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Entry
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- #609056 - SALT AND PEPPER DEVELOPMENTAL REGRESSION SYNDROME; SPDRS
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- OMIM
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<p>
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<span class="h4">#609056</span>
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<br />
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<strong>Table of Contents</strong>
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<a href="#title"><strong>Title</strong></a>
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<a href="#phenotypeMap"><strong>Phenotype-Gene Relationships</strong></a>
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<a href="/clinicalSynopsis/609056"><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="#biochemicalFeatures">Biochemical Features</a>
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<a href="#inheritance">Inheritance</a>
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<a href="#clinicalManagement">Clinical Management</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="#nomenclature">Nomenclature</a>
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<a href="#animalModel">Animal Model</a>
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<li role="presentation">
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<a href="#references"><strong>References</strong></a>
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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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<div class="panel-heading mim-panel-heading" role="tab" id="mimExternalLinks">
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<div id="mimExternalLinksToggleTriangle" class="small" style="color: white; display: table-cell;">▼</div>
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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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</div>
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<div class="panel-group" id="mimExternalLinksAccordion" role="tablist" aria-multiselectable="true">
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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="mimClinicalResources">
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<span class="panel-title">
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<span class="small">
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<a href="#mimClinicalResourcesLinksFold" id="mimClinicalResourcesLinksToggle" class=" mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimClinicalResourcesLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">▼</div>
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<div style="display: table-cell;">Clinical Resources</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimClinicalResourcesLinksFold" class="panel-collapse collapse in mimLinksFold" role="tabpanel" aria-labelledby="clinicalResources">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://clinicaltrials.gov/search?cond=SALT AND PEPPER DEVELOPMENTAL REGRESSION 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="https://www.orpha.net/consor/cgi-bin/ClinicalLabs_Search_Simple.php?lng=EN&LnkId=22504&Typ=Pat" class="mim-tip-hint" title="A list of European laboratories that offer genetic testing." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'EuroGentest', 'domain': 'orpha.net'})">EuroGentest</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/books/NBK593237/" class="mim-tip-hint" title="Expert-authored, peer-reviewed descriptions of inherited disorders including the uses of genetic testing in diagnosis, management, and genetic counseling." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Gene Reviews', 'domain': 'ncbi.nlm.nih.gov'})">Gene Reviews</a></div>
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<div><a href="https://www.diseaseinfosearch.org/x/7682" class="mim-tip-hint" title="Network of disease-specific advocacy organizations, universities, private companies, government agencies, and public policy organizations." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Genetic Alliance', 'domain': 'diseaseinfosearch.org'})">Genetic Alliance</a></div>
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<div><a href="https://medlineplus.gov/genetics/condition/gm3-synthase-deficiency" 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=609056[mim]" class="mim-tip-hint" title="Genetic Testing Registry." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'GTR', 'domain': 'ncbi.nlm.nih.gov'})">GTR</a></div>
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<div><a href="https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=370933" class="mim-tip-hint" title="European reference portal for information on rare diseases and orphan drugs." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'OrphaNet', 'domain': 'orpha.net'})">OrphaNet</a></div>
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<div><a href="https://www.possumcore.com/nuxeo/nxdoc/default/24cfd65e-07a7-4c25-b156-fb80a48f973e/view_documents?source=omim" class="mim-tip-hint" title="A dysmorphology database of multiple malformations; metabolic, teratogenic, chromosomal, and skeletal syndromes; and their images." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'POSSUM', 'domain': 'possum.net.au'})">POSSUM</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimAnimalModels">
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<span class="panel-title">
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<span class="small">
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<a href="#mimAnimalModelsLinksFold" id="mimAnimalModelsLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimAnimalModelsLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Animal Models</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimAnimalModelsLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.alliancegenome.org/disease/DOID:0060470" 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/609056" 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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<span>
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<span class="mim-tip-bottom" qtip_title="<strong>Looking for this gene or this phenotype in other resources?</strong>" qtip_text="Select a related resource from the dropdown menu and click for a targeted link to information directly relevant.">
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</span>
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</div>
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<div class="col-lg-8 col-lg-pull-2 col-md-8 col-md-pull-2 col-sm-8 col-sm-pull-2 col-xs-12">
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<div>
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<a id="title" class="mim-anchor"></a>
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<div>
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<a id="number" class="mim-anchor"></a>
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<div class="text-right">
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<a href="#" class="mim-tip-icd" qtip_title="<strong>ICD+</strong>" qtip_text="
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<strong>SNOMEDCT:</strong> 722762005<br />
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<strong>ORPHA:</strong> 370933<br />
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<strong>DO:</strong> 0060470<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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609056
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</span>
|
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</span>
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</div>
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</div>
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<div>
|
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<a id="preferredTitle" class="mim-anchor"></a>
|
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<h3>
|
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<span class="mim-font">
|
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SALT AND PEPPER DEVELOPMENTAL REGRESSION SYNDROME; SPDRS
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</span>
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</h3>
|
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</div>
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<div>
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<br />
|
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</div>
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<div>
|
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<a id="alternativeTitles" class="mim-anchor"></a>
|
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<div>
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<p>
|
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<span class="mim-font">
|
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<em>Alternative titles; symbols</em>
|
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</span>
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</p>
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</div>
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<div>
|
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<h4>
|
|
<span class="mim-font">
|
|
AMISH INFANTILE EPILEPSY SYNDROME<br />
|
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EPILEPSY SYNDROME, INFANTILE-ONSET SYMPTOMATIC<br />
|
|
GM3 SYNTHASE DEFICIENCY<br />
|
|
SALT AND PEPPER MENTAL RETARDATION SYNDROME
|
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</span>
|
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</h4>
|
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</div>
|
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
|
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<a id="phenotypeMap" class="mim-anchor"></a>
|
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<h4>
|
|
<span class="mim-font">
|
|
<strong>Phenotype-Gene Relationships</strong>
|
|
</span>
|
|
</h4>
|
|
<div>
|
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<table class="table table-bordered table-condensed table-hover small mim-table-padding">
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<thead>
|
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<tr class="active">
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<th>
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Location
|
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</th>
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<th>
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Phenotype
|
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</th>
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<th>
|
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Phenotype <br /> MIM number
|
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</th>
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<th>
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Inheritance
|
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</th>
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<th>
|
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Phenotype <br /> mapping key
|
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</th>
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<th>
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Gene/Locus
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</th>
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<th>
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Gene/Locus <br /> MIM number
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</th>
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</tr>
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</thead>
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<tbody>
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<tr>
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<td>
|
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<span class="mim-font">
|
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<a href="/geneMap/2/435?start=-3&limit=10&highlight=435">
|
|
2p11.2
|
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</a>
|
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</span>
|
|
</td>
|
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<td>
|
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<span class="mim-font">
|
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Salt and pepper developmental regression syndrome
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</span>
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</td>
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<td>
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<span class="mim-font">
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<a href="/entry/609056"> 609056 </a>
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</span>
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</td>
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<td>
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<span class="mim-font">
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<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
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</span>
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</td>
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<td>
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<span class="mim-font">
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<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
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</span>
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</td>
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<td>
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<span class="mim-font">
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SIAT9
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</span>
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</td>
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<td>
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<span class="mim-font">
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<a href="/entry/604402"> 604402 </a>
