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Entry
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- #272800 - TAY-SACHS DISEASE; TSD
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- OMIM
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<p>
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<span class="h4">#272800</span>
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<br />
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<strong>Table of Contents</strong>
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</p>
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<a href="#title"><strong>Title</strong></a>
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<li role="presentation">
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<a href="#phenotypeMap"><strong>Phenotype-Gene Relationships</strong></a>
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<li role="presentation">
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<a href="/clinicalSynopsis/272800"><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="#pathogenesis">Pathogenesis</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="#diagnosis">Diagnosis</a>
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<a href="#populationGenetics">Population Genetics</a>
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<a href="#history">History</a>
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<a href="#animalModel">Animal Model</a>
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<li role="presentation">
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<a href="#seeAlso"><strong>See Also</strong></a>
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<li role="presentation">
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<a href="#references"><strong>References</strong></a>
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<li role="presentation">
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<a href="#contributors"><strong>Contributors</strong></a>
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<li role="presentation">
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<a href="#creationDate"><strong>Creation Date</strong></a>
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<li role="presentation">
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<a href="#editHistory"><strong>Edit History</strong></a>
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<h4 class="panel-title">
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<div style="display: table-row">
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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 class="panel-heading mim-panel-heading" role="tab" id="mimClinicalResources">
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<a href="#mimClinicalResourcesLinksFold" id="mimClinicalResourcesLinksToggle" class=" mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimClinicalResourcesLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">▼</div>
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<div style="display: table-cell;">Clinical Resources</div>
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</div>
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</a>
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</span>
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</span>
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<div id="mimClinicalResourcesLinksFold" class="panel-collapse collapse in mimLinksFold" role="tabpanel" aria-labelledby="clinicalResources">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://clinicaltrials.gov/search?cond=TAY-SACHS DISEASE" class="mim-tip-hint" title="A registry of federally and privately supported clinical trials conducted in the United States and around the world." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Clinical Trials', 'domain': 'clinicaltrials.gov'})">Clinical Trials</a></div>
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<div><a href="#mimEuroGentestFold" id="mimEuroGentestToggle" data-toggle="collapse" class="mim-tip-hint mimTriangleToggle" title="A list of European laboratories that offer genetic testing."><span id="mimEuroGentestToggleTriangle" class="small" style="margin-left: -0.8em;">►</span>EuroGentest</div>
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<div id="mimEuroGentestFold" class="collapse">
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<div style="margin-left: 0.5em;"><a href="https://www.orpha.net/consor/cgi-bin/ClinicalLabs_Search_Simple.php?lng=EN&LnkId=21356&Typ=Pat" title="Tay-Sachs disease, infantile form" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'EuroGentest', 'domain': 'orpha.net'})">Tay-Sachs disease, infanti… </a></div><div style="margin-left: 0.5em;"><a href="https://www.orpha.net/consor/cgi-bin/ClinicalLabs_Search_Simple.php?lng=EN&LnkId=21357&Typ=Pat" title="Tay-Sachs disease, juvenile form" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'EuroGentest', 'domain': 'orpha.net'})">Tay-Sachs disease, juvenil… </a></div><div style="margin-left: 0.5em;"><a href="https://www.orpha.net/consor/cgi-bin/ClinicalLabs_Search_Simple.php?lng=EN&LnkId=21358&Typ=Pat" title="Tay-Sachs disease, adult form" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'EuroGentest', 'domain': 'orpha.net'})">Tay-Sachs disease, adult f… </a></div><div style="margin-left: 0.5em;"><a href="https://www.orpha.net/consor/cgi-bin/ClinicalLabs_Search_Simple.php?lng=EN&LnkId=888&Typ=Pat" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'EuroGentest', 'domain': 'orpha.net'})">Tay-Sachs disease </a></div>
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</div>
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<div><a href="https://www.ncbi.nlm.nih.gov/books/NBK1218/" 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/7008" 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/tay-sachs-disease" class="mim-tip-hint" title="Consumer-friendly information about the effects of genetic variation on human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MedlinePlus Genetics', 'domain': 'medlineplus.gov'})">MedlinePlus Genetics</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/gtr/all/tests/?term=272800[mim]" class="mim-tip-hint" title="Genetic Testing Registry." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'GTR', 'domain': 'ncbi.nlm.nih.gov'})">GTR</a></div>
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<div><a href="#mimOrphanetFold" id="mimOrphanetToggle" data-toggle="collapse" class="mim-tip-hint mimTriangleToggle" title="European reference portal for information on rare diseases and orphan drugs."><span id="mimOrphanetToggleTriangle" class="small" style="margin-left: -0.8em;">►</span>Orphanet</div>
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<div id="mimOrphanetFold" class="collapse">
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<div style="margin-left: 0.5em;"><a href="https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=309178" title="Tay-Sachs disease, infantile form" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'OrphaNet', 'domain': 'orpha.net'})">Tay-Sachs disease, infanti…</a></div><div style="margin-left: 0.5em;"><a href="https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=309185" title="Tay-Sachs disease, juvenile form" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'OrphaNet', 'domain': 'orpha.net'})">Tay-Sachs disease, juvenil…</a></div><div style="margin-left: 0.5em;"><a href="https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=309192" title="Tay-Sachs disease, adult form" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'OrphaNet', 'domain': 'orpha.net'})">Tay-Sachs disease, adult f…</a></div><div style="margin-left: 0.5em;"><a href="https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=845" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'OrphaNet', 'domain': 'orpha.net'})">Tay-Sachs disease</a></div>
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</div>
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<div><a href="https://www.possumcore.com/nuxeo/nxdoc/default/d9226cd9-ea10-452f-a555-76b947fcda57/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 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:3320" 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/272800" class="mim-tip-hint" title="Phenotypes, alleles, and disease models from Mouse Genome Informatics." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MGI Mouse Phenotype', 'domain': 'informatics.jax.org'})">MGI Mouse Phenotype</a></div>
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<div><a href="https://omia.org/OMIA001461/" class="mim-tip-hint" title="Online Mendelian Inheritance in Animals (OMIA) is a database of genes, inherited disorders and traits in 191 animal species (other than human and mouse.)" target="_blank">OMIA</a></div>
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<div><a href="https://wormbase.org/resources/disease/DOID:3320" class="mim-tip-hint" title="Database of the biology and genome of Caenorhabditis elegans and related nematodes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Wormbase Disease Ontology', 'domain': 'wormbase.org'})">Wormbase Disease Ontology</a></div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimCellLines">
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<span class="panel-title">
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<span class="small">
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<a href="#mimCellLinesLinksFold" id="mimCellLinesLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimCellLinesLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Cell Lines</div>
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</span>
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<div id="mimCellLinesLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://catalog.coriell.org/Search?q=OmimNum:272800" class="definition" title="Coriell Cell Repositories; cell cultures and DNA derived from cell cultures." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'CCR', 'domain': 'ccr.coriell.org'})">Coriell</a></div>
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<span class="mim-tip-bottom" qtip_title="<strong>Looking for this gene or this phenotype in other resources?</strong>" qtip_text="Select a related resource from the dropdown menu and click for a targeted link to information directly relevant.">
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</span>
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</span>
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</div>
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<div class="col-lg-8 col-lg-pull-2 col-md-8 col-md-pull-2 col-sm-8 col-sm-pull-2 col-xs-12">
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<div>
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<a id="title" class="mim-anchor"></a>
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<div>
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<a id="number" class="mim-anchor"></a>
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<div class="text-right">
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<a href="#" class="mim-tip-icd" qtip_title="<strong>ICD+</strong>" qtip_text="
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<strong>SNOMEDCT:</strong> 111385000<br />
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<strong>ICD10CM:</strong> E75.02<br />
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<strong>ORPHA:</strong> 309178, 309185, 309192, 845<br />
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<strong>DO:</strong> 3320<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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272800
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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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TAY-SACHS DISEASE; TSD
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</span>
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</h3>
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</div>
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<div>
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<br />
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</div>
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<div>
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<a id="alternativeTitles" class="mim-anchor"></a>
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<div>
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<p>
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<span class="mim-font">
|
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<em>Alternative titles; symbols</em>
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</span>
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</p>
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</div>
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<div>
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<h4>
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<span class="mim-font">
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|
GM2-GANGLIOSIDOSIS, TYPE I<br />
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B VARIANT GM2-GANGLIOSIDOSIS<br />
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HEXOSAMINIDASE A DEFICIENCY<br />
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|
HEXA DEFICIENCY
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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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<a id="includedTitles" 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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|
Other entities represented in this entry:
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</span>
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</p>
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</div>
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<div>
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<span class="h3 mim-font">
|
|
TAY-SACHS DISEASE, JUVENILE, INCLUDED
|
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</span>
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</div>
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<div>
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<span class="h4 mim-font">
|
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|
|
HEXOSAMINIDASE A DEFICIENCY, ADULT TYPE, INCLUDED<br />
|
|
GM2-GANGLIOSIDOSIS, ADULT CHRONIC TYPE, INCLUDED<br />
|
|
GM2-GANGLIOSIDOSIS, VARIANT B1, INCLUDED<br />
|
|
TAY-SACHS DISEASE, VARIANT B1, INCLUDED<br />
|
|
TAY-SACHS DISEASE, PSEUDO-AB VARIANT, INCLUDED
|
|
</span>
|
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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>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>Phenotype-Gene Relationships</strong>
|
|
</span>
|
|
</h4>
|
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<div>
|
|
<table class="table table-bordered table-condensed table-hover small mim-table-padding">
|
|
<thead>
|
|
