cells examined. Methylation studies showed that the ring X was of paternal origin. No mutation was found in the MECP2 gene after sequencing of the whole coding region. The authors proposed a model invoking a second X-linked gene for RTT. Given the model, the second putative RTT gene could account for the minority of sporadic and the majority of familial cases that are negative for MECP2 mutations. To manifest as RTT, the disease allele would have to be expressed in a majority of cells, i.e., be associated with skewing of X inactivation as in cases of X-chromosome rearrangements. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11313755" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#32" class="mim-tip-reference" title="Gill, H., Cheadle, J. P., Maynard, J., Fleming, N., Whatley, S., Cranston, T., Thompson, E. M., Leonard, H., Davis, M., Christodoulou, J., Skjeldal, O., Hanefeld, F., Kerr, A., Tandy, A., Ravine, D., Clarke, A. <strong>Mutation analysis in the MECP2 gene and genetic counselling for Rett syndrome.</strong> J. Med. Genet. 40: 380-384, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12746405/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12746405</a>] [<a href="https://doi.org/10.1136/jmg.40.5.380" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12746405">Gill et al. (2003)</a> studied 11 families in each of which 2 females were thought to have Rett syndrome. In 1 family, an identical MECP2 mutation was found in 2 affected sisters and their healthy mother. In 5 families, an MECP2 mutation was found in 1 affected female but not in the other, possibly affected female. In 5 families, no MECP2 mutation was found. <a href="#32" class="mim-tip-reference" title="Gill, H., Cheadle, J. P., Maynard, J., Fleming, N., Whatley, S., Cranston, T., Thompson, E. M., Leonard, H., Davis, M., Christodoulou, J., Skjeldal, O., Hanefeld, F., Kerr, A., Tandy, A., Ravine, D., Clarke, A. <strong>Mutation analysis in the MECP2 gene and genetic counselling for Rett syndrome.</strong> J. Med. Genet. 40: 380-384, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12746405/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12746405</a>] [<a href="https://doi.org/10.1136/jmg.40.5.380" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12746405">Gill et al. (2003)</a> concluded that Rett syndrome is only rarely familial and that if girls with Rett syndrome who have MECP2 mutations have sisters with developmental difficulties, the disorder in the sisters is more likely to have a separate cause. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12746405" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#30" class="mim-tip-reference" title="Evans, J. C., Archer, H. L., Whatley, S. D., Clarke, A. <strong>Germline mosaicism for a MECP2 mutation in a man with two Rett daughters.</strong> Clin. Genet. 70: 336-338, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16965328/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16965328</a>] [<a href="https://doi.org/10.1111/j.1399-0004.2006.00691.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16965328">Evans et al. (2006)</a> reported a family in which 2 half sisters with the same father were found to have Rett syndrome caused by the same mutation in the MECP2 gene. Genetic analysis detected the mutation in approximately 5% of the father's sperm, but not in his buccal or lymphocyte DNA, indicating paternal germline mosaicism. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16965328" 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="#100" class="mim-tip-reference" title="Venancio, M., Santos, M., Pereira, S. A., Maciel, P., Saraiva, J. M. <strong>An explanation for another familial case of Rett syndrome: maternal germline mosaicism.</strong> Europ. J. Hum. Genet. 15: 902-904, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17440498/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17440498</a>] [<a href="https://doi.org/10.1038/sj.ejhg.5201835" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17440498">Venancio et al. (2007)</a> reported a rare familial case of Rett syndrome due to maternal germline mosaicism. A mutation in the MECP2 gene was identified in a girl with classic Rett syndrome and in her brother, who had severe congenital encephalopathy. The mutation was absent in DNA extracted from the blood of both parents. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17440498" 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>X-Inactivation Studies</em></strong></p><p>
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In the unaffected mother of 2 affected half sisters, <a href="#116" class="mim-tip-reference" title="Zoghbi, H. Y., Percy, A. K., Schultz, R. J., Fill, C. <strong>Patterns of X chromosome inactivation in the Rett syndrome.</strong> Brain Dev. 12: 131-135, 1990.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2344009/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2344009</a>] [<a href="https://doi.org/10.1016/s0387-7604(12)80194-x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2344009">Zoghbi et al. (1990)</a> found nonrandom X-chromosome inactivation in leukocyte DNA. They also found an increased incidence of nonrandom X inactivation in sporadic RTT patients (36%), as compared to healthy controls (8%). <a href="#54" class="mim-tip-reference" title="Kormann-Bortolotto, M. H., Woods, C. G., Green, S. H., Webb, T. <strong>X-inactivation in girls with Rett syndrome.</strong> Clin. Genet. 42: 296-301, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1283565/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1283565</a>] [<a href="https://doi.org/10.1111/j.1399-0004.1992.tb03259.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1283565">Kormann-Bortolotto et al. (1992)</a> found no abnormality of the X chromosome in 9 girls with Rett syndrome or the 6 mothers who were studied. X-inactivation studies suggested that there 'may be an alteration in the timing of the X-inactivation process in the region Xp11.3 or 4-Xp21' in patients with RTT. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=2344009+1283565" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#19" class="mim-tip-reference" title="Camus, P., Abbadi, N., Perrier, M.-C., Chery, M., Gilgenkrantz, S. <strong>X chromosome inactivation in 30 girls with Rett syndrome: analysis using the probe.</strong> Hum. Genet. 97: 247-250, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8566963/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8566963</a>] [<a href="https://doi.org/10.1007/BF02265275" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8566963">Camus et al. (1996)</a> studied X-chromosome inactivation in 30 girls with Rett syndrome, in 30 control girls, 8 sisters, and their mothers. There was a significant increased frequency of partial paternal X inactivation (more than 65%) in lymphocytes from 16 of 30 RTT patients compared with 4 of 30 controls (P = 0.001). These results did not support the hypothesis of a monogenic X-linked mutation, but the authors suggested that there may be a complex secondary role played by X-inactivation in this disorder. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8566963" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In a family with recurrence of Rett syndrome in a maternal aunt and niece, <a href="#88" class="mim-tip-reference" title="Schanen, N. C., Dahle, E. J. R., Capozzoli, F., Holm, V. A., Zoghbi, H. Y., Francke, U. <strong>A new Rett syndrome family consistent with X-linked inheritance expands the X chromosome exclusion map.</strong> Am. J. Hum. Genet. 61: 634-641, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9326329/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9326329</a>] [<a href="https://doi.org/10.1086/515525" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9326329">Schanen et al. (1997)</a> and <a href="#86" class="mim-tip-reference" title="Schanen, C., Francke, U. <strong>A severely affected male born into a Rett syndrome kindred supports X-linked inheritance and allows extension of the exclusion map. (Letter)</strong> Am. J. Hum. Genet. 63: 267-269, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9637791/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9637791</a>] [<a href="https://doi.org/10.1086/301932" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9637791">Schanen and Francke (1998)</a> found skewing of the X-chromosome inactivation pattern in the obligatory carrier in this family, supporting the hypothesis that RTT is an X-linked disorder. However, evaluation of the X-inactivation pattern in the mother of affected half sisters showed random X-inactivation, suggesting germline mosaicism as the cause of repeated transmission in that family. There was an affected male in the family, who was a maternal half brother of the affected niece, also suggesting germline mosaicism in the mother. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=9326329+9637791" 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="Brown, D. <strong>Hoping for the impossible in Baltimore: Brazilian girls with Rett syndrome may aid research that can't help them.</strong> Washington Post, October 18, 1997."None>Brown (1997)</a> noted that males who carry a Rett mutation may survive. The identification of such cases in sibships with diagnosed RTT females requires a carrier mother who either is a germline mosaic or has a favorably skewed X-inactivation pattern.</p>
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<p>On the basis of a girl with Rett syndrome and a translocation t(X;22)(p11.22;p11), <a href="#52" class="mim-tip-reference" title="Journel, H., Melki, J., Turleau, C., Munnich, A., de Grouchy, J. <strong>Rett phenotype with X/autosome translocation: possible mapping to the short arm of chromosome X.</strong> Am. J. Med. Genet. 35: 142-147, 1990.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2301467/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2301467</a>] [<a href="https://doi.org/10.1002/ajmg.1320350130" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2301467">Journel et al. (1990)</a> suggested that the gene for this disorder may be located on the short arm of the X chromosome. The same translocation was present in her unaffected mother and in her sister, who was affected with a neurologic disorder compatible with a forme fruste of Rett syndrome. In the course of a systematic high-resolution chromosome analysis on 28 patients with Rett syndrome, <a href="#114" class="mim-tip-reference" title="Zoghbi, H. Y., Ledbetter, D. H., Schultz, R., Percy, A. K., Glaze, D. G. <strong>A de novo X;3 translocation in Rett syndrome.</strong> Am. J. Med. Genet. 35: 148-151, 1990.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2301468/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2301468</a>] [<a href="https://doi.org/10.1002/ajmg.1320350131" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2301468">Zoghbi et al. (1990)</a> found a patient with a de novo balanced translocation t(X;3)(p22.1;q13.31). <a href="#114" class="mim-tip-reference" title="Zoghbi, H. Y., Ledbetter, D. H., Schultz, R., Percy, A. K., Glaze, D. G. <strong>A de novo X;3 translocation in Rett syndrome.</strong> Am. J. Med. Genet. 35: 148-151, 1990.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2301468/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2301468</a>] [<a href="https://doi.org/10.1002/ajmg.1320350131" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2301468">Zoghbi et al. (1990)</a> noted, however, that the Rett syndrome locus may map to a different location on the X chromosome than the breakpoint, as has occurred in incontinentia pigmenti (<a href="/entry/308300">308300</a>). <a href="#9" class="mim-tip-reference" title="Archidiacono, N., Lerone, M., Rocchi, M., Anvret, M., Ozcelik, T., Francke, U., Romeo, G. <strong>Rett syndrome: exclusion mapping following the hypothesis of germinal mosaicism for new X-linked mutations.</strong> Hum. Genet. 86: 604-606, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1673961/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1673961</a>] [<a href="https://doi.org/10.1007/BF00201549" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1673961">Archidiacono et al. (1991)</a> studied the unaffected mother of 2 half sisters with Rett syndrome for evidence of germinal mosaicism. The analysis of 34 X-linked RFLPs in these 2 affected females and in their unaffected mother and half brother, together with the reconstruction of phase for 15 informative RFLPs in somatic cell hybrids retaining a single X chromosome from each female, made it possible to exclude some regions of the X chromosome as sites of the mutation causing the disorder. The 2 regions with X chromosome breakpoints found in RTT patients with X-autosome translocations, Xp22.11 (<a href="#114" class="mim-tip-reference" title="Zoghbi, H. Y., Ledbetter, D. H., Schultz, R., Percy, A. K., Glaze, D. G. <strong>A de novo X;3 translocation in Rett syndrome.</strong> Am. J. Med. Genet. 35: 148-151, 1990.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2301468/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2301468</a>] [<a href="https://doi.org/10.1002/ajmg.1320350131" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2301468">Zoghbi et al., 1990</a>) and Xp11.22 (<a href="#52" class="mim-tip-reference" title="Journel, H., Melki, J., Turleau, C., Munnich, A., de Grouchy, J. <strong>Rett phenotype with X/autosome translocation: possible mapping to the short arm of chromosome X.</strong> Am. J. Med. Genet. 35: 142-147, 1990.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2301467/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2301467</a>] [<a href="https://doi.org/10.1002/ajmg.1320350130" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2301467">Journel et al., 1990</a>), were not excluded as the localization of the RTT gene. In 2 families with maternally related, affected half sisters, <a href="#29" class="mim-tip-reference" title="Ellison, K. A., Fill, C. P., Terwilliger, J., DeGennaro, L. J., Martin-Gallardo, A., Anvret, M., Percy, A. K., Ott, J., Zoghbi, H. <strong>Examination of X chromosome markers in Rett syndrome: exclusion mapping with a novel variation on multilocus linkage analysis.</strong> Am. J. Hum. Genet. 50: 278-287, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1734712/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1734712</a>]" pmid="1734712">Ellison et al. (1992)</a> performed genotypic analysis using 63 DNA markers from the X chromosome. In at least 1 of the 2 families, 36 markers were informative, and 25 markers were informative in both families. On the basis of discordance for maternal alleles in the half sisters, they excluded 20 loci as candidates for the Rett syndrome gene. Using the exclusion criterion of a lod score less than -2, they excluded the region from Xp21.2 to Xq21-q23. <a href="#24" class="mim-tip-reference" title="Curtis, A. R. J., Headland, S., Lindsay, S., Thomas, N. S. T., Boye, E., Kamakari, S., Roustan, P., Anvret, M., Wahlstrom, J., McCarthy, G., Clarke, A. J., Bhattacharya, S. <strong>X chromosome linkage studies in familial Rett syndrome.</strong> Hum. Genet. 90: 551-555, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8094068/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8094068</a>] [<a href="https://doi.org/10.1007/BF00217457" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8094068">Curtis et al. (1993)</a> did linkage studies in 4 families, each with 2 individuals affected by Rett syndrome. In 2 of the families, X-linked dominant inheritance of the RTT defect from a germinally mosaic mother could be assumed. Using maternal X chromosome markers showing discordant inheritance they excluded much of Xp, including 3 candidate genes, OTC (<a href="/entry/311250">311250</a>), synapsin I (SYN1; <a href="/entry/313440">313440</a>), and synaptophysin (<a href="/entry/313475">313475</a>). Although most of the long arm was inherited in common, it was possible to exclude a centromeric region. <a href="#24" class="mim-tip-reference" title="Curtis, A. R. J., Headland, S., Lindsay, S., Thomas, N. S. T., Boye, E., Kamakari, S., Roustan, P., Anvret, M., Wahlstrom, J., McCarthy, G., Clarke, A. J., Bhattacharya, S. <strong>X chromosome linkage studies in familial Rett syndrome.</strong> Hum. Genet. 90: 551-555, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8094068/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8094068</a>] [<a href="https://doi.org/10.1007/BF00217457" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8094068">Curtis et al. (1993)</a> also presented information on 2 families with affected aunt-niece pairs. To determine which regions of the X chromosome were inherited concordantly and discordantly in an affected maternal aunt and niece, <a href="#88" class="mim-tip-reference" title="Schanen, N. C., Dahle, E. J. R., Capozzoli, F., Holm, V. A., Zoghbi, H. Y., Francke, U. <strong>A new Rett syndrome family consistent with X-linked inheritance expands the X chromosome exclusion map.</strong> Am. J. Hum. Genet. 61: 634-641, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9326329/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9326329</a>] [<a href="https://doi.org/10.1086/515525" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9326329">Schanen et al. (1997)</a> genotyped the individuals in the aunt-niece family and 2 previously reported pairs of half sisters. The combined exclusion mapping data allowed exclusion of the RTT locus from the interval between DXS1053 in Xp22.2 and DXS1222 in Xq22.3. In a family with 3 affected individuals, including a male, <a href="#86" class="mim-tip-reference" title="Schanen, C., Francke, U. <strong>A severely affected male born into a Rett syndrome kindred supports X-linked inheritance and allows extension of the exclusion map. (Letter)</strong> Am. J. Hum. Genet. 63: 267-269, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9637791/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9637791</a>] [<a href="https://doi.org/10.1086/301932" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9637791">Schanen and Francke (1998)</a> compared haplotypes to narrow the RTT candidate region to a small interval on Xp and the distal long arm. The authors noted that identification of a severely affected male in a family with recurrent classic Rett syndrome strengthened the hypothesis that RTT is caused by an X-linked gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=1734712+8094068+9326329+2301467+9637791+2301468+1673961" 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="#110" class="mim-tip-reference" title="Xiang, F., Zhang, Z., Clarke, A., Joseluiz, P., Sakkubai, N., Sarojini, B., Delozier-Blanchet, C. D., Hansmann, I., Edstrom, L., Anvret, M. <strong>Chromosome mapping of Rett syndrome: a likely candidate region on the telomere of Xq.</strong> J. Med. Genet. 35: 297-300, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9598723/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9598723</a>] [<a href="https://doi.org/10.1136/jmg.35.4.297" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9598723">Xiang et al. (1998)</a> presented haplotype analysis of 9 families with at least 2 closely related females affected by classic Rett syndrome. They concluded that the Rett syndrome locus is likely to lie within Xq28, close to marker DXS15. <a href="#110" class="mim-tip-reference" title="Xiang, F., Zhang, Z., Clarke, A., Joseluiz, P., Sakkubai, N., Sarojini, B., Delozier-Blanchet, C. D., Hansmann, I., Edstrom, L., Anvret, M. <strong>Chromosome mapping of Rett syndrome: a likely candidate region on the telomere of Xq.</strong> J. Med. Genet. 35: 297-300, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9598723/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9598723</a>] [<a href="https://doi.org/10.1136/jmg.35.4.297" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9598723">Xiang et al. (1998)</a> suggested that the GABRE (<a href="/entry/300093">300093</a>) and GABRA3 (<a href="/entry/305660">305660</a>) genes are candidate genes for Rett syndrome. <a href="#107" class="mim-tip-reference" title="Webb, T., Clarke, A., Hanefeld, F., Pereira, J.-L., Rosenbloom, L., Woods, C. G. <strong>Linkage analysis in Rett syndrome families suggests that there may be a critical region at Xq28.</strong> J. Med. Genet. 35: 997-1003, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9863596/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9863596</a>] [<a href="https://doi.org/10.1136/jmg.35.12.997" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9863596">Webb et al. (1998)</a> presented a study of 6 families with more than 1 female affected with Rett syndrome. They showed weak linkage to loci in Xq28, with a maximum lod score of 1.935 at theta = 0.0 at DXYS154. <a href="#107" class="mim-tip-reference" title="Webb, T., Clarke, A., Hanefeld, F., Pereira, J.-L., Rosenbloom, L., Woods, C. G. <strong>Linkage analysis in Rett syndrome families suggests that there may be a critical region at Xq28.</strong> J. Med. Genet. 35: 997-1003, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9863596/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9863596</a>] [<a href="https://doi.org/10.1136/jmg.35.12.997" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9863596">Webb et al. (1998)</a> also noted the presence of the candidate genes GABRA3 and L1CAM (<a href="/entry/308840">308840</a>) in this region, but cautioned that their lod scores did not quite reach significance. <a href="#92" class="mim-tip-reference" title="Sirianni, N., Naidu, S., Pereira, J., Pillotto, R. F., Hoffman, E. P. <strong>Rett syndrome: confirmation of X-linked dominant inheritance, and localization of the gene to Xq28. (Letter)</strong> Am. J. Hum. Genet. 63: 1552-1558, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9792883/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9792883</a>] [<a href="https://doi.org/10.1086/302105" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9792883">Sirianni et al. (1998)</a> presented information that they interpreted as confirming X-linked dominant inheritance of Rett syndrome. They described a family with the largest number (3) of female sibs affected with Rett syndrome identified to that time, and used data from this family, as well as from families previously described, to demonstrate the mode of inheritance and to localize the gene to Xq28. Concordance analysis with DNA markers showed that only Xq28 was shared among the 3 affected girls, whereas the same region was not shared with the unaffected sisters. The data complemented the exclusion-mapping data described by <a href="#110" class="mim-tip-reference" title="Xiang, F., Zhang, Z., Clarke, A., Joseluiz, P., Sakkubai, N., Sarojini, B., Delozier-Blanchet, C. D., Hansmann, I., Edstrom, L., Anvret, M. <strong>Chromosome mapping of Rett syndrome: a likely candidate region on the telomere of Xq.</strong> J. Med. Genet. 35: 297-300, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9598723/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9598723</a>] [<a href="https://doi.org/10.1136/jmg.35.4.297" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9598723">Xiang et al. (1998)</a> who could not exclude the distal region of the long arm of the X chromosome. In a Brazilian family, <a href="#92" class="mim-tip-reference" title="Sirianni, N., Naidu, S., Pereira, J., Pillotto, R. F., Hoffman, E. P. <strong>Rett syndrome: confirmation of X-linked dominant inheritance, and localization of the gene to Xq28. (Letter)</strong> Am. J. Hum. Genet. 63: 1552-1558, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9792883/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9792883</a>] [<a href="https://doi.org/10.1086/302105" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9792883">Sirianni et al. (1998)</a> found that the mother had extreme skewing of X inactivation with the unaffected X active in 95% of cells. Thus, the finding of highly skewed X inactivation in the mother, with preferential use of the unaffected X chromosome, strongly suggested that she was a nonpenetrant carrier of Rett syndrome. An unaffected daughter and an affected daughter did not show the skewed X inactivation. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=9792883+9598723+9863596" 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><strong><em>Exclusion of Linked Genes</em></strong></p><p>