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</span>
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</td>
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</tr>
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</tbody>
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</table>
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</div>
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</div>
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<div>
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<div class="btn-group ">
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<a href="/clinicalSynopsis/609056" class="btn btn-warning" role="button"> Clinical Synopsis </a>
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<button type="button" id="mimPhenotypicSeriesToggle" class="btn btn-warning dropdown-toggle mimSingletonFoldToggle" data-toggle="collapse" href="#mimClinicalSynopsisFold" onclick="ga('send', 'event', 'Unfurl', 'ClinicalSynopsis', 'omim.org')">
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<span class="caret"></span>
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<span class="sr-only">Toggle Dropdown</span>
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</button>
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</div>
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<div class="btn-group">
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<button type="button" class="btn btn-success dropdown-toggle" data-toggle="dropdown" aria-haspopup="true" aria-expanded="false">
|
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PheneGene Graphics <span class="caret"></span>
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</button>
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<ul class="dropdown-menu" style="width: 17em;">
|
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<li><a href="/graph/linear/609056" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Linear'})"> Linear </a></li>
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<li><a href="/graph/radial/609056" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Radial'})"> Radial </a></li>
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</ul>
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</div>
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<span class="glyphicon glyphicon-question-sign mim-tip-hint" title="OMIM PheneGene graphics depict relationships between phenotypes, groups of related phenotypes (Phenotypic Series), and genes.<br /><a href='/static/omim/pdf/OMIM_Graphics.pdf' target='_blank'>A quick reference overview and guide (PDF)</a>"></span>
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<div>
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<p />
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</div>
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<div id="mimClinicalSynopsisFold" class="well well-sm collapse mimSingletonToggleFold">
|
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<div class="small" style="margin: 5px">
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<div>
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<div>
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<span class="h5 mim-font">
|
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<strong> INHERITANCE </strong>
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</span>
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</div>
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<div style="margin-left: 2em;">
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<div>
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<span class="mim-font">
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- Autosomal recessive <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/258211005" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">258211005</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0441748&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0441748</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000007" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000007</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000007" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000007</a>]</span><br />
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</span>
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</div>
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</div>
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</div>
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<div>
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<div>
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<span class="h5 mim-font">
|
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<strong> GROWTH </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> Other </em>
|
|
</span>
|
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</div>
|
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<div style="margin-left: 2em;">
|
|
<span class="mim-font">
|
|
|
|
- Failure to thrive <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/432788009" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">432788009</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/54840006" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">54840006</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/783.41" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">783.41</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0015544&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0015544</a>, <a href="https://bioportal.bioontology.org/search?q=C2315100&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C2315100</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001508" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001508</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001508" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001508</a>]</span><br />
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|
|
</span>
|
|
</div>
|
|
</div>
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|
</div>
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|
|
</div>
|
|
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|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<strong> HEAD & NECK </strong>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
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<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<em> Head </em>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
<span class="mim-font">
|
|
|
|
- Microcephaly (in some patients) <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/1148757008" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">1148757008</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/Q02" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">Q02</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/742.1" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">742.1</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C4551563&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C4551563</a>, <a href="https://bioportal.bioontology.org/search?q=C0025958&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0025958</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000252" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000252</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000252" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000252</a>]</span> <a href="https://elementsofmorphology.nih.gov/index.cgi?tid=0584d323b99dcd7001cc50e224947aca" target="_blank" class="small mim-tip-eom" title="<img src="https://elementsofmorphology.nih.gov/images/terms/Microcephaly-small.jpg"> <br/>Further Information: <a href="https://elementsofmorphology.nih.gov/index.cgi?tid=0584d323b99dcd7001cc50e224947aca" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'EOM\', \'domain\': \'elementsofmorphology.nih.gov\'})">Elements of Morphology</a>"><span class="glyphicon glyphicon-user" aria-hidden="true"></span></a><br />
|
|
|
|
</span>
|
|
</div>
|
|
</div>
|
|
|
|
|
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|
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<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<em> Ears </em>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
<span class="mim-font">
|
|
|
|
- Deafness (in some patients) <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/343087000" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">343087000</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/H91.9" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">H91.9</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0018772&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0018772</a>, <a href="https://bioportal.bioontology.org/search?q=C0011053&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0011053</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000365" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000365</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000365" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000365</a>]</span><br />
|
|
|
|
</span>
|
|
</div>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<em> Eyes </em>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
<span class="mim-font">
|
|
|
|
- Optic atrophy <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/76976005" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">76976005</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/H47.2" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">H47.2</a>, <a href="https://purl.bioontology.org/ontology/ICD10CM/H47.20" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">H47.20</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/377.10" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">377.10</a>, <a href="https://purl.bioontology.org/ontology/ICD9CM/377.1" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">377.1</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0029124&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0029124</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000648" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000648</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000648" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000648</a>]</span><br /> -
|
|
Loss of vision <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/246635007" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">246635007</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/7973008" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">7973008</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/H54.7" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">H54.7</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/369.9" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">369.9</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C3665346&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C3665346</a>, <a href="https://bioportal.bioontology.org/search?q=C3665386&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C3665386</a>, <a href="https://bioportal.bioontology.org/search?q=C0042798&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0042798</a>, <a href="https://bioportal.bioontology.org/search?q=C0456909&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0456909</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000618" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000618</a>, <a href="https://hpo.jax.org/app/browse/term/HP:0000572" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000572</a>, <a href="https://hpo.jax.org/app/browse/term/HP:0000505" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000505</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000572" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000572</a>]</span><br /> -
|
|
Decreased eye contact <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1836840&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1836840</a>]</span><br /> -
|
|
Eye deviation <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/22066006" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">22066006</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/H50.9" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">H50.9</a>, <a href="https://purl.bioontology.org/ontology/ICD10CM/H50.40" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">H50.40</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0038379&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0038379</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000486" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000486</a>]</span><br /> -
|
|
Cortical visual impairment <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/413924001" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">413924001</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/432141000124105" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">432141000124105</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C4048268&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C4048268</a>, <a href="https://bioportal.bioontology.org/search?q=C3810365&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C3810365</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0100704" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0100704</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0100704" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0100704</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> ABDOMEN </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>
|
|
<span class="h5 mim-font">
|
|
<em> Gastrointestinal </em>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
<span class="mim-font">
|
|
|
|
- Poor feeding <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/299698007" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">299698007</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/78164000" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">78164000</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/R63.3" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">R63.3</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0576456&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0576456</a>, <a href="https://bioportal.bioontology.org/search?q=C0232466&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0232466</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0011968" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0011968</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0011968" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0011968</a>]</span><br /> -