<tr class="active">
|
|
<th>
|
|
Location
|
|
</th>
|
|
<th>
|
|
Phenotype
|
|
</th>
|
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<th>
|
|
Phenotype <br /> MIM number
|
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</th>
|
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<th>
|
|
Inheritance
|
|
</th>
|
|
<th>
|
|
Phenotype <br /> mapping key
|
|
</th>
|
|
<th>
|
|
Gene/Locus
|
|
</th>
|
|
<th>
|
|
Gene/Locus <br /> MIM number
|
|
</th>
|
|
</tr>
|
|
</thead>
|
|
<tbody>
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/geneMap/15/353?start=-3&limit=10&highlight=353">
|
|
15q23
|
|
</a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
Tay-Sachs disease
|
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|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/272800"> 272800 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
|
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|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
|
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|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
HEXA
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/606869"> 606869 </a>
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/geneMap/15/353?start=-3&limit=10&highlight=353">
|
|
15q23
|
|
</a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
GM2-gangliosidosis, several forms
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/272800"> 272800 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
HEXA
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/606869"> 606869 </a>
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/geneMap/15/353?start=-3&limit=10&highlight=353">
|
|
15q23
|
|
</a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
[Hex A pseudodeficiency]
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/272800"> 272800 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
HEXA
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/606869"> 606869 </a>
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
</tbody>
|
|
</table>
|
|
</div>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
|
|
|
|
<div class="btn-group ">
|
|
<a href="/clinicalSynopsis/272800" class="btn btn-warning" role="button"> Clinical Synopsis </a>
|
|
<button type="button" id="mimPhenotypicSeriesToggle" class="btn btn-warning dropdown-toggle mimSingletonFoldToggle" data-toggle="collapse" href="#mimClinicalSynopsisFold" onclick="ga('send', 'event', 'Unfurl', 'ClinicalSynopsis', 'omim.org')">
|
|
<span class="caret"></span>
|
|
<span class="sr-only">Toggle Dropdown</span>
|
|
</button>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
<div class="btn-group">
|
|
<button type="button" class="btn btn-success dropdown-toggle" data-toggle="dropdown" aria-haspopup="true" aria-expanded="false">
|
|
PheneGene Graphics <span class="caret"></span>
|
|
</button>
|
|
<ul class="dropdown-menu" style="width: 17em;">
|
|
<li><a href="/graph/linear/272800" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Linear'})"> Linear </a></li>
|
|
<li><a href="/graph/radial/272800" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Radial'})"> Radial </a></li>
|
|
</ul>
|
|
</div>
|
|
<span class="glyphicon glyphicon-question-sign mim-tip-hint" title="OMIM PheneGene graphics depict relationships between phenotypes, groups of related phenotypes (Phenotypic Series), and genes.<br /><a href='/static/omim/pdf/OMIM_Graphics.pdf' target='_blank'>A quick reference overview and guide (PDF)</a>"></span>
|
|
|
|
|
|
|
|
<div>
|
|
<p />
|
|
</div>
|
|
|
|
|
|
<div id="mimClinicalSynopsisFold" class="well well-sm collapse mimSingletonToggleFold">
|
|
<div class="small" style="margin: 5px">
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<strong> INHERITANCE </strong>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
|
|
<div>
|
|
<span class="mim-font">
|
|
|
|
- Autosomal recessive <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/258211005" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">258211005</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0441748&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0441748</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000007" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000007</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000007" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000007</a>]</span><br />
|
|
|
|
</span>
|
|
</div>
|
|
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<strong> HEAD & NECK </strong>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<em> Eyes </em>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
<span class="mim-font">
|
|
|
|
- Macular pallor with prominence of fovea centralis (cherry red spot) <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1848919&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1848919</a>]</span><br /> -
|
|
Blindness <span class="mim-feature-ids hidden">[UMLS: <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>]</span> <span class="mim-feature-ids hidden">[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>]</span><br />
|
|
|
|
</span>
|
|
</div>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<strong> RESPIRATORY </strong>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<em> Airways </em>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
<span class="mim-font">
|
|
|
|
- Aspiration <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/413585005" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">413585005</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/14766002" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">14766002</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/68052005" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">68052005</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/129316008" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">129316008</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/278847003" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">278847003</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0349707&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0349707</a>, <a href="https://bioportal.bioontology.org/search?q=C0700198&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0700198</a>, <a href="https://bioportal.bioontology.org/search?q=C1720922&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1720922</a>, <a href="https://bioportal.bioontology.org/search?q=C2712334&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C2712334</a>, <a href="https://bioportal.bioontology.org/search?q=C0220787&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0220787</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002835" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002835</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002835" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002835</a>]</span><br />
|
|
|
|
</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> 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">
|
|
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- Increased startle response <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1848918&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1848918</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002267" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002267</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002267" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002267</a>]</span><br /> -
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Hypotonia <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/398151007" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">398151007</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/398152000" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">398152000</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0026827&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0026827</a>, <a href="https://bioportal.bioontology.org/search?q=C1858120&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1858120</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001290" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001290</a>, <a href="https://hpo.jax.org/app/browse/term/HP:0001252" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001252</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001252" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001252</a>]</span><br /> -
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Late hypertonia <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1855482&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1855482</a>]</span><br /> -
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Poor head control <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1836038&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1836038</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002421" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002421</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002421" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002421</a>]</span><br /> -
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Psychomotor degeneration <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1836842&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1836842</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002361" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002361</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002361" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002361</a>]</span><br /> -
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Seizures <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/91175000" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">91175000</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0036572&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0036572</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001250" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001250</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001250" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001250</a>]</span><br /> -
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Dementia <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/52448006" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">52448006</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/12348006" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">12348006</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/F03.90" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">F03.90</a>, <a href="https://purl.bioontology.org/ontology/ICD10CM/F03" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">F03</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/290.1" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">290.1</a>, <a href="https://purl.bioontology.org/ontology/ICD9CM/294.2" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">294.2</a>, <a href="https://purl.bioontology.org/ontology/ICD9CM/290" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">290</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0011265&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0011265</a>, <a href="https://bioportal.bioontology.org/search?q=C0497327&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0497327</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000726" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000726</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000726" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000726</a>]</span><br />
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</span>
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<div>
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<div>
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<span class="h5 mim-font">
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<em> Behavioral Psychiatric Manifestations </em>
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</span>
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</div>
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<div style="margin-left: 2em;">
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<span class="mim-font">
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- Apathy <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/20602000" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">20602000</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0436596&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0436596</a>, <a href="https://bioportal.bioontology.org/search?q=C0085632&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0085632</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000741" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000741</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000741" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000741</a>]</span><br />
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</span>
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</div>
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</div>
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<div>
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<div>
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<span class="h5 mim-font">
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<strong> LABORATORY ABNORMALITIES </strong>
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</span>
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</div>
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<div style="margin-left: 2em;">
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<div>
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<span class="mim-font">
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- Gm2-ganglioside accumulation <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1848920&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1848920</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003495" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003495</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003495" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003495</a>]</span><br /> -
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Ballooned neurons <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1848921&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1848921</a>]</span><br /> -
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Hexosaminidase A deficiency <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/111385000" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">111385000</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/E75.02" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">E75.02</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1848922&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1848922</a>, <a href="https://bioportal.bioontology.org/search?q=C0039373&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0039373</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0025754" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0025754</a>]</span><br />