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<a href="#31" class="mim-tip-reference" title="Ferlini, A., Ansaloni, L., Nobile, C., Forabosco, A. <strong>Molecular analysis of the Rett syndrome using cDNA synapsin I as a probe.</strong> Brain Dev. 12: 136-139, 1990.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2111640/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2111640</a>] [<a href="https://doi.org/10.1016/s0387-7604(12)80195-1" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2111640">Ferlini et al. (1990)</a> excluded the synapsin I gene as the cause of RTT. <a href="#70" class="mim-tip-reference" title="Narayanan, V., Olinsky, S., Dahle, E., Naidu, S., Zoghbi, H. Y. <strong>Mutation analysis of the M6b gene in patients with Rett syndrome.</strong> Am. J. Med. Genet. 78: 165-168, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9674909/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9674909</a>] [<a href="https://doi.org/10.1002/(sici)1096-8628(19980630)78:2<165::aid-ajmg13>3.0.co;2-l" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9674909">Narayanan et al. (1998)</a> excluded the M6b gene (<a href="/entry/300051">300051</a>), <a href="#103" class="mim-tip-reference" title="Wan, M., Francke, U. <strong>Evaluation of two X chromosomal candidate genes for Rett syndrome: glutamate dehydrogenase-2 (GLUD2) and Rab GDP-dissociation inhibitor (GDI1).</strong> Am. J. Med. Genet. 78: 169-172, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9674910/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9674910</a>]" pmid="9674910">Wan and Francke (1998)</a> excluded glutamate dehydrogenase-2 (GLUD2; <a href="/entry/300144">300144</a>) and Rab GDP-dissociation inhibitor GDI1 (<a href="/entry/300104">300104</a>), which were chosen because of their location in the nonexcluded region of Xq. <a href="#44" class="mim-tip-reference" title="Heidary, G., Hampton, L. L., Schanen, N. C., Rivkin, M. J., Darras, B. T., Battey, J., Francke, U. <strong>Exclusion of the gastrin-releasing peptide receptor (GRPR) locus as a candidate gene for Rett syndrome.</strong> Am. J. Med. Genet. 78: 173-175, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9674911/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9674911</a>] [<a href="https://doi.org/10.1002/(sici)1096-8628(19980630)78:2<173::aid-ajmg15>3.0.co;2-k" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9674911">Heidary et al. (1998)</a> excluded the gastrin-releasing peptide receptor gene (GRPR; <a href="/entry/305670">305670</a>), <a href="#23" class="mim-tip-reference" title="Cummings, C. J., Dahle, E. J. R., Zoghbi, H. Y. <strong>Analysis of the genomic structure of the human glycine receptor alpha-2 subunit gene and exclusion of this gene as a candidate for Rett syndrome.</strong> Am. J. Med. Genet. 78: 176-178, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9674912/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9674912</a>]" pmid="9674912">Cummings et al. (1998)</a> excluded the glycine receptor alpha-2 subunit gene (GLRA2; <a href="/entry/305990">305990</a>), and <a href="#99" class="mim-tip-reference" title="Van den Veyver, I. B., Subramanian, S., Zoghbi, H. Y. <strong>Genomic structure of a human holocytochrome c-type synthetase gene in Xp22.3 and mutation analysis in patients with Rett syndrome.</strong> Am. J. Med. Genet. 78: 179-181, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9674913/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9674913</a>] [<a href="https://doi.org/10.1002/(sici)1096-8628(19980630)78:2<179::aid-ajmg17>3.3.co;2-3" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9674913">Van den Veyver et al. (1998)</a> excluded the holocytochrome c-type synthetase gene (HCCS; <a href="/entry/300056">300056</a>), all of which had been candidate genes for Rett syndrome because they mapped to a region on Xp. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=9674913+9674910+2111640+9674912+9674911+9674909" 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>Mutations in the MECP2 Gene</em></strong></p><p>
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In 5 of 21 sporadic patients with RTT, <a href="#5" class="mim-tip-reference" title="Amir, R. E., Van den Veyver, I. B., Wan, M., Tran, C. Q., Francke, U., Zoghbi, H. Y. <strong>Rett syndrome is caused by mutations in X-linked MECP2, encoding methyl-CpG-binding protein 2.</strong> Nature Genet. 23: 185-188, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10508514/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10508514</a>] [<a href="https://doi.org/10.1038/13810" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10508514">Amir et al. (1999)</a> identified 3 de novo missense mutations in the MECP2 gene (<a href="/entry/300005#0001">300005.0001</a>, <a href="/entry/300005#0002">300005.0002</a>, <a href="/entry/300005#0007">300005.0007</a>). Among 8 cases of familial Rett syndrome, <a href="#5" class="mim-tip-reference" title="Amir, R. E., Van den Veyver, I. B., Wan, M., Tran, C. Q., Francke, U., Zoghbi, H. Y. <strong>Rett syndrome is caused by mutations in X-linked MECP2, encoding methyl-CpG-binding protein 2.</strong> Nature Genet. 23: 185-188, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10508514/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10508514</a>] [<a href="https://doi.org/10.1038/13810" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10508514">Amir et al. (1999)</a> found an additional missense mutation (<a href="/entry/300005#0008">300005.0008</a>) in a family with 2 affected half sisters. The mutation was not detected in their obligate carrier mother, suggesting that the mother was a germline mosaic for the mutation. The authors suggested that abnormal epigenetic regulation may be a mechanism underlying the pathogenesis of Rett syndrome. <a href="#104" class="mim-tip-reference" title="Wan, M., Lee, S. S. J., Zhang, X., Houwink-Manville, I., Song, H.-R., Amir, R. E., Budden, S., Naidu, S., Pereira, J. L. P., Lo, I. F. M., Zoghbi, H. Y., Schanen, N. C., Francke, U. <strong>Rett syndrome and beyond: recurrent spontaneous and familial MECP2 mutations at CpG hotspots.</strong> Am. J. Hum. Genet. 65: 1520-1529, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10577905/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10577905</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=10577905[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/10.1086/302690" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10577905">Wan et al. (1999)</a> identified 5 additional mutations in the MECP2 gene (see, e.g., <a href="/entry/300005#0003">300005.0003</a>) in patients with RTT. They found that the mutations were de novo, and that female heterozygotes with favorably skewed X-inactivation patterns may have little or no involvement. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=10508514+10577905" 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="#101" class="mim-tip-reference" title="Villard, L., Kpebe, A., Cardoso, C., Chelly, J., Tardieu, M., Fontes, M. <strong>Two affected boys in a Rett syndrome family: clinical and molecular findings.</strong> Neurology 55: 1188-1193, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11071498/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11071498</a>] [<a href="https://doi.org/10.1212/wnl.55.8.1188" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11071498">Villard et al. (2000)</a> reported a family in which a daughter had classic Rett syndrome and her 2 brothers died in infancy from severe encephalopathy. The affected girl and one brother tested showed a mutation in the MECP2 gene (<a href="/entry/300005#0007">300005.0007</a>). The unaffected carrier mother had a completely biased pattern of X-chromosome inactivation that favored expression of the normal allele. One of the affected boys showed severe mental retardation and hypotonia soon after birth and died at age 11 months. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11071498" 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="#112" class="mim-tip-reference" title="Zappella, M., Meloni, I., Longo, I., Hayek, G., Renieri, A. <strong>Preserved speech variants of the Rett syndrome: molecular and clinical analysis.</strong> Am. J. Med. Genet. 104: 14-22, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11746022/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11746022</a>] [<a href="https://doi.org/10.1002/ajmg.10005" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11746022">Zappella et al. (2001)</a> reported clinical and mutation analysis findings in 18 patients with the preserved speech variant form of Rett syndrome. Ten (55%) had an MECP2 mutation. All had slow recovery of verbal and praxic abilities, evident autistic behavior, and normal head circumference. Six were overweight, often obese, had kyphosis, coarse face, and mental age of 2 to 3 years, and were able to speak in sentences; 4 had normal weight, mental age not beyond 1 to 2 years, and spoke in single words and 2-word phrases. The course of the disorder was in stages as in classic Rett syndrome. Hand washing was present in the first years of life but often subsequently disappeared. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11746022" 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="Clayton-Smith, J., Watson, P., Ramsden, S., Black, G. C. M. <strong>Somatic mutation in MECP2 as a non-fatal neurodevelopmental disorder in males.</strong> Lancet 356: 830-832, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11022934/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11022934</a>] [<a href="https://doi.org/10.1016/s0140-6736(00)02661-1" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11022934">Clayton-Smith et al. (2000)</a> presented a male with somatic mosaicism for an MECP2 mutation (<a href="/entry/300005#0010">300005.0010</a>), leading to a progressive but nonfatal neurodevelopmental disorder. In an affected boy, <a href="#98" class="mim-tip-reference" title="Topcu, M., Akyerli, C., Sayi, A., Toruner, G. A., Kocoglu, S. R., Cimbis, M., Ozcelik, T. <strong>Somatic mosaicism for a MECP2 mutation associated with classic Rett syndrome in a boy.</strong> Europ. J. Hum. Genet. 10: 77-81, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11896459/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11896459</a>] [<a href="https://doi.org/10.1038/sj.ejhg.5200745" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11896459">Topcu et al. (2002)</a> identified an R270X mutation (<a href="/entry/300005#0005">300005.0005</a>) along with the wildtype allele. The authors speculated that the somatic mosaicism could be the result of an early postzygotic mutation or chimerism. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=11896459+11022934" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#14" class="mim-tip-reference" title="Bourdon, V., Philippe, C., Bienvenu, T., Koenig, B., Tardieu, M., Chelly, J., Jonveaux, P. <strong>Evidence of somatic mosaicism for a MECP2 mutation in females with Rett syndrome: diagnostic implications. (Letter)</strong> J. Med. Genet. 38: 867-870, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11768391/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11768391</a>] [<a href="https://doi.org/10.1136/jmg.38.12.867" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11768391">Bourdon et al. (2001)</a> reported somatic mosaicism for deletions of the MECP2 gene in 2 girls, 1 with a classic Rett phenotype and 1 with an atypical Rett phenotype without a period of regression. The deletions in these girls were detected not by sequence analysis but by CSGE or DGGE. <a href="#14" class="mim-tip-reference" title="Bourdon, V., Philippe, C., Bienvenu, T., Koenig, B., Tardieu, M., Chelly, J., Jonveaux, P. <strong>Evidence of somatic mosaicism for a MECP2 mutation in females with Rett syndrome: diagnostic implications. (Letter)</strong> J. Med. Genet. 38: 867-870, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11768391/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11768391</a>] [<a href="https://doi.org/10.1136/jmg.38.12.867" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11768391">Bourdon et al. (2001)</a> suggested that this had implications for diagnostic methods used in Rett cases and cases of possible Rett syndrome. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11768391" 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="#64" class="mim-tip-reference" title="Mnatzakanian, G. N., Lohi, H., Munteanu, I., Alfred, S. E., Yamada, T., MacLeod, P. J. M., Jones, J. R., Scherer, S. W., Schanen, N. C., Friez, M. J., Vincent, J. B., Minassian, B. A. <strong>A previously unidentified MECP2 open reading frame defines a new protein isoform relevant to Rett syndrome.</strong> Nature Genet. 36: 339-341, 2004. Note: Erratum: Nature Genet. 36: 540 only, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15034579/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15034579</a>] [<a href="https://doi.org/10.1038/ng1327" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15034579">Mnatzakanian et al. (2004)</a> identified a theretofore unknown isoform of MECP2 that they called MECP2B, which utilizes exon 1 and exons 3 and 4, skipping exon 2. They screened 19 girls with typical Rett syndrome in whom no mutations had been found in exons 2, 3, or 4. In 1 affected individual, they identified a deletion of 11 basepairs in exon 1 (<a href="/entry/300005#0028">300005.0028</a>). <a href="#78" class="mim-tip-reference" title="Ravn, K., Nielsen, J. B., Schwartz, M. <strong>Mutations found within exon 1 of MECP2 in Danish patients with Rett syndrome. (Letter)</strong> Clin. Genet. 67: 532-533, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15857422/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15857422</a>] [<a href="https://doi.org/10.1111/j.1399-0004.2005.00444.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15857422">Ravn et al. (2005)</a> identified a mutation in exon 1 of the MECP2 gene (<a href="/entry/300005#0029">300005.0029</a>) in a patient with typical Rett syndrome. <a href="#78" class="mim-tip-reference" title="Ravn, K., Nielsen, J. B., Schwartz, M. <strong>Mutations found within exon 1 of MECP2 in Danish patients with Rett syndrome. (Letter)</strong> Clin. Genet. 67: 532-533, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15857422/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15857422</a>] [<a href="https://doi.org/10.1111/j.1399-0004.2005.00444.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15857422">Ravn et al. (2005)</a> emphasized the importance of mutation screening of MECP2 exon 1. <a href="#11" class="mim-tip-reference" title="Bartholdi, D., Klein, A., Weissert, M., Koenig, N., Baumer, A., Boltshauser, E., Schinzel, A., Berger, W., Matyas, G. <strong>Clinical profiles of four patients with Rett syndrome carrying a novel exon 1 mutation or genomic rearrangement in the MECP2 gene.</strong> Clin. Genet. 69: 319-326, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16630165/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16630165</a>] [<a href="https://doi.org/10.1111/j.1399-0004.2006.00604.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16630165">Bartholdi et al. (2006)</a> reported 2 unrelated girls with Rett syndrome caused by 2 different mutations affecting exon 1 of the MECP2 gene (see, e.g., <a href="/entry/300005#0031">300005.0031</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=16630165+15857422+15034579" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Using multiplex ligation-dependent probe amplification (MLPA), <a href="#43" class="mim-tip-reference" title="Hardwick, S. A., Reuter, K., Williamson, S. L., Vasudevan, V., Donald, J., Slater, K., Bennetts, B., Bebbington, A., Leonard, H., Williams, S. R., Smith, R. L., Cloosterman, D., Christodoulou, J. <strong>Delineation of large deletions of the MECP2 gene in Rett syndrome patients, including a familial case with a male proband.</strong> Europ. J. Hum. Genet. 15: 1218-1229, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17712354/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17712354</a>] [<a href="https://doi.org/10.1038/sj.ejhg.5201911" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17712354">Hardwick et al. (2007)</a> identified multiexonic deletions in the MECP2 gene in 12 (8.1%) of 149 apparently mutation-negative patients with Rett syndrome. All of the deletions involved exon 3, exon 4, or both. There was no correlation between phenotypic severity and deletion size. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17712354" 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="#85" class="mim-tip-reference" title="Saunders, C. J., Minassian, B. E., Chow, E. W. C., Zhao, W., Vincent, J. B. <strong>Novel exon 1 mutations in MECP2 implicate isoform MeCP2_1 in classical Rett syndrome.</strong> Am. J. Med. Genet. 149A: 1019-1023, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19365833/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19365833</a>] [<a href="https://doi.org/10.1002/ajmg.a.32776" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19365833">Saunders et al. (2009)</a> identified 4 patients with classic Rett syndrome associated with mutations in exon 1 of the MECP2 gene, affecting the MeCP2_e1 isoform. Three of the mutations were predicted to result in absent translation of the isoform. Three of the mutations were proven to be de novo; the fourth was likely de novo, but the unaffected father was not available for DNA analysis. Two of the patients had previously tested negative for MECP2 mutation, which at the time only included sequencing of exons 2 to 4 of the gene (MeCP2_e2 isoform). The findings suggested that mutations affecting exon 1 of MECP2 are important in the etiology of RTT. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19365833" 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>Disruption of the NTNG1 Gene</em></strong></p><p>
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<a href="#13" class="mim-tip-reference" title="Borg, I., Freude, K., Kubart, S., Hoffmann, K., Menzel, C., Laccone, F., Firth, H., Ferguson-Smith, M. A., Tommerup, N., Ropers, H.-H., Sargan, D., Kalscheuer, V. M. <strong>Disruption of Netrin G1 by a balanced chromosome translocation in a girl with Rett syndrome.</strong> Europ. J. Hum. Genet. 13: 921-927, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15870826/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15870826</a>] [<a href="https://doi.org/10.1038/sj.ejhg.5201429" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15870826">Borg et al. (2005)</a> reported a girl with characteristic features of Rett syndrome who had no mutations in MECP2 or CDKL5 but carried a de novo balanced translocation, t(1;7)(p13.3;q31.3). No known gene was disrupted by the chromosome 7 breakpoint, but the chromosome 1 breakpoint was located within intron 6 of the NTNG1 gene (<a href="/entry/608818">608818</a>) and affected alternatively spliced transcripts. <a href="#13" class="mim-tip-reference" title="Borg, I., Freude, K., Kubart, S., Hoffmann, K., Menzel, C., Laccone, F., Firth, H., Ferguson-Smith, M. A., Tommerup, N., Ropers, H.-H., Sargan, D., Kalscheuer, V. M. <strong>Disruption of Netrin G1 by a balanced chromosome translocation in a girl with Rett syndrome.</strong> Europ. J. Hum. Genet. 13: 921-927, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15870826/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15870826</a>] [<a href="https://doi.org/10.1038/sj.ejhg.5201429" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15870826">Borg et al. (2005)</a> suggested that NTNG1 is a candidate disease gene for RTT. <a href="#7" class="mim-tip-reference" title="Archer, H. L., Evans, J. C., Millar, D. S., Thompson, P. W., Kerr, A. M., Leonard, H., Christodoulou, J., Ravine, D., Lazarou, L., Grove, L., Verity, C., Whatley, S. D., Pilz, D. T., Sampson, J. R., Clarke, A. J. <strong>NTNG1 mutations are a rare cause of Rett syndrome.</strong> Am. J. Med. Genet. 140A: 691-694, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16502428/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16502428</a>] [<a href="https://doi.org/10.1002/ajmg.a.31133" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16502428">Archer et al. (2006)</a> failed to identify any pathogenic mutations in coding exons of the NTNG1 gene among 115 patients with Rett syndrome. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=15870826+16502428" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Associations Pending Confirmation</em></strong></p><p>
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For discussion of a possible association between Rett syndrome and variation in the JMJD1C gene, see <a href="/entry/604503#0001">604503.0001</a>.</p>