|
|
Vomiting <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/422400008" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">422400008</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/300359004" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">300359004</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/249497008" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">249497008</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/R11.1" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">R11.1</a>, <a href="https://purl.bioontology.org/ontology/ICD10CM/R11.10" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">R11.10</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0042963&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0042963</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002013" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002013</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002013" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002013</a>]</span><br />
|
|
|
|
</span>
|
|
</div>
|
|
</div>
|
|
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
|
|
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|
|
|
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<strong> SKIN, NAILS, & HAIR </strong>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
|
|
|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<em> Skin </em>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
<span class="mim-font">
|
|
|
|
- Dyspigmentation <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1260926&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1260926</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001000" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001000</a>]</span><br /> -
|
|
Hyperpigmented 2 to 5-mm macules mainly on the extremities <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C3807852&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C3807852</a>]</span><br /> -
|
|
De- or hypo-pigmented macules (less common) <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C3807853&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C3807853</a>]</span><br />
|
|
|
|
</span>
|
|
</div>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
|
|
|
|
|
|
|
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|
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<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<strong> NEUROLOGIC </strong>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
|
|
|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<em> Central Nervous System </em>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
<span class="mim-font">
|
|
|
|
- Delayed psychomotor development <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/224958001" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">224958001</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/F88" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">F88</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0557874&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0557874</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001263" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001263</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001263" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001263</a>]</span><br /> -
|
|
Seizures (may be difficult to control) <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C4013225&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C4013225</a>]</span> <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">[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 /> -
|
|
Generalized clonic-tonic seizures <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/1217136003" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">1217136003</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/G40.4" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">G40.4</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0494475&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0494475</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002069" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002069</a>]</span><br /> -
|
|
Status epilepticus <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/230456007" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">230456007</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0038220&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0038220</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002133" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002133</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002133" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002133</a>]</span><br /> -
|
|
Tonic spasms <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1836825&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1836825</a>]</span><br /> -
|
|
Startle myoclonus <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1836826&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1836826</a>]</span><br /> -
|
|
Multifocal epileptiform discharges on diffuse slow background <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C4013226&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C4013226</a>]</span><br /> -
|
|
Developmental stagnation at onset of seizures <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1836829&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1836829</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0006834" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0006834</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0006834" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0006834</a>]</span><br /> -
|
|
Developmental regression <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/609225004" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">609225004</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1836830&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1836830</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002376" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002376</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002376" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002376</a>]</span><br /> -
|
|
Hypotonia <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/398151007" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">398151007</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/398152000" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">398152000</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0026827&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0026827</a>, <a href="https://bioportal.bioontology.org/search?q=C1858120&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1858120</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001290" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001290</a>, <a href="https://hpo.jax.org/app/browse/term/HP:0001252" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001252</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001252" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001252</a>]</span><br /> -
|
|
Inability to sit unsupported <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/225602000" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">225602000</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0578714&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0578714</a>]</span><br /> -
|
|
Inability to reach <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1836832&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1836832</a>]</span><br /> -
|
|
No speech or language development <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1854882&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1854882</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001344" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001344</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001344" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001344</a>]</span><br /> -
|
|
Non-purposeful arm movements, choreoathetoid-like <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1836834&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1836834</a>]</span><br /> -
|
|
Diffuse brain atrophy <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0241816&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0241816</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002283" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002283</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002283" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002283</a>]</span><br />
|
|
|
|
</span>
|
|
</div>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<em> Peripheral Nervous System </em>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
<span class="mim-font">
|
|
|
|
- Hyporeflexia in the upper limbs <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1836835&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1836835</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0012391" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0012391</a>]</span><br /> -
|
|
Hyperreflexia in the lower limbs <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1836696&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1836696</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002395" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002395</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002395" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002395</a>]</span><br />
|
|
|
|
</span>
|
|
</div>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<em> Behavioral Psychiatric Manifestations </em>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
<span class="mim-font">
|
|
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- Caused by mutation in the sialyltransferase-9 gene (SIAT9, <a href="/entry/604402#0001">604402.0001</a>)<br />
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<p>A number sign (#) is used with this entry because of evidence that salt and pepper developmental regression syndrome (SPDRS) is caused by homozygous or compound heterozygous mutation in the ST3GAL5 gene (<a href="/entry/604402">604402</a>), which encodes sialyltransferase-9 (SIAT9), also known as GM3 synthase, on chromosome 2p11.</p>
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<p>Salt and pepper developmental regression syndrome, also known as Amish infantile epilepsy syndrome, is an autosomal recessive neurocutaneous disorder characterized by infantile onset of refractory and recurrent seizures associated with profoundly delayed psychomotor development and/or developmental regression as well as abnormal movements and visual loss (summary by <a href="#7" class="mim-tip-reference" title="Fragaki, K., Ait-El-Mkadem, S., Chaussenot, A., Gire, C., Mengual, R., Bonesso, L., Beneteau, M., Ricci, J.-E., Desquiret-Dumas, V., Procaccio, V., Rotig, A., Paquis-Flucklinger, V. <strong>Refractory epilepsy and mitochondrial dysfunction due to GM3 synthase deficiency.</strong> Europ. J. Hum. Genet. 21: 528-534, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22990144/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22990144</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22990144[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/ejhg.2012.202" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22990144">Fragaki et al., 2013</a>). Affected individuals develop hypo- or hyperpigmented skin macules on the trunk, face, and extremities in early childhood (summary by <a href="#2" class="mim-tip-reference" title="Boccuto, L., Aoki, K., Flanagan-Steet, H., Chen, C.-F., Fan, X., Bartel, F., Petukh, M., Pittman, A., Saul, R., Chaubey, A., Alexov, E., Tiemeyer, M., Steet, R., Schwartz, C. E. <strong>A mutation in a ganglioside biosynthetic enzyme, ST3GAL5, results in salt & pepper syndrome, a neurocutaneous disorder with altered glycolipid and glycoprotein glycosylation.</strong> Hum. Molec. Genet. 23: 418-433, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24026681/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24026681</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=24026681[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1093/hmg/ddt434" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24026681">Boccuto et al., 2014</a>). Not all patients have overt seizures (<a href="#8" class="mim-tip-reference" title="Lee, J. S., Yoo, Y., Lim, B. C., Kim, K. J., Song, J., Choi, M., Chae, J.-H. <strong>GM3 synthase deficiency due to ST3GAL5 variants in two Korean female siblings: masquerading as Rett syndrome-like phenotype.</strong> Am. J. Med. Genet. 170A: 2200-2205, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27232954/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27232954</a>] [<a href="https://doi.org/10.1002/ajmg.a.37773" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27232954">Lee et al., 2016</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=24026681+27232954+22990144" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#11" class="mim-tip-reference" title="Simpson, M. A., Cross, H., Proukakis, C., Priestman, D. A., Neville, D. C. A., Reinkensmeier, G., Wang, H., Wiznitzer, M., Gurtz, K., Verganelaki, A., Pryde, A., Patton, M. A., Dwek, R. A., Butters, T. D., Platt, F. M., Crosby, A. H. <strong>Infantile-onset symptomatic epilepsy syndrome caused by a homozygous loss-of-function mutation of GM3 synthase.</strong> Nature Genet. 