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</span>
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<div>
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<div>
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<span class="h5 mim-font">
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<strong> MISCELLANEOUS </strong>
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</span>
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</div>
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<div style="margin-left: 2em;">
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<div>
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<span class="mim-font">
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- Infantile onset <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1848924&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1848924</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003593" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003593</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003593" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003593</a>]</span><br /> -
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Usually fatal by age 5 years<br /> -
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Incidence of 1 in 3,900 births among Jewish persons<br /> -
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Incidence of 1 in 320,000 births among non-Jewish persons<br />
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</span>
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</div>
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</div>
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<div>
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<div>
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<span class="h5 mim-font">
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<strong> MOLECULAR BASIS </strong>
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</span>
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</div>
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<div style="margin-left: 2em;">
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<div>
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<span class="mim-font">
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- Caused by mutations in the hexosaminidase A, alpha polypeptide gene (HEXA, <a href="/entry/606869#0001">606869.0001</a>)<br />
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</span>
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<div class="text-right">
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<a href="#mimClinicalSynopsisFold" data-toggle="collapse">▲ Close</a>
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<div>
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<br />
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<div>
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<a id="text" class="mim-anchor"></a>
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<h4 href="#mimTextFold" id="mimTextToggle" class="mimTriangleToggle" style="cursor: pointer;" data-toggle="collapse">
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<span id="mimTextToggleTriangle" class="small mimTextToggleTriangle">▼</span>
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<span class="mim-font">
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<span class="mim-tip-floating" qtip_title="<strong>Looking For More References?</strong>" qtip_text="Click the 'reference plus' icon <span class='glyphicon glyphicon-plus-sign'></span> at the end of each OMIM text paragraph to see more references related to the content of the preceding paragraph.">
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<strong>TEXT</strong>
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<span class="mim-text-font">
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<p>A number sign (#) is used with this entry because Tay-Sachs disease (TSD) is caused by homozygous or compound heterozygous mutation in the alpha subunit of the hexosaminidase A gene (HEXA; <a href="/entry/606869">606869</a>) on chromosome 15q23.</p>
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<br />
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<a id="description" class="mim-anchor"></a>
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<h4 href="#mimDescriptionFold" id="mimDescriptionToggle" class="mimTriangleToggle" style="cursor: pointer;" data-toggle="collapse">
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<span id="mimDescriptionToggleTriangle" class="small mimTextToggleTriangle">▼</span>
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<span class="mim-font">
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<strong>Description</strong>
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<p>Tay-Sachs disease is an autosomal recessive, progressive neurodegenerative disorder which, in the classic infantile form, is usually fatal by age 2 or 3 years.</p>
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<br />
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<a id="clinicalFeatures" class="mim-anchor"></a>
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<span id="mimClinicalFeaturesToggleTriangle" class="small mimTextToggleTriangle">▼</span>
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<span class="mim-font">
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<strong>Clinical Features</strong>
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<span class="mim-text-font">
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<p>Classic Tay-Sachs disease is characterized by the onset in infancy of developmental retardation, followed by paralysis, dementia and blindness, with death in the second or third year of life. A gray-white area around the retinal fovea centralis, due to lipid-laden ganglion cells, leaving a central 'cherry-red' spot is a typical funduscopic finding. Pathologic verification is provided by the finding of the typically ballooned neurons in the central nervous system. An early and persistent extension response to sound ('startle reaction') is useful for recognizing the disorder.</p><p><a href="#41" class="mim-tip-reference" title="Kolodny, E. H. <strong>Personal Communication.</strong> Boston, Mass. 1972."None>Kolodny (1972)</a>, who studied the proband described by <a href="#73" class="mim-tip-reference" title="Okada, S., Veath, M. L., Leroy, J. G., O'Brien, J. S. <strong>Ganglioside Gm(2) storage diseases: hexosaminidase deficiencies in cultured fibroblasts.</strong> Am. J. Hum. Genet. 23: 55-61, 1971.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/5581981/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">5581981</a>]" pmid="5581981">Okada et al. (1971)</a>, stated that visual function was retained and optic atrophy was not present at age 20 months. At death at 32 months, microscopic findings in the central nervous system were similar to those in Tay-Sachs disease. The patients showed normal results in tests that usually demonstrate the Tay-Sachs heterozygote. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=5581981" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#95" class="mim-tip-reference" title="Suzuki, K., Suzuki, K., Rapin, I., Suzuki, Y., Ishii, N. <strong>Juvenile Gm(2)-gangliosidosis: clinical variant of Tay-Sachs disease or a new disease.</strong> Neurology 20: 190-204, 1970.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/5460705/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">5460705</a>] [<a href="https://doi.org/10.1212/wnl.20.2.190" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="5460705">Suzuki et al. (1970)</a> and <a href="#65" class="mim-tip-reference" title="O'Brien, J. S. <strong>Ganglioside storage diseases. In: Harris, H.; Hirschhorn, K. (eds.): Advances in Human Genetics. Vol. 3.</strong> New York: Plenum Press (pub.) 1972. Pp. 39-98."None>O'Brien (1972)</a> reported non-Jewish patients with the Tay-Sachs variant of juvenile-onset GM2-gangliosidosis. Onset occurred with ataxia between ages 2 and 6 years. Thereafter deterioration to decerebrate rigidity took place. Blindness occurred late in the course in only some patients, unlike the situation in classic Tay-Sachs disease in which blindness is an invariable and early development. Death occurred between ages 5 and 15 years. The defect is a partial deficiency of hexosaminidase A. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=5460705" 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="#81" class="mim-tip-reference" title="Rapin, I., Suzuki, K., Suzuki, K., Valsamis, M. P. <strong>Adult (chronic) Gm2 gangliosidosis.</strong> Arch. Neurol. 33: 120-130, 1976.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/175770/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">175770</a>] [<a href="https://doi.org/10.1001/archneur.1976.00500020048008" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="175770">Rapin et al. (1976)</a> described a brother and 2 sisters of Ashkenazi extraction who had slowly progressive deterioration of gait and posture beginning in early childhood, muscle atrophy beginning distally, pes cavus, foot drop, spasticity, mild ataxia of limbs and trunk, dystonia, and dysarthria. Intelligence was little affected, vision and optic fundi were normal, and no seizures had occurred. One sister died at age 16 following a drug reaction. Autopsy showed diffuse neuronal storage with zebra bodies and increased GM2-ganglioside. Hexosaminidase A was decreased in the serum and leukocytes of the 2 living patients, and in their parents was in the range of carriers of Tay-Sachs disease. The 2 living sibs were 31 and 34 years old at the time of the report. This may be an allelic variety of Tay-Sachs disease. <a href="#38" class="mim-tip-reference" title="Kaback, M., Miles, J., Yaffe, M., Itabashi, H., McIntyre, H., Goldberg, M., Mohandas, T. <strong>Hexosaminidase-A (Hex A) deficiency in early adulthood: a new type of GM-2 gangliosidosis. (Abstract)</strong> Am. J. Hum. Genet. 30: 31A, 1978."None>Kaback et al. (1978)</a> described a similar but possibly distinct case. The son of an Ashkenazi couple was entirely normal until age 16 when slight leg muscle cramps began. Hex-A deficiency was found in a screening program at age 20. Both parents and a sister were heterozygotes. Heterokaryon complementation showed the development of Hex-A when the proband's cells were fused with Sandhoff cells, but showed no complementation with Tay-Sachs cells. Between ages 20 and 22, the patient showed dramatically progressive proximal muscle wasting, weakness, fasciculations, EMG abnormality, and elevated CPK. Ophthalmologic, audiologic and intellectual function remained normal. Muscle biopsy suggested anterior horn disease. Rectal ganglion cells showed ballooning and onion-skin cytoplasmic bodies. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=175770" 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="#107" class="mim-tip-reference" title="Willner, J. P., Grabowski, G. A., Gordon, R. E., Bender, A. N., Desnick, R. J. <strong>Chronic GM(2) gangliosidosis masquerading as atypical Friedreich ataxia: clinical morphologic and biochemical studies of nine cases.</strong> Neurology 31: 787-798, 1981.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/6454083/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">6454083</a>] [<a href="https://doi.org/10.1212/wnl.31.7.787" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="6454083">Willner et al. (1981)</a> reported 9 patients from 4 unrelated Ashkenazi Jewish families with a variant form of Hex-A deficiency masquerading as atypical Friedreich ataxia. They proposed that the affected individuals may be genetic compounds for the Tay-Sachs allele and another distinctive allele. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=6454083" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#36" class="mim-tip-reference" title="Johnson, W. G., Wigger, H. J., Karp, H. R., Glaubiger, L. M., Rowland, L. P. <strong>Juvenile spinal muscular atrophy: a new hexosaminidase deficiency phenotype.</strong> Ann. Neurol. 11: 11-16, 1982.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/6460466/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">6460466</a>] [<a href="https://doi.org/10.1002/ana.410110103" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="6460466">Johnson et al. (1982)</a> observed a 24-year-old Ashkenazi man with a 9-year history of progressive leg weakness and fasciculations. Other data were consistent with anterior horn cell disease. Hex-A was markedly decreased in the patient and partially decreased in both parents and a brother. A paternal relative had classic Tay-Sachs disease. The clinical picture, which suggested the Kugelberg-Welander phenotype, may have resulted, according to the suggestion of the authors, from a genetic compound state of the classic allele and a mild allele. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=6460466" 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="#29" class="mim-tip-reference" title="Griffin, J. W. <strong>Personal Communication.</strong> Baltimore, Md. 5/16/1984."None>Griffin (1984)</a> had a 31-year-old patient with hexosaminidase deficiency and marked cerebellar atrophy, dementia, and denervation motor neuron disease. Both parents showed a partial deficiency. In 3 patients in 2 unrelated families, <a href="#48" class="mim-tip-reference" title="Mitsumoto, H., Sliman, R. J., Schafer, I. A., Sternick, C. S., Kaufman, B., Wilbourn, A., Horwitz, S. J. <strong>Motor neuron disease and adult hexosaminidase A deficiency in two families: evidence for multisystem degeneration.</strong> Ann. Neurol. 17: 378-385, 1985.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3159334/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3159334</a>] [<a href="https://doi.org/10.1002/ana.410170413" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3159334">Mitsumoto et al. (1985)</a> described adult variants of hexosaminidase A deficiency. A 30-year-old non-Jewish proband in the first family had juvenile amyotrophic lateral sclerosis beginning at age 16 years and evolving to mild dementia, ataxia, and axonal (neuronal) motor-sensory peripheral neuropathy. A supposedly healthy brother, aged 32, had difficulty with memory in college but had obtained 2 degrees in 8 years and worked in an electronics company. He was dismissed from his job for poor memory and comprehension. He showed mild spasticity and ataxia but no evidence of motor neuron disease. In the second family, a 36-year-old man with Ashkenazi mother and Syrian Sephardic father had 'pure' spinal muscular atrophy; he had lifelong physical limitation with inability to run or throw a ball as a child. All 3 had marked cerebellar atrophy. Against artificial substrates, Hex-A activity was in the range of Tay-Sachs disease homozygotes but was higher when GM2 substrates were used. Hex-A activity in the parents was in the heterozygous range. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=3159334" 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 34-year-old English Canadian man described by <a href="#74" class="mim-tip-reference" title="Parnes, S., Karpati, G., Carpenter, S., Ng Ying Kin, N. M. K., Wolfe, L. S., Suranyi, L. <strong>Hexosaminidase--a deficiency presenting as atypical juvenile-onset spinal muscular atrophy.</strong> Arch. Neurol. 42: 1176-1180, 1985.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2933015/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2933015</a>] [<a href="https://doi.org/10.1001/archneur.1985.04060110058016" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2933015">Parnes et al. (1985)</a>, the clinical picture was that of juvenile-onset spinal muscular atrophy. Atypical features were prominent muscle cramps, postural and action tremor, recurrent psychosis, incoordination, corticospinal and corticobulbar involvement, and dysarthria. With the report of a 24-year-old, non-Jewish man with dystonia, dementia, amyotrophy, choreoathetosis, and ataxia, <a href="#67" class="mim-tip-reference" title="Oates, C. E., Bosch, E. P., Hart, M. N. <strong>Movement disorders associated with chronic GM(2) gangliosidosis: case report and review of the literature.</strong> Europ. Neurol. 25: 154-159, 1986.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3081350/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3081350</a>] [<a href="https://doi.org/10.1159/000116100" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3081350">Oates et al. (1986)</a> emphasized that presumably allelic forms of Hex-A deficiency can take unusual clinical forms. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=3081350+2933015" 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 Israel, <a href="#57" class="mim-tip-reference" title="Navon, R., Argov, Z., Frisch, A. <strong>Hexosaminidase A deficiency in adults.</strong> Am. J. Med. Genet. 24: 179-196, 1986.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2939718/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2939718</a>] [<a href="https://doi.org/10.1002/ajmg.1320240123" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2939718">Navon et al. (1986)</a> identified 18 Hex-A-deficient adults by the end of 1985. All were Ashkenazi. The clinical picture varied between and within families and included spinocerebellar, various motor neuron, and cerebellar syndromes. The possibility exists that many of the affected persons are compound heterozygotes of the TSD allele with another rare allele. The relatively high frequency of the atypical adult disorder(s) in Ashkenazim is the result of the high frequency of the TSD allele to create genetic compounds. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2939718" 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="#26" class="mim-tip-reference" title="Grebner, E. E., Mansfield, D. A., Raghavan, S. S., Kolodny, E. H., d'Azzo, A., Neufeld, E. F., Jackson, L. G. <strong>Two abnormalities of hexosaminidase A in clinically normal individuals.</strong> Am. J. Hum. Genet. 38: 505-515, 1986.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2939713/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2939713</a>]" pmid="2939713">Grebner et al. (1986)</a> studied 3 clinically normal persons, aged 6 to 30 years, with absent serum Hex-A activity against artificial substrates and concluded that they were probably genetic compounds of the usual Tay-Sachs allele and a different mutant allele that in combination with it gave the abnormal phenotype. <a href="#39" class="mim-tip-reference" title="Karni, A., Navon, R., Sadeh, M. <strong>Hexosaminidase A deficiency manifesting as spinal muscular atrophy of late onset.</strong> Ann. Neurol. 24: 451-453, 1988.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2976262/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2976262</a>] [<a href="https://doi.org/10.1002/ana.410240316" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2976262">Karni et al. (1988)</a> described a 39-year-old Israeli woman with proximal lower limb weakness and fasciculations as the only manifestations of Hex-A deficiency. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=2976262+2939713" 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="Bayleran, J., Hechtman, P., Kolodny, E., Kaback, M. <strong>Tay-Sachs disease with hexosaminidase A: characterization of the defective enzyme in two patients.</strong> Am. J. Hum. Genet. 41: 532-548, 1987.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2959149/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2959149</a>]" pmid="2959149">Bayleran et al. (1987)</a> characterized the defective enzyme in 2 patients with Tay-Sachs disease and a high residual Hex-A activity. Clinical presentation was identical to that found among Ashkenazi patients. Both patients appeared to be heterozygous for the B1 phenotype, having virtually no capacity for hydrolysis of the sulfated HEXA substrate 4-methylumbelliferyl-beta-D-N-acetylglucosamine-6-sulfate (4MUGS). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2959149" 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="Barnes, D., Misra, V. P., Young, E. P., Thomas, P. K., Harding, A. E. <strong>An adult onset hexosaminidase A deficiency syndrome with sensory neuropathy and internuclear ophthalmoplegia.</strong> J. Neurol. Neurosurg. Psychiat. 54: 1112-1113, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1838393/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1838393</a>] [<a href="https://doi.org/10.1136/jnnp.54.12.1112" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1838393">Barnes et al. (1991)</a> described a 42-year-old man of non-Jewish ancestry who in his 20s and 30s had the onset of slowly progressive gait disturbance, generalized weakness, dysarthria, clumsiness and tremor of his hands, and involuntary jerks. Two previously unreported features were clinically evident sensory neuropathy and internuclear ophthalmoplegia. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1838393" 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="#77" class="mim-tip-reference" title="Perlman, S. L. <strong>Late-onset Tay-Sachs disease as a Friedreich ataxia phenocopy. (Letter)</strong> Arch. Neurol. 59: 1832 only, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12433276/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12433276</a>] [<a href="https://doi.org/10.1001/archneur.59.11.1832" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12433276">Perlman (2002)</a> commented on late-onset Tay-Sachs disease as a Friedreich ataxia phenocopy. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12433276" 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="#87" class="mim-tip-reference" title="Rucker, J. C., Shapiro, B. E., Han, Y. H., Kumar, A. N., Garbutt, S., Keller, E. L., Leigh, R. J. <strong>Neuro-ophthalmology of late-onset Tay-Sachs disease (LOTS).</strong> Neurology 63: 1918-1926, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15557512/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15557512</a>] [<a href="https://doi.org/10.1212/01.wnl.0000144275.76658.f4" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15557512">Rucker et al. (2004)</a> evaluated eye movements in 14 patients with late-onset Tay-Sachs disease (average age, 39 years). The main clinical features included childhood clumsiness or incoordination, proximal muscle weakness, ataxia, dysarthria, and tremor. All patients had normal visual function and normal optic fundi without cherry red spots. Saccades were hypometric and multistep with transient decelerations. Peak acceleration values of the saccades were normal, but decelerations occurred sooner and faster than in controls. Smooth pursuit was also impaired. <a href="#87" class="mim-tip-reference" title="Rucker, J. C., Shapiro, B. E., Han, Y. H., Kumar, A. N., Garbutt, S., Keller, E. L., Leigh, R. J. <strong>Neuro-ophthalmology of late-onset Tay-Sachs disease (LOTS).</strong> Neurology 63: 1918-1926, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15557512/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15557512</a>] [<a href="https://doi.org/10.1212/01.wnl.0000144275.76658.f4" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15557512">Rucker et al. (2004)</a> postulated a disruption in a 'latch circuit' that normally inhibits pontine 'omnipause' neurons to allow completion of eye movement. Saccade measurements may be a means of evaluating responses to treatment in patients with late-onset Tay-Sachs disease. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15557512" 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="#86" class="mim-tip-reference" title="Rowe, O. E., Rangaprakash, D., Weerasekera, A., Godbole, N., Haxton, E., James, P. F., Stephen, C. D., Barry, R. L., Eichler, F. S., Ratai, E.-M. <strong>Magnetic resonance imaging and spectroscopy in late-onset GM2-gangliosidosis.</strong> Molec. Genet. Metab. 133: 386-396, 2021.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/34226107/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">34226107</a>] [<a href="https://doi.org/10.1016/j.ymgme.2021.06.008" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="34226107">Rowe et al. (2021)</a> examined MRI and MR spectroscopy in 7 patients with late-onset Tay-Sachs disease and 3 patients with late-onset Sandhoff disease (<a href="/entry/268800">268800</a>). Compared to age-matched controls, patients with late-onset Tay-Sachs disease had decreased total cerebellar volume and cerebellar gray matter. On MR spectroscopy of the cerebellum, patients with late-onset Tay-Sachs disease had significantly decreased N-acetylaspartate, combined glutamine and glutamate, and creatine as well as significantly increased myo-inositol compared to controls. <a href="#86" class="mim-tip-reference" title="Rowe, O. E., Rangaprakash, D., Weerasekera, A., Godbole, N., Haxton, E., James, P. F., Stephen, C. D., Barry, R. L., Eichler, F. S., Ratai, E.-M. <strong>Magnetic resonance imaging and spectroscopy in late-onset GM2-gangliosidosis.</strong> Molec. Genet. Metab. 133: 386-396, 2021.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/34226107/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">34226107</a>] [<a href="https://doi.org/10.1016/j.ymgme.2021.06.008" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="34226107">Rowe et al. (2021)</a> concluded that the changes in these metabolites indicated widespread neuronal dysfunction, inflammation, and altered energy metabolism in late-onset Tay-Sachs disease. Among the 10 patients with late-onset Tay-Sachs or Sandhoff disease, there was a significant association between cerebellar volume and the Scale for the Assessment and Rating of Ataxia (SARA). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=34226107" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Reviews</em></strong></p><p>
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<a href="#60" class="mim-tip-reference" title="Neufeld, E. F. <strong>Natural history and inherited disorders of a lysosomal enzyme, beta-hexosaminidase.</strong> J. Biol. Chem. 264: 10927-10930, 1989.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2525553/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2525553</a>]" pmid="2525553">Neufeld (1989)</a> provided a review of the disorders related to mutations in the HEXA (<a href="/entry/606869">606869</a>) and HEXB genes (<a href="/entry/606873">606873</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2525553" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#6" class="mim-tip-reference" title="Balint, J. A., Kyriakides, E. C. <strong>Studies of red cell stromal proteins in Tay-Sachs disease.</strong> J. Clin. Invest. 47: 1858-1864, 1968.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/5666115/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">5666115</a>] [<a href="https://doi.org/10.1172/JCI105876" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="5666115">Balint and Kyriakides (1968)</a> demonstrated accumulation of a glycoprotein in red cells of patients with Tay-Sachs disease. The basic enzyme defect was shown by <a href="#72" class="mim-tip-reference" title="Okada, S., O'Brien, J. S. <strong>Tay-Sachs disease: generalized absence of a beta-D-N-acetylhexosaminidase component.</strong> Science 165: 698-700, 1969.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/5793973/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">5793973</a>] [<a href="https://doi.org/10.1126/science.165.3894.698" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="5793973">Okada and O'Brien (1969)</a> to concern one component of hexosaminidase. Total hexosaminidase activity was normal but when components A (HEXA; <a href="/entry/606869">606869</a>) and B (HEXB; <a href="/entry/606873">606873</a>) were separated, component A was found to be absent. <a href="#33" class="mim-tip-reference" title="Hultberg, B. <strong>N-acetylhexosaminidase activities in Tay-Sachs disease. (Letter)</strong> Lancet 294: 1195 only, 1969. Note: Originally Volume II.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/4187227/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">4187227</a>] [<a href="https://doi.org/10.1016/s0140-6736(69)92520-3" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="4187227">Hultberg (1969)</a> confirmed the findings of <a href="#72" class="mim-tip-reference" title="Okada, S., O'Brien, J. S. <strong>Tay-Sachs disease: generalized absence of a beta-D-N-acetylhexosaminidase component.</strong> Science 165: 698-700, 1969.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/5793973/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">5793973</a>] [<a href="https://doi.org/10.1126/science.165.3894.698" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="5793973">Okada and O'Brien (1969)</a>. <a href="#73" class="mim-tip-reference" title="Okada, S., Veath, M. L., Leroy, J. G., O'Brien, J. S. <strong>Ganglioside Gm(2) storage diseases: hexosaminidase deficiencies in cultured fibroblasts.</strong> Am. J. Hum. Genet. 23: 55-61, 1971.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/5581981/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">5581981</a>]" pmid="5581981">Okada et al. (1971)</a> compared the findings in regard to hexosaminidases A and B in 3 forms of ganglioside GM2 storage disease--Tay-Sachs disease, Sandhoff disease (<a href="/entry/268800">268800</a>), and juvenile GM2-gangliosidosis. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=4187227+5793973+5666115+5581981" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#24" class="mim-tip-reference" title="Galjaard, H., Hoogeveen, A., deWit-Verbeek, H. A., Reuser, A. J. J., Keijzer, W., Westerveld, A., Bootsma, D. <strong>Tay-Sachs and Sandhoff's disease: intergenic complementation after somatic cell hybridization.</strong> Exp. Cell Res. 87: 444-448, 1974.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/4416048/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">4416048</a>] [<a href="https://doi.org/10.1016/0014-4827(74)90515-1" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="4416048">Galjaard et al. (1974)</a>, <a href="#100" class="mim-tip-reference" title="Thomas, G. H., Taylor, H. A., Miller, C. S., Axelman, J., Migeon, B. R. <strong>Genetic complementation after fusion of Tay-Sachs and Sandhoff cells.