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<p><a href="#112" class="mim-tip-reference" title="Zappella, M., Meloni, I., Longo, I., Hayek, G., Renieri, A. <strong>Preserved speech variants of the Rett syndrome: molecular and clinical analysis.</strong> Am. J. Med. Genet. 104: 14-22, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11746022/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11746022</a>] [<a href="https://doi.org/10.1002/ajmg.10005" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11746022">Zappella et al. (2001)</a> noted that all MECP2 mutations found in PSV patients have been either missense or late truncating mutations. In particular, the 4 early truncating hotspot mutations, R168X (<a href="/entry/300005#0020">300005.0020</a>), R255X (<a href="/entry/300005#0021">300005.0021</a>), R270X (<a href="/entry/300005#0005">300005.0005</a>), and R294X (<a href="/entry/300005#0011">300005.0011</a>), have not been found in PSV patients. These results suggested that early truncating mutations lead to a poor prognosis (classic Rett), whereas late truncating missense mutations lead either to classic Rett or to PSV. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11746022" 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="#93" class="mim-tip-reference" title="Smeets, E., Schollen, E., Moog, U., Matthijs, G., Herbergs, J., Smeets, H., Curfs, L., Schrander-Stumpel, C., Fryns, J. P. <strong>Rett syndrome in adolescent and adult females: clinical and molecular genetic findings.</strong> Am. J. Med. Genet. 122A: 227-233, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12966523/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12966523</a>] [<a href="https://doi.org/10.1002/ajmg.a.20321" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12966523">Smeets et al. (2003)</a> reported on 30 adolescent and adult females with classic or atypical Rett syndrome, of whom 24 had an MECP2 mutation. Mutations were found in all of the classic cases and in 64% of the variant cases. No correlation was found between skewing and milder phenotype. Early truncating mutations were associated with a more severe course of the disorder. A deletion hotspot in the C-terminal segment was predominantly characterized by rapid progressive neurogenic scoliosis. The R133C mutation (<a href="/entry/300005#0001">300005.0001</a>) was associated with a predominantly autistic presentation, whereas the R306C mutation (<a href="/entry/300005#0016">300005.0016</a>) was associated with a slower disease progression. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12966523" 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="#94" class="mim-tip-reference" title="Smeets, E., Terhal, P., Casaer, P., Peters, A., Midro, A., Schollen, E., van Roozendaal, K., Moog, U., Matthijs, G., Herbergs, J., Smeets, H., Curfs, L., Schrander-Stumpel, C., Fryns, J. P. <strong>Rett syndrome in females with CTS hot spot deletions: a disorder profile.</strong> Am. J. Med. Genet. 132A: 117-120, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15578576/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15578576</a>] [<a href="https://doi.org/10.1002/ajmg.a.30410" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15578576">Smeets et al. (2005)</a> described the long-term history of 10 females with a deletion in the C terminus of the MECP2 gene. Although their disease appeared 'classic' at an older age, in the beginning their symptoms resembled the forme fruste described by <a href="#35" class="mim-tip-reference" title="Hagberg, B. A., Skjeldal, O. H. <strong>Rett variants: a suggested model for inclusion criteria.</strong> Pediat. Neurol. 11: 5-11, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7986294/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7986294</a>] [<a href="https://doi.org/10.1016/0887-8994(94)90082-5" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7986294">Hagberg and Skjeldal (1994)</a>. All had a more slowly progressive course with better-preserved cognitive functions in adolescence and adulthood. Their primary clinical problems were a gradual decline in gross motor ability despite preventive measures and a rapidly progressive spine deformation due to marked dystonia present from childhood. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=7986294+15578576" 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="#41" class="mim-tip-reference" title="Hammer, S., Dorrani, N., Hartiala, J., Stein, S., Schanen, N. C. <strong>Rett syndrome in a 47,XXX patient with a de novo MECP2 mutation.</strong> Am. J. Med. Genet. 122A: 223-226, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12966522/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12966522</a>] [<a href="https://doi.org/10.1002/ajmg.a.20320" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12966522">Hammer et al. (2003)</a> reported a 5-year-old girl with a 47,XXX karyotype who had relatively mild atypical Rett syndrome leading initially to a diagnosis of infantile autism with regression. Mutation analysis identified a de novo MECP2 mutation (L100V; <a href="/entry/300005#0027">300005.0027</a>). The supernumerary X chromosome was maternally derived. X-inactivation patterns indicated preferential inactivation of the paternal allele. <a href="#41" class="mim-tip-reference" title="Hammer, S., Dorrani, N., Hartiala, J., Stein, S., Schanen, N. C. <strong>Rett syndrome in a 47,XXX patient with a de novo MECP2 mutation.</strong> Am. J. Med. Genet. 122A: 223-226, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12966522/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12966522</a>] [<a href="https://doi.org/10.1002/ajmg.a.20320" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12966522">Hammer et al. (2003)</a> suggested that the patient illustrated the importance of allele dosage on phenotypic presentation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12966522" 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="#106" class="mim-tip-reference" title="Weaving, L. S., Williamson, S. L., Bennetts, B., Davis, M., Ellaway, C. J., Leonard, H., Thong, M.-K., Delatycki, M., Thompson, E. M., Laing, N., Christodoulou, J. <strong>Effects of MECP2 mutation type, location and X-inactivation in modulating Rett syndrome phenotype.</strong> Am. J. Med. Genet. 118A: 103-114, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12655490/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12655490</a>] [<a href="https://doi.org/10.1002/ajmg.a.10053" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12655490">Weaving et al. (2003)</a> reported a large MECP2 screening project in patients diagnosed with Rett syndrome. Composite phenotype severity scores did not correlate with mutation type, domain affected, or X inactivation. Other correlations, including head circumference, height, presence of speech, and age at development of hand stereotypies, suggested that truncating mutations and mutations affecting the methyl-CpG-binding domain (MBD) tend to lead to a more severe phenotype. Skewed X inactivation was found in 31 (43%) of 72 patients tested, primarily in those with truncating mutations and mutations affecting the MBD. <a href="#106" class="mim-tip-reference" title="Weaving, L. S., Williamson, S. L., Bennetts, B., Davis, M., Ellaway, C. J., Leonard, H., Thong, M.-K., Delatycki, M., Thompson, E. M., Laing, N., Christodoulou, J. <strong>Effects of MECP2 mutation type, location and X-inactivation in modulating Rett syndrome phenotype.</strong> Am. J. Med. Genet. 118A: 103-114, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12655490/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12655490</a>] [<a href="https://doi.org/10.1002/ajmg.a.10053" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12655490">Weaving et al. (2003)</a> concluded that it is likely that X inactivation modulates the phenotype in RTT. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12655490" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In a study of genotype/phenotype correlations, <a href="#87" class="mim-tip-reference" title="Schanen, C., Houwink, E. J. F., Dorrani, N., Lane, J., Everett, R., Feng, A., Cantor, R. M., Percy, A. <strong>Phenotypic manifestations of MECP2 mutations in classical and atypical Rett syndrome.</strong> Am. J. Med. Genet. 126A: 129-140, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15057977/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15057977</a>] [<a href="https://doi.org/10.1002/ajmg.a.20571" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15057977">Schanen et al. (2004)</a> analyzed 85 Rett syndrome patients with mutation in the MECP2 gene. Sixty-five (76%) carried 1 of the 8 common mutations. Patients with missense mutations had lower total severity scores and better language performance than those with nonsense mutations. No difference was noted between severity scores for mutations in the MBD and the TRD. However, patients with missense mutations in TRD had the best overall scores and better preservation of head growth and language skills. Analysis of specific mutation groups demonstrated a striking difference for patients with the R306C mutation (<a href="/entry/300005#0016">300005.0016</a>), including better overall score, later regression, and better language with less motor impairment. Indeed, these patients as a group accounted for the differences in overall scores between the missense and nonsense groups <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15057977" 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 524 females with Rett syndrome and an identified MECP2 mutation, <a href="#50" class="mim-tip-reference" title="Jian, L., Archer, H. L., Ravine, D., Kerr, A., de Klerk, N., Christodoulou, J., Bailey, M. E. S., Laurvick, C., Leonard, H. <strong>p.R270X MECP2 mutation and mortality in Rett syndrome.</strong> Europ. J. Hum. Genet. 13: 1235-1238, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16077729/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16077729</a>] [<a href="https://doi.org/10.1038/sj.ejhg.5201479" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16077729">Jian et al. (2005)</a> prospectively analyzed mortality data and found significant differences in survival among the 8 most common mutations. Survival among cases with the R270X (<a href="/entry/300005#0005">300005.0005</a>) mutation was reduced compared to all the other mutations (p = 0.01). <a href="#50" class="mim-tip-reference" title="Jian, L., Archer, H. L., Ravine, D., Kerr, A., de Klerk, N., Christodoulou, J., Bailey, M. E. S., Laurvick, C., Leonard, H. <strong>p.R270X MECP2 mutation and mortality in Rett syndrome.</strong> Europ. J. Hum. Genet. 13: 1235-1238, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16077729/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16077729</a>] [<a href="https://doi.org/10.1038/sj.ejhg.5201479" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16077729">Jian et al. (2005)</a> concluded that this might explain the apparent underrepresentation of R270X in older subjects with Rett syndrome in 2 published reports of the MECP2 mutation spectrum (<a href="#93" class="mim-tip-reference" title="Smeets, E., Schollen, E., Moog, U., Matthijs, G., Herbergs, J., Smeets, H., Curfs, L., Schrander-Stumpel, C., Fryns, J. P. <strong>Rett syndrome in adolescent and adult females: clinical and molecular genetic findings.</strong> Am. J. Med. Genet. 122A: 227-233, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12966523/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12966523</a>] [<a href="https://doi.org/10.1002/ajmg.a.20321" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12966523">Smeets et al., 2003</a> and <a href="#87" class="mim-tip-reference" title="Schanen, C., Houwink, E. J. F., Dorrani, N., Lane, J., Everett, R., Feng, A., Cantor, R. M., Percy, A. <strong>Phenotypic manifestations of MECP2 mutations in classical and atypical Rett syndrome.</strong> Am. J. Med. Genet. 126A: 129-140, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15057977/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15057977</a>] [<a href="https://doi.org/10.1002/ajmg.a.20571" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15057977">Schanen et al., 2004</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=12966523+15057977+16077729" 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="Bartholdi, D., Klein, A., Weissert, M., Koenig, N., Baumer, A., Boltshauser, E., Schinzel, A., Berger, W., Matyas, G. <strong>Clinical profiles of four patients with Rett syndrome carrying a novel exon 1 mutation or genomic rearrangement in the MECP2 gene.</strong> Clin. Genet. 69: 319-326, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16630165/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16630165</a>] [<a href="https://doi.org/10.1111/j.1399-0004.2006.00604.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16630165">Bartholdi et al. (2006)</a> reported 2 unrelated girls with Rett syndrome caused by 2 different mutations affecting exon 1 of the MECP2 gene (see, e.g., <a href="/entry/300005#0031">300005.0031</a>). The phenotype of both girls was more severe than that of 2 additional unrelated girls with Rett syndrome caused by MECP2 mutations not affecting exon 1. The authors speculated that MECP2 mutations involving exon 1 result in a more severe phenotype because MECP2B is more abundantly expressed in the brain than MECP2A. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16630165" 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>Among 110 patients with Rett syndrome in whom an MECP2 mutation was not identified, <a href="#8" class="mim-tip-reference" title="Archer, H. L., Whatley, S. D., Evans, J. C., Ravine, D., Huppke, P., Kerr, A., Bunyan, D., Kerr, B., Sweeney, E., Davies, S. J., Reardon, W., Horn, J., and 14 others. <strong>Gross rearrangements of the MECP2 gene are found in both classical and atypical Rett syndrome patients. (Letter)</strong> J. Med. Genet. 43: 451-456, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16183801/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16183801</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16183801[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1136/jmg.2005.033464" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16183801">Archer et al. (2006)</a> used dosage analysis to detect large deletions in 37.8% (14 of 37) patients with classic Rett syndrome and 7.5% (4 of 53) patients with atypical Rett syndrome. Most large deletions contained a breakpoint in the deletion prone region of exon 4. Five patients with large MECP2 deletions had additional congenital anomalies, which was significantly more than in RTT patients with other MECP2 mutations. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16183801" 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="#83" class="mim-tip-reference" title="Robertson, L., Hall, S. E., Jacoby, P., Ellaway, C., de Klerk, N., Leonard, H. <strong>The association between behavior and genotype in Rett syndrome using the Australian Rett Syndrome Database.</strong> Am. J. Med. Genet. 141B: 177-183, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16389588/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16389588</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16389588[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/10.1002/ajmg.b.30270" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16389588">Robertson et al. (2006)</a> compared the behavioral profile of cases in the Australian Rett Syndrome Database with those of a British study using the Rett Syndrome Behavioral Questionnaire (<a href="#68" class="mim-tip-reference" title="Mount, R. H., Charman, T., Hastings, R. P., Reilly, S., Cass, H. <strong>The Rett Syndrome Behaviour Questionnaire (RSBQ): refining the behavioural phenotype of Rett syndrome.</strong> J. Child. Psychol. Psychiat. 43: 1099-1110, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12455930/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12455930</a>] [<a href="https://doi.org/10.1111/1469-7610.00236" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12455930">Mount et al., 2002</a>). Behavioral patterns were compared to MECP2 gene findings in the probands. Fear/anxiety was more commonly reported in those individuals with R133C and R306C. R294X was more likely to be associated with mood difficulties and body rocking but less likely to have hand behaviors and to display repetitive face movements. Hand behaviors were more commonly reported in those with R270X or R255X. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=12455930+16389588" 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="#48" class="mim-tip-reference" title="Huppke, P., Maier, E. M., Warnke, A., Brendel, C., Laccone, F., Gartner, J. <strong>Very mild cases of Rett syndrome with skewed X inactivation.</strong> J. Med. Genet. 43: 814-816, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16690727/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16690727</a>] [<a href="https://doi.org/10.1136/jmg.2006.042077" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16690727">Huppke et al. (2006)</a> reported 3 unrelated girls with very mild forms of Rett syndrome due to mutations in the MECP2 gene and skewed X inactivation (X-inactivation ratios of 84:16, 95:5, and 76:24, respectively). All 3 patients had normal hand function, communicated well, and showed hyperventilation only under stress; only 2 patients had a subtle history of developmental regression. None of the patients met the established diagnostic criteria for classic Rett syndrome. The findings indicated that X-inactivation patterns can influence the phenotypic severity of Rett syndrome. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16690727" 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="#46" class="mim-tip-reference" title="Hendrich, B., Bickmore, W. <strong>Human diseases with underlying defects in chromatin structure and modification.</strong> Hum. Molec. Genet. 10: 2233-2242, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11673406/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11673406</a>] [<a href="https://doi.org/10.1093/hmg/10.20.2233" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11673406">Hendrich and Bickmore (2001)</a> reviewed human disorders that share in common defects of chromatin structure or modification, including the ATR-X spectrum of disorders (<a href="/entry/301040">301040</a>), ICF syndrome (<a href="/entry/242860">242860</a>), Rett syndrome, Rubinstein-Taybi syndrome (<a href="/entry/180849">180849</a>), and Coffin-Lowry syndrome (<a href="/entry/303600">303600</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11673406" 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 rodent brain tissue, <a href="#26" class="mim-tip-reference" title="Deng, V., Matagne, V., Banine, F., Frerking, M., Ohliger, P., Budden, S., Pevsner, J., Dissen, G. A., Sherman, L. S., Ojeda, S. R. <strong>FXYD1 is an MeCP2 target gene overexpressed in the brains of Rett syndrome patients and Mecp2-null mice.</strong> Hum. Molec. Genet. 16: 640-650, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17309881/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17309881</a>] [<a href="https://doi.org/10.1093/hmg/ddm007" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17309881">Deng et al. (2007)</a> identified the FXYD1 (<a href="/entry/602359">602359</a>) promoter as an endogenous target of MECP2, which can cause transcriptional regulation of FXYD1. Transgenic Mecp2-null mice had increased Fxyd1 mRNA and protein levels in the frontal cortex, similar to that observed in patients with Rett syndrome. Increased Fxyd1 expression in Mecp2-null mice was associated with decreased Na,K-ATPase activity in the frontal cortex. In cultured mouse neurons, overexpression of Fxyd1 was associated with decreased neuronal dendritic tree and spine formation compared to controls, findings that have been observed in Rett syndrome. Overall, the results suggested that derepression of FXYD1, resulting from inactivation of MECP2, may contribute to the neuropathogenesis of Rett syndrome. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17309881" 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="#61" class="mim-tip-reference" title="Marchetto, M. C. N., Carromeu, C., Acab, A., Yu, D., Yeo, G. W., Mu, Y., Chen, G., Gage, F. H., Muotri, A. R. <strong>A model for neural development and treatment of Rett syndrome using human induced pluripotent stem cells.</strong> Cell 143: 527-539, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21074045/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21074045</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21074045[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.cell.2010.10.016" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21074045">Marchetto et al. (2010)</a> generated neurons with RTT-associated MECP2 mutations from induced pluripotent stem cells derived from fibroblasts isolated from patients with Rett syndrome. These cells were able to undergo X inactivation and generate functional neurons. Studies of these neurons in culture showed fewer synapses, reduced spine density, and small soma size compared to controls. In addition, these cells showed altered calcium signaling and electrophysiologic defects, particularly affecting glutamate signaling, compared to controls. The findings demonstrated that human RTT neurons have early developmental defects. Pharmacologic treatment of these cells with IGF1 (<a href="/entry/147440">147440</a>) and gentamicin, which causes read-through of nonsense mutations, showed some promising results. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21074045" 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="#69" class="mim-tip-reference" title="Muotri, A. R., Marchetto, M. C. N., Coufal, N. G., Oefner, R., Yeo, G., Nakashima, K., Gage, F. H. <strong>L1 retrotransposition in neurons is modulated by MeCP2.</strong> Nature 468: 443-446, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21085180/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21085180</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21085180[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nature09544" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21085180">Muotri et al. (2010)</a> showed that L1 neuronal transcription and retrotransposition in rodents are increased in the absence of Mecp2. Using neuronal progenitor cells derived from human induced pluripotent stem cells and human tissues, they revealed that patients with Rett syndrome, carrying MeCP2 mutations, have increased susceptibility for L1 retrotransposition. <a href="#69" class="mim-tip-reference" title="Muotri, A. R., Marchetto, M. C. N., Coufal, N. G., Oefner, R., Yeo, G., Nakashima, K., Gage, F. H. <strong>L1 retrotransposition in neurons is modulated by MeCP2.</strong> Nature 468: 443-446, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21085180/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21085180</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21085180[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nature09544" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21085180">Muotri et al. (2010)</a> concluded that L1 retrotransposition can be controlled in a tissue-specific manner and that disease-related genetic mutations can influence the frequency of neuronal L1 retrotransposition. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21085180" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#39" class="mim-tip-reference" title="Hagberg, B. <strong>Rett syndrome: Swedish approach to analysis of prevalence and cause.</strong> Brain Dev. 7: 277-280, 1985."None>Hagberg (1985)</a> estimated the frequency of Rett syndrome to be about 1 in 15,000 in southwestern Sweden. Among girls aged 0 to 18 years in North Dakota, <a href="#18" class="mim-tip-reference" title="Burd, L., Vesley, B., Martsolf, J. T., Kerbeshian, J. <strong>Prevalence study of Rett syndrome in North Dakota children.</strong> Am. J. Med. Genet. 38: 565-568, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2063900/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2063900</a>] [<a href="https://doi.org/10.1002/ajmg.1320380414" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2063900">Burd et al. (1991)</a> found the frequency of Rett syndrome to be 1 in 19,786. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2063900" 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="#63" class="mim-tip-reference" title="Miyamoto, A., Yamamoto, M., Takahashi, S., Oki, J. <strong>Classical Rett syndrome in sisters: variability of clinical expression.