36: 1225-1229, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15502825/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15502825</a>] [<a href="https://doi.org/10.1038/ng1460" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15502825">Simpson et al. (2004)</a> described an autosomal recessive infantile-onset epilepsy syndrome associated with developmental stagnation and blindness in the Old Order Amish of Geauga County, Ohio. All surviving members of the 2 branches of the single large family could be traced back to a fifth-generation common ancestor. All affected children were born at full term. The first symptoms were noted between the ages of 2 weeks and 3 months, and consisted primarily of irritability with additional poor feeding, vomiting, and failure to thrive. Gastrostomy feeding tubes were required in 2 of the 4 affected children in family A and in all affected children in family B. Seizure activity started during the first year of life, with all affected children suffering from generalized tonic-clonic (grand mal) seizures, as well as other seizure types. In at least one case, startle myoclonus was observed before generalized tonic-clonic seizures. Seizure control was difficult, requiring multiple medications and, for 2 children in 1 family, vagus nerve stimulators. Although the generalized seizures were eventually largely controlled, other seizure types, including brief tonic spasms, episodes of eye deviation, or startle from sleep, were not fully suppressed. The onset of seizure activity was accompanied by profound developmental stagnation, with evidence of regression. Affected children were unable to sit unsupported, reach, or walk, and were nonverbal. Nonpurposeful arm movements had a choreoathetoid component. Eye contact and visual function deteriorated, probably owing to cortical impairment, although there was some evidence of optic atrophy. Electroencephalograms ultimately showed multifocal epileptiform discharges superimposed on diffuse slow background activity. Brain MRI initially showed no structural abnormalities, but studies at older ages showed diffuse atrophy. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15502825" 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 2 sibships with this disorder reported by <a href="#11" class="mim-tip-reference" title="Simpson, M. A., Cross, H., Proukakis, C., Priestman, D. A., Neville, D. C. A., Reinkensmeier, G., Wang, H., Wiznitzer, M., Gurtz, K., Verganelaki, A., Pryde, A., Patton, M. A., Dwek, R. A., Butters, T. D., Platt, F. M., Crosby, A. H. <strong>Infantile-onset symptomatic epilepsy syndrome caused by a homozygous loss-of-function mutation of GM3 synthase.</strong> Nature Genet. 36: 1225-1229, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15502825/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15502825</a>] [<a href="https://doi.org/10.1038/ng1460" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15502825">Simpson et al. (2004)</a>, related as double fifth cousins, contained a total of 9 affected individuals. Only 1 had died (aged 27 months). Four of the other individuals had survived into their teens, the oldest being aged 18, thanks to excellent home care which included gastric tube feeding (<a href="#5" class="mim-tip-reference" title="Cross, H. E. <strong>Personal Communication.</strong> Tuscon, AZ 11/14/2004."None>Cross, 2004</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15502825" 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 same disorder may have been described by <a href="#9" class="mim-tip-reference" title="Max, S. R., Maclaren, N. K., Brady, R. O., Bradley, R. M., Rennels, M. B., Tanaka, J., Garcia, J. H., Cornblath, M. <strong>GM3 (Hematoside) sphingolipodystrophy.</strong> New Eng. J. Med. 291: 929-931, 1974.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/4213132/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">4213132</a>] [<a href="https://doi.org/10.1056/NEJM197410312911802" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="4213132">Max et al. (1974)</a>. They studied an infant who had poor physical and motor development, coarse facies, macroglossia, gingival hypertrophy, squat hands and feet, flexor contractures of the fingers, thickened, loose, hirsute skin, bilateral large inguinal hernias, an enlarged liver and spleen, and normal fundi. Shortly after birth the patient became limp and unresponsive, dying at 3 and a half months of age. The accumulation of ganglioside GM3 (hematoside) was established by quantitative lipid analysis of fresh-frozen postmortem samples of brain and liver. Higher ganglioside homologs were completely absent. This unusual ganglioside pattern suggested that the defect in GM3 sphingolipodystrophy was in ganglioside biosynthesis, in contrast to previously described sphingolipidoses, which are due to deficiencies of catabolic enzymes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=4213132" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#10" class="mim-tip-reference" title="Saul, R. A., Wilkes, G., Stevenson, R. E. <strong>'Salt-and-pepper' pigmentary changes with severe mental retardation: a new neurocutaneous syndrome?</strong> Proc. Greenwood Genet. Center 2: 6-9, 1983."None>Saul et al. (1983)</a> reported 3 African American sibs with delayed psychomotor development from infancy, resulting in severe mental retardation associated with pigmentary skin changes that developed after age 2 years. The patients also had dysmorphic facial features, including midface hypoplasia and prognathism. Other features included microcephaly, choreoathetosis, hypertonicity, scoliosis, and nonspecific EKG changes. One patient had seizures. The pigmentary changes were described as 'salt and pepper' macules ranging from 1 to 5 mm in diameter on the trunk, extremities, and face. Histologic examination of a hyperpigmented lesion showed increased pigmentation consistent with a freckle. The patients were nonverbal and nonambulatory in their early teenage years.</p><p><a href="#6" class="mim-tip-reference" title="Farukhi, F., Dakkouri, C., Wang, H., Wiztnitzer, M., Traboulsi, E. I. <strong>Etiology of vision loss in ganglioside GM3 synthase deficiency.</strong> Ophthal. Genet. 27: 89-91, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17050284/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17050284</a>] [<a href="https://doi.org/10.1080/13816810600862626" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17050284">Farukhi et al. (2006)</a> reported detailed ophthalmologic studies of 4 Amish patients from 2 related sibships with GM3 synthase deficiency. The children were 13 months, 6 years, 6 years, and 13 years of age. All had normal slit-lamp examinations and preserved retinal function. However, all had pale optic nerves with atrophy. These findings suggested that visual loss in this disorder results from cortical visual impairment and optic nerve defects rather than retinal involvement. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17050284" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#7" class="mim-tip-reference" title="Fragaki, K., Ait-El-Mkadem, S., Chaussenot, A., Gire, C., Mengual, R., Bonesso, L., Beneteau, M., Ricci, J.-E., Desquiret-Dumas, V., Procaccio, V., Rotig, A., Paquis-Flucklinger, V. <strong>Refractory epilepsy and mitochondrial dysfunction due to GM3 synthase deficiency.</strong> Europ. J. Hum. Genet. 21: 528-534, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22990144/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22990144</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22990144[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/ejhg.2012.202" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22990144">Fragaki et al. (2013)</a> reported 2 sibs, born of consanguineous French parents, with infantile onset of severe refractory epilepsy with myoclonus and status epilepticus. Both had delayed psychomotor development and failure to thrive. Choreoathetoid movements appeared at around 15 months of age, and both showed further neurologic deterioration at 2 to 3 years of age. One developed hypotonic tetraparesis with visual impairment, and the other was deaf and blind with pallor of the optic nerve. Serum lactate was increased. Brain MRI showed white matter lesions and cortical atrophy, including in the occipital cortex, which indicated cortical blindness rather than retinal disease. Fibroblasts from 1 of the sibs showed decreased oxygen consumption, and liver biopsy showed decreased activity of quinone-dependent complexes I+III and II+III, consistent with a respiratory chain defect. Treatment with CoQ10 supplements resulted in transient subjective improvement in eye contact and interactivity, but the results were not sustained. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22990144" 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 38 Amish patients with GM3 synthase deficiency, who ranged in age from 0.5 to 25 years, <a href="#12" class="mim-tip-reference" title="Wang, H., Bright, A., Xin, B., Bockoven, J. R., Paller, A. S. <strong>Cutaneous dyspigmentation in patients with ganglioside GM3 synthase deficiency.</strong> Am. J. Med. Genet. 161A: 875-879, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23436467/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23436467</a>] [<a href="https://doi.org/10.1002/ajmg.a.35826" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23436467">Wang et al. (2013)</a> found that 20 patients had hyperpigmented macules that increased in number with age. The macules resembled large freckles or small lentigines, were between 2 and 5 mm in diameter, and were usually found bilaterally on the extremities, especially the dorsal aspects of the hands and feet. Occasional sites included the hips, face, chest wall, and back. No pigmentary lesions were seen on mucosal surfaces or nailbeds. Lesions were found in 86% of patients aged 6 years or older and in 93% of patients aged 11 years or older, but no lesions were found in children younger than 3 years of age. Seven of the 20 patients also had areas of depigmentation that had well-defined borders and showed variation in size and shape. In at least 3 cases, the parents reported that the hyperpigmentation, after being present for years, almost disappeared. The findings suggested that these cutaneous pigmentary changes may serve as useful clues to aid in the diagnosis of this metabolic disorder. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23436467" 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="#8" class="mim-tip-reference" title="Lee, J. S., Yoo, Y., Lim, B. C., Kim, K. J., Song, J., Choi, M., Chae, J.-H. <strong>GM3 synthase deficiency due to ST3GAL5 variants in two Korean female siblings: masquerading as Rett syndrome-like phenotype.</strong> Am. J. Med. Genet. 170A: 2200-2205, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27232954/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27232954</a>] [<a href="https://doi.org/10.1002/ajmg.a.37773" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27232954">Lee et al. (2016)</a> reported 2 Korean sisters, born of unrelated parents, with severe mental retardation associated with GM3 synthase deficiency. The proband presented with developmental regression at age 6 months after normal early development for the first 4 months of life. She was irritable and had jerky movements and nystagmus without seizures. Brain imaging was normal. At age 4 years, she could not sit, roll over, make eye contact, or speak. Her older sister, who was less severely affected, presented at age 2 years with global developmental delay and inability to walk. She had microcephaly, irritability, and choreoathetotic movements. She could eventually walk a few steps without assistance, but did not speak. Both patients developed hand stereotypies with a lack of purposeful hand movements suggestive of Rett syndrome (RTT; <a href="/entry/312750">312750</a>), but sequencing of Rett-associated genes showed no abnormalities. Both patients also had increased serum lactate. Neither patient had abnormalities of the optic nerve or clinical seizures; only the older patient showed pepper-like skin pigmentation on the hands and feet at age 6 years. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27232954" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#3" class="mim-tip-reference" title="Bowser, L. E., Young, M., Wenger, O. K., Ammous, Z., Brigatti, K. W., Carson, V. J., Moser, T., Deline, J., Aoki, K., Morlet, T., Scott, E. M., Puffenberger, E. G., Robinson, D. L., Hendrickson, C., Salvin, J., Gottlieb, S., Heaps, A. D., Tiemeyer, M., Strauss, K. A. <strong>Recessive GM3 synthase deficiency: natural history, biochemistry, and therapeutic frontier.</strong> Molec. Genet. Metab. 126: 475-488, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30691927/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30691927</a>] [<a href="https://doi.org/10.1016/j.ymgme.2019.01.013" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30691927">Bowser et al. (2019)</a> reported the natural history of GM3 synthase deficiency in 50 Amish patients. The median age of molecular diagnosis in 32 patients was 11.4 months, with a range of 1 day to 22 years (molecular testing was not done in the other 18 patients). Polyhydramnios was reported in 20% of pregnancies. In infancy, all patients had developmental delay, most had slow weight gain, and 50% had abnormal tone. Head growth decelerated shortly after birth, although brain MRIs were typically normal until later childhood. The majority of infants developed constipation, gastrointestinal reflux, and/or abnormal movements, including chorea, athetosis, dystonia, hyperkinesia, dyskinesia, and tremor. Scoliosis and pneumonia were described in some patients. <a href="#3" class="mim-tip-reference" title="Bowser, L. E., Young, M., Wenger, O. K., Ammous, Z., Brigatti, K. W., Carson, V. J., Moser, T., Deline, J., Aoki, K., Morlet, T., Scott, E. M., Puffenberger, E. G., Robinson, D. L., Hendrickson, C., Salvin, J., Gottlieb, S., Heaps, A. D., Tiemeyer, M., Strauss, K. A. <strong>Recessive GM3 synthase deficiency: natural history, biochemistry, and therapeutic frontier.</strong> Molec. Genet. Metab. 126: 475-488, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30691927/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30691927</a>] [<a href="https://doi.org/10.1016/j.ymgme.2019.01.013" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30691927">Bowser et al. (2019)</a> found that the majority of patients who had newborn hearing screens failed the screen, and that auditory brainstem responses typically had elevated thresholds but normal latency. Ninety percent of EEGs showed signs of epileptic encephalopathy, although the majority of electrographic seizures were clinically silent. Sleep problems were common and severe between 8 and 23 months of age. 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<p><a href="#3" class="mim-tip-reference" title="Bowser, L. E., Young, M., Wenger, O. K., Ammous, Z., Brigatti, K. W., Carson, V. J., Moser, T., Deline, J., Aoki, K., Morlet, T., Scott, E. M., Puffenberger, E. G., Robinson, D. L., Hendrickson, C., Salvin, J., Gottlieb, S., Heaps, A. D., Tiemeyer, M., Strauss, K. A. <strong>Recessive GM3 synthase deficiency: natural history, biochemistry, and therapeutic frontier.