</strong> Nature 250: 580-582, 1974.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/4367631/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">4367631</a>] [<a href="https://doi.org/10.1038/250580a0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="4367631">Thomas et al. (1974)</a>, and <a href="#82" class="mim-tip-reference" title="Rattazzi, M. C., Brown, J. A., Davidson, R. G., Shows, T. B. <strong>Tay-Sachs and Sandhoff-Jatzkewitz diseases: complementation of hexosaminidase A deficiency by somatic cell hybridization.</strong> Birth Defects Orig. Art. Ser. XI(3): 232-235, 1975. Note: Alternate: Cytogenet. Cell Genet. 14: 402-405, 1975."None>Rattazzi et al. (1975)</a> showed that Hex-A activity appears after fusion of Tay-Sachs and Sandhoff cells, suggesting genetic (or at least metabolic) complementation. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=4367631+4416048" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#11" class="mim-tip-reference" title="Beutler, E., Kuhl, W., Comings, D. <strong>Hexosaminidase isozyme in type O Gm2 gangliosidosis (Sandhoff-Jatzkewitz disease).</strong> Am. J. Hum. Genet. 27: 628-638, 1975.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/808963/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">808963</a>]" pmid="808963">Beutler et al. (1975)</a> concluded that Hex-A has the structure alpha-beta, whereas Hex-B is beta-beta; Tay-Sachs disease is an alpha-minus mutation, whereas Sandhoff disease is a beta-minus mutation; in the absence of beta subunits there is increased polymerization of alpha units to form Hex-S, which is a normal constituent of plasma and probably has a structure of alpha-6. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=808963" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#66" class="mim-tip-reference" title="O'Brien, J. S. <strong>Suggestions for a nomenclature for the GM2-gangliosidoses making certain (possibly unwarranted) assumptions. (Comments).</strong> Am. J. Hum. Genet. 30: 672-675, 1978.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/747190/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">747190</a>]" pmid="747190">O'Brien (1978)</a> made suggestions for nomenclature of the various hexosaminidase A and B mutations. Three loci were postulated: alpha, responsible for the alpha subunit, mapped to chromosome 15; beta, responsible for the beta subunit, mapped to chromosome 5; and an activator locus or loci determining the structure of one or more proteins that stimulate Hex-A to cleave GM2 and GA2 gangliosides. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=747190" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#17" class="mim-tip-reference" title="Conzelmann, E., Kytzia, H.-J., Navon, R., Sandhoff, K. <strong>Ganglioside GM2 N-acetyl-beta-D-galactosaminidase activity in cultured fibroblasts of late-infantile and adult GM2 gangliosidosis patients and of healthy probands with low hexosaminidase level.</strong> Am. J. Hum. Genet. 35: 900-913, 1983.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/6614006/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">6614006</a>]" pmid="6614006">Conzelmann et al. (1983)</a> used a sensitive assay to demonstrate a correlation between level of residual activity and clinical severity: Tay-Sachs disease, 0.1% of normal; late infantile, 0.5%; adult GM2-gangliosidosis, 2-4%; healthy persons with 'low hexosaminidase,' 11% and 20%. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=6614006" 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>Several patients with a chronic type of Tay-Sachs disease were found by <a href="#19" class="mim-tip-reference" title="d'Azzo, A., Proia, R. L., Kolodny, E. H., Kaback, M. M., Neufeld, E. F. <strong>Faulty association of alpha- and beta-subunits in some forms of beta-hexosaminidase A deficiency.</strong> J. Biol. Chem. 259: 11070-11074, 1984.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/6236221/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">6236221</a>]" pmid="6236221">d'Azzo et al. (1984)</a> to produce alpha-hexosaminidase A. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=6236221" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>GM2-Gangliosidosis, B1 Variant</em></strong></p><p>
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Patients with the GM2-gangliosidosis B1 variant produce hexosaminidase A, which appears catalytically normal when tested with substrates such as 4-methylumbelliferyl N-acetyl-glucosaminidase that are split by an active site of the beta subunit, but is catalytically defective against substrates that are hydrolyzed by the active site on the alpha subunit of normal hexosaminidase A, which is inactivated in patients' enzyme (<a href="#42" class="mim-tip-reference" title="Kytzia, H. J., Sandhoff, K. <strong>Evidence for two different active sites on human beta-hexosaminidase A: interaction of G(M2) activator protein with beta-hexosaminidase A.</strong> J. Biol. Chem. 260: 7568-7572, 1985.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3158659/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3158659</a>]" pmid="3158659">Kytzia and Sandhoff, 1985</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=3158659" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#46" class="mim-tip-reference" title="Li, S. C., Hirabayashi, Y., Li, Y. T. <strong>A new variant of type-AB GM2-gangliosidosis.</strong> Biochem. Biophys. Res. Commun. 101: 479-485, 1981.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7306091/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7306091</a>] [<a href="https://doi.org/10.1016/0006-291x(81)91285-7" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7306091">Li et al. (1981)</a> described a patient described as having a variant of type AB GM2-gangliosidosis but with a probable defect in beta-hexosaminidase A and not in the GM2 activator. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7306091" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#34" class="mim-tip-reference" title="Inui, K., Grebner, E. E., Jackson, L. G., Wenger, D. A. <strong>Juvenile GM2 gangliosidosis (A(M)B variant): inability to activate hexosaminidase A by activator protein.</strong> Am. J. Hum. Genet. 35: 551-564, 1983.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/6224417/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">6224417</a>]" pmid="6224417">Inui et al. (1983)</a> described a brother and sister from a consanguineous Puerto Rican marriage who had a juvenile-onset lipidosis first evident clinically at age 2.5 years by difficulties in motor function and delay in development. The sibs continued to deteriorate, showing muscle atrophy, spasticity, and loss of speech, and died at ages 7 and 8. Examination of the brains from these patients showed that the disorder was a GM2-gangliosidosis. HEXA and other lysosomal enzymes were normal and the GM2-activator protein was present in high normal concentrations in the liver. The defect in these patients appeared to reside in HEXA, which although normal in heat stability, electrophoretic mobility, and activity toward fluorogenic substrates, was resistant to activation, possibly because of defective binding to the activator. <a href="#34" class="mim-tip-reference" title="Inui, K., Grebner, E. E., Jackson, L. G., Wenger, D. A. <strong>Juvenile GM2 gangliosidosis (A(M)B variant): inability to activate hexosaminidase A by activator protein.</strong> Am. J. Hum. Genet. 35: 551-564, 1983.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/6224417/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">6224417</a>]" pmid="6224417">Inui et al. (1983)</a> suggested that this be called the A(M)B variant of juvenile GM2-gangliosidosis to distinguish it from the disorder in patients missing the activator protein. (M = mutant.) <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=6224417" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#92" class="mim-tip-reference" title="Sonderfeld, S., Brendler, S., Sandhoff, K., Galjaard, H., Hoogeveen, A. T. <strong>Genetic complementation in somatic cell hybrids of four variants of infantile G(M2) gangliosidosis.</strong> Hum. Genet. 71: 196-200, 1985.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2933318/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2933318</a>] [<a href="https://doi.org/10.1007/BF00284572" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2933318">Sonderfeld et al. (1985)</a> showed the expected complementation between the B (Tay-Sachs disease) and 0 (Sandhoff disease) variants and between the AB variant (activator deficiency) and any of the 3 variants: B, 0, and B1. Hex-A was shown to have 2 distinct catalytic sites. Complementation was demonstrated between B1 cells and variant 0 but not with variant B. Thus, the B1 cells must carry a mutation in the gene for the alpha subunit. Confirmation came from studies of the processing of immature enzyme in variant B1 cells showing the presence of alpha precursors and mature alpha chains but at a lower level than normal cells. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2933318" 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>Through serial analysis of gene expression (SAGE), <a href="#52" class="mim-tip-reference" title="Myerowitz, R., Lawson, D., Mizukami, H., Mi, Y., Tifft, C. J., Proia, R. L. <strong>Molecular pathophysiology in Tay-Sachs and Sandhoff diseases as revealed by gene expression profiling.</strong> Hum. Molec. Genet. 11: 1343-1350, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12019216/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12019216</a>] [<a href="https://doi.org/10.1093/hmg/11.11.1343" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12019216">Myerowitz et al. (2002)</a> determined gene expression profiles in cerebral cortex from a Tay-Sachs patient, a Sandhoff disease patient, and a pediatric control. Examination of genes that showed altered expression in both patients revealed molecular details of the pathophysiology of the disorders relating to neuronal dysfunction and loss. A large fraction of the elevated genes in the patients could be attributed to activated macrophages/microglia and astrocytes, and included class II histocompatibility antigens, the proinflammatory cytokine osteopontin (SPP1; <a href="/entry/166490">166490</a>), complement components, proteinases and inhibitors, galectins, osteonectin (SPARC; <a href="/entry/182120">182120</a>), and prostaglandin D2 synthase (PTGDS; <a href="/entry/176803">176803</a>). The authors proposed a model of neurodegeneration that includes inflammation as a factor leading to the precipitous loss of neurons in individuals with these disorders. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12019216" 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 study of somatic cell hybrids, <a href="#43" class="mim-tip-reference" title="Lalley, P. A., Rattazzi, M. C., Shows, T. B. <strong>Human beta-D-N-acetylhexosaminidases A and B: expression and linkage relationships in somatic cell hybrids.</strong> Proc. Nat. Acad. Sci. 71: 1569-1573, 1974.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/4524661/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">4524661</a>] [<a href="https://doi.org/10.1073/pnas.71.4.1569" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="4524661">Lalley et al. (1974)</a> suggested that a locus determining hexosaminidase A is on chromosome 7. Subsequently, <a href="#104" class="mim-tip-reference" title="Van Heyningen, V., Bobrow, M., Bodmer, W. F., Gardiner, S. E., Povey, S., Hopkinson, D. A. <strong>Chromosome assignment of some human enzyme loci: mitochondrial malate dehydrogenase to 7, mannosephosphate isomerase and pyruvate kinase to 15 and probably, esterase D to 13.</strong> Ann. Hum. Genet. 38: 295-303, 1975.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1137344/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1137344</a>] [<a href="https://doi.org/10.1111/j.1469-1809.1975.tb00613.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1137344">Van Heyningen et al. (1975)</a> found that the MPI (<a href="/entry/154550">154550</a>) and PK3 (<a href="/entry/179050">179050</a>) loci are on chromosome 15, and <a href="#25" class="mim-tip-reference" title="Gilbert, F., Kucherlapati, R. S., Creagan, R. P., Murnane, M. J., Darlington, G. J., Ruddle, F. H. <strong>Tay-Sachs' and Sandhoff's diseases: the assignment of genes for hexosaminidase A and B to individual human chromosomes.</strong> Proc. Nat. Acad. Sci. 72: 263-267, 1975.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1054503/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1054503</a>] [<a href="https://doi.org/10.1073/pnas.72.1.263" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1054503">Gilbert et al. (1975)</a> concluded that MPI, PK3 and HEXA are syntenic. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=4524661+1054503+1137344" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#15" class="mim-tip-reference" title="Chern, C. J., Beutler, E., Kuhl, W., Gilbert, F., Mellman, W. J., Croce, C. M. <strong>Characterization of heteropolymeric hexosaminidase A in human x mouse hybrid cells.</strong> Proc. Nat. Acad. Sci. 73: 3637-3640, 1976.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/62363/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">62363</a>] [<a href="https://doi.org/10.1073/pnas.73.10.3637" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="62363">Chern et al. (1976)</a> studied heteropolymeric hexosaminidase A formed by human-mouse hybrid cells that contained an X-15 translocation chromosome but lacked human chromosome 5. Tests with specific antisera suggested that the hybrid molecule had human alpha units and mouse beta units. The findings are consistent with hexosaminidase A being composed of alpha and beta subunits coded by genes on chromosomes 15 and 5, respectively. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=62363" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#23" class="mim-tip-reference" title="Formiga, L. de F., Poenaru, L., Couronne, F., Flori, E., Eibel, J. L., Deminatti, M. M., Savary, J. B., Lai, J. L., Gilgenkrantz, S., Pierson, M. <strong>Interstitial deletion of chromosome 15: two cases.</strong> Hum. Genet. 80: 401-404, 1988.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3198122/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3198122</a>] [<a href="https://doi.org/10.1007/BF00273663" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3198122">Formiga et al. (1988)</a> reported 2 cases of interstitial deletion of chromosome 15. Assay of hexosaminidase A in 1 enabled them to confirm that the structural gene is located between 15q22 and 15q25 and is included in the deletion. By high resolution in situ hybridization, <a href="#97" class="mim-tip-reference" title="Takeda, K., Nakai, H., Hagiwara, H., Tada, K., Shows, T. B., Byers, M. G., Myerowitz, R. <strong>Fine assignment of beta-hexosaminidase A alpha-subunit on 15q23-q24 by high resolution in situ hybridization.