</strong> Brain Dev. 19: 492-494, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9408598/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9408598</a>] [<a href="https://doi.org/10.1016/s0387-7604(97)00052-1" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9408598">Miyamoto et al. (1997)</a> quoted data suggesting that Rett syndrome has a frequency of 1 in 20,000 girls in metropolitan Tokyo. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9408598" 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="#113" class="mim-tip-reference" title="Zimprich, F., Ronen, G. M., Stogmann, W., Baumgartner, C., Stogmann, E., Rett, B., Pappas, C., Leppert, M., Singh, N., Anderson, V. E. <strong>Andreas Rett and benign familial neonatal convulsions revisited.</strong> Neurology 67: 864-866, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16966552/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16966552</a>] [<a href="https://doi.org/10.1212/01.wnl.0000234066.46806.90" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16966552">Zimprich et al. (2006)</a> provided a historical perspective of the work of Andreas Rett (1924-1997), a pediatric neurologist and social reformer in postwar Austria, who first described Rett syndrome. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16966552" 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>Because of the progressive character of the disease and occasional reports of elevated blood and CSF lactate, it has been suggested that Rett syndrome may be a mitochondrial disorder. <a href="#55" class="mim-tip-reference" title="Lappalainen, R., Riikonen, R. S. <strong>Elevated CSF lactate in the Rett syndrome: cause or consequence?</strong> Brain Dev. 16: 399-401, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7892961/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7892961</a>] [<a href="https://doi.org/10.1016/0387-7604(94)90129-5" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7892961">Lappalainen and Riikonen (1994)</a> assessed the acid-base balance CSF and blood lactate from 8 girls with Rett syndrome. Only the 3 patients with severe hyperventilation had elevated CSF lactate values. The authors suggested that elevation of CSF lactate is secondary to the intensive hyperventilation in alkalosis rather than a sign of any mitochondriopathy. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7892961" 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="#91" class="mim-tip-reference" title="Shahbazian, M. D., Young, J. I., Yuva-Paylor, L. A., Spencer, C. M., Antalffy, B. A., Noebels, J. L., Armstrong, D. L., Paylor, R., Zoghbi, H. Y. <strong>Mice with truncated MeCP2 recapitulate many Rett syndrome features and display hyperacetylation of histone H3.</strong> Neuron 35: 243-254, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12160743/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12160743</a>] [<a href="https://doi.org/10.1016/s0896-6273(02)00768-7" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12160743">Shahbazian et al. (2002)</a> generated mice expressing a truncated Mecp2 protein similar to those found in RTT patients. The mutant mice exhibited normal motor function for approximately 6 weeks, but then developed a progressive neurologic disease that included many features of RTT: tremors, motor impairments, hypoactivity, increased anxiety-related behavior, seizures, kyphosis, and stereotypic forelimb motions. <a href="#91" class="mim-tip-reference" title="Shahbazian, M. D., Young, J. I., Yuva-Paylor, L. A., Spencer, C. M., Antalffy, B. A., Noebels, J. L., Armstrong, D. L., Paylor, R., Zoghbi, H. Y. <strong>Mice with truncated MeCP2 recapitulate many Rett syndrome features and display hyperacetylation of histone H3.</strong> Neuron 35: 243-254, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12160743/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12160743</a>] [<a href="https://doi.org/10.1016/s0896-6273(02)00768-7" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12160743">Shahbazian et al. (2002)</a> showed that although the truncated Mecp2 protein in these mice localized normally to heterochromatic domains in vivo, histone H3 (<a href="/entry/142780">142780</a>) was hyperacetylated. They presented this as evidence that, in this mouse model of RTT, the chromatin architecture is abnormal and gene expression may be misregulated. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12160743" 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="#66" class="mim-tip-reference" title="Moretti, P., Bouwknecht, J. A., Teague, R., Paylor, R., Zoghbi, H. Y. <strong>Abnormalities of social interactions and home-cage behavior in a mouse model of Rett syndrome.</strong> Hum. Molec. Genet. 14: 205-220, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15548546/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15548546</a>] [<a href="https://doi.org/10.1093/hmg/ddi016" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15548546">Moretti et al. (2005)</a> studied home cage behavior and social interactions in a mouse model of Rett syndrome. Young adult mutant mice showed abnormal home cage diurnal activity in the absence of motor skill deficits. Mutant mice showed deficits in nest building, decreased nest use, and impaired social interaction. They also took less initiative and were less decisive approaching unfamiliar males and spent less time in close vicinity to them in several social interaction paradigms. Abnormalities of diurnal activity and social behavior in Mecp2-mutant mice were reminiscent of the sleep/wake dysfunction and autistic features of RTT. <a href="#66" class="mim-tip-reference" title="Moretti, P., Bouwknecht, J. A., Teague, R., Paylor, R., Zoghbi, H. Y. <strong>Abnormalities of social interactions and home-cage behavior in a mouse model of Rett syndrome.</strong> Hum. Molec. Genet. 14: 205-220, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15548546/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15548546</a>] [<a href="https://doi.org/10.1093/hmg/ddi016" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15548546">Moretti et al. (2005)</a> suggested that MECP2 may regulate expression and/or function of genes involved in social behavior. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15548546" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Using cDNA microarrays, <a href="#73" class="mim-tip-reference" title="Nuber, U. A., Kriaucionis, S., Roloff, T. C., Guy, J., Selfridge, J., Steinhoff, C., Schulz, R., Lipkowitz, B., Ropers, H. H., Holmes, M. C., Bird, A. <strong>Up-regulation of glucocorticoid-regulated genes in a mouse model of Rett syndrome.</strong> Hum. Molec. Genet. 14: 2247-2256, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16002417/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16002417</a>] [<a href="https://doi.org/10.1093/hmg/ddi229" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16002417">Nuber et al. (2005)</a> found that Mecp2-null mice differentially expressed several genes that are induced during the stress response by glucocorticoids. Increased levels of mRNAs for SGK1 (<a href="/entry/602958">602958</a>) and FK506-binding protein-51 (FKBP5; <a href="/entry/602623">602623</a>) were observed before and after onset of neurologic symptoms, but plasma glucocorticoid was not significantly elevated in Mecp2-null mice. MeCP2 binds to Fkbp5 and Sgk1 in brain and may function as a modulator of glucocorticoid-inducible gene expression. Given the known deleterious effect of glucocorticoid exposure on brain development, <a href="#73" class="mim-tip-reference" title="Nuber, U. A., Kriaucionis, S., Roloff, T. C., Guy, J., Selfridge, J., Steinhoff, C., Schulz, R., Lipkowitz, B., Ropers, H. H., Holmes, M. C., Bird, A. <strong>Up-regulation of glucocorticoid-regulated genes in a mouse model of Rett syndrome.</strong> Hum. Molec. Genet. 14: 2247-2256, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16002417/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16002417</a>] [<a href="https://doi.org/10.1093/hmg/ddi229" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16002417">Nuber et al. (2005)</a> proposed that disruption of MeCP2-dependent regulation of stress-responsive genes may contribute to the symptoms of Rett syndrome. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16002417" 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="Chao, H.-T., Chen, H., Samaco, R. C., Xue, M., Chahrour, M., Yoo, J., Neul, J. L., Gong, S., Lu, H.-C., Heintz, N., Ekker, M., Rubenstein, J. L. R., Noebels, J. L., Rosenmund, C., Zoghbi, H. Y. <strong>Dysfunction in GABA signalling mediates autism-like stereotypies and Rett syndrome phenotypes.</strong> Nature 468: 263-269, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21068835/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21068835</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21068835[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nature09582" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21068835">Chao et al. (2010)</a> generated mice lacking Mecp2 from GABA-releasing neurons, designated Viaat-Mecp2(-/y), and showed that they recapitulate numerous Rett syndrome and autistic features, including repetitive behaviors. Viaat-Mecp2(-/y) mice were indistinguishable from controls until approximately 5 weeks of age, when they began to exhibit repetitive behavior such as forelimb stereotypies reminiscent of midline hand-wringing that characterizes Rett syndrome and hindlimb clasping. Viaat-Mecp2(-/y) mice spent 300% more time grooming than wildtype mice, leading to fur loss and epidermal lesions in group- and single-housed mice. Viaat-Mecp2(-/y) mice showed progressive motor dysfunction. The mice also developed motor weakness and by 12 weeks showed a trend toward reduced activity, becoming clearly hypoactive by 19 weeks. MeCP2 deficiency in GABAergic neurons also impaired hippocampal learning and memory. Roughly one-half of Viaat-Mecp2(-/y) mice died by 26 weeks of age after a period of marked weight loss. Coinciding with the weight loss, mice developed severe respiratory dysfunction. Next, <a href="#20" class="mim-tip-reference" title="Chao, H.-T., Chen, H., Samaco, R. C., Xue, M., Chahrour, M., Yoo, J., Neul, J. L., Gong, S., Lu, H.-C., Heintz, N., Ekker, M., Rubenstein, J. L. R., Noebels, J. L., Rosenmund, C., Zoghbi, H. Y. <strong>Dysfunction in GABA signalling mediates autism-like stereotypies and Rett syndrome phenotypes.</strong> Nature 468: 263-269, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21068835/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21068835</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21068835[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nature09582" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21068835">Chao et al. (2010)</a> generated male conditional deletion mice, designed Dlx5/6-Mecp2(-/y), missing MeCP2 from a subset of forebrain GABAergic neurons. These mice showed repetitive behavior, impaired motor coordination, increased social interaction preference, reduced acoustic startle response, and enhanced prepulse inhibition. In contrast to Viaat-Mecp2(-/y) mice, Dlx5/6-Mecp2(-/y) mice survived at least 80 weeks without apparent alterations in respiratory function. MeCP2-deficient GABAergic neurons showed reduced inhibitory quantal size, consistent with a presynaptic reduction in glutamic acid decarboxylase-1 (GAD1; <a href="/entry/605363">605363</a>) and -2 (GAD2; <a href="/entry/138275">138275</a>) levels. <a href="#20" class="mim-tip-reference" title="Chao, H.-T., Chen, H., Samaco, R. C., Xue, M., Chahrour, M., Yoo, J., Neul, J. L., Gong, S., Lu, H.-C., Heintz, N., Ekker, M., Rubenstein, J. L. R., Noebels, J. L., Rosenmund, C., Zoghbi, H. Y. <strong>Dysfunction in GABA signalling mediates autism-like stereotypies and Rett syndrome phenotypes.</strong> Nature 468: 263-269, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21068835/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21068835</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21068835[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nature09582" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21068835">Chao et al. (2010)</a> concluded that MeCP2 is critical for normal function of GABA-releasing neurons and that subtle dysfunction of GABAergic neurons contributes to numerous neuropsychiatric phenotypes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21068835" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#59" class="mim-tip-reference" title="Lioy, D. T., Garg, S. K., Monaghan, C. E., Raber, J., Foust, K. D., Kaspar, B. K., Hirrlinger, P. G., Kirchhoff, F., Bissonnette, J. M., Ballas, N., Mandel, G. <strong>A role for glia in the progression of Rett's syndrome.</strong> Nature 475: 497-500, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21716289/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21716289</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21716289[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nature10214" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21716289">Lioy et al. (2011)</a> showed that in globally Mecp2-deficient mice, reexpression of Mecp2 preferentially in astrocytes significantly improved locomotion and anxiety levels, restored respiratory abnormalities to a normal pattern, and greatly prolonged life span compared to globally null mice. Furthermore, restoration of Mecp2 in the mutant astrocytes exerted a non-cell-autonomous positive effect on mutant neurons in vivo, restoring normal dendritic morphology and increasing levels of the excitatory glutamate transporter VGLUT1. <a href="#59" class="mim-tip-reference" title="Lioy, D. T., Garg, S. K., Monaghan, C. E., Raber, J., Foust, K. D., Kaspar, B. K., Hirrlinger, P. G., Kirchhoff, F., Bissonnette, J. M., Ballas, N., Mandel, G. <strong>A role for glia in the progression of Rett's syndrome.</strong> Nature 475: 497-500, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21716289/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21716289</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21716289[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nature10214" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21716289">Lioy et al. (2011)</a> concluded their study showed that glia, like neurons, are integral components of the neuropathology of Rett syndrome, and supported the targeting of glia as a strategy for improving the associated symptoms. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21716289" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#27" class="mim-tip-reference" title="Derecki, N. C., Cronk, J. C., Lu, Z., Xu, E., Abbott, S. B. G., Guyenet, P. G., Kipnis, J. <strong>Wild-type microglia arrest pathology in a mouse model of Rett syndrome.</strong> Nature 484: 105-109, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22425995/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22425995</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22425995[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nature10907" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22425995">Derecki et al. (2012)</a> examined the role of microglia in a murine model of Rett syndrome and showed that transplantation of wildtype bone marrow into irradiation-conditioned Mecp2-null hosts resulted in engraftment of brain parenchyma by bone marrow-derived myeloid cells of microglial phenotype and arrest of disease development. However, when cranial irradiation was blocked by lead shield and microglial engraftment was prevented, disease was not arrested. Similarly, targeted expression of MECP2 in myeloid cells, driven by Lysm(cre) on an Mecp2-null background, markedly attenuated disease symptoms. Thus, through multiple approaches, wildtype Mecp2-expressing microglia within the context of an Mecp2-null male mouse arrested numerous facets of disease pathology: life span was increased, breathing patterns were normalized, apneas were reduced, body weight was increased to near that of wildtype, and locomotor activity was improved. Mecp2 +/- females also showed significant improvements as a result of wildtype microglial engraftment. These benefits mediated by wildtype microglia, however, were diminished when phagocytic activity was inhibited pharmacologically by using annexin V (<a href="/entry/131230">131230</a>) to block phosphatidylserine residues on apoptotic targets, thus preventing recognition and engulfment by tissue-resident phagocytes. <a href="#27" class="mim-tip-reference" title="Derecki, N. C., Cronk, J. C., Lu, Z., Xu, E., Abbott, S. B. G., Guyenet, P. G., Kipnis, J. <strong>Wild-type microglia arrest pathology in a mouse model of Rett syndrome.</strong> Nature 484: 105-109, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22425995/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22425995</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22425995[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nature10907" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22425995">Derecki et al. (2012)</a> concluded that their results suggested the importance of microglial activity in Rett syndrome, implicated microglia as major players in the pathophysiology of Rett syndrome, and suggested bone marrow transplantation as a possible therapy. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22425995" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#42" class="mim-tip-reference" title="Hao, S., Tang, B., Wu, Z., Ure, K., Sun, Y., Tao, H., Gao, Y., Patel, A. J., Curry, D. J., Samaco, R. C., Zoghbi, H. Y., Tang, J. <strong>Forniceal deep brain stimulation rescues hippocampal memory in Rett syndrome mice.</strong> Nature 526: 430-434, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26469053/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26469053</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=26469053[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nature15694" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26469053">Hao et al. (2015)</a> studied the effects of forniceal deep brain stimulation (DBS) in a well-characterized mouse model of Rett syndrome (RTT), and showed that it rescued contextual fear memory as well as spatial learning and memory. In parallel, forniceal DBS restored in vivo hippocampal long-term potentiation and hippocampal neurogenesis. The authors concluded that forniceal DBS might mitigate cognitive dysfunction in RTT. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26469053" 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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et al. (1984)</a>; <a href="#Rett1986" class="mim-tip-reference" title="Rett, A. <strong>Rett syndrome: history and general overview.</strong> Am. J. Med. Genet. Suppl. 1: 21-25, 1986.">Rett (1986)</a>; <a href="#Yang-Feng1986" class="mim-tip-reference" title="Yang-Feng, T. L., DeGennaro, L. J., Francke, U. <strong>Genes for synapsin I, a neuronal phosphoprotein, map to conserved regions of human and murine X chromosomes.</strong> Proc. Nat. Acad. Sci. 83: 8679-8683, 1986.">Yang-Feng et al. (1986)</a>; <a href="#Zoghbi1985" class="mim-tip-reference" title="Zoghbi, H. Y., Percy, A. K., Glaze, D. G., Butler, I. J., Riccardi, V. M. <strong>Reduction of biogenic amine levels in the Rett syndrome.</strong> New Eng. J. Med. 313: 921-924, 1985.">Zoghbi et al.
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Adegbola, A. A., Gonzales, M. L., Chess, A., LaSalle, J. M., Cox, G. F.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18989701/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18989701</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18989701" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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Akesson, H. O., Hagberg, B., Wahlstrom, J., Witt Engerstrom, I.
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<strong>Rett syndrome: a search for gene sources.</strong>
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[<a href="https://doi.org/10.1002/ajmg.1320420121" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1136/jmg.33.9.764" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1111/j.1399-0004.1995.tb04082.x" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1038/13810" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1002/ajmg.1320370109" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1002/ajmg.a.31133" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1136/jmg.2005.033464" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1007/BF00201549" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1097/00005072-199503000-00006" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1111/j.1399-0004.2006.00604.x" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1002/ajmg.1320440131" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1038/sj.ejhg.5201429" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1136/jmg.38.12.867" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1002/ajmg.1320390411" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1002/ajmg.1320360125" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1002/ajmg.1320380414" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1007/BF02265275" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1086/515525" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1086/302424" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1016/s0022-3476(94)70128-8" target="_blank">Full Text</a>]
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11283202/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11283202</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11283202" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1136/jmg.38.4.224" target="_blank">Full Text</a>]
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<a id="Weaving2003" class="mim-anchor"></a>
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Weaving, L. S., Williamson, S. L., Bennetts, B., Davis, M., Ellaway, C. J., Leonard, H., Thong, M.-K., Delatycki, M., Thompson, E. M., Laing, N., Christodoulou, J.
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<strong>Effects of MECP2 mutation type, location and X-inactivation in modulating Rett syndrome phenotype.</strong>
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Am. J. Med. Genet. 118A: 103-114, 2003.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12655490/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12655490</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12655490" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1002/ajmg.a.10053" target="_blank">Full Text</a>]
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<a id="Webb1998" class="mim-anchor"></a>
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Webb, T., Clarke, A., Hanefeld, F., Pereira, J.-L., Rosenbloom, L., Woods, C. G.
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<strong>Linkage analysis in Rett syndrome families suggests that there may be a critical region at Xq28.</strong>
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J. Med. Genet. 35: 997-1003, 1998.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9863596/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9863596</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9863596" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1136/jmg.35.12.997" target="_blank">Full Text</a>]
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<a id="Webb1993" class="mim-anchor"></a>
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Webb, T., Watkiss, E., Woods, C. G.