</strong> Molec. Genet. Metab. 126: 475-488, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30691927/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30691927</a>] [<a href="https://doi.org/10.1016/j.ymgme.2019.01.013" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30691927">Bowser et al. (2019)</a> performed glycosphingolipid analysis via nanospray ionization mass spectrometry on plasma from patients with GM3 deficiency, heterozygous carriers of GM3 deficiency, and normal controls. Relative to normal controls, GD3, GM3, and their downstream derivatives were undetectable, and unsialylated lactosylceramide was elevated 2-fold along with excess o-series gangliosides in patients. Relative to normal controls, heterozygous carriers of GM3 deficiency had normal GM3 and GD3 levels, but elevated glycosylceramide and lactosylceramide. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30691927" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>The transmission pattern of GM3 synthase deficiency in the family reported by <a href="#7" class="mim-tip-reference" title="Fragaki, K., Ait-El-Mkadem, S., Chaussenot, A., Gire, C., Mengual, R., Bonesso, L., Beneteau, M., Ricci, J.-E., Desquiret-Dumas, V., Procaccio, V., Rotig, A., Paquis-Flucklinger, V. <strong>Refractory epilepsy and mitochondrial dysfunction due to GM3 synthase deficiency.</strong> Europ. J. Hum. Genet. 21: 528-534, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22990144/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22990144</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22990144[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/ejhg.2012.202" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22990144">Fragaki et al. (2013)</a> was consistent with autosomal recessive inheritance. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22990144" 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>Based on a review of antiepileptic medications prescribed in 29 Amish patients with GM3 deficiency, <a href="#3" class="mim-tip-reference" title="Bowser, L. E., Young, M., Wenger, O. K., Ammous, Z., Brigatti, K. W., Carson, V. J., Moser, T., Deline, J., Aoki, K., Morlet, T., Scott, E. M., Puffenberger, E. G., Robinson, D. L., Hendrickson, C., Salvin, J., Gottlieb, S., Heaps, A. D., Tiemeyer, M., Strauss, K. A. <strong>Recessive GM3 synthase deficiency: natural history, biochemistry, and therapeutic frontier.</strong> Molec. Genet. Metab. 126: 475-488, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30691927/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30691927</a>] [<a href="https://doi.org/10.1016/j.ymgme.2019.01.013" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30691927">Bowser et al. (2019)</a> found that half of patients were treated with a single medication, whereas the remainder were prescribed 2 to 3 medications. Most commonly prescribed antiseizure medications were benzodiazepines, phenobarbital, and valproic acid. Most parents reported that antiseizure medications had some effect on insomnia, irritability, and seizures. <a href="#3" class="mim-tip-reference" title="Bowser, L. E., Young, M., Wenger, O. K., Ammous, Z., Brigatti, K. W., Carson, V. J., Moser, T., Deline, J., Aoki, K., Morlet, T., Scott, E. M., Puffenberger, E. G., Robinson, D. L., Hendrickson, C., Salvin, J., Gottlieb, S., Heaps, A. D., Tiemeyer, M., Strauss, K. A. <strong>Recessive GM3 synthase deficiency: natural history, biochemistry, and therapeutic frontier.</strong> Molec. Genet. Metab. 126: 475-488, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30691927/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30691927</a>] [<a href="https://doi.org/10.1016/j.ymgme.2019.01.013" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30691927">Bowser et al. (2019)</a> also reported that oral administration of enteral buttermilk extract, which is mildly enriched in gangliosides, had no effect on plasma levels of GM3 or GD3 gangliosides, although neutral glycosphingolipids decreased to levels similar to controls. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30691927" 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>By homozygosity mapping in an Amish family segregating an infantile-onset epilepsy syndrome, <a href="#11" class="mim-tip-reference" title="Simpson, M. A., Cross, H., Proukakis, C., Priestman, D. A., Neville, D. C. A., Reinkensmeier, G., Wang, H., Wiznitzer, M., Gurtz, K., Verganelaki, A., Pryde, A., Patton, M. A., Dwek, R. A., Butters, T. D., Platt, F. M., Crosby, A. H. <strong>Infantile-onset symptomatic epilepsy syndrome caused by a homozygous loss-of-function mutation of GM3 synthase.</strong> Nature Genet. 36: 1225-1229, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15502825/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15502825</a>] [<a href="https://doi.org/10.1038/ng1460" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15502825">Simpson et al. (2004)</a> demonstrated linkage to a 5.1-cM region on 2p12-p11.2, with a maximum multipoint lod score of 6.84 around marker D2S2162. None of the unaffected sibs or parents were homozygous across this interval. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15502825" 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>By sequencing several genes in the region of linkage on 2p12-p11.2 identified in an Amish family segregating an infantile-onset epilepsy syndrome, <a href="#11" class="mim-tip-reference" title="Simpson, M. A., Cross, H., Proukakis, C., Priestman, D. A., Neville, D. C. A., Reinkensmeier, G., Wang, H., Wiznitzer, M., Gurtz, K., Verganelaki, A., Pryde, A., Patton, M. A., Dwek, R. A., Butters, T. D., Platt, F. M., Crosby, A. H. <strong>Infantile-onset symptomatic epilepsy syndrome caused by a homozygous loss-of-function mutation of GM3 synthase.</strong> Nature Genet. 36: 1225-1229, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15502825/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15502825</a>] [<a href="https://doi.org/10.1038/ng1460" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15502825">Simpson et al. (2004)</a> identified a nonsense mutation in the SIAT9 gene (<a href="/entry/604402#0001">604402.0001</a>), whose product functions as a GM3 synthase. The affected children completely lacked GM3 and its downstream biosynthetic derivatives but had increased levels of the immediate precursor to GM3, lactosylceramide. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15502825" 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 2 sibs, born of consanguineous French parents, with refractory epilepsy and delayed psychomotor development, <a href="#7" class="mim-tip-reference" title="Fragaki, K., Ait-El-Mkadem, S., Chaussenot, A., Gire, C., Mengual, R., Bonesso, L., Beneteau, M., Ricci, J.-E., Desquiret-Dumas, V., Procaccio, V., Rotig, A., Paquis-Flucklinger, V. <strong>Refractory epilepsy and mitochondrial dysfunction due to GM3 synthase deficiency.</strong> Europ. J. Hum. Genet. 21: 528-534, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22990144/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22990144</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22990144[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/ejhg.2012.202" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22990144">Fragaki et al. (2013)</a> identified a homozygous R288X mutation in the SIAT9 gene, which was the same mutation identified by <a href="#11" class="mim-tip-reference" title="Simpson, M. A., Cross, H., Proukakis, C., Priestman, D. A., Neville, D. C. A., Reinkensmeier, G., Wang, H., Wiznitzer, M., Gurtz, K., Verganelaki, A., Pryde, A., Patton, M. A., Dwek, R. A., Butters, T. D., Platt, F. M., Crosby, A. H. <strong>Infantile-onset symptomatic epilepsy syndrome caused by a homozygous loss-of-function mutation of GM3 synthase.</strong> Nature Genet. 36: 1225-1229, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15502825/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15502825</a>] [<a href="https://doi.org/10.1038/ng1460" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15502825">Simpson et al. (2004)</a> in Amish patients with a similar disorder. The mutation, which was identified by exome sequencing, segregated with the disorder in the family. Mass spectrometry analysis of patient fibroblasts showed complete absence of GM3 ganglioside and its biosynthetic derivatives and an upregulation of the alternative globoside pathway. Fibroblasts also showed a decrease in mitochondrial membrane potential, consistent with secondary dysfunction of the respiratory chain, as well as increased apoptosis. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=15502825+22990144" 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 2 sibs originally reported by <a href="#10" class="mim-tip-reference" title="Saul, R. A., Wilkes, G., Stevenson, R. E. <strong>'Salt-and-pepper' pigmentary changes with severe mental retardation: a new neurocutaneous syndrome?</strong> Proc. Greenwood Genet. Center 2: 6-9, 1983."None>Saul et al. (1983)</a> as having 'salt and pepper' mental retardation syndrome, <a href="#2" class="mim-tip-reference" title="Boccuto, L., Aoki, K., Flanagan-Steet, H., Chen, C.-F., Fan, X., Bartel, F., Petukh, M., Pittman, A., Saul, R., Chaubey, A., Alexov, E., Tiemeyer, M., Steet, R., Schwartz, C. E. <strong>A mutation in a ganglioside biosynthetic enzyme, ST3GAL5, results in salt & pepper syndrome, a neurocutaneous disorder with altered glycolipid and glycoprotein glycosylation.</strong> Hum. Molec. Genet. 23: 418-433, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24026681/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24026681</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=24026681[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1093/hmg/ddt434" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24026681">Boccuto et al. (2014)</a> identified a homozygous missense mutation in the ST3GAL5 gene (E332K; <a href="/entry/604402#0002">604402.0002</a>). The mutation was found by whole-exome sequencing. Patient fibroblasts showed no GM2 or GM3, consistent with a loss of ST3GAL5 function. Analysis of the glycolipid profile in patient cells and plasma showed a shift toward ceramides with longer fatty acid chain length. Microarray analysis of glycosyltransferase mRNAs detected modestly increased expression of ST3GAL5 and greater changes in transcripts encoding enzymes that lie downstream of ST3GAL5 and in other glycosphingolipid biosynthetic pathways. Comprehensive glycomic analysis of N-linked, O-linked, and glycosphingolipid glycans revealed collateral modulation of glycoprotein sialylation in response to the loss of complex gangliosides. Morpholino knockdown of st3gal5 in zebrafish embryos caused increased neuronal cell death that could be rescued by expression of the wildtype gene. The findings indicated that human neural cells are extremely sensitive to ST3GAL5 deficiency and altered glycosphingolipid synthesis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24026681" 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 2 Korean sisters with salt and pepper developmental regression syndrome, <a href="#8" class="mim-tip-reference" title="Lee, J. S., Yoo, Y., Lim, B. C., Kim, K. J., Song, J., Choi, M., Chae, J.-H. <strong>GM3 synthase deficiency due to ST3GAL5 variants in two Korean female siblings: masquerading as Rett syndrome-like phenotype.</strong> Am. J. Med. Genet. 170A: 2200-2205, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27232954/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27232954</a>] [<a href="https://doi.org/10.1002/ajmg.a.37773" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27232954">Lee et al. (2016)</a> identified compound heterozygous missense mutations in the ST3GAL5 gene (C195S; <a href="/entry/604402#0003">604402.0003</a> and G201R; <a href="/entry/604402#0004">604402.0004</a>). The mutations, which were found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Plasma gangliosides in the 2 sibs were barely detectable, suggesting a loss of function. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27232954" 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>Purists insist that this disorder should be called a symptomatic epilepsy syndrome since epilepsy is only a manifestation of the underlying defect in GM3 synthesis (<a href="#4" class="mim-tip-reference" title="Crosby, A. H. <strong>Personal Communication.</strong> London, England 11/14/2004."None>Crosby, 2004</a>).</p>
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<p><a href="#1" class="mim-tip-reference" title="Bharathi, S. S., Zhang, B. B., Paul, E., Zhang, Y., Schmidt, A. V., Fowler, B., Wu, Y., Tiemeyer, M., Inamori, K. I., Inokuchi, J. I., Goetzman, E. S. <strong>GM3 synthase deficiency increases brain glucose metabolism in mice.</strong> Molec. Genet. Metab. 137: 342-348, 2022.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/36335793/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">36335793</a>] [<a href="https://doi.org/10.1016/j.ymgme.2022.10.006" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="36335793">Bharathi et al. (2022)</a> demonstrated that, compared to wildtype mice, Gm3 synthase knockout mice (Gm3s -/-) had increased whole-body energy expenditure as evidenced by increased oxygen consumption and carbon dioxide production and a higher respiratory exchange rate, indicative of increased reliance on glucose for energy. PET scanning also demonstrated that the Gm3s -/- mice had greater brain glucose uptake compared to wildtype mice after short fasting. Complex I respiration and ADP-stimulated state 3 mitochondrial respiration was increased in brain homogenates from Gm3s -/- mice, which was attributed to increased expression of pyruvate dehydrogenase deficiency. Inhibition of glycolysis resulted in a decrease in kainate-induced seizures in the mutant mice. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=36335793" 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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Bharathi, S. S., Zhang, B. B., Paul, E., Zhang, Y., Schmidt, A. V., Fowler, B., Wu, Y., Tiemeyer, M., Inamori, K. I., Inokuchi, J. I., Goetzman, E. S.