</strong> Tohoku J. Exp. Med. 160: 203-211, 1990.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2141199/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2141199</a>] [<a href="https://doi.org/10.1620/tjem.160.203" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2141199">Takeda et al. (1990)</a> narrowed the assignment to 15q23-q24. Using a cDNA clone for in situ hybridization, <a href="#56" class="mim-tip-reference" title="Nakai, H., Byers, M. G., Nowak, N. J., Shows, T. B. <strong>Assignment of beta-hexosaminidase A alpha-subunit to human chromosomal region 15q23-q24.</strong> Cytogenet. Cell Genet. 56: 164, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1829032/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1829032</a>] [<a href="https://doi.org/10.1159/000133077" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1829032">Nakai et al. (1991)</a> assigned the HEXA gene to 15q23-q24. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=2141199+3198122+1829032" 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="#51" class="mim-tip-reference" title="Myerowitz, R., Costigan, F. C. <strong>The major defect in Ashkenazi Jews with Tay-Sachs disease is an insertion in the gene for the alpha-chain of beta-hexosaminidase.</strong> J. Biol. Chem. 263: 18587-18589, 1988.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2848800/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2848800</a>]" pmid="2848800">Myerowitz and Costigan (1988)</a> demonstrated that the most frequent DNA lesion in Tay-Sachs disease in Ashkenazi Jews is a 4-bp insertion in exon 11 of the HEXA gene (<a href="/entry/606869#0001">606869.0001</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2848800" 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 gene responsible for the juvenile form has been shown by molecular analysis of the HEXA gene to be allelic to that responsible for the classic infantile form of Tay-Sachs disease (<a href="#75" class="mim-tip-reference" title="Paw, B. H., Moskowitz, S. M., Uhrhammer, N., Wright, N., Kaback, M. M., Neufeld, E. F. <strong>Juvenile G(M2) gangliosidosis caused by substitution of histidine for arginine at position 499 or 504 of the alpha-subunit of beta-hexosaminidase.</strong> J. Biol. Chem. 265: 9452-9457, 1990.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2140574/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2140574</a>]" pmid="2140574">Paw et al., 1990</a>). Whereas classic Tay-Sachs patients with complete deficiency of hexosaminidase A die before age 5 years, patients with the partial deficiency die by age 15 years. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2140574" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#98" class="mim-tip-reference" title="Tanaka, A., Ohno, K., Sandhoff, K., Maire, I., Kolodny, E. H., Brown, A., Suzuki, K. <strong>GM2-gangliosidosis B1 variant: analysis of beta-hexosaminidase alpha gene abnormalities in seven patients.</strong> Am. J. Hum. Genet. 46: 329-339, 1990. Note: Erratum: Am. J. Hum. Genet. 48: 176 only, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2137287/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2137287</a>]" pmid="2137287">Tanaka et al. (1990)</a> studied 7 patients with the enzymologic characteristics of the B1 variant. All of the patients, except 1 from Czechoslovakia, carried the same arg178-to-his mutation referred to as DN (see <a href="/entry/606869#0006">606869.0006</a>). The Czechoslovakian patient had a mutation in the same codon: a change at nucleotide 532 from C to T resulting in an arg178-to-cys change in the protein (see <a href="/entry/606869#0007">606869.0007</a>). Site-directed mutagenesis and expression studies in COS-1 cells demonstrated that either of the point mutations abolished catalytic activity of the alpha subunit. The HEXA gene has 1 intron that is exceptionally large. Is it possible that it contains a sequence that codes for an unrelated protein, with an allelic form in linkage disequilibrium with the Tay-Sachs gene accounting for the high frequency of the gene in Ashkenazim? <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2137287" 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="#54" class="mim-tip-reference" title="Myerowitz, R. <strong>Tay-Sachs disease-causing mutations and neutral polymorphisms in the Hex A gene.</strong> Hum. Mutat. 9: 195-208, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9090523/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9090523</a>] [<a href="https://doi.org/10.1002/(SICI)1098-1004(1997)9:3<195::AID-HUMU1>3.0.CO;2-7" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9090523">Myerowitz (1997)</a> stated that 78 mutations in the HEXA gene had been described, including 65 single-base substitutions, 1 large and 10 small deletions, and 2 small insertions. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9090523" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#106" class="mim-tip-reference" title="Wicklow, B. A., Ivanovich, J. L., Plews, M. M., Salo, T. J., Noetzel, M. J., Lueder, G. T., Cartegni, L., Kaback, M. M., Sandhoff, K., Steiner, R. D., Triggs-Raine, B. L. <strong>Severe subacute GM2 gangliosidosis caused by an apparently silent HEXA mutation (V324V) that results in aberrant splicing and reduced HEXA mRNA.</strong> Am. J. Med. Genet. 127A: 158-166, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15108204/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15108204</a>] [<a href="https://doi.org/10.1002/ajmg.a.20633" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15108204">Wicklow et al. (2004)</a> described a child with severe subacute GM2-gangliosidosis who presented at age 22 months with classic cherry-red spots of the fundus but did not develop any neurologic deficit until almost age 4. They identified 3 mutations in the HEXA gene: 10T-C (S4P; <a href="/entry/606869#0014">606869.0014</a>) and 972T-A (V324V; <a href="/entry/606869#0057">606869.0057</a>) on the maternal allele, and 1A-T (M1L; <a href="/entry/606869#0027">606869.0027</a>) on the paternal allele. Because the delay in onset of neurologic symptoms indicated the presence of residual HEXA, <a href="#106" class="mim-tip-reference" title="Wicklow, B. A., Ivanovich, J. L., Plews, M. M., Salo, T. J., Noetzel, M. J., Lueder, G. T., Cartegni, L., Kaback, M. M., Sandhoff, K., Steiner, R. D., Triggs-Raine, B. L. <strong>Severe subacute GM2 gangliosidosis caused by an apparently silent HEXA mutation (V324V) that results in aberrant splicing and reduced HEXA mRNA.</strong> Am. J. Med. Genet. 127A: 158-166, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15108204/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15108204</a>] [<a href="https://doi.org/10.1002/ajmg.a.20633" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15108204">Wicklow et al. (2004)</a> analyzed the effects of the amino acid substitutions on HEXA expression in COS-7 cells and discovered that the 972T-A mutation created a new exon 8 donor site, causing a 17-bp deletion and destabilization of the resulting abnormal transcript. <a href="#106" class="mim-tip-reference" title="Wicklow, B. A., Ivanovich, J. L., Plews, M. M., Salo, T. J., Noetzel, M. J., Lueder, G. T., Cartegni, L., Kaback, M. M., Sandhoff, K., Steiner, R. D., Triggs-Raine, B. L. <strong>Severe subacute GM2 gangliosidosis caused by an apparently silent HEXA mutation (V324V) that results in aberrant splicing and reduced HEXA mRNA.</strong> Am. J. Med. Genet. 127A: 158-166, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15108204/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15108204</a>] [<a href="https://doi.org/10.1002/ajmg.a.20633" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15108204">Wicklow et al. (2004)</a> concluded that the remaining normal mRNA produced from the 972T-A allele must account for the delayed onset of symptoms in this child. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15108204" 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>By homozygosity mapping followed by exon enrichment and next-generation sequencing in 136 consanguineous families (over 90% Iranian and less than 10% Turkish or Arab) segregating syndromic or nonsyndromic forms of autosomal recessive intellectual disability, <a href="#55" class="mim-tip-reference" title="Najmabadi, H., Hu, H., Garshasbi, M., Zemojtel, T., Abedini, S. S., Chen, W., Hosseini, M., Behjati, F., Haas, S., Jamali, P., Zecha, A., Mohseni, M., and 33 others. <strong>Deep sequencing reveals 50 novel genes for recessive cognitive disorders.</strong> Nature 478: 57-63, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21937992/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21937992</a>] [<a href="https://doi.org/10.1038/nature10423" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21937992">Najmabadi et al. (2011)</a> identified a missense mutation in the HEXA gene (<a href="/entry/606869#0058">606869.0058</a>) in a family (M165) in which first-cousin parents had 5 healthy children and 3 children with moderate intellectual disability and seizures. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21937992" 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="#5" class="mim-tip-reference" title="Balint, J. A., Kyriakides, E. C., Spitzer, H. L. <strong>On the chemical changes in the red cell stroma in Tay-Sachs disease: their value as genetic tracers. In: Aronson, S. M.; Volk, B. W.: Inborn Disorders of Sphingolipid Metabolism.</strong> Oxford: Pergamon Press (pub.) 1967. Pp. 423-430."None>Balint et al. (1967)</a> found that both homozygotes and heterozygotes show reduced sphingomyelin in red blood cells and suggested that this reduction is useful in carrier identification.</p><p><a href="#101" class="mim-tip-reference" title="Triggs-Raine, B. L., Feigenbaum, A. S. J., Natowicz, M., Skomorowski, M.-A., Schuster, S. M., Clarke, J. T. R., Mahuran, D. J., Kolodny, E. H., Gravel, R. A. <strong>Screening for carriers of Tay-Sachs disease among Ashkenazi Jews: a comparison of DNA-based and enzyme-based tests.</strong> New Eng. J. Med. 323: 6-12, 1990.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2355960/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2355960</a>] [<a href="https://doi.org/10.1056/NEJM199007053230102" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2355960">Triggs-Raine et al. (1990)</a> compared DNA-based and enzyme-based screening tests for carriers of TSD among Ashkenazim. Among 62 Ashkenazi obligate carriers, 3 specific mutations, indicated as <a href="/entry/606869#0001">606869.0001</a>, <a href="/entry/606869#0002">606869.0002</a>, and <a href="/entry/606869#0008">606869.0008</a> among the allelic variants, accounted for all but one of the mutant alleles (98%). In 216 Ashkenazi carriers identified by the enzyme tests, DNA analysis showed that 177 (82%) had 1 of the identified mutations. Of the 177, 79% had the exon 11 insertion mutation (<a href="/entry/606869#0001">606869.0001</a>), 18% had the intron 12 splice junction mutation (<a href="/entry/606869#0002">606869.0002</a>), and 3% had the less severe exon 7 mutation associated with adult-onset disease (<a href="/entry/606869#0008">606869.0008</a>). The results of the enzyme tests in 39 subjects (18%) who were defined as carriers but in whom DNA analysis did not identify a mutant allele were probably false positive (although there remained some possibility of unidentified mutations). Of 152 persons defined as noncarriers by the enzyme-based test, 1 was identified as a carrier by DNA analysis (i.e., a false-negative enzyme-test result). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2355960" 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>Tay-Sachs disease was one of the disorders used as a trial for preamplification DNA diagnosis of multiple disorders by <a href="#91" class="mim-tip-reference" title="Snabes, M. C., Chong, S. S., Subramanian, S. B., Kristjansson, K., DiSepio, D., Hughes, M. R. <strong>Preimplantation single-cell analysis of multiple genetic loci by whole-genome amplification.</strong> Proc. Nat. Acad. Sci. 91: 6181-6185, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7517043/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7517043</a>] [<a href="https://doi.org/10.1073/pnas.91.13.6181" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7517043">Snabes et al. (1994)</a>. They applied single-cell whole-genome preamplification to PCR-based analysis of multiple disease loci from the same diploid cell. The method they described allowed diagnosis of multiple disease genes, analysis of multiple exons/introns within a gene, or corroborative embryo-sex assignment and specific mutation detection at sex-linked loci. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7517043" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Although Tay-Sachs mutations are rare in the general population, non-Jewish individuals may be screened as spouses of Jewish carriers or as relatives of probands. To define a panel of alleles that might account for most mutations in non-Jewish carriers, <a href="#1" class="mim-tip-reference" title="Akerman, B. R., Natowicz, M. R., Kaback, M. M., Loyer, M., Campeau, E., Gravel, R. A. <strong>Novel mutations and DNA-based screening in non-Jewish carriers of Tay-Sachs disease.</strong> Am. J. Hum. Genet. 60: 1099-1106, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9150157/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9150157</a>]" pmid="9150157">Akerman et al. (1997)</a> investigated 26 independent alleles from 20 obligate carriers and 3 affected individuals. Eighteen alleles were represented by 12 previously identified mutations, 7 that were newly identified and 1 that remained unidentified. They then investigated 46 enzyme-defined carrier alleles: 19 were pseudodeficiency alleles and 5 mutations accounted for 15 other alleles. An eighth new mutation was detected among enzyme-defined carriers. Eleven alleles remained unidentified, despite the testing for 23 alleles. Some may represent false positives for the enzyme test. The results indicated that predominant mutations, other than the 2 pseudodeficiency alleles (739C-T, <a href="/entry/606869#0035">606869.0035</a> and 745C-T) and 1 disease allele (IVS9+1G-A; <a href="/entry/606869#0033">606869.0033</a>) do not occur in the general population. Thus, <a href="#1" class="mim-tip-reference" title="Akerman, B. R., Natowicz, M. R., Kaback, M. M., Loyer, M., Campeau, E., Gravel, R. A. <strong>Novel mutations and DNA-based screening in non-Jewish carriers of Tay-Sachs disease.</strong> Am. J. Hum. Genet. 60: 1099-1106, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9150157/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9150157</a>]" pmid="9150157">Akerman et al. (1997)</a> concluded that determination of carrier status by DNA analysis alone is inefficient because of the large proportion of rare alleles. Notwithstanding the possibility of false positives inherent to enzyme screening, this method remains an essential component of carrier screening in non-Jews. DNA screening can be best used as an adjunct to enzyme testing to exclude known HEXA pseudodeficiency alleles, the IVS9+1G-A disease allele, and other mutations relevant to the subject's genetic heritage. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9150157" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#4" class="mim-tip-reference" title="Bach, G., Tomczak, J., Risch, N., Ekstein, J. <strong>Tay-Sachs screening in the Jewish Ashkenazi population: DNA testing is the preferred procedure.</strong> Am. J. Med. Genet. 99: 70-75, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11170098/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11170098</a>] [<a href="https://doi.org/10.1002/1096-8628(20010215)99:1<70::aid-ajmg1120>3.0.co;2-0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11170098">Bach et al. (2001)</a> presented results strongly supporting the use of DNA testing alone as the most cost-effective and efficient approach to carrier screening for TSD in individuals of confirmed Ashkenazi Jewish ancestry. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11170098" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#13" class="mim-tip-reference" title="Chamoles, N. A., Blanco, M., Gaggioli, D., Casentini, C. <strong>Tay-Sachs and Sandhoff diseases: enzymatic diagnosis in dried blood spots on filter paper: retrospective diagnoses in newborn-screening cards.</strong> Clin. Chim. Acta 318: 133-137, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11880123/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11880123</a>] [<a href="https://doi.org/10.1016/s0009-8981(02)00002-5" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11880123">Chamoles et al. (2002)</a> described methods for the assay of hexosaminidase A activity in dried blood spots on filter paper for the screening of newborns. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11880123" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#102" class="mim-tip-reference" title="Vallance, H., Morris, T. J., Coulter-Mackie, M., Lim-Steele, J., Kaback, M. <strong>Common HEXB polymorphisms reduce serum HexA and HexB enzymatic activities, potentially masking Tay-Sachs disease carrier identification.</strong> Molec. Genet. Metab. 87: 122-127, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16352452/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16352452</a>] [<a href="https://doi.org/10.1016/j.ymgme.2005.10.012" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16352452">Vallance et al. (2006)</a> reported 2 clinically unaffected Ashkenazi Jewish brothers who had discrepant results on diagnosis of Tay-Sachs disease carrier status. Both had low-normal serum percent HexA enzyme activity above the cut-off for carrier detection, but leukocyte HexA activity was in the carrier range. DNA analysis showed that both brothers carried the common 4-bp insertion in the HEXA gene (1277_1278insTATC; <a href="/entry/606869#0001">606869.0001</a>) gene. Both also had 2 common polymorphisms in the HEXB gene: 619A-G (I207V) and a 2-bp deletion (delTG) in the 3-prime untranslated region. Genotyping of a larger sample of 72 Jewish and 104 non-Jewish alleles samples found that the HEXB variants were in strong linkage disequilibrium with haplotype frequencies of 9.7% and 7.7%, respectively. Three additional TSD carriers with the unusual biochemical phenotype (normal serum HexA activity and decreased leukocyte HexA activity) all carried the same HEXB I207V/delTG haplotype. Finally, analysis of a larger sample of 69 alleles found that the frequency of this HexB haplotype was significantly associated with low serum HexB activity. These findings indicated that this haplotype lowers HexB activity in serum, which has the effect of raising the percent of HexA activity as determined by heat inactivation methods of total Hex activity. This can result in masking of carrier status in carriers of TSD alleles that are measured solely by serum percentage of HexA activity. <a href="#102" class="mim-tip-reference" title="Vallance, H., Morris, T. J., Coulter-Mackie, M., Lim-Steele, J., Kaback, M. <strong>Common HEXB polymorphisms reduce serum HexA and HexB enzymatic activities, potentially masking Tay-Sachs disease carrier identification.</strong> Molec. Genet. Metab. 87: 122-127, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16352452/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16352452</a>] [<a href="https://doi.org/10.1016/j.ymgme.2005.10.012" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16352452">Vallance et al. (2006)</a> noted that the high prevalence of this HexB haplotype may become clinically relevant in diagnosis of TSD carrier status, and that additional diagnostic methods should be used. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16352452" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Prenatal Diagnosis</em></strong></p><p>
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<a href="#18" class="mim-tip-reference" title="Conzelmann, E., Nehrkorn, H., Kytzia, H.-J., Sandhoff, K., Macek, M., Lehovsky, M., Elleder, M., Jirasek, A., Kobilkova, J. <strong>Prenatal diagnosis of G(M)2 gangliosidosis with high residual hexosaminidase A activity (variant B-1; pseudo AB variant).</strong> Pediat. Res. 19: 1220-1224, 1985.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2933632/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2933632</a>] [<a href="https://doi.org/10.1203/00006450-198511000-00022" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2933632">Conzelmann et al. (1985)</a> performed prenatal diagnosis in a family with the pseudo-AB variant (B1 variant) of GM2-gangliosidosis. These patients have a late infantile form with nearly normal beta-hexosaminidase A levels when assayed with the usual synthetic substrate 4-methylumbelliferyl-N-acetyl-beta-D-glucosaminide. Since the enzyme is also inactive against another substrate that is thought to be hydrolyzed predominantly by Hex-A, the mutation is in the alpha subunit. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2933632" 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>Many aspects of Tay-Sachs disease and related disorders were discussed in the proceedings of a conference edited by <a href="#37" class="mim-tip-reference" title="Kaback, M. M., Rimoin, D. L., O'Brien, J. S. <strong>Tay-Sachs Disease: Screening and Prevention.</strong> New York: Alan R. Liss (pub.) 1977."None>Kaback et al. (1977)</a>. Tay-Sachs disease is approximately 100 times more common in infants of Ashkenazi Jewish ancestry (central-eastern Europe) than in non-Jewish infants (<a href="#37" class="mim-tip-reference" title="Kaback, M. M., Rimoin, D. L., O'Brien, J. S. <strong>Tay-Sachs Disease: Screening and Prevention.</strong> New York: Alan R. Liss (pub.) 1977."None>Kaback et al., 1977</a>). Tay-Sachs disease and Sandhoff disease in French Canadians of Quebec was discussed by <a href="#2" class="mim-tip-reference" title="Andermann, E., Scriver, C. R., Wolfe, L. S., Dansky, L., Andermann, F. <strong>Genetic variants of Tay-Sachs disease and Sandhoff's disease in French-Canadians, juvenile Tay-Sachs disease in Lebanese Canadians, and a Tay-Sachs screening program in the French-Canadian population. In: Kaback, M. M.; Rimoin, D. L.; O'Brien, J. S.: Tay-Sachs Disease: Screening and Prevention.</strong> New York: Alan R. Liss (pub.) 1977. Pp. 161-168."None>Andermann et al. (1977)</a>. Whether this represents an infusion of the Tay-Sachs gene from Jewish fur traders or an independent mutation was not known at that time, but was settled when the intragenic lesions were identified; see <a href="/entry/606869#0003">606869.0003</a>.</p><p><a href="#78" class="mim-tip-reference" title="Petersen, G. M., Rotter, J. I., Cantor, R. M., Field, L. L., Greenwald, S., Lim, J. S. T., Roy, C., Schoenfeld, V., Lowden, J. A., Kaback, M. M. <strong>The Tay-Sachs disease gene in North American Jewish populations: geographic variations and origin.</strong> Am. J. Hum. Genet. 35: 1258-1269, 1983.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/6650504/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">6650504</a>]" pmid="6650504">Petersen et al. (1983)</a> concluded that proliferation of the TSD gene occurred among the antecedents of modern Ashkenazi Jewry after the second Diaspora (70 A.D.) and before the major migrations to regions of Poland and Russia (1100 A.D. and later). Among Moroccan Jews, the carriers of a Tay-Sachs mutation were estimated to have a frequency of 1 in 45 (<a href="#59" class="mim-tip-reference" title="Navon, R. <strong>Personal Communication.</strong> Kfar Saba, Israel 6/13/1990."None>Navon, 1990</a>), a figure not greatly different from that found in North American Jews. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=6650504" 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="#78" class="mim-tip-reference" title="Petersen, G. M., Rotter, J. I., Cantor, R. M., Field, L. L., Greenwald, S., Lim, J. S. T., Roy, C., Schoenfeld, V., Lowden, J. A., Kaback, M. M. <strong>The Tay-Sachs disease gene in North American Jewish populations: geographic variations and origin.</strong> Am. J. Hum. Genet. 35: 1258-1269, 1983.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/6650504/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">6650504</a>]" pmid="6650504">Petersen et al. (1983)</a> found a TSD carrier frequency in 46,304 North American Jews to be 0.0324 (1 in 31). Jews with Polish and/or Russian ancestry constituted 88% of this sample and had a carrier frequency of 0.0327. No carrier was found among the 166 Jews of Near Eastern origins. Relative to Jews of Polish and Russian origins, there was a 2-fold increase in carrier frequency in Jews of Austrian, Hungarian, and Czechoslovakian origins. Among U.S. Jews originating from Austria, a carrier frequency of 0.1092 was observed. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=6650504" 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="#109" class="mim-tip-reference" title="Yokoyama, S. <strong>Role of genetic drift in the high frequency of Tay-Sachs disease among Ashkenazic Jews.</strong> Ann. Hum. Genet. 43: 133-136, 1979.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/525971/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">525971</a>] [<a href="https://doi.org/10.1111/j.1469-1809.1979.tb02005.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="525971">Yokoyama (1979)</a> concluded that it is unlikely that drift alone was responsible for the high frequency of Tay-Sachs disease in Ashkenazim. Heterozygote advantage was considered a likely additional factor. <a href="#93" class="mim-tip-reference" title="Spyropoulos, B., Moens, P. B., Davidson, J., Lowden, J. A. <strong>Heterozygote advantage in Tay-Sachs carriers?</strong> Am. J. Hum. Genet. 33: 375-380, 1981.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7246543/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7246543</a>]" pmid="7246543">Spyropoulos et al. (1981)</a> showed that proportionally the grandparents of Tay-Sachs disease carriers died from the same causes as grandparents of noncarriers. They suggested that the finding indirectly supports the notion that the high frequency of the TSD gene in Ashkenazim is 'caused by a combination of founder effect, genetic drift, and differential immigration patterns.' <a href="https://pubmed.ncbi.nlm.nih.gov/?term=7246543+525971" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#20" class="mim-tip-reference" title="Diamond, J. M. <strong>Tay-Sachs carriers and tuberculosis resistance. Reply. (Letter)</strong> Nature 331: 666, 1988."None>Diamond (1988)</a> defended selective advantage as the cause of the high frequency of the TS gene in Ashkenazi Jews.</p><p><a href="#76" class="mim-tip-reference" title="Paw, B. H., Tieu, P. T., Kaback, M. M., Lim, J., Neufeld, E. F. <strong>Frequency of three Hex A mutant alleles among Jewish and non-Jewish carriers identified in a Tay-Sachs screening program.</strong> Am. J. Hum. Genet. 47: 698-705, 1990.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2220809/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2220809</a>]" pmid="2220809">Paw et al. (1990)</a> analyzed the frequency of 3 HEXA mutations among heterozygotes identified in a Tay-Sachs screening program: the 4-nucleotide insertion in exon 11 (<a href="/entry/606869#0001">606869.0001</a>), the G-to-C transversion at the 5-prime splice site in intron 12 (<a href="/entry/606869#0002">606869.0002</a>), and the gly269-to-ser mutation in exon 7 (<a href="/entry/606869#0008">606869.0008</a>). Mutation analysis included PCR amplification of the relevant regions followed by allele-specific oligonucleotide (ASO) hybridization and, in the case of the exon 11 insertion, the formation of heteroduplex PCR fragments of low electrophoretic mobility. The percentage distribution of the exon 11, intron 12, exon 7, and unidentified mutant alleles was 73:15:4:8 among 156 Jewish carriers of HEXA deficiency and 16:0:3:81 among 51 non-Jewish carriers. Regardless of the mutation, the ancestral origin of the Jewish carriers was primarily eastern and (somewhat less often) central Europe, whereas for non-Jewish carriers it was western Europe. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2220809" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Among 148 Ashkenazi Jews carrying the Tay-Sachs gene, <a href="#27" class="mim-tip-reference" title="Grebner, E. E., Tomczak, J. <strong>Distribution of three alpha-chain beta-hexosaminidase A mutations among Tay-Sachs carriers.</strong> Am. J. Hum. Genet. 48: 604-607, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1825595/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1825595</a>]" pmid="1825595">Grebner and Tomczak (1991)</a> found that 108 had the insertion mutation (<a href="/entry/606869#0001">606869.0001</a>), 26 had the splice junction mutation (<a href="/entry/606869#0002">606869.0002</a>), 5 had the adult mutation (<a href="/entry/606869#0008">606869.0008</a>), and 9 had none of the 3. Among 28 non-Jewish carriers tested, most of whom were obligate carriers, 4 had the insertion mutation, 1 had the adult mutation, and the remaining 23 had none of the 3. The 2 patients with the asp258-to-his type of B1 allele (<a href="/entry/606869#0038">606869.0038</a>) had infantile TSD with serum and fibroblasts containing heterozygote levels of HEXA. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1825595" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#84" class="mim-tip-reference" title="Risch, N., Tang, H., Katzenstein, H., Ekstein, J. <strong>Geographic distribution of disease mutations in the Ashkenazi Jewish population supports genetic drift over selection.</strong> Am. J. Hum. Genet. 