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<strong>Neither uniparental disomy nor skewed X-inactivation explains Rett syndrome.</strong>
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Clin. Genet. 44: 236-240, 1993.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7906210/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7906210</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7906210" 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.1399-0004.1993.tb03889.x" target="_blank">Full Text</a>]
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<a id="Xiang2002" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Xiang, F., Stenbom, Y., Anvret, M.
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<strong>MECP2 mutations in Swedish Rett syndrome clusters. (Letter)</strong>
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Clin. Genet. 61: 384-385, 2002.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12081725/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12081725</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12081725" 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/10.1034/j.1399-0004.2002.610512.x" target="_blank">Full Text</a>]
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Xiang, F., Zhang, Z., Clarke, A., Joseluiz, P., Sakkubai, N., Sarojini, B., Delozier-Blanchet, C. D., Hansmann, I., Edstrom, L., Anvret, M.
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<strong>Chromosome mapping of Rett syndrome: a likely candidate region on the telomere of Xq.</strong>
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J. Med. Genet. 35: 297-300, 1998.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9598723/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9598723</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9598723" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1136/jmg.35.4.297" target="_blank">Full Text</a>]
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Yang-Feng, T. L., DeGennaro, L. J., Francke, U.
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<strong>Genes for synapsin I, a neuronal phosphoprotein, map to conserved regions of human and murine X chromosomes.</strong>
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Proc. Nat. Acad. Sci. 83: 8679-8683, 1986.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3095840/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3095840</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=3095840" 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/10.1073/pnas.83.22.8679" target="_blank">Full Text</a>]
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Zappella, M., Meloni, I., Longo, I., Hayek, G., Renieri, A.
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<strong>Preserved speech variants of the Rett syndrome: molecular and clinical analysis.</strong>
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Am. J. Med. Genet. 104: 14-22, 2001.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11746022/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11746022</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11746022" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1002/ajmg.10005" target="_blank">Full Text</a>]
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Zimprich, F., Ronen, G. M., Stogmann, W., Baumgartner, C., Stogmann, E., Rett, B., Pappas, C., Leppert, M., Singh, N., Anderson, V. E.
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<strong>Andreas Rett and benign familial neonatal convulsions revisited.</strong>
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Neurology 67: 864-866, 2006.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16966552/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16966552</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16966552" 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.0000234066.46806.90" target="_blank">Full Text</a>]
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Zoghbi, H. Y., Ledbetter, D. H., Schultz, R., Percy, A. K., Glaze, D. G.
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<strong>A de novo X;3 translocation in Rett syndrome.</strong>
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Am. J. Med. Genet. 35: 148-151, 1990.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2301468/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2301468</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2301468" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1002/ajmg.1320350131" target="_blank">Full Text</a>]
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Zoghbi, H. Y., Percy, A. K., Glaze, D. G., Butler, I. J., Riccardi, V. M.
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<strong>Reduction of biogenic amine levels in the Rett syndrome.</strong>
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New Eng. J. Med. 313: 921-924, 1985.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2412119/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2412119</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2412119" 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/10.1056/NEJM198510103131504" target="_blank">Full Text</a>]
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Zoghbi, H. Y., Percy, A. K., Schultz, R. J., Fill, C.
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<strong>Patterns of X chromosome inactivation in the Rett syndrome.</strong>
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Brain Dev. 12: 131-135, 1990.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2344009/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2344009</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2344009" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1016/s0387-7604(12)80194-x" target="_blank">Full Text</a>]
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Ada Hamosh - updated : 11/20/2015
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Ada Hamosh - updated : 4/24/2012<br>Ada Hamosh - updated : 8/30/2011<br>Ada Hamosh - updated : 5/19/2011<br>Cassandra L. Kniffin - updated : 3/23/2011<br>Cassandra L. Kniffin - updated : 1/21/2011<br>Ada Hamosh - updated : 11/29/2010<br>Cassandra L. Kniffin - updated : 7/13/2010<br>Cassandra L. Kniffin - updated : 10/16/2009<br>Cassandra L. Kniffin - updated : 7/14/2009<br>Cassandra L. Kniffin - updated : 2/25/2009<br>George E. Tiller - updated : 11/21/2008<br>Cassandra L. Kniffin - updated : 3/6/2008<br>George E. Tiller - updated : 11/8/2007<br>Cassandra L. Kniffin - updated : 7/31/2007<br>Cassandra L. Kniffin - updated : 11/9/2006<br>Cassandra L. Kniffin - updated : 11/1/2006<br>Cassandra L. Kniffin - updated : 8/31/2006<br>John Logan Black, III - updated : 8/4/2006<br>Cassandra L. Kniffin - updated : 6/13/2006<br>Cassandra L. Kniffin - updated : 6/2/2006<br>Marla J. F. O'Neill - updated : 2/14/2006<br>Marla J. F. O'Neill - updated : 12/1/2005<br>Marla J. F. O'Neill - updated : 10/6/2005<br>Cassandra L. Kniffin - updated : 5/18/2005<br>Cassandra L. Kniffin - updated : 3/18/2005<br>Marla J. F. O'Neill - updated : 3/1/2005<br>Marla J. F. O'Neill - updated : 1/28/2005<br>Victor A. McKusick - updated : 11/18/2004<br>Ada Hamosh - updated : 3/30/2004<br>Cassandra L. Kniffin - reorganized : 12/23/2003<br>Cassandra L. Kniffin - updated : 12/23/2003<br>Felicity Collins - updated : 12/10/2003<br>Victor A. McKusick - updated : 11/6/2003<br>Victor A. McKusick - updated : 1/8/2003<br>Victor A. McKusick - updated : 1/8/2003<br>Dawn Watkins-Chow - updated : 12/16/2002<br>Michael J. Wright - updated : 10/22/2002<br>Victor A. McKusick - updated : 9/19/2002<br>Michael B. Petersen - updated : 9/10/2002<br>Victor A. McKusick - updated : 8/27/2002<br>George E. Tiller - updated : 2/12/2002<br>Victor A. McKusick - updated : 11/13/2001<br>Michael B. Petersen - updated : 10/23/2001<br>Michael J. Wright - updated : 10/8/2001<br>Ada Hamosh - updated : 3/2/2001<br>Ada Hamosh - updated : 10/30/2000<br>Paul Brennan - updated : 4/10/2000<br>Wilson H. Y. Lo - updated : 2/1/2000<br>Victor A. McKusick - updated : 9/28/1999<br>Victor A. McKusick - updated : 5/28/1999<br>Ada Hamosh - updated : 3/26/1999<br>Michael J. Wright - updated : 2/10/1999<br>Michael J. Wright - updated : 9/18/1998<br>Victor A. McKusick - updated : 9/3/1998<br>Victor A. McKusick - updated : 7/20/1998<br>Ada Hamosh - updated : 6/15/1998<br>Victor A. McKusick - updated : 4/6/1998<br>Victor A. McKusick - updated : 10/7/1997<br>Iosif W. Lurie - updated : 12/4/1996<br>Orest Hurko - updated : 9/8/1995
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Creation Date:
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Victor A. McKusick : 6/4/1986
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joanna : 10/25/2023
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carol : 08/18/2023<br>alopez : 08/11/2023<br>carol : 03/24/2021<br>carol : 12/04/2020<br>carol : 06/10/2019<br>carol : 02/02/2017<br>carol : 10/26/2016<br>carol : 10/25/2016<br>ckniffin : 10/25/2016<br>carol : 10/10/2016<br>alopez : 11/20/2015<br>carol : 4/1/2014<br>alopez : 6/10/2013<br>alopez : 10/3/2012<br>carol : 6/25/2012<br>alopez : 4/24/2012<br>terry : 4/24/2012<br>carol : 11/22/2011<br>alopez : 9/2/2011<br>terry : 8/30/2011<br>alopez : 5/19/2011<br>wwang : 4/5/2011<br>ckniffin : 3/23/2011<br>wwang : 2/16/2011<br>ckniffin : 1/21/2011<br>alopez : 12/1/2010<br>terry : 11/29/2010<br>wwang : 7/14/2010<br>ckniffin : 7/13/2010<br>ckniffin : 7/13/2010<br>wwang : 2/2/2010<br>wwang : 11/6/2009<br>ckniffin : 10/16/2009<br>wwang : 7/31/2009<br>ckniffin : 7/14/2009<br>wwang : 3/6/2009<br>ckniffin : 2/25/2009<br>wwang : 11/21/2008<br>terry : 9/26/2008<br>carol : 9/12/2008<br>terry : 8/26/2008<br>wwang : 8/20/2008<br>ckniffin : 8/11/2008<br>wwang : 4/10/2008<br>ckniffin : 3/6/2008<br>wwang : 11/30/2007<br>terry : 11/8/2007<br>carol : 9/5/2007<br>ckniffin : 8/28/2007<br>ckniffin : 8/24/2007<br>wwang : 8/20/2007<br>ckniffin : 7/31/2007<br>carol : 1/17/2007<br>ckniffin : 11/9/2006<br>carol : 11/3/2006<br>ckniffin : 11/1/2006<br>wwang : 8/31/2006<br>carol : 8/29/2006<br>terry : 8/4/2006<br>wwang : 6/16/2006<br>ckniffin : 6/13/2006<br>wwang : 6/5/2006<br>ckniffin : 6/2/2006<br>wwang : 2/16/2006<br>terry : 2/14/2006<br>wwang : 12/1/2005<br>wwang : 10/17/2005<br>terry : 10/6/2005<br>tkritzer : 5/19/2005<br>ckniffin : 5/18/2005<br>tkritzer : 3/28/2005<br>ckniffin : 3/18/2005<br>terry : 3/1/2005<br>carol : 2/3/2005<br>terry : 1/28/2005<br>alopez : 11/18/2004<br>alopez : 11/18/2004<br>alopez : 11/18/2004<br>terry : 6/3/2004<br>terry : 6/3/2004<br>alopez : 4/29/2004<br>alopez : 4/2/2004<br>alopez : 3/30/2004<br>terry : 3/30/2004<br>carol : 12/23/2003<br>carol : 12/23/2003<br>ckniffin : 12/16/2003<br>carol : 12/10/2003<br>carol : 11/13/2003<br>tkritzer : 11/10/2003<br>terry : 11/6/2003<br>carol : 7/9/2003<br>ckniffin : 6/23/2003<br>terry : 5/15/2003<br>tkritzer : 1/16/2003<br>tkritzer : 1/9/2003<br>terry : 1/8/2003<br>terry : 1/8/2003<br>carol : 12/19/2002<br>tkritzer : 12/16/2002<br>tkritzer : 12/16/2002<br>tkritzer : 10/24/2002<br>terry : 10/22/2002<br>tkritzer : 9/19/2002<br>tkritzer : 9/19/2002<br>cwells : 9/10/2002<br>tkritzer : 9/10/2002<br>tkritzer : 8/30/2002<br>terry : 8/27/2002<br>cwells : 2/18/2002<br>cwells : 2/12/2002<br>cwells : 12/7/2001<br>cwells : 12/3/2001<br>terry : 11/13/2001<br>cwells : 10/26/2001<br>cwells : 10/23/2001<br>cwells : 10/9/2001<br>cwells : 10/8/2001<br>alopez : 3/2/2001<br>mcapotos : 2/2/2001<br>mcapotos : 1/29/2001<br>mcapotos : 12/14/2000<br>carol : 11/16/2000<br>mcapotos : 11/6/2000<br>mgross : 11/2/2000<br>mgross : 11/2/2000<br>terry : 10/30/2000<br>alopez : 4/10/2000<br>terry : 2/24/2000<br>carol : 2/1/2000<br>terry : 2/1/2000<br>alopez : 9/30/1999<br>alopez : 9/29/1999<br>terry : 9/28/1999<br>mgross : 6/7/1999<br>mgross : 6/4/1999<br>terry : 5/28/1999<br>carol : 4/5/1999<br>alopez : 3/26/1999<br>mgross : 2/17/1999<br>mgross : 2/16/1999<br>terry : 2/10/1999<br>carol : 12/13/1998<br>terry : 12/8/1998<br>carol : 9/22/1998<br>terry : 9/18/1998<br>alopez : 9/8/1998<br>alopez : 9/8/1998<br>terry : 9/3/1998<br>terry : 8/20/1998<br>carol : 7/22/1998<br>terry : 7/20/1998<br>alopez : 6/15/1998<br>carol : 4/18/1998<br>terry : 4/6/1998<br>mark : 10/9/1997<br>terry : 10/7/1997<br>terry : 10/7/1997<br>jamie : 12/4/1996<br>jamie : 12/4/1996<br>terry : 4/15/1996<br>mark : 2/21/1996<br>mark : 2/19/1996<br>mark : 2/19/1996<br>mark : 2/19/1996<br>mark : 2/16/1996<br>mark : 2/13/1996<br>mark : 1/24/1996<br>mark : 1/20/1996<br>mark : 12/13/1995<br>terry : 12/11/1995<br>mark : 9/13/1995<br>terry : 3/2/1995<br>carol : 1/23/1995<br>mimadm : 4/18/1994<br>warfield : 3/14/1994
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<h3>
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<span class="mim-font">
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<strong>#</strong> 312750
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</h3>
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<h3>
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<span class="mim-font">
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RETT SYNDROME; RTT
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<span class="mim-font">
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<em>Alternative titles; symbols</em>
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<h4>
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<span class="mim-font">
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RTS<br />
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AUTISM, DEMENTIA, ATAXIA, AND LOSS OF PURPOSEFUL HAND USE
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</h4>
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<span class="mim-font">
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Other entities represented in this entry:
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</span>
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</p>
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<span class="h3 mim-font">
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RETT SYNDROME, ZAPPELLA VARIANT, INCLUDED
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<span class="h4 mim-font">
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RETT SYNDROME, PRESERVED SPEECH VARIANT, INCLUDED<br />
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RETT SYNDROME, ATYPICAL, INCLUDED
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<span class="mim-text-font">
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<strong>SNOMEDCT:</strong> 68618008;
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<strong>ICD10CM:</strong> F84.2;
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<strong>ORPHA:</strong> 3095, 778;
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<strong>DO:</strong> 1206;
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<strong>Phenotype-Gene Relationships</strong>
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<table class="table table-bordered table-condensed small mim-table-padding">
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<thead>
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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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Gene/Locus
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Gene/Locus <br /> MIM number
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<tbody>
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<span class="mim-font">
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Xq28
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</span>
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<td>
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<span class="mim-font">
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Rett syndrome
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<span class="mim-font">
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312750
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</span>
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<span class="mim-font">
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X-linked dominant
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<span class="mim-font">
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3
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<span class="mim-font">
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MECP2
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<span class="mim-font">
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300005
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<span class="mim-font">
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Xq28
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</span>
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<td>
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<span class="mim-font">
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Rett syndrome, atypical
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<span class="mim-font">
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312750
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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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X-linked dominant
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<span class="mim-font">
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3
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<td>
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<span class="mim-font">
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MECP2
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</td>
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<span class="mim-font">
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300005
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</span>
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<span class="mim-font">
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Xq28
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<span class="mim-font">
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Rett syndrome, preserved speech variant
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<span class="mim-font">
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312750
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<span class="mim-font">
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X-linked dominant
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<span class="mim-font">
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3
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<span class="mim-font">
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MECP2
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<span class="mim-font">
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300005
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</span>
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</table>
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<h4>
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<span class="mim-font">
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<strong>TEXT</strong>
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</span>
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</h4>
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<span class="mim-text-font">
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<p>A number sign (#) is used with this entry because Rett syndrome (RTT) is caused by mutation in the gene encoding methyl-CpG-binding protein-2 (MECP2; 300005) on chromosome Xq28.</p><p>See also the congenital variant of Rett syndrome (613454), which is caused by mutation in the FOXG1 gene (164874) on chromosome 14q13.</p>
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<h4>
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<span class="mim-font">
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<strong>Description</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Rett syndrome is a neurodevelopmental disorder that occurs almost exclusively in females. It is characterized by arrested development between 6 and 18 months of age, regression of acquired skills, loss of speech, stereotypic movements (classically of the hands), microcephaly, seizures, and mental retardation. Rarely, classically affected males with somatic mosaicism or an extra X chromosome have been described (Moog et al., 2003). </p>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Clinical Features</strong>