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<strong>GM3 synthase deficiency increases brain glucose metabolism in mice.</strong>
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Molec. Genet. Metab. 137: 342-348, 2022.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/36335793/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">36335793</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=36335793" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1016/j.ymgme.2022.10.006" target="_blank">Full Text</a>]
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Boccuto, L., Aoki, K., Flanagan-Steet, H., Chen, C.-F., Fan, X., Bartel, F., Petukh, M., Pittman, A., Saul, R., Chaubey, A., Alexov, E., Tiemeyer, M., Steet, R., Schwartz, C. E.
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<strong>A mutation in a ganglioside biosynthetic enzyme, ST3GAL5, results in salt & pepper syndrome, a neurocutaneous disorder with altered glycolipid and glycoprotein glycosylation.</strong>
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Hum. Molec. Genet. 23: 418-433, 2014.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24026681/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24026681</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=24026681[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24026681" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1093/hmg/ddt434" target="_blank">Full Text</a>]
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<a id="Bowser2019" class="mim-anchor"></a>
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Bowser, L. E., Young, M., Wenger, O. K., Ammous, Z., Brigatti, K. W., Carson, V. J., Moser, T., Deline, J., Aoki, K., Morlet, T., Scott, E. M., Puffenberger, E. G., Robinson, D. L., Hendrickson, C., Salvin, J., Gottlieb, S., Heaps, A. D., Tiemeyer, M., Strauss, K. A.
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<strong>Recessive GM3 synthase deficiency: natural history, biochemistry, and therapeutic frontier.</strong>
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Molec. Genet. Metab. 126: 475-488, 2019.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30691927/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30691927</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30691927" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1016/j.ymgme.2019.01.013" target="_blank">Full Text</a>]
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Crosby, A. H.
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<strong>Personal Communication.</strong>
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London, England 11/14/2004.
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Cross, H. E.
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<strong>Personal Communication.</strong>
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Tuscon, AZ 11/14/2004.
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Farukhi, F., Dakkouri, C., Wang, H., Wiztnitzer, M., Traboulsi, E. I.
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<strong>Etiology of vision loss in ganglioside GM3 synthase deficiency.</strong>
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Ophthal. Genet. 27: 89-91, 2006.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17050284/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17050284</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17050284" 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/10.1080/13816810600862626" target="_blank">Full Text</a>]
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<a id="Fragaki2013" class="mim-anchor"></a>
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Fragaki, K., Ait-El-Mkadem, S., Chaussenot, A., Gire, C., Mengual, R., Bonesso, L., Beneteau, M., Ricci, J.-E., Desquiret-Dumas, V., Procaccio, V., Rotig, A., Paquis-Flucklinger, V.
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<strong>Refractory epilepsy and mitochondrial dysfunction due to GM3 synthase deficiency.</strong>
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Europ. J. Hum. Genet. 21: 528-534, 2013.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22990144/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22990144</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22990144[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22990144" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1038/ejhg.2012.202" target="_blank">Full Text</a>]
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<a id="Lee2016" class="mim-anchor"></a>
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Lee, J. S., Yoo, Y., Lim, B. C., Kim, K. J., Song, J., Choi, M., Chae, J.-H.
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<strong>GM3 synthase deficiency due to ST3GAL5 variants in two Korean female siblings: masquerading as Rett syndrome-like phenotype.</strong>
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Am. J. Med. Genet. 170A: 2200-2205, 2016.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27232954/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27232954</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27232954" 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.37773" target="_blank">Full Text</a>]
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<a id="Max1974" class="mim-anchor"></a>
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Max, S. R., Maclaren, N. K., Brady, R. O., Bradley, R. M., Rennels, M. B., Tanaka, J., Garcia, J. H., Cornblath, M.
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<strong>GM3 (Hematoside) sphingolipodystrophy.</strong>
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New Eng. J. Med. 291: 929-931, 1974.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/4213132/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">4213132</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=4213132" 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/NEJM197410312911802" target="_blank">Full Text</a>]
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Saul, R. A., Wilkes, G., Stevenson, R. E.
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<strong>'Salt-and-pepper' pigmentary changes with severe mental retardation: a new neurocutaneous syndrome?</strong>
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Proc. Greenwood Genet. Center 2: 6-9, 1983.
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<a id="Simpson2004" class="mim-anchor"></a>
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Simpson, M. A., Cross, H., Proukakis, C., Priestman, D. A., Neville, D. C. A., Reinkensmeier, G., Wang, H., Wiznitzer, M., Gurtz, K., Verganelaki, A., Pryde, A., Patton, M. A., Dwek, R. A., Butters, T. D., Platt, F. M., Crosby, A. H.
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<strong>Infantile-onset symptomatic epilepsy syndrome caused by a homozygous loss-of-function mutation of GM3 synthase.</strong>
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Nature Genet. 36: 1225-1229, 2004.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15502825/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15502825</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15502825" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1038/ng1460" target="_blank">Full Text</a>]
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<a id="Wang2013" class="mim-anchor"></a>
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Wang, H., Bright, A., Xin, B., Bockoven, J. R., Paller, A. S.
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<strong>Cutaneous dyspigmentation in patients with ganglioside GM3 synthase deficiency.</strong>
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Am. J. Med. Genet. 161A: 875-879, 2013.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23436467/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23436467</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23436467" 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.35826" target="_blank">Full Text</a>]
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Hilary J. Vernon - updated : 02/10/2023
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Hilary J. Vernon - updated : 05/15/2020<br>Cassandra L. Kniffin - updated : 09/12/2016<br>Cassandra L. Kniffin - updated : 7/15/2014<br>Cassandra L. Kniffin - updated : 5/20/2013<br>Cassandra L. Kniffin - updated : 5/13/2013<br>Victor A. McKusick - updated : 12/20/2004
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Victor A. McKusick : 11/30/2004
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carol : 02/10/2023
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carol : 05/15/2020<br>carol : 06/07/2017<br>carol : 09/19/2016<br>carol : 09/19/2016<br>carol : 09/16/2016<br>ckniffin : 09/12/2016<br>alopez : 07/21/2014<br>mcolton : 7/16/2014<br>ckniffin : 7/15/2014<br>carol : 5/22/2013<br>ckniffin : 5/20/2013<br>carol : 5/20/2013<br>ckniffin : 5/13/2013<br>alopez : 9/16/2009<br>tkritzer : 1/6/2005<br>terry : 12/20/2004<br>alopez : 11/30/2004
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<strong>#</strong> 609056
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SALT AND PEPPER DEVELOPMENTAL REGRESSION SYNDROME; SPDRS
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AMISH INFANTILE EPILEPSY SYNDROME<br />
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EPILEPSY SYNDROME, INFANTILE-ONSET SYMPTOMATIC<br />
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GM3 SYNTHASE DEFICIENCY<br />
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SALT AND PEPPER MENTAL RETARDATION SYNDROME
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<strong>SNOMEDCT:</strong> 722762005;
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<strong>ORPHA:</strong> 370933;
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<strong>DO:</strong> 0060470;
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<strong>Phenotype-Gene Relationships</strong>
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Phenotype
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Phenotype <br /> MIM number
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Inheritance
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Phenotype <br /> mapping key
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2p11.2
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Salt and pepper developmental regression syndrome
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609056
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Autosomal recessive
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3
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SIAT9
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604402
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<p>A number sign (#) is used with this entry because of evidence that salt and pepper developmental regression syndrome (SPDRS) is caused by homozygous or compound heterozygous mutation in the ST3GAL5 gene (604402), which encodes sialyltransferase-9 (SIAT9), also known as GM3 synthase, on chromosome 2p11.</p>
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<strong>Description</strong>
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<p>Salt and pepper developmental regression syndrome, also known as Amish infantile epilepsy syndrome, is an autosomal recessive neurocutaneous disorder characterized by infantile onset of refractory and recurrent seizures associated with profoundly delayed psychomotor development and/or developmental regression as well as abnormal movements and visual loss (summary by Fragaki et al., 2013). Affected individuals develop hypo- or hyperpigmented skin macules on the trunk, face, and extremities in early childhood (summary by Boccuto et al., 2014). Not all patients have overt seizures (Lee et al., 2016). </p>
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<strong>Clinical Features</strong>
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<p>Simpson et al. (2004) described an autosomal recessive infantile-onset epilepsy syndrome associated with developmental stagnation and blindness in the Old Order Amish of Geauga County, Ohio. All surviving members of the 2 branches of the single large family could be traced back to a fifth-generation common ancestor. All affected children were born at full term. The first symptoms were noted between the ages of 2 weeks and 3 months, and consisted primarily of irritability with additional poor feeding, vomiting, and failure to thrive. Gastrostomy feeding tubes were required in 2 of the 4 affected children in family A and in all affected children in family B. Seizure activity started during the first year of life, with all affected children suffering from generalized tonic-clonic (grand mal) seizures, as well as other seizure types. In at least one case, startle myoclonus was observed before generalized tonic-clonic seizures. Seizure control was difficult, requiring multiple medications and, for 2 children in 1 family, vagus nerve stimulators. Although the generalized seizures were eventually largely controlled, other seizure types, including brief tonic spasms, episodes of eye deviation, or startle from sleep, were not fully suppressed. The onset of seizure activity was accompanied by profound developmental stagnation, with evidence of regression. Affected children were unable to sit unsupported, reach, or walk, and were nonverbal. Nonpurposeful arm movements had a choreoathetoid component. Eye contact and visual function deteriorated, probably owing to cortical impairment, although there was some evidence of optic atrophy. Electroencephalograms ultimately showed multifocal epileptiform discharges superimposed on diffuse slow background activity. Brain MRI initially showed no structural abnormalities, but studies at older ages showed diffuse atrophy. </p><p>The 2 sibships with this disorder reported by Simpson et al. (2004), related as double fifth cousins, contained a total of 9 affected individuals. Only 1 had died (aged 27 months). Four of the other individuals had survived into their teens, the oldest being aged 18, thanks to excellent home care which included gastric tube feeding (Cross, 2004). </p><p>The same disorder may have been described by Max et al. (1974). They studied an infant who had poor physical and motor development, coarse facies, macroglossia, gingival hypertrophy, squat hands and feet, flexor contractures of the fingers, thickened, loose, hirsute skin, bilateral large inguinal hernias, an enlarged liver and spleen, and normal fundi. Shortly after birth the patient became limp and unresponsive, dying at 3 and a half months of age. The accumulation of ganglioside GM3 (hematoside) was established by quantitative lipid analysis of fresh-frozen postmortem samples of brain and liver. Higher ganglioside homologs were completely absent. This unusual ganglioside pattern suggested that the defect in GM3 sphingolipodystrophy was in ganglioside biosynthesis, in contrast to previously described sphingolipidoses, which are due to deficiencies of catabolic enzymes. </p><p>Saul et al. (1983) reported 3 African American sibs with delayed psychomotor development from infancy, resulting in severe mental retardation associated with pigmentary skin changes that developed after age 2 years. The patients also had dysmorphic facial features, including midface hypoplasia and prognathism. Other features included microcephaly, choreoathetosis, hypertonicity, scoliosis, and nonspecific EKG changes. One patient had seizures. The pigmentary changes were described as 'salt and pepper' macules ranging from 1 to 5 mm in diameter on the trunk, extremities, and face. Histologic examination of a hyperpigmented lesion showed increased pigmentation consistent with a freckle. The patients were nonverbal and nonambulatory in their early teenage years.</p><p>Farukhi et al. (2006) reported detailed ophthalmologic studies of 4 Amish patients from 2 related sibships with GM3 synthase deficiency. The children were 13 months, 6 years, 6 years, and 13 years of age. All had normal slit-lamp examinations and preserved retinal function. However, all had pale optic nerves with atrophy. These findings suggested that visual loss in this disorder results from cortical visual impairment and optic nerve defects rather than retinal involvement. </p><p>Fragaki et al. (2013) reported 2 sibs, born of consanguineous French parents, with infantile onset of severe refractory epilepsy with myoclonus and status epilepticus. Both had delayed psychomotor development and failure to thrive. Choreoathetoid movements appeared at around 15 months of age, and both showed further neurologic deterioration at 2 to 3 years of age. One developed hypotonic tetraparesis with visual impairment, and the other was deaf and blind with pallor of the optic nerve. Serum lactate was increased. Brain MRI showed white matter lesions and cortical atrophy, including in the occipital cortex, which indicated cortical blindness rather than retinal disease. Fibroblasts from 1 of the sibs showed decreased oxygen consumption, and liver biopsy showed decreased activity of quinone-dependent complexes I+III and II+III, consistent with a respiratory chain defect. Treatment with CoQ10 supplements resulted in transient subjective improvement in eye contact and interactivity, but the results were not sustained. </p><p>In a study of 38 Amish patients with GM3 synthase deficiency, who ranged in age from 0.5 to 25 years, Wang et al. (2013) found that 20 patients had hyperpigmented macules that increased in number with age. The macules resembled large freckles or small lentigines, were between 2 and 5 mm in diameter, and were usually found bilaterally on the extremities, especially the dorsal aspects of the hands and feet. Occasional sites included the hips, face, chest wall, and back. No pigmentary lesions were seen on mucosal surfaces or nailbeds. Lesions were found in 86% of patients aged 6 years or older and in 93% of patients aged 11 years or older, but no lesions were found in children younger than 3 years of age. Seven of the 20 patients also had areas of depigmentation that had well-defined borders and showed variation in size and shape. In at least 3 cases, the parents reported that the hyperpigmentation, after being present for years, almost disappeared. The findings suggested that these cutaneous pigmentary changes may serve as useful clues to aid in the diagnosis of this metabolic disorder. </p><p>Lee et al. (2016) reported 2 Korean sisters, born of unrelated parents, with severe mental retardation associated with GM3 synthase deficiency. The proband presented with developmental regression at age 6 months after normal early development for the first 4 months of life. She was irritable and had jerky movements and nystagmus without seizures. Brain imaging was normal. At age 4 years, she could not sit, roll over, make eye contact, or speak. Her older sister, who was less severely affected, presented at age 2 years with global developmental delay and inability to walk. She had microcephaly, irritability, and choreoathetotic movements. She could eventually walk a few steps without assistance, but did not speak. Both patients developed hand stereotypies with a lack of purposeful hand movements suggestive of Rett syndrome (RTT; 312750), but sequencing of Rett-associated genes showed no abnormalities. Both patients also had increased serum lactate. Neither patient had abnormalities of the optic nerve or clinical seizures; only the older patient showed pepper-like skin pigmentation on the hands and feet at age 6 years. </p><p>Bowser et al. (2019) reported the natural history of GM3 synthase deficiency in 50 Amish patients. The median age of molecular diagnosis in 32 patients was 11.4 months, with a range of 1 day to 22 years (molecular testing was not done in the other 18 patients). Polyhydramnios was reported in 20% of pregnancies. In infancy, all patients had developmental delay, most had slow weight gain, and 50% had abnormal tone. Head growth decelerated shortly after birth, although brain MRIs were typically normal until later childhood. The majority of infants developed constipation, gastrointestinal reflux, and/or abnormal movements, including chorea, athetosis, dystonia, hyperkinesia, dyskinesia, and tremor. Scoliosis and pneumonia were described in some patients. Bowser et al. (2019) found that the majority of patients who had newborn hearing screens failed the screen, and that auditory brainstem responses typically had elevated thresholds but normal latency. Ninety percent of EEGs showed signs of epileptic encephalopathy, although the majority of electrographic seizures were clinically silent. Sleep problems were common and severe between 8 and 23 months of age. Irritability was also common. </p>
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<strong>Biochemical Features</strong>
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<p>Bowser et al. (2019) performed glycosphingolipid analysis via nanospray ionization mass spectrometry on plasma from patients with GM3 deficiency, heterozygous carriers of GM3 deficiency, and normal controls. Relative to normal controls, GD3, GM3, and their downstream derivatives were undetectable, and unsialylated lactosylceramide was elevated 2-fold along with excess o-series gangliosides in patients. Relative to normal controls, heterozygous carriers of GM3 deficiency had normal GM3 and GD3 levels, but elevated glycosylceramide and lactosylceramide. </p>
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<p>The transmission pattern of GM3 synthase deficiency in the family reported by Fragaki et al. (2013) was consistent with autosomal recessive inheritance. </p>
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<p>Based on a review of antiepileptic medications prescribed in 29 Amish patients with GM3 deficiency, Bowser et al. (2019) found that half of patients were treated with a single medication, whereas the remainder were prescribed 2 to 3 medications. Most commonly prescribed antiseizure medications were benzodiazepines, phenobarbital, and valproic acid. Most parents reported that antiseizure medications had some effect on insomnia, irritability, and seizures. Bowser et al. (2019) also reported that oral administration of enteral buttermilk extract, which is mildly enriched in gangliosides, had no effect on plasma levels of GM3 or GD3 gangliosides, although neutral glycosphingolipids decreased to levels similar to controls. </p>
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<p>By homozygosity mapping in an Amish family segregating an infantile-onset epilepsy syndrome, Simpson et al. (2004) demonstrated linkage to a 5.1-cM region on 2p12-p11.2, with a maximum multipoint lod score of 6.84 around marker D2S2162. None of the unaffected sibs or parents were homozygous across this interval. </p>