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</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>Rett (1966, 1977), a Viennese pediatrician, first described Rett syndrome after observing 2 girls who exhibited the same unusual behavior who happened to be seated next to each other in the waiting room. </p><p>Hagberg et al. (1983) described 35 patients, all girls from 3 countries (France, Portugal, and Sweden), with a uniform and striking, progressive encephalopathy. After normal development up to the age of 7 to 18 months, developmental stagnation occurred, followed by rapid deterioration of high brain functions. Within 1.5 years, this deterioration progressed to severe dementia, autism, loss of purposeful use of the hands, jerky truncal ataxia, and 'acquired' microcephaly. Thereafter, a period of apparent stability lasted for decades. Additional neurologic abnormalities intervened insidiously, mainly spastic paraparesis, vasomotor disturbances of the lower limbs, and epilepsy. </p><p>Bruck et al. (1991) described a set of monozygotic female twins with Rett syndrome. The authors noted that normal early development has generally been insisted on as an essential criterion for the diagnosis; however, twin 1 was considered to be abnormal from birth, while delay was not suspected in twin 2 until she was about 1 year old. Some regression occurred during the second year in both twins, who at age 4 years were clinically indistinguishable. </p><p>A striking deceleration of growth has been found across all measurements in 85 to 94% of girls with Rett syndrome and may provide the earliest clinical indication of this disorder. Motil et al. (1994) studied dietary intake and energy production in 9 Rett syndrome girls, comparing them to 7 healthy controls. Metabolic rate while sleeping was 23% lower in Rett syndrome girls than in controls, while metabolic rates during waking hours did not differ between the 2 groups. Dietary intake and fecal fat loss were also the same. The energy balance in girls with Rett syndrome was 55 +/- 43 kcal/kg lean body mass daily; in controls, the balance was 58 +/- 22 kcal/kg lean body mass per day. Motil et al. (1994) speculated that a small difference in energy balance would be sufficient to account for the growth failure in Rett syndrome girls and may explain the greater time that the Rett syndrome girls spent in involuntary motor activity. </p><p>Hagberg (1995) reviewed a Swedish series of 170 affected females, aged 2 to 52 years. The well-recognized classic phenotype was found in 75% of cases. Atypical variant forms, mainly more mildly affected mentally retarded girls and adolescent women, were still in a minority, but constituted an expanding cohort. </p><p>The presence of metatarsal and metacarpal abnormalities in some patients with Rett syndrome prompted Leonard et al. (1995) to conduct radiologic studies of 17 cases. Short fourth and/or fifth metatarsals were identified in 11 (65%), short fourth and/or fifth metacarpals in 8 of 14 (57%), and reduced bone density in the hands was found in 12 of 14 cases (86%). Leonard et al. (1999) examined hand radiographs of 100 girls with Rett syndrome, representing 73% of the known Australian population of girls with Rett syndrome, aged 20 and under. A metacarpophalangeal pattern profile was established, revealing that the shortest bone was the second metacarpal. Short distal phalanx of the thumb was seen in all age groups and in classic and atypical cases. In girls less than 15 years old, bone age was more advanced in Rett syndrome patients compared with controls (left hand p = 0.03, right hand p = 0.004), but was most advanced in the younger group. Bone age normalized with chronological age. </p><p>Miyamoto et al. (1997) described 2 Japanese sisters with classic RTT. The youngest sister, aged 6 years and 6 months, never stood or walked alone, showed severe spasticity, growth retardation, and microcephaly, developed sleep-wake rhythm disturbance from age 4, and seizures from age 5 years. The elder, 7 years and 9 months old at the time of report, walked alone and had mild spasticity, no growth retardation, normal sleep-wakefulness rhythm, and no seizures. The variability in the sisters stood in contrast to that in monozygotic twins with RTT who usually show little clinical difference. </p><p>Sirianni et al. (1998) reported 3 affected sisters of a Brazilian family who showed rapid deceleration of head growth with subsequent progressive mental deterioration. Two surviving affected daughters, examined at ages 9 and 5.5 years, showed no purposeful hand movements, but had persistent hand stereotypes and rubbing of the torso. They had significant muscle wasting and inability to walk, and showed spontaneous episodes of hyperventilation while awake. They had a severe attention deficit and no language development, with intellectual and adaptive behavior at the 1- to 6-month level. Although the younger daughter was still able to reach for food, she was without other purposeful hand use. Leonard and Bower (1998) retrospectively studied the neonatal characteristics and early development of Australian girls with Rett syndrome. The mean weight and head circumference of newborn girls later identified as Rett patients was lower than that of the reference Australian population. Girls who had learned to walk had larger heads at birth than those who had not; girls who had never been ambulant had the smallest heads at birth. In 46.5% of girls, parents reported unusual development or behavior in the first 6 months. The authors stated that these results provided evidence that girls with Rett syndrome may not be normal at birth. They further suggested that using normal development in the first 6 months and normal neonatal head circumference as diagnostic criteria may cause missed or delayed diagnoses. </p><p><strong><em>Neuropathologic Findings</em></strong></p><p>
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Papadimitriou et al. (1988) reported light-microscopic evidence of white matter disease in the brain biopsy of a patient with Rett syndrome. Ultrastructurally, many neurons and oligodendroglia contained membrane-bound electron-dense inclusions with a distinct lamellar and granular substructure. Armstrong et al. (1995) systematically studied brains of 16 girls with Rett syndrome who ranged in age from 2 to 35 years. They found no evidence that the pyramidal neurons in Rett syndrome degenerate progressively with increasing age. Instead, they found a striking decrease in the dendritic trees of selected cortical areas, chiefly projection neurons of the motor, association, and limbic cortices. They suggested that this may result in abnormalities of trophic factors. </p><p><strong><em>Neuroradiographic Findings</em></strong></p><p>
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Horska et al. (2009) performed proton magnetic resonance spectroscopy (MRS) on 40 girls with Rett syndrome with a mean age of 6.1 years. Compared to 12 controls, Rett syndrome patients had a decreased N-acetylaspartate (NAA)/creatine (Cr) ratio and increased myoinositol/Cr ratio with age (p = 0.03), suggestive of progressive axonal damage and astrocytosis. The mean NAA/Cr ratio was 12.6% lower in RTT patients with seizures compared with those without seizures (p = 0.017), and NAA/Cr ratios decreased with increasing clinical severity score (p = 0.031). The mean glutamate and glutamine/Cr ratio was 36% greater in RTT patients than in controls (p = 0.043), which may have been secondary to increasing glutamate/glutamine cycling at the synaptic level. The findings indicated that Rett syndrome is associated with mild white matter pathology, and suggested that MRS can provide a noninvasive measure of cerebral involvement in RTT. </p><p><strong><em>Cardiac Abnormalities</em></strong></p><p>
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Kerr et al. (1997) found an annual mortality rate in Rett syndrome of 1.2%; a high proportion (26%) of these deaths were sudden and unexplained. Sekul et al. (1994) reported prolonged QT interval in patients with Rett syndrome. </p><p>Guideri et al. (1999) studied the heart rate variability and corrected QT interval in 54 females (mean age, 10 +/- 5.5 years) in various clinical stages of Rett syndrome, using continuous 12-lead ECG monitoring for 10 minutes in the supine position. The total power spectrum of heart rate variability (from 0.03 to 0.4 Hz), mainly its low frequency (LF) and high frequency (HF) components, was significantly lower in children with Rett syndrome compared with that in controls. The sympathovagal balance, expressed by the ratio LF/HF, was significantly higher in patients, reflecting the prevalence of sympathetic activity. The RR interval was significantly shorter and the corrected QT interval longer in the patient group than in the control group. The authors suggested that in children with Rett syndrome, loss of physiologic heart rate variability associated with an increase of adrenergic tone, represents the electrophysiologic basis of cardiac instability and sudden death. Ellaway et al. (1999) determined the prevalence of QT prolongation in a cohort of 34 Australian patients. Nine patients had significantly longer corrected QT values than a group of healthy, age-matched controls. There was no apparent correlation between the presence of QT prolongation and phenotypic severity. The authors concluded that QT prolongation should be considered in all patients with Rett syndrome. </p><p><strong><em>Zappella Variant</em></strong></p><p>
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De Bona et al. (2000) stated that preserved speech variant (PSV) Rett syndrome shares with classic Rett syndrome the same course and the stereotypic hand-washing activities, but differs in that patients typically recover some degree of speech and hand use, and usually do not show growth failure. Progressive scoliosis, epilepsy, and other minor handicaps, usually present in Rett syndrome, are rare in the preserved speech variant. The authors reported mutations in the MECP2 gene in both classic and PSV Rett syndrome (see 300005.0012), establishing that the 2 forms are allelic disorders. </p><p>Zappella et al. (2001) reported clinical and mutation analysis findings in 18 patients with preserved speech variant Rett syndrome. Ten (55%) had an MECP2 mutation. All had slow recovery of verbal and praxic abilities, evident autistic behavior, and normal head circumference. Six were overweight, often obese, had kyphosis, coarse face, and mental age of 2 to 3 years, and were able to speak in sentences; 4 had normal weight, mental age not beyond 1 to 2 years, and spoke in single words and 2-word phrases. The course of the disorder was in stages as in classic Rett syndrome. Hand washing was present in the first years of life but often subsequently disappeared. </p><p>Renieri et al. (2009) presented a detailed evaluation of 29 patients with Zappella variant, also known as preserved speech variant, Rett syndrome. All 29 patients had mutation in the MECP2 gene, of which 28 were missense (see, e.g., R133C; 312750.0001) or late truncating mutations. There was great variability with respect to language, manual abilities, and somatic features, allowing for further statistical subdivision into low, intermediate, and high functioning. In general, patients with Zappella variant Rett syndrome had less microcephaly, later onset of regression, a tendency to be overweight, better hand use, and better speech acquisition compared to patients with classic Rett syndrome. The majority (76%) of patients with Zappella variant had autistic features. Diagnostic criteria was presented. Renieri et al. (2009) proposed the term 'Zappella variant' rather than 'preserved speech variant' to described milder forms of Rett syndrome because other aspects besides speech are involved. </p><p>Adegbola et al. (2009) reported a 10-year-old girl who had slowing of motor skills and hypotonia at age 12 months. She had purposeful hand movements with occasional hand-wringing stereotypes, was morbidly obese, was prone to aggressive outbursts, and had mild autistic features. EEG showed multifocal spike and wave discharges without overt seizures. Full-scale IQ was 70 at age 6 years and 58 at age 8 years. Her father had an IQ of 85, had special schooling, and showed behavioral dyscontrol and hyperactivity in childhood and adolescence. His behavioral difficulties improved with age. Both father and daughter were found to have a mutation in the MECP2 gene (300005.0036), that resulted in decreased, but not absent MECP2 function. The findings were consistent with a hypomorphic MECP2 allele contributing to a neuropsychiatric phenotype in this family. </p><p><strong><em>Affected Males</em></strong></p><p>
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Coleman (1990) reported a possible case of Rett syndrome in a male, and Philippart (1990) reported 2 such cases. </p><p>Schwartzman et al. (1999) described a male patient with Rett syndrome and the 47,XXY karyotype of Klinefelter syndrome. The propositus showed normal development until age 8 months. At that time, he sat without support, played normally, and was able to grasp objects and to put food into his mouth. He had started to say some words comprehensibly. At age 11 months, it was noted that he had lost purposeful hand movements and language skills. He also began to show regression in social contact. At age 1 year, he began to show stereotypic hand movements, bruxism, and constipation. At age 28 months, he presented severe global retardation and slight diffuse hypotonia. At the time of the last observation, at age 37 months, loss of purposeful hand movements, manual apraxia, and slight global hypotonia were persistent. The clinical and laboratory findings did not overlap with any described for Klinefelter syndrome. DNA studies indicated that the additional sex chromosome was paternal in origin, i.e., that the nondisjunction occurred in the paternal first meiotic division. </p><p>Clayton-Smith et al. (2000) presented a male with somatic mosaicism for an MECP2 mutation (300005.0010) leading to a progressive but nonfatal neurodevelopmental disorder. The patient was a normal-sized product of a full-term gestation. He was a placid baby who never crawled, but walked at 15 months and learned to say some single words in the second year of life. At around 2 years of age, he lost interest in his surroundings and lost his speech. At age 3 years, he began to have generalized seizures, and magnetic resonance imaging (MRI) revealed atrophy of the brainstem and frontal and temporal lobes. Electroencephalography (EEG) showed excessive slow-wave activity during sleep and a relative poverty of rhythmic activity while awake. At 6 years of age, he had a thoracic scoliosis and poor lower-limb musculature, and he walked with an ataxic gait. He had abnormal muscle tone with rigidity of the limbs and truncal hypotonia. His feet were small, blue, and puffy. His hand use was very limited, but there were no obvious hand-wringing movements. </p><p>Maiwald et al. (2002) reported a 46,XX male with Rett syndrome caused by mutation in the MECP2 gene (300005.0026). Upon amniocentesis performed because of advanced maternal age, a female karyotype was detected in a sonographically male fetus. Both the phenotype and the karyotype were confirmed after birth, and the absence of mullerian structures was demonstrated by ultrasonography. Motor development was delayed; he was able to sit only at 14 months of age. He was still not able to walk and there was no speech at the age of 24 months. At the age of 2 years, he showed truncal muscular hypotonia, microcephaly, spasticity, and convergent strabismus of the left eye. There was a loss of purposeful hand skills at approximately 6 months of age, and a deceleration of head growth at approximately 7 months. The clinical appearance of the boy resembled female Rett cases, which was explained by the karyotype. In addition, preferential expression of the normal allele may have contributed to the rather mild phenotype. The authors noted that similar features had been described in male patients with MECP2 mutations and a Klinefelter karyotype (46,XXY). </p><p>Topcu et al. (2002) reported a boy with features of classic Rett syndrome who was a somatic mosaic for a mutation in the MECP2 gene (300005.0005). He had normal psychomotor development through the first 6 months. Loss of acquired purposeful hand skills began around 11 months, and stereotypic hand movements became apparent at 15 months. He never crawled or walked and had never spoken. On examination at 12 years of age he was microcephalic with stereotypic hand movements, tremors, and apraxia. He had a thoracic scoliosis and poor lower limb musculature, small and cold hands and feet, hypospadias, and cryptorchidism. Electroencephalography showed an excess of slow wave activity and paroxysmal sharp theta wave activity prominent on wake recordings of frontal regions. </p><p><strong><em>Atypical Rett Syndrome</em></strong></p><p>
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Molecular analysis has allowed the broadening of the phenotype of MECP2 mutations beyond RTT to include girls who have mild mental retardation, autism, and a phenotype resembling Angelman syndrome (105830), as well as males with severe encephalopathy. Heilstedt et al. (2002) reported a girl with a phenotype of atypical RTT who had a heterozygous mutation in the MECP2 gene (300005.0016). She presented with hypotonia and developmental delay in infancy without a clear period of normal development. As part of her evaluation for hypotonia, muscle biopsy and respiratory chain enzyme analysis showed a slight decrease in respiratory chain enzyme activity consistent with previous reports of RTT. The mother did not carry an MECP2 mutation. </p><p>Watson et al. (2001) identified MECP2 mutations in 5 of 47 patients with a clinical diagnosis of Angelman-like phenotype and no cytogenetic or molecular abnormality of chromosome 15q11-q13. Four of these patients were female and 1 male. By the time of diagnosis, 3 of the patients were showing signs of regression and had features suggestive of Rett syndrome; in the remaining 2, the clinical phenotype was still considered to be Angelman-like. </p><p>Imessaoudene et al. (2001) identified MECP2 mutations in 6 of 78 patients with possible Angelman syndrome but with normal methylation pattern at the UBE3A locus (601623). Of these, 4 were females with a phenotype consistent with Rett syndrome, one was a female with progressive encephalopathy of neonatal onset, and one was a male with a nonprogressive encephalopathy of neonatal onset. This boy had a gly428-to-ser mutation (300005.0023). </p>
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<h4>
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<strong>Diagnosis</strong>
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<p>Hagberg and Skjeldal (1994) suggested a model of inclusion and exclusion criteria for the diagnosis of Rett syndrome that relaxed the international criteria originally drawn up in Vienna in September 1984. The new model permitted the diagnosis of forme frustes, cases with late regression, and congenital variants. Hagberg et al. (2002) provided an updated diagnostic criteria. </p><p>Neul et al. (2010) provided revised diagnostic criteria for Rett syndrome and emphasized that it remains a clinical diagnosis, since not all Rett patients have MECP2 mutations and not all patients with MECP2 mutations have Rett syndrome. The most important feature for classic Rett syndrome is a period of clear developmental regression followed by limited recovery or stabilization. Other main criteria include loss of purposeful hand skills, loss of spoken language, gait abnormalities, and stereotypic hand movements. Although deceleration of head growth is a supportive feature, it is no longer necessary for diagnosis. Exclusion criteria include other primary causes of neurologic dysfunction and abnormal psychomotor development in the first 6 months of life. Criteria for variant or atypical forms of Rett syndrome were also presented. </p><p>Percy et al. (2010) validated the revised diagnostic criteria provided by Neul et al. (2010) in an analysis of 819 patients enrolled in a natural history study of Rett syndrome. Of the 819 patients, 765 females fulfilled 2002 criteria (Hagberg et al., 2002) for classic (85.4%) or variant (14.6%) Rett syndrome. All those classified as having classic Rett syndrome fulfilled the revised main criteria, and all those with variant Rett syndrome met 3 of 6 main criteria in the 2002 classification, 2 or 4 main criteria in the revised system, and 5 of 11 supportive criteria in both. </p><p>See developmental and epileptic encephalopathy-2 (DEE2; 300672) for discussion of a Rett syndrome-like phenotype caused by mutation in the CDKL5 gene (300203).</p><p><strong><em>Prenatal Diagnosis</em></strong></p><p>
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As pointed out by Amir et al. (1999), the discovery of MECP2 as the gene responsible for Rett syndrome enabled testing for early diagnosis and prenatal detection. In addition, the finding that epigenetic regulation has a role in the pathogenesis of RTT opened possible opportunities for therapy. Amir et al. (1999) suggested that partial loss of function of MECP2 may decrease transcriptional repression of some genes. The relatively normal development during the first 6 to 18 months of life may allow for presymptomatic therapeutic intervention, especially if newborn screening programs can identify affected females. </p>
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<strong>Inheritance</strong>
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</h4>
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<p>Schanen et al. (1997) stated that familial recurrences of Rett syndrome comprise only approximately 1% of the total reported cases; the vast majority of cases are sporadic. However, it is the familial cases that are key for understanding the genetic basis of the disorder. </p><p>Hagberg et al. (1983) suggested that the exclusive involvement of females is best explained by X-linked dominant inheritance with lethality in the hemizygous males. </p><p>Tariverdian et al. (1987) and Tariverdian (1990) reported 5-year-old monozygotic Turkish female twins concordant for Rett syndrome, suggesting a genetic cause of RTT. Partington (1988) described affected monozygotic twin sisters. Buhler et al. (1990) pointed to the existence of about 10 familial cases of Rett syndrome and to an elevated parental consanguinity rate of 2.4%. They suggested a model involving autosomal modifying genes that function as a suppressor in relation to an X-chromosomal mutation causing Rett syndrome. Zoghbi et al. (1990) reviewed familial instances including 6 pairs of concordantly affected monozygotic twins; 4 families with 2 affected sisters; and 2 families with 2 affected half sisters. The affected half sisters had the same mother. Anvret et al. (1990) described Rett syndrome in 2 generations of a family. The index case was a 12-year-old girl with classic Rett syndrome; her maternal aunt, aged 44 years, had mild Rett syndrome. Studies with X-linked DNA markers detected no deletions. </p><p>Martinho et al. (1990), in agreement with others, found no increase in parental age or in spontaneous abortion rates among the mothers of affected children and found a normal sex ratio among sibs. They found no chromosome rearrangements and no correlation between the fragile site at Xp22 and Rett syndrome. In 2 isolated cases of RTT, Benedetti et al. (1992) excluded both maternal uniparental heterodisomy and isodisomy. Webb et al. (1993) likewise excluded unilateral parental disomy through study of the locus DXS255 using the probe M27-beta; all informative probands had inherited an allele from each of their parents. </p><p>Akesson et al. (1992) presented genealogic data on 77 Swedish females with Rett syndrome suggesting that there is a genetic component in transmission of the disorder. In most cases, ancestry was traced back to 1720-1750. Common ancestry was seen in 2 pairs of females with Rett syndrome. In 39 of the 77 cases, it was possible to trace ancestry to 9 small and separate rural areas, and 17 pairs even originated from the same farm or small group of dwellings. The common origin was found equally often among descendants of the father as of the mother, and there was a raised rate of consanguineous marriages. In what they referred to as 'an a priori test of the first study,' Akesson et al. (1995) examined an additional 20 Rett syndrome females who were consecutively traced. Of these, 10 of 19 (53%) originated from the earlier defined 'Rett areas,' and 11 of 19 (58%) could be traced to the same homestead. In 2 clusters, each consisting of 3 Rett syndrome females, all 6 subjects were descendants of the same 2 couples several generations ago. Consanguineous marriages among grandparents on both sides were found to have occurred in 11% (4 of 37), compared to 1% in the general Swedish population. The authors considered the findings a confirmation of the first study, and postulated that transmission starting with a premutation may result in a full mutation over generations, most likely if the parents have the premutation in homozygous form. A genealogic study of 32 Swedish patients with atypical Rett syndrome led Akesson et al. (1996) to conclude that most atypical cases are variants of classic Rett syndrome. Eleven persons (34%) were traced to a small number of parishes in areas in which classic patients had been found. In 4 cases, typical and atypical Rett syndrome patients were found in the same pedigree. The authors proposed a 2-gene model, including one autosomal and one X-linked gene, to explain the