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<p>By sequencing several genes in the region of linkage on 2p12-p11.2 identified in an Amish family segregating an infantile-onset epilepsy syndrome, Simpson et al. (2004) identified a nonsense mutation in the SIAT9 gene (604402.0001), whose product functions as a GM3 synthase. The affected children completely lacked GM3 and its downstream biosynthetic derivatives but had increased levels of the immediate precursor to GM3, lactosylceramide. </p><p>In 2 sibs, born of consanguineous French parents, with refractory epilepsy and delayed psychomotor development, Fragaki et al. (2013) identified a homozygous R288X mutation in the SIAT9 gene, which was the same mutation identified by Simpson et al. (2004) in Amish patients with a similar disorder. The mutation, which was identified by exome sequencing, segregated with the disorder in the family. Mass spectrometry analysis of patient fibroblasts showed complete absence of GM3 ganglioside and its biosynthetic derivatives and an upregulation of the alternative globoside pathway. Fibroblasts also showed a decrease in mitochondrial membrane potential, consistent with secondary dysfunction of the respiratory chain, as well as increased apoptosis. </p><p>In 2 sibs originally reported by Saul et al. (1983) as having 'salt and pepper' mental retardation syndrome, Boccuto et al. (2014) identified a homozygous missense mutation in the ST3GAL5 gene (E332K; 604402.0002). The mutation was found by whole-exome sequencing. Patient fibroblasts showed no GM2 or GM3, consistent with a loss of ST3GAL5 function. Analysis of the glycolipid profile in patient cells and plasma showed a shift toward ceramides with longer fatty acid chain length. Microarray analysis of glycosyltransferase mRNAs detected modestly increased expression of ST3GAL5 and greater changes in transcripts encoding enzymes that lie downstream of ST3GAL5 and in other glycosphingolipid biosynthetic pathways. Comprehensive glycomic analysis of N-linked, O-linked, and glycosphingolipid glycans revealed collateral modulation of glycoprotein sialylation in response to the loss of complex gangliosides. Morpholino knockdown of st3gal5 in zebrafish embryos caused increased neuronal cell death that could be rescued by expression of the wildtype gene. The findings indicated that human neural cells are extremely sensitive to ST3GAL5 deficiency and altered glycosphingolipid synthesis. </p><p>In 2 Korean sisters with salt and pepper developmental regression syndrome, Lee et al. (2016) identified compound heterozygous missense mutations in the ST3GAL5 gene (C195S; 604402.0003 and G201R; 604402.0004). The mutations, which were found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Plasma gangliosides in the 2 sibs were barely detectable, suggesting a loss of function. </p>
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<strong>Nomenclature</strong>
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<p>Purists insist that this disorder should be called a symptomatic epilepsy syndrome since epilepsy is only a manifestation of the underlying defect in GM3 synthesis (Crosby, 2004).</p>
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<strong>Animal Model</strong>
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<p>Bharathi et al. (2022) demonstrated that, compared to wildtype mice, Gm3 synthase knockout mice (Gm3s -/-) had increased whole-body energy expenditure as evidenced by increased oxygen consumption and carbon dioxide production and a higher respiratory exchange rate, indicative of increased reliance on glucose for energy. PET scanning also demonstrated that the Gm3s -/- mice had greater brain glucose uptake compared to wildtype mice after short fasting. Complex I respiration and ADP-stimulated state 3 mitochondrial respiration was increased in brain homogenates from Gm3s -/- mice, which was attributed to increased expression of pyruvate dehydrogenase deficiency. Inhibition of glycolysis resulted in a decrease in kainate-induced seizures in the mutant mice. </p>
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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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<p class="mim-text-font">
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Bharathi, S. S., Zhang, B. B., Paul, E., Zhang, Y., Schmidt, A. V., Fowler, B., Wu, Y., Tiemeyer, M., Inamori, K. I., Inokuchi, J. I., Goetzman, E. S.
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<strong>GM3 synthase deficiency increases brain glucose metabolism in mice.</strong>
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Molec. Genet. Metab. 137: 342-348, 2022.
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[PubMed: 36335793]
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[Full Text: https://doi.org/10.1016/j.ymgme.2022.10.006]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Boccuto, L., Aoki, K., Flanagan-Steet, H., Chen, C.-F., Fan, X., Bartel, F., Petukh, M., Pittman, A., Saul, R., Chaubey, A., Alexov, E., Tiemeyer, M., Steet, R., Schwartz, C. E.
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<strong>A mutation in a ganglioside biosynthetic enzyme, ST3GAL5, results in salt & pepper syndrome, a neurocutaneous disorder with altered glycolipid and glycoprotein glycosylation.</strong>
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Hum. Molec. Genet. 23: 418-433, 2014.
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[PubMed: 24026681]
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[Full Text: https://doi.org/10.1093/hmg/ddt434]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Bowser, L. E., Young, M., Wenger, O. K., Ammous, Z., Brigatti, K. W., Carson, V. J., Moser, T., Deline, J., Aoki, K., Morlet, T., Scott, E. M., Puffenberger, E. G., Robinson, D. L., Hendrickson, C., Salvin, J., Gottlieb, S., Heaps, A. D., Tiemeyer, M., Strauss, K. A.
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<strong>Recessive GM3 synthase deficiency: natural history, biochemistry, and therapeutic frontier.</strong>
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Molec. Genet. Metab. 126: 475-488, 2019.
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[PubMed: 30691927]
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[Full Text: https://doi.org/10.1016/j.ymgme.2019.01.013]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Crosby, A. H.
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<strong>Personal Communication.</strong>
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London, England 11/14/2004.
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Cross, H. E.
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<strong>Personal Communication.</strong>
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Tuscon, AZ 11/14/2004.
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Farukhi, F., Dakkouri, C., Wang, H., Wiztnitzer, M., Traboulsi, E. I.
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<strong>Etiology of vision loss in ganglioside GM3 synthase deficiency.</strong>
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Ophthal. Genet. 27: 89-91, 2006.
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[PubMed: 17050284]
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[Full Text: https://doi.org/10.1080/13816810600862626]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Fragaki, K., Ait-El-Mkadem, S., Chaussenot, A., Gire, C., Mengual, R., Bonesso, L., Beneteau, M., Ricci, J.-E., Desquiret-Dumas, V., Procaccio, V., Rotig, A., Paquis-Flucklinger, V.
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<strong>Refractory epilepsy and mitochondrial dysfunction due to GM3 synthase deficiency.</strong>
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Europ. J. Hum. Genet. 21: 528-534, 2013.
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[PubMed: 22990144]
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[Full Text: https://doi.org/10.1038/ejhg.2012.202]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Lee, J. S., Yoo, Y., Lim, B. C., Kim, K. J., Song, J., Choi, M., Chae, J.-H.
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<strong>GM3 synthase deficiency due to ST3GAL5 variants in two Korean female siblings: masquerading as Rett syndrome-like phenotype.</strong>
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Am. J. Med. Genet. 170A: 2200-2205, 2016.
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[PubMed: 27232954]
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[Full Text: https://doi.org/10.1002/ajmg.a.37773]
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Max, S. R., Maclaren, N. K., Brady, R. O., Bradley, R. M., Rennels, M. B., Tanaka, J., Garcia, J. H., Cornblath, M.
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<strong>GM3 (Hematoside) sphingolipodystrophy.</strong>
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New Eng. J. Med. 291: 929-931, 1974.
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[PubMed: 4213132]
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[Full Text: https://doi.org/10.1056/NEJM197410312911802]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Saul, R. A., Wilkes, G., Stevenson, R. E.
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<strong>'Salt-and-pepper' pigmentary changes with severe mental retardation: a new neurocutaneous syndrome?</strong>
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Proc. Greenwood Genet. Center 2: 6-9, 1983.
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Simpson, M. A., Cross, H., Proukakis, C., Priestman, D. A., Neville, D. C. A., Reinkensmeier, G., Wang, H., Wiznitzer, M., Gurtz, K., Verganelaki, A., Pryde, A., Patton, M. A., Dwek, R. A., Butters, T. D., Platt, F. M., Crosby, A. H.
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<strong>Infantile-onset symptomatic epilepsy syndrome caused by a homozygous loss-of-function mutation of GM3 synthase.</strong>
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Nature Genet. 36: 1225-1229, 2004.
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[PubMed: 15502825]
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[Full Text: https://doi.org/10.1038/ng1460]
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<p class="mim-text-font">
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Wang, H., Bright, A., Xin, B., Bockoven, J. R., Paller, A. S.
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<strong>Cutaneous dyspigmentation in patients with ganglioside GM3 synthase deficiency.</strong>
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Am. J. Med. Genet. 161A: 875-879, 2013.
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[PubMed: 23436467]
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[Full Text: https://doi.org/10.1002/ajmg.a.35826]
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Hilary J. Vernon - updated : 02/10/2023<br>Hilary J. Vernon - updated : 05/15/2020<br>Cassandra L. Kniffin - updated : 09/12/2016<br>Cassandra L. Kniffin - updated : 7/15/2014<br>Cassandra L. Kniffin - updated : 5/20/2013<br>Cassandra L. Kniffin - updated : 5/13/2013<br>Victor A. McKusick - updated : 12/20/2004
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Victor A. McKusick : 11/30/2004
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