genetics of this disorder. In a follow-up study looking for mutations of the MECP2 gene in 3 clusters and 2 pedigrees chosen at random in Sweden, Xiang et al. (2002) could not demonstrate that patients with Rett syndrome from the same cluster area share a common genetic defect. All of the identified mutations in the MECP2 gene were de novo and not premutations such as trinucleotide expansion. Recurrence of cases with the syndrome present in Rett clusters appeared to be the result of independent mutational events. </p><p>Thomas (1996) suggested that the exclusive occurrence of RTT in females, without evidence of male lethality, can be explained by de novo X-linked mutations occurring exclusively in male germ cells that result in affected daughters. Thus, he suggested that it is the high male:female de novo germline mutation rate that explains the absence of affected males in Rett syndrome. </p><p>Villard et al. (2001) identified a mutation in the MECP2 gene in only 1 of 5 families with RTT, suggesting an alternative molecular basis for the phenotype in the other 4 familial cases. X-chromosome inactivation studies showed that all the mothers and 6 of 8 affected girls had a totally skewed pattern of X inactivation, whereas only 9% of 43 sporadic RTT females had a skewed pattern of X inactivation, and all of their mothers had random X inactivation. In the familial cases, it was the paternal X chromosome that was active. Genotype analysis suggested that the skewed X-inactivation phenotype was due to a locus in the region between markers at DXS1068 and DXS1024, although the lod score for this analysis was not significant. The results suggested that the 2 traits, completely skewed X inactivation and RTT, are not linked. Villard et al. (2001) proposed that familial Rett syndrome transmission is due to 2 traits being inherited: an X-linked locus abnormally escaping X inactivation, and the presence of a skewed X inactivation in carrier women. </p><p>Rosenberg et al. (2001) reported a female patient with Rett syndrome and 46,X,r(X) karyotype. The X-derived marker was about one-tenth the size of a normal X chromosome, with FISH analysis showing that the breakpoint on Xq was proximal to the MECP2 gene. X-inactivation studies demonstrated that the normal X chromosome was active and the ring X chromosome inactive in all cells examined. Methylation studies showed that the ring X was of paternal origin. No mutation was found in the MECP2 gene after sequencing of the whole coding region. The authors proposed a model invoking a second X-linked gene for RTT. Given the model, the second putative RTT gene could account for the minority of sporadic and the majority of familial cases that are negative for MECP2 mutations. To manifest as RTT, the disease allele would have to be expressed in a majority of cells, i.e., be associated with skewing of X inactivation as in cases of X-chromosome rearrangements. </p><p>Gill et al. (2003) studied 11 families in each of which 2 females were thought to have Rett syndrome. In 1 family, an identical MECP2 mutation was found in 2 affected sisters and their healthy mother. In 5 families, an MECP2 mutation was found in 1 affected female but not in the other, possibly affected female. In 5 families, no MECP2 mutation was found. Gill et al. (2003) concluded that Rett syndrome is only rarely familial and that if girls with Rett syndrome who have MECP2 mutations have sisters with developmental difficulties, the disorder in the sisters is more likely to have a separate cause. </p><p>Evans et al. (2006) reported a family in which 2 half sisters with the same father were found to have Rett syndrome caused by the same mutation in the MECP2 gene. Genetic analysis detected the mutation in approximately 5% of the father's sperm, but not in his buccal or lymphocyte DNA, indicating paternal germline mosaicism. </p><p>Venancio et al. (2007) reported a rare familial case of Rett syndrome due to maternal germline mosaicism. A mutation in the MECP2 gene was identified in a girl with classic Rett syndrome and in her brother, who had severe congenital encephalopathy. The mutation was absent in DNA extracted from the blood of both parents. </p><p><strong><em>X-Inactivation Studies</em></strong></p><p>
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In the unaffected mother of 2 affected half sisters, Zoghbi et al. (1990) found nonrandom X-chromosome inactivation in leukocyte DNA. They also found an increased incidence of nonrandom X inactivation in sporadic RTT patients (36%), as compared to healthy controls (8%). Kormann-Bortolotto et al. (1992) found no abnormality of the X chromosome in 9 girls with Rett syndrome or the 6 mothers who were studied. X-inactivation studies suggested that there 'may be an alteration in the timing of the X-inactivation process in the region Xp11.3 or 4-Xp21' in patients with RTT. </p><p>Camus et al. (1996) studied X-chromosome inactivation in 30 girls with Rett syndrome, in 30 control girls, 8 sisters, and their mothers. There was a significant increased frequency of partial paternal X inactivation (more than 65%) in lymphocytes from 16 of 30 RTT patients compared with 4 of 30 controls (P = 0.001). These results did not support the hypothesis of a monogenic X-linked mutation, but the authors suggested that there may be a complex secondary role played by X-inactivation in this disorder. </p><p>In a family with recurrence of Rett syndrome in a maternal aunt and niece, Schanen et al. (1997) and Schanen and Francke (1998) found skewing of the X-chromosome inactivation pattern in the obligatory carrier in this family, supporting the hypothesis that RTT is an X-linked disorder. However, evaluation of the X-inactivation pattern in the mother of affected half sisters showed random X-inactivation, suggesting germline mosaicism as the cause of repeated transmission in that family. There was an affected male in the family, who was a maternal half brother of the affected niece, also suggesting germline mosaicism in the mother. </p><p>Brown (1997) noted that males who carry a Rett mutation may survive. The identification of such cases in sibships with diagnosed RTT females requires a carrier mother who either is a germline mosaic or has a favorably skewed X-inactivation pattern.</p>
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<h4>
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<span class="mim-font">
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<strong>Mapping</strong>
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</span>
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</h4>
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<p>On the basis of a girl with Rett syndrome and a translocation t(X;22)(p11.22;p11), Journel et al. (1990) suggested that the gene for this disorder may be located on the short arm of the X chromosome. The same translocation was present in her unaffected mother and in her sister, who was affected with a neurologic disorder compatible with a forme fruste of Rett syndrome. In the course of a systematic high-resolution chromosome analysis on 28 patients with Rett syndrome, Zoghbi et al. (1990) found a patient with a de novo balanced translocation t(X;3)(p22.1;q13.31). Zoghbi et al. (1990) noted, however, that the Rett syndrome locus may map to a different location on the X chromosome than the breakpoint, as has occurred in incontinentia pigmenti (308300). Archidiacono et al. (1991) studied the unaffected mother of 2 half sisters with Rett syndrome for evidence of germinal mosaicism. The analysis of 34 X-linked RFLPs in these 2 affected females and in their unaffected mother and half brother, together with the reconstruction of phase for 15 informative RFLPs in somatic cell hybrids retaining a single X chromosome from each female, made it possible to exclude some regions of the X chromosome as sites of the mutation causing the disorder. The 2 regions with X chromosome breakpoints found in RTT patients with X-autosome translocations, Xp22.11 (Zoghbi et al., 1990) and Xp11.22 (Journel et al., 1990), were not excluded as the localization of the RTT gene. In 2 families with maternally related, affected half sisters, Ellison et al. (1992) performed genotypic analysis using 63 DNA markers from the X chromosome. In at least 1 of the 2 families, 36 markers were informative, and 25 markers were informative in both families. On the basis of discordance for maternal alleles in the half sisters, they excluded 20 loci as candidates for the Rett syndrome gene. Using the exclusion criterion of a lod score less than -2, they excluded the region from Xp21.2 to Xq21-q23. Curtis et al. (1993) did linkage studies in 4 families, each with 2 individuals affected by Rett syndrome. In 2 of the families, X-linked dominant inheritance of the RTT defect from a germinally mosaic mother could be assumed. Using maternal X chromosome markers showing discordant inheritance they excluded much of Xp, including 3 candidate genes, OTC (311250), synapsin I (SYN1; 313440), and synaptophysin (313475). Although most of the long arm was inherited in common, it was possible to exclude a centromeric region. Curtis et al. (1993) also presented information on 2 families with affected aunt-niece pairs. To determine which regions of the X chromosome were inherited concordantly and discordantly in an affected maternal aunt and niece, Schanen et al. (1997) genotyped the individuals in the aunt-niece family and 2 previously reported pairs of half sisters. The combined exclusion mapping data allowed exclusion of the RTT locus from the interval between DXS1053 in Xp22.2 and DXS1222 in Xq22.3. In a family with 3 affected individuals, including a male, Schanen and Francke (1998) compared haplotypes to narrow the RTT candidate region to a small interval on Xp and the distal long arm. The authors noted that identification of a severely affected male in a family with recurrent classic Rett syndrome strengthened the hypothesis that RTT is caused by an X-linked gene. </p><p>Xiang et al. (1998) presented haplotype analysis of 9 families with at least 2 closely related females affected by classic Rett syndrome. They concluded that the Rett syndrome locus is likely to lie within Xq28, close to marker DXS15. Xiang et al. (1998) suggested that the GABRE (300093) and GABRA3 (305660) genes are candidate genes for Rett syndrome. Webb et al. (1998) presented a study of 6 families with more than 1 female affected with Rett syndrome. They showed weak linkage to loci in Xq28, with a maximum lod score of 1.935 at theta = 0.0 at DXYS154. Webb et al. (1998) also noted the presence of the candidate genes GABRA3 and L1CAM (308840) in this region, but cautioned that their lod scores did not quite reach significance. Sirianni et al. (1998) presented information that they interpreted as confirming X-linked dominant inheritance of Rett syndrome. They described a family with the largest number (3) of female sibs affected with Rett syndrome identified to that time, and used data from this family, as well as from families previously described, to demonstrate the mode of inheritance and to localize the gene to Xq28. Concordance analysis with DNA markers showed that only Xq28 was shared among the 3 affected girls, whereas the same region was not shared with the unaffected sisters. The data complemented the exclusion-mapping data described by Xiang et al. (1998) who could not exclude the distal region of the long arm of the X chromosome. In a Brazilian family, Sirianni et al. (1998) found that the mother had extreme skewing of X inactivation with the unaffected X active in 95% of cells. Thus, the finding of highly skewed X inactivation in the mother, with preferential use of the unaffected X chromosome, strongly suggested that she was a nonpenetrant carrier of Rett syndrome. An unaffected daughter and an affected daughter did not show the skewed X inactivation. </p>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Molecular Genetics</strong>
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<p><strong><em>Exclusion of Linked Genes</em></strong></p><p>
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Ferlini et al. (1990) excluded the synapsin I gene as the cause of RTT. Narayanan et al. (1998) excluded the M6b gene (300051), Wan and Francke (1998) excluded glutamate dehydrogenase-2 (GLUD2; 300144) and Rab GDP-dissociation inhibitor GDI1 (300104), which were chosen because of their location in the nonexcluded region of Xq. Heidary et al. (1998) excluded the gastrin-releasing peptide receptor gene (GRPR; 305670), Cummings et al. (1998) excluded the glycine receptor alpha-2 subunit gene (GLRA2; 305990), and Van den Veyver et al. (1998) excluded the holocytochrome c-type synthetase gene (HCCS; 300056), all of which had been candidate genes for Rett syndrome because they mapped to a region on Xp. </p><p><strong><em>Mutations in the MECP2 Gene</em></strong></p><p>
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In 5 of 21 sporadic patients with RTT, Amir et al. (1999) identified 3 de novo missense mutations in the MECP2 gene (300005.0001, 300005.0002, 300005.0007). Among 8 cases of familial Rett syndrome, Amir et al. (1999) found an additional missense mutation (300005.0008) in a family with 2 affected half sisters. The mutation was not detected in their obligate carrier mother, suggesting that the mother was a germline mosaic for the mutation. The authors suggested that abnormal epigenetic regulation may be a mechanism underlying the pathogenesis of Rett syndrome. Wan et al. (1999) identified 5 additional mutations in the MECP2 gene (see, e.g., 300005.0003) in patients with RTT. They found that the mutations were de novo, and that female heterozygotes with favorably skewed X-inactivation patterns may have little or no involvement. </p><p>Villard et al. (2000) reported a family in which a daughter had classic Rett syndrome and her 2 brothers died in infancy from severe encephalopathy. The affected girl and one brother tested showed a mutation in the MECP2 gene (300005.0007). The unaffected carrier mother had a completely biased pattern of X-chromosome inactivation that favored expression of the normal allele. One of the affected boys showed severe mental retardation and hypotonia soon after birth and died at age 11 months. </p><p>Zappella et al. (2001) reported clinical and mutation analysis findings in 18 patients with the preserved speech variant form of Rett syndrome. Ten (55%) had an MECP2 mutation. All had slow recovery of verbal and praxic abilities, evident autistic behavior, and normal head circumference. Six were overweight, often obese, had kyphosis, coarse face, and mental age of 2 to 3 years, and were able to speak in sentences; 4 had normal weight, mental age not beyond 1 to 2 years, and spoke in single words and 2-word phrases. The course of the disorder was in stages as in classic Rett syndrome. Hand washing was present in the first years of life but often subsequently disappeared. </p><p>Clayton-Smith et al. (2000) presented a male with somatic mosaicism for an MECP2 mutation (300005.0010), leading to a progressive but nonfatal neurodevelopmental disorder. In an affected boy, Topcu et al. (2002) identified an R270X mutation (300005.0005) along with the wildtype allele. The authors speculated that the somatic mosaicism could be the result of an early postzygotic mutation or chimerism. </p><p>Bourdon et al. (2001) reported somatic mosaicism for deletions of the MECP2 gene in 2 girls, 1 with a classic Rett phenotype and 1 with an atypical Rett phenotype without a period of regression. The deletions in these girls were detected not by sequence analysis but by CSGE or DGGE. Bourdon et al. (2001) suggested that this had implications for diagnostic methods used in Rett cases and cases of possible Rett syndrome. </p><p>Mnatzakanian et al. (2004) identified a theretofore unknown isoform of MECP2 that they called MECP2B, which utilizes exon 1 and exons 3 and 4, skipping exon 2. They screened 19 girls with typical Rett syndrome in whom no mutations had been found in exons 2, 3, or 4. In 1 affected individual, they identified a deletion of 11 basepairs in exon 1 (300005.0028). Ravn et al. (2005) identified a mutation in exon 1 of the MECP2 gene (300005.0029) in a patient with typical Rett syndrome. Ravn et al. (2005) emphasized the importance of mutation screening of MECP2 exon 1. Bartholdi et al. (2006) reported 2 unrelated girls with Rett syndrome caused by 2 different mutations affecting exon 1 of the MECP2 gene (see, e.g., 300005.0031). </p><p>Using multiplex ligation-dependent probe amplification (MLPA), Hardwick et al. (2007) identified multiexonic deletions in the MECP2 gene in 12 (8.1%) of 149 apparently mutation-negative patients with Rett syndrome. All of the deletions involved exon 3, exon 4, or both. There was no correlation between phenotypic severity and deletion size. </p><p>Saunders et al. (2009) identified 4 patients with classic Rett syndrome associated with mutations in exon 1 of the MECP2 gene, affecting the MeCP2_e1 isoform. Three of the mutations were predicted to result in absent translation of the isoform. Three of the mutations were proven to be de novo; the fourth was likely de novo, but the unaffected father was not available for DNA analysis. Two of the patients had previously tested negative for MECP2 mutation, which at the time only included sequencing of exons 2 to 4 of the gene (MeCP2_e2 isoform). The findings suggested that mutations affecting exon 1 of MECP2 are important in the etiology of RTT. </p><p><strong><em>Disruption of the NTNG1 Gene</em></strong></p><p>
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Borg et al. (2005) reported a girl with characteristic features of Rett syndrome who had no mutations in MECP2 or CDKL5 but carried a de novo balanced translocation, t(1;7)(p13.3;q31.3). No known gene was disrupted by the chromosome 7 breakpoint, but the chromosome 1 breakpoint was located within intron 6 of the NTNG1 gene (608818) and affected alternatively spliced transcripts. Borg et al. (2005) suggested that NTNG1 is a candidate disease gene for RTT. Archer et al. (2006) failed to identify any pathogenic mutations in coding exons of the NTNG1 gene among 115 patients with Rett syndrome. </p><p><strong><em>Associations Pending Confirmation</em></strong></p><p>
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For discussion of a possible association between Rett syndrome and variation in the JMJD1C gene, see 604503.0001.</p>
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<h4>
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<span class="mim-font">
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<strong>Genotype/Phenotype Correlations</strong>
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</h4>
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<p>Zappella et al. (2001) noted that all MECP2 mutations found in PSV patients have been either missense or late truncating mutations. In particular, the 4 early truncating hotspot mutations, R168X (300005.0020), R255X (300005.0021), R270X (300005.0005), and R294X (300005.0011), have not been found in PSV patients. These results suggested that early truncating mutations lead to a poor prognosis (classic Rett), whereas late truncating missense mutations lead either to classic Rett or to PSV. </p><p>Smeets et al. (2003) reported on 30 adolescent and adult females with classic or atypical Rett syndrome, of whom 24 had an MECP2 mutation. Mutations were found in all of the classic cases and in 64% of the variant cases. No correlation was found between skewing and milder phenotype. Early truncating mutations were associated with a more severe course of the disorder. A deletion hotspot in the C-terminal segment was predominantly characterized by rapid progressive neurogenic scoliosis. The R133C mutation (300005.0001) was associated with a predominantly autistic presentation, whereas the R306C mutation (300005.0016) was associated with a slower disease progression. </p><p>Smeets et al. (2005) described the long-term history of 10 females with a deletion in the C terminus of the MECP2 gene. Although their disease appeared 'classic' at an older age, in the beginning their symptoms resembled the forme fruste described by Hagberg and Skjeldal (1994). All had a more slowly progressive course with better-preserved cognitive functions in adolescence and adulthood. Their primary clinical problems were a gradual decline in gross motor ability despite preventive measures and a rapidly progressive spine deformation due to marked dystonia present from childhood. </p><p>Hammer et al. (2003) reported a 5-year-old girl with a 47,XXX karyotype who had relatively mild atypical Rett syndrome leading initially to a diagnosis of infantile autism with regression. Mutation analysis identified a de novo MECP2 mutation (L100V; 300005.0027). The supernumerary X chromosome was maternally derived. X-inactivation patterns indicated preferential inactivation of the paternal allele. Hammer et al. (2003) suggested that the patient illustrated the importance of allele dosage on phenotypic presentation. </p><p>Weaving et al. (2003) reported a large MECP2 screening project in patients diagnosed with Rett syndrome. Composite phenotype severity scores did not correlate with mutation type, domain affected, or X inactivation. Other correlations, including head circumference, height, presence of speech, and age at development of hand stereotypies, suggested that truncating mutations and mutations affecting the methyl-CpG-binding domain (MBD) tend to lead to a more severe phenotype. Skewed X inactivation was found in 31 (43%) of 72 patients tested, primarily in those with truncating mutations and mutations affecting the MBD. Weaving et al. (2003) concluded that it is likely that X inactivation modulates the phenotype in RTT. </p><p>In a study of genotype/phenotype correlations, Schanen et al. (2004) analyzed 85 Rett syndrome patients with mutation in the MECP2 gene. Sixty-five (76%) carried 1 of the 8 common mutations. Patients with missense mutations had lower total severity scores and better language performance than those with nonsense mutations. No difference was noted between severity scores for mutations in the MBD and the TRD. However, patients with missense mutations in TRD had the best overall scores and better preservation of head growth and language skills. Analysis of specific mutation groups demonstrated a striking difference for patients with the R306C mutation (300005.0016), including better overall score, later regression, and better language with less motor impairment. Indeed, these patients as a group accounted for the differences in overall scores between the missense and nonsense groups </p><p>In 524 females with Rett syndrome and an identified MECP2 mutation, Jian et al. (2005) prospectively analyzed mortality data and found significant differences in survival among the 8 most common mutations. Survival among cases with the R270X (300005.0005) mutation was reduced compared to all the other mutations (p = 0.01). Jian et al. (2005) concluded that this might explain the apparent underrepresentation of R270X in older subjects with Rett syndrome in 2 published reports of the MECP2 mutation spectrum (Smeets et al., 2003 and Schanen et al., 2004). </p><p>Bartholdi et al. (2006) reported 2 unrelated girls with Rett syndrome caused by 2 different mutations affecting exon 1 of the MECP2 gene (see, e.g., 300005.0031). The phenotype of both girls was more severe than that of 2 additional unrelated girls with Rett syndrome caused by MECP2 mutations not affecting exon 1. The authors speculated that MECP2 mutations involving exon 1 result in a more severe phenotype because MECP2B is more abundantly expressed in the brain than MECP2A. </p><p>Among 110 patients with Rett syndrome in whom an MECP2 mutation was not identified, Archer et al. (2006) used dosage analysis to detect large deletions in 37.8% (14 of 37) patients with classic Rett syndrome and 7.5% (4 of 53) patients with atypical Rett syndrome. Most large deletions contained a breakpoint in the deletion prone region of exon 4. Five patients with large MECP2 deletions had additional congenital anomalies, which was significantly more than in RTT patients with other MECP2 mutations. </p><p>Robertson et al. (2006) compared the behavioral profile of cases in the Australian Rett Syndrome Database with those of a British study using the Rett Syndrome Behavioral Questionnaire (Mount et al., 2002). Behavioral patterns were compared to MECP2 gene findings in the probands. Fear/anxiety was more commonly reported in those individuals with R133C and R306C. R294X was more likely to be associated with mood difficulties and body rocking but less likely to have hand behaviors and to display repetitive face movements. Hand behaviors were more commonly reported in those with R270X or R255X. </p><p>Huppke et al. (2006) reported 3 unrelated girls with very mild forms of Rett syndrome due to mutations in the MECP2 gene and skewed X inactivation (X-inactivation ratios of 84:16, 95:5, and 76:24, respectively). All 3 patients had normal hand function, communicated well, and showed hyperventilation only under stress; only 2 patients had a subtle history of developmental regression. None of the patients met the established diagnostic criteria for classic Rett syndrome. The findings indicated that X-inactivation patterns can influence the phenotypic severity of Rett syndrome. </p>
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<h4>
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<span class="mim-font">
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<strong>Pathogenesis</strong>
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</span>
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</h4>
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<p>Hendrich and Bickmore (2001) reviewed human disorders that share in common defects of chromatin structure or modification, including the ATR-X spectrum of disorders (301040), ICF syndrome (242860), Rett syndrome, Rubinstein-Taybi syndrome (180849), and Coffin-Lowry syndrome (303600). </p><p>In rodent brain tissue, Deng et al. (2007) identified the FXYD1 (602359) promoter as an endogenous target of MECP2, which can cause transcriptional regulation of FXYD1. Transgenic Mecp2-null mice had increased Fxyd1 mRNA and protein levels in the frontal cortex, similar to that observed in patients with Rett syndrome. Increased Fxyd1 expression in Mecp2-null mice was associated with decreased Na,K-ATPase activity in the frontal cortex. In cultured mouse neurons, overexpression of Fxyd1 was associated with decreased neuronal dendritic tree and spine formation compared to controls, findings that have been observed in Rett syndrome. Overall, the results suggested that derepression of FXYD1, resulting from inactivation of MECP2, may contribute to the neuropathogenesis of Rett syndrome. </p><p>Marchetto et al. (2010) generated neurons with RTT-associated MECP2 mutations from induced pluripotent stem cells derived from fibroblasts isolated from patients with Rett syndrome. These cells were able to undergo X inactivation and generate functional neurons. Studies of these neurons in culture showed fewer synapses, reduced spine density, and small soma size compared to controls. In addition, these cells showed altered calcium signaling and electrophysiologic defects, particularly affecting glutamate signaling, compared to controls. The findings demonstrated that human RTT neurons have early developmental defects. Pharmacologic treatment of these cells with IGF1 (147440) and gentamicin, which causes read-through of nonsense mutations, showed some promising results. </p><p>Muotri et al. (2010) showed that L1 neuronal transcription and retrotransposition in rodents are increased in the absence of Mecp2. Using neuronal progenitor cells derived from human induced pluripotent stem cells and human tissues, they revealed that patients with Rett syndrome, carrying MeCP2 mutations, have increased susceptibility for L1 retrotransposition. Muotri et al. (2010) concluded that L1 retrotransposition can be controlled in a tissue-specific manner and that disease-related genetic mutations can influence the frequency of neuronal L1 retrotransposition. </p>
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<h4>
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<span class="mim-font">
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<strong>Population Genetics</strong>
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</h4>
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<span class="mim-text-font">
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<p>Hagberg (1985) estimated the frequency of Rett syndrome to be about 1 in 15,000 in southwestern Sweden. Among girls aged 0 to 18 years in North Dakota, Burd et al. (1991) found the frequency of Rett syndrome to be 1 in 19,786. </p><p>Miyamoto et al. (1997) quoted data suggesting that Rett syndrome has a frequency of 1 in 20,000 girls in metropolitan Tokyo. </p>
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</span>
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<h4>
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<span class="mim-font">
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<strong>History</strong>
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</span>
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</h4>
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<span class="mim-text-font">
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<p>Zimprich et al. (2006) provided a historical perspective of the work of Andreas Rett (1924-1997), a pediatric neurologist and social reformer in postwar Austria, who first described Rett syndrome. </p><p>Because of the progressive character of the disease and occasional reports of elevated blood and CSF lactate, it has been suggested that Rett syndrome may be a mitochondrial disorder. Lappalainen and Riikonen (1994) assessed the acid-base balance CSF and blood lactate from 8 girls with Rett syndrome. Only the 3 patients with severe hyperventilation had elevated CSF lactate values. The authors suggested that elevation of CSF lactate is secondary to the intensive hyperventilation in alkalosis rather than a sign of any mitochondriopathy. </p>
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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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<span class="mim-text-font">
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<p>Shahbazian et al. (2002) generated mice expressing a truncated Mecp2 protein similar to those found in RTT patients. The mutant mice exhibited normal motor function for approximately 6 weeks, but then developed a progressive neurologic disease that included many features of RTT: tremors, motor impairments, hypoactivity, increased anxiety-related behavior, seizures, kyphosis, and stereotypic forelimb motions. Shahbazian et al. (2002) showed that although the truncated Mecp2 protein in these mice localized normally to heterochromatic domains in vivo, histone H3 (142780) was hyperacetylated. They presented this as evidence that, in this mouse model of RTT, the chromatin architecture is abnormal and gene expression may be misregulated. </p><p>Moretti et al. (2005) studied home cage behavior and social interactions in a mouse model of Rett syndrome. Young adult mutant mice showed abnormal home cage diurnal activity in the absence of motor skill deficits. Mutant mice showed deficits in nest building, decreased nest use, and impaired social interaction. They also took less initiative and were less decisive approaching unfamiliar males and spent less time in close vicinity to them in several social interaction paradigms. Abnormalities of diurnal activity and social behavior in Mecp2-mutant mice were reminiscent of the sleep/wake dysfunction and autistic features of RTT. Moretti et al. (2005) suggested that MECP2 may regulate expression and/or function of genes involved in social behavior. </p><p>Using cDNA microarrays, Nuber et al. (2005) found that Mecp2-null mice differentially expressed several genes that are induced during the stress response by glucocorticoids. Increased levels of mRNAs for SGK1 (602958) and FK506-binding protein-51 (FKBP5; 602623) were observed before and after onset of neurologic symptoms, but plasma glucocorticoid was not significantly elevated in Mecp2-null mice. MeCP2 binds to Fkbp5 and Sgk1 in brain and may function as a modulator of glucocorticoid-inducible gene expression. Given the known deleterious effect of glucocorticoid exposure on brain development, Nuber et al. (2005) proposed that disruption of MeCP2-dependent regulation of stress-responsive genes may contribute to the symptoms of Rett syndrome. </p><p>Chao et al. (2010) generated mice lacking Mecp2 from GABA-releasing neurons, designated Viaat-Mecp2(-/y), and showed that they recapitulate numerous Rett syndrome and autistic features, including repetitive behaviors. Viaat-Mecp2(-/y) mice were indistinguishable from controls until approximately 5 weeks of age, when they began to exhibit repetitive behavior such as forelimb stereotypies reminiscent of midline hand-wringing that characterizes Rett syndrome and hindlimb clasping. Viaat-Mecp2(-/y) mice spent 300% more time grooming than wildtype mice, leading to fur loss and epidermal lesions in group- and single-housed mice. Viaat-Mecp2(-/y) mice showed progressive motor dysfunction. The mice also developed motor weakness and by 12 weeks showed a trend toward reduced activity, becoming clearly hypoactive by 19 weeks. MeCP2 deficiency in GABAergic neurons also impaired hippocampal learning and memory. Roughly one-half of Viaat-Mecp2(-/y) mice died by 26 weeks of age after a period of marked weight loss. Coinciding with the weight loss, mice developed severe respiratory dysfunction. Next, Chao et al. (2010) generated male conditional deletion mice, designed Dlx5/6-Mecp2(-/y), missing MeCP2 from a subset of forebrain GABAergic neurons. These mice showed repetitive behavior, impaired motor coordination, increased social interaction preference, reduced acoustic startle response, and enhanced prepulse inhibition. In contrast to Viaat-Mecp2(-/y) mice, Dlx5/6-Mecp2(-/y) mice survived at least 80 weeks without apparent alterations in respiratory function. MeCP2-deficient GABAergic neurons showed reduced inhibitory quantal size, consistent with a presynaptic reduction in glutamic acid decarboxylase-1 (GAD1; 605363) and -2 (GAD2; 138275) levels. Chao et al. (2010) concluded that MeCP2 is critical for normal function of GABA-releasing neurons and that subtle dysfunction of GABAergic neurons contributes to numerous neuropsychiatric phenotypes. </p><p>Lioy et al. (2011) showed that in globally Mecp2-deficient mice, reexpression of Mecp2 preferentially in astrocytes significantly improved locomotion and anxiety levels, restored respiratory abnormalities to a normal pattern, and greatly prolonged life span compared to globally null mice. Furthermore, restoration of Mecp2 in the mutant astrocytes exerted a non-cell-autonomous positive effect on mutant neurons in vivo, restoring normal dendritic morphology and increasing levels of the excitatory glutamate transporter VGLUT1. Lioy et al. (2011) concluded their study showed that glia, like neurons, are integral components of the neuropathology of Rett syndrome, and supported the targeting of glia as a strategy for improving the associated symptoms. </p><p>Derecki et al. (2012) examined the role of microglia in a murine model of Rett syndrome and showed that transplantation of wildtype bone marrow into irradiation-conditioned Mecp2-null hosts resulted in engraftment of brain parenchyma by bone marrow-derived myeloid cells of microglial phenotype and arrest of disease development. However, when cranial irradiation was blocked by lead shield and microglial engraftment was prevented, disease was not arrested. Similarly, targeted expression of MECP2 in myeloid cells, driven by Lysm(cre) on an Mecp2-null background, markedly attenuated disease symptoms. Thus, through multiple approaches, wildtype Mecp2-expressing microglia within the context of an Mecp2-null male mouse arrested numerous facets of disease pathology: life span was increased, breathing patterns were normalized, apneas were reduced, body weight was increased to near that of wildtype, and locomotor activity was improved. Mecp2 +/- females also showed significant improvements as a result of wildtype microglial engraftment. These benefits mediated by wildtype microglia, however, were diminished when phagocytic activity was inhibited pharmacologically by using annexin V (131230) to block phosphatidylserine residues on apoptotic targets, thus preventing recognition and engulfment by tissue-resident phagocytes. Derecki et al. (2012) concluded that their results suggested the importance of microglial activity in Rett syndrome, implicated microglia as major players in the pathophysiology of Rett syndrome, and suggested bone marrow transplantation as a possible therapy. </p><p>Hao et al. (2015) studied the effects of forniceal deep brain stimulation (DBS) in a well-characterized mouse model of Rett syndrome (RTT), and showed that it rescued contextual fear memory as well as spatial learning and memory. In parallel, forniceal DBS restored in vivo hippocampal long-term potentiation and hippocampal neurogenesis. The authors concluded that forniceal DBS might mitigate cognitive dysfunction in RTT. </p>
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</span>
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<div>
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<h4>
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<span class="mim-font">
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<strong>See Also:</strong>
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</span>
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</h4>
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<span class="mim-text-font">
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Guerrini et al. (1998); Hagberg et al. (1985); Johnson (1980); Nomura
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et al. (1984); Rett (1986); Yang-Feng et al. (1986); Zoghbi et al.
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(1985)
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</span>
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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>REFERENCES</strong>
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</span>
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</h4>
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Adegbola, A. A., Gonzales, M. L., Chess, A., LaSalle, J. M., Cox, G. F.
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<strong>A novel hypomorphic MECP2 point mutation is associated with a neuropsychiatric phenotype.</strong>
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Hum. Genet. 124: 615-623, 2009.
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[PubMed: 18989701]
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[Full Text: https://doi.org/10.1007/s00439-008-0585-6]
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<p class="mim-text-font">
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Akesson, H. O., Hagberg, B., Wahlstrom, J., Witt Engerstrom, I.
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<strong>Rett syndrome: a search for gene sources.</strong>
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Am. J. Med. Genet. 42: 104-108, 1992.
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[PubMed: 1308347]
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[Full Text: https://doi.org/10.1002/ajmg.1320420121]
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Akesson, H. O., Hagberg, B., Wahlstrom, J.
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<strong>Rett syndrome, classical and atypical: genealogical support for common origin.</strong>
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J. Med. Genet. 33: 764-766, 1996.
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[PubMed: 8880578]
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[Full Text: https://doi.org/10.1136/jmg.33.9.764]
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<p class="mim-text-font">
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Akesson, H. O., Wahlstrom, J., Witt Engerstrom, I., Hagberg, B.
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<strong>Rett syndrome: potential gene sources: phenotypical variability.</strong>
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Clin. Genet. 48: 169-172, 1995.
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[PubMed: 8591665]
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[Full Text: https://doi.org/10.1111/j.1399-0004.1995.tb04082.x]
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<p class="mim-text-font">
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Amir, R. E., Van den Veyver, I. B., Wan, M., Tran, C. Q., Francke, U., Zoghbi, H. Y.
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<strong>Rett syndrome is caused by mutations in X-linked MECP2, encoding methyl-CpG-binding protein 2.</strong>
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Nature Genet. 23: 185-188, 1999.
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[PubMed: 10508514]
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[Full Text: https://doi.org/10.1038/13810]
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<p class="mim-text-font">
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Anvret, M., Wahlstrom, J., Skogsberg, P., Hagberg, B.
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<strong>Segregation analysis of the X-chromosome in a family with Rett syndrome in two generations.</strong>
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Am. J. Med. Genet. 37: 31-35, 1990.
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[PubMed: 2240040]
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[Full Text: https://doi.org/10.1002/ajmg.1320370109]
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Xiang, F., Zhang, Z., Clarke, A., Joseluiz, P., Sakkubai, N., Sarojini, B., Delozier-Blanchet, C. D., Hansmann, I., Edstrom, L., Anvret, M.
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<strong>Genes for synapsin I, a neuronal phosphoprotein, map to conserved regions of human and murine X chromosomes.</strong>
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Zimprich, F., Ronen, G. M., Stogmann, W., Baumgartner, C., Stogmann, E., Rett, B., Pappas, C., Leppert, M., Singh, N., Anderson, V. E.
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Zoghbi, H. Y., Ledbetter, D. H., Schultz, R., Percy, A. K., Glaze, D. G.
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<strong>A de novo X;3 translocation in Rett syndrome.</strong>
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Zoghbi, H. Y., Percy, A. K., Glaze, D. G., Butler, I. J., Riccardi, V. M.
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<strong>Reduction of biogenic amine levels in the Rett syndrome.</strong>
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Zoghbi, H. Y., Percy, A. K., Schultz, R. J., Fill, C.
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<strong>Patterns of X chromosome inactivation in the Rett syndrome.</strong>
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Ada Hamosh - updated : 11/20/2015<br>Ada Hamosh - updated : 4/24/2012<br>Ada Hamosh - updated : 8/30/2011<br>Ada Hamosh - updated : 5/19/2011<br>Cassandra L. Kniffin - updated : 3/23/2011<br>Cassandra L. Kniffin - updated : 1/21/2011<br>Ada Hamosh - updated : 11/29/2010<br>Cassandra L. Kniffin - updated : 7/13/2010<br>Cassandra L. Kniffin - updated : 10/16/2009<br>Cassandra L. Kniffin - updated : 7/14/2009<br>Cassandra L. Kniffin - updated : 2/25/2009<br>George E. Tiller - updated : 11/21/2008<br>Cassandra L. Kniffin - updated : 3/6/2008<br>George E. Tiller - updated : 11/8/2007<br>Cassandra L. Kniffin - updated : 7/31/2007<br>Cassandra L. Kniffin - updated : 11/9/2006<br>Cassandra L. Kniffin - updated : 11/1/2006<br>Cassandra L. Kniffin - updated : 8/31/2006<br>John Logan Black, III - updated : 8/4/2006<br>Cassandra L. Kniffin - updated : 6/13/2006<br>Cassandra L. Kniffin - updated : 6/2/2006<br>Marla J. F. O'Neill - updated : 2/14/2006<br>Marla J. F. O'Neill - updated : 12/1/2005<br>Marla J. F. O'Neill - updated : 10/6/2005<br>Cassandra L. Kniffin - updated : 5/18/2005<br>Cassandra L. Kniffin - updated : 3/18/2005<br>Marla J. F. O'Neill - updated : 3/1/2005<br>Marla J. F. O'Neill - updated : 1/28/2005<br>Victor A. McKusick - updated : 11/18/2004<br>Ada Hamosh - updated : 3/30/2004<br>Cassandra L. Kniffin - reorganized : 12/23/2003<br>Cassandra L. Kniffin - updated : 12/23/2003<br>Felicity Collins - updated : 12/10/2003<br>Victor A. McKusick - updated : 11/6/2003<br>Victor A. McKusick - updated : 1/8/2003<br>Victor A. McKusick - updated : 1/8/2003<br>Dawn Watkins-Chow - updated : 12/16/2002<br>Michael J. Wright - updated : 10/22/2002<br>Victor A. McKusick - updated : 9/19/2002<br>Michael B. Petersen - updated : 9/10/2002<br>Victor A. McKusick - updated : 8/27/2002<br>George E. Tiller - updated : 2/12/2002<br>Victor A. McKusick - updated : 11/13/2001<br>Michael B. Petersen - updated : 10/23/2001<br>Michael J. Wright - updated : 10/8/2001<br>Ada Hamosh - updated : 3/2/2001<br>Ada Hamosh - updated : 10/30/2000<br>Paul Brennan - updated : 4/10/2000<br>Wilson H. Y. Lo - updated : 2/1/2000<br>Victor A. McKusick - updated : 9/28/1999<br>Victor A. McKusick - updated : 5/28/1999<br>Ada Hamosh - updated : 3/26/1999<br>Michael J. Wright - updated : 2/10/1999<br>Michael J. Wright - updated : 9/18/1998<br>Victor A. McKusick - updated : 9/3/1998<br>Victor A. McKusick - updated : 7/20/1998<br>Ada Hamosh - updated : 6/15/1998<br>Victor A. McKusick - updated : 4/6/1998<br>Victor A. McKusick - updated : 10/7/1997<br>Iosif W. Lurie - updated : 12/4/1996<br>Orest Hurko - updated : 9/8/1995
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Victor A. McKusick : 6/4/1986
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