72: 812-822, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12612865/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12612865</a>] [<a href="https://doi.org/10.1086/373882" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12612865">Risch et al. (2003)</a> postulated that geographic distribution of disease mutations in the Ashkenazi Jewish population supports genetic drift, rather than selection, as the mechanism of unusually high frequency of conditions such as TSD. <a href="#110" class="mim-tip-reference" title="Zlotogora, J., Bach, G. <strong>The possibility of a selection process in the Ashkenazi Jewish population. (Letter)</strong> Am. J. Hum. Genet. 73: 438-440, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12868052/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12868052</a>] [<a href="https://doi.org/10.1086/377008" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12868052">Zlotogora and Bach (2003)</a> provided a rebuttal in support of selection as the determining factor. They stated that the occurrence of several mutations in the same gene or mutations in different genes responsible for the high prevalence of some genetic diseases in relatively small populations is most easily explained by selection, and pointed out that Bardet-Biedl syndrome (<a href="/entry/209900">209900</a>) has a high frequency among the Bedouins of the Negev, owing to mutations in 3 different genes. They pointed to the occurrence of the high frequency of 4 lysosomal storage diseases among Ashkenazim--TSD, Gaucher disease type I (<a href="/entry/230800">230800</a>), Niemann-Pick disease (see <a href="/entry/257200">257200</a>), and mucolipidosis type IV (<a href="/entry/252650">252650</a>)--in which the mutations are in genes that encode enzymes from a common biochemical pathway. In all 4, the main storage substances are sphingolipids. A further indication of a nonrandom process is the number of mutations responsible for each disorder. In almost all of the nonlysosomal disorders, 1 mutation is prevalent, and, if more than 1 mutation is found in a given population, its frequency is significantly less than 10% of the first mutation. This is true for almost all the nonlysosomal disorders, except cystic fibrosis (<a href="/entry/219700">219700</a>), in which a selection process had been suggested, and factor XI deficiency (<a href="/entry/612416">612416</a>). On the other hand, in all 4 lysosomal disorders among Ashkenazim, the second allele is more than 10% prevalent, when compared with the frequency of the major mutation. <a href="#85" class="mim-tip-reference" title="Risch, N., Tang, H. <strong>Selection in the Ashkenazi Jewish population unlikely--reply to Zlotogora and Bach. (Letter)</strong> Am. J. Hum. Genet. 73: 440-441, 2003."None>Risch and Tang (2003)</a> presented counterarguments. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=12612865+12868052" 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 Table 4 of their report, <a href="#45" class="mim-tip-reference" title="Lazarin, G. A., Haque, I. S., Nazareth, S., Iori, K., Patterson, A. S., Jacobson, J. L., Marshall, J. R., Seltzer, W. K., Patrizio, P., Evans, E. A., Srinivasan, B. S. <strong>An empirical estimate of carrier frequencies for 400+ causal Mendelian variants: results from an ethnically diverse clinical sample of 23,453 individuals.</strong> Genet. Med. 15: 178-186, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22975760/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22975760</a>] [<a href="https://doi.org/10.1038/gim.2012.114" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22975760">Lazarin et al. (2013)</a> noted that among 21,985 ethnically diverse individuals screened for Tay-Sachs disease/HexA deficiency carrier status, they identified 151 carriers. These 151 carriers included 90 carriers of Ashkenazi Jewish ethnicity from a subset of 2,386 Ashkenazi Jewish individuals screened. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22975760" 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="#22" class="mim-tip-reference" title="Fernandes Filho, J. A., Shapiro, B. E. <strong>Tay-Sachs disease.</strong> Arch. Neurol. 61: 1466-1468, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15364698/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15364698</a>] [<a href="https://doi.org/10.1001/archneur.61.9.1466" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15364698">Fernandes Filho and Shapiro (2004)</a> reviewed the early history of Tay-Sachs disease. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15364698" 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="#99" class="mim-tip-reference" title="Taniike, M., Yamanaka, S., Proia, R. L., Langaman, C., Bone-Turrentine, T., Suzuki, K. <strong>Neuropathology of mice with targeted disruption of Hexa gene, a model of Tay-Sachs disease.</strong> Acta Neuropath. 89: 296-304, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7610760/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7610760</a>] [<a href="https://doi.org/10.1007/BF00309622" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7610760">Taniike et al. (1995)</a> produced a mouse model of Tay-Sachs disease by targeted disruption of the HEXA gene. The mice were devoid of beta-hexosaminidase A activity, accumulated GM2 ganglioside in the central nervous system, and displayed neurons with membranous cytoplasmic bodies identical to those of Tay-Sachs disease in humans. Unlike human Tay-Sachs disease in which all neurons store GM2 ganglioside, no storage was evident in the olfactory bulb, cerebellar cortex, or spinal anterior horn cells of these mice. <a href="#88" class="mim-tip-reference" title="Sango, K., Yamanaka, S., Hoffmann, A., Okuda, Y., Grinberg, A., Westphal, H., McDonald, M. P., Crawley, J. N., Sandhoff, K., Suzuki, K., Proia, R. L. <strong>Mouse models of Tay-Sachs and Sandhoff diseases differ in neurologic phenotype and ganglioside metabolism.</strong> Nature Genet. 11: 170-176, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7550345/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7550345</a>] [<a href="https://doi.org/10.1038/ng1095-170" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7550345">Sango et al. (1995)</a> likewise found that disruption of the Hexa gene in mouse embryonic stem cells resulted in mice that showed no neurologic abnormalities, although they exhibited biochemical and pathologic features of the disease. In contrast, mice in whom the Hexb gene was disrupted as a model of Sandhoff disease were severely affected. The authors suggested that the phenotypic differences between the 2 mouse models was the result of differences in the ganglioside degradation pathway between mice and humans. The authors postulated that alternative ganglioside degradative pathway revealed by the hexosaminidase-deficient mice may be significant in the analysis of other mouse models of the sphingolipidoses, as well as suggest novel therapies for Tay-Sachs disease. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=7610760+7550345" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#16" class="mim-tip-reference" title="Cohen-Tannoudji, M., Marchand, P., Akli, S., Sheardown, S. A., Puech, J.-P., Kress, C., Gressens, P., Nassogne, M.-C., Beccari, T., Muggleton-Harris, A. L., Evrard, P., Stirling, J. L., Poenaru, L., Babinet, C. <strong>Disruption of murine Hexa gene leads to enzymatic deficiency and to neuronal lysosomal storage, similar to that observed in Tay-Sachs disease.</strong> Mammalian Genome 6: 844-849, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8747922/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8747922</a>] [<a href="https://doi.org/10.1007/BF00292433" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8747922">Cohen-Tannoudji et al. (1995)</a> used gene targeting in embryonic stem (ES) cells to disrupt the mouse Hexa gene. Mice homozygous for the disrupted allele mimicked some of the biochemical and histologic features of human Tay-Sachs disease. They displayed, for example, total deficiency of Hexa activity and membranous cytoplasmic inclusions typical of GM2-gangliosidoses found in the cytoplasm of their neurons. However, while the number of storage neurons increased with age, it remained low compared with that found in the human, and no apparent motor or behavioral disorders could be observed. This suggested that beta-hexosaminidase A is not an absolute requirement for ganglioside degradation in mice. Nonetheless, the authors stated that animal models should be useful for the testing of new forms of therapy. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8747922" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#79" class="mim-tip-reference" title="Phaneuf, D., Wakamatsu, N., Huang, J.-Q., Borowski, A., Peterson, A. C., Fortunato, S. R., Ritter, G., Igdoura, S. A., Morales, C. R., Benoit, G., Akerman, B. R., Leclerc, D., Hanai, N., Marth, J. D., Trasler, J. M., Gravel, R. A. <strong>Dramatically different phenotypes in mouse models of human Tay-Sachs and Sandhoff disease.</strong> Hum. Molec. Genet. 5: 1-14, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8789434/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8789434</a>] [<a href="https://doi.org/10.1093/hmg/5.1.1" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8789434">Phaneuf et al. (1996)</a> likewise found that mice with disruption of the Hexa gene suffered no obvious behavioral or neurologic deficit whereas those homozygous for a disruption of the Hexb gene developed a fatal neurodegenerative disease with spasticity, muscle weakness, rigidity, tremor, and ataxia. They proposed that homozygous Hexa-deficient mice escaped disease through particle catabolism of accumulated G(M2) via G(A2) through the combined action of sialidase and beta-hexosaminidase B. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8789434" 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 mouse model of Tay-Sachs disease, <a href="#80" class="mim-tip-reference" title="Platt, F. M., Neises, G. R., Reinkensmeier, G., Townsend, M. J., Perry, V. H., Proia, R. L., Winchester, B., Dwek, R. A., Butters, T. D. <strong>Prevention of lysosomal storage in Tay-Sachs mice treated with N-butyldeoxynojirimycin.</strong> Science 276: 428-431, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9103204/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9103204</a>] [<a href="https://doi.org/10.1126/science.276.5311.428" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9103204">Platt et al. (1997)</a> evaluated a strategy for treatment of the disorder based on N-butyldeoxynojirimycin, an inhibitor of glycosphingolipid (GSL) biosynthesis. When Tay Sachs mice were treated with this agent, the accumulation of GM2 in the brain was prevented, with the number of storage neurons and the quantity of ganglioside stored per cell markedly reduced. Thus, the authors concluded that limiting the biosynthesis of the substrate for the defective Hexa enzyme prevented GSL accumulation and the neuropathology associated with its storage in lysosomes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9103204" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#30" class="mim-tip-reference" title="Guidotti, J. E., Mignon, A., Haase, G., Caillaud, C., McDonell, N., Kahn, A., Poenaru, L. <strong>Adenoviral gene therapy of the Tay-Sachs disease in hexosaminidase A-deficient knock-out mice.</strong> Hum. Molec. Genet. 8: 831-838, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10196372/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10196372</a>] [<a href="https://doi.org/10.1093/hmg/8.5.831" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10196372">Guidotti et al. (1999)</a> determined the in vivo strategy leading to the highest Hexa activity in the maximum number of tissues in Hexa-deficient knockout mice. They demonstrated that intravenous coadministration of adenoviral vectors coding for both alpha- and beta-subunits, resulting in preferential liver transduction, was essential to obtain the most successful results. Only the supply of both subunits allowed for Hexa overexpression, leading to massive secretion of the enzyme in serum, and full or partial restoration of enzymatic activity in all peripheral tissues tested. These results emphasized the need to overexpress both subunits of heterodimeric proteins in order to obtain a high level of secretion in animals defective in only 1 subunit. Otherwise, the endogenous nondefective subunit is limiting. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10196372" 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="Bertani, V., Prioni, S., Di Lecce, R., Gazza, F., Ragionieri, L., Merialdi, G., Bonilauri, P., Jagannathan, V., Grassi, S., Cabitta, L., Paoli, A., Morrone, A., Sonnino, S., Drogemuller, C., Cantoni, A. M. <strong>A pathogenic HEXA missense variant in wild boars with Tay-Sachs disease.</strong> Molec. Genet. Metab. 133: 297-306, 2021.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/34119419/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">34119419</a>] [<a href="https://doi.org/10.1016/j.ymgme.2021.05.001" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="34119419">Bertani et al. (2021)</a> described 2 captive-bred wild boar littermates with a homozygous arg499-to-cys (R499C) mutation in the HEXA gene that was homologous to the R499C mutation (<a href="/entry/606869#0028">606869.0028</a>) present in compound heterozygous state in some patients with infantile or juvenile forms of Tay-Sachs disease. A third similarly affected littermate did not undergo gene sequencing, and an unaffected littermate did not have the mutation. The affected boars showed neurologic decline starting at 6 months of age with behavioral changes, twitching, and dysmetria, and progressing to seizures and quadriplegia. They were euthanized at 12 months of age. Analysis of CNS gangliosides demonstrated accumulation of GM2 ganglioside and reduction in sphingomyelin, sulfatides, and cerebrosides. Lysosomal HexA enzyme activity in lymphocytes was almost absent. Neurons in the central and peripheral nervous systems from the affected animals were enlarged and foamy, with diffuse cytoplasmic vacuolization. Transmission electron microscopy of CNS neurons showed lysosomes with membranous cytoplasmic bodies. <a href="#10" class="mim-tip-reference" title="Bertani, V., Prioni, S., Di Lecce, R., Gazza, F., Ragionieri, L., Merialdi, G., Bonilauri, P., Jagannathan, V., Grassi, S., Cabitta, L., Paoli, A., Morrone, A., Sonnino, S., Drogemuller, C., Cantoni, A. M. <strong>A pathogenic HEXA missense variant in wild boars with Tay-Sachs disease.</strong> Molec. Genet. Metab. 133: 297-306, 2021.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/34119419/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">34119419</a>] [<a href="https://doi.org/10.1016/j.ymgme.2021.05.001" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="34119419">Bertani et al. (2021)</a> proposed that because brain growth, composition, and myelination during development in pigs is similar to humans, wild boars serve as a better large animal model for Tay-Sachs disease compared to other models. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=34119419" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#94" class="mim-tip-reference" title="Story, B., Taghian, T., Gallagher, J., Koehler, J., Taylor, A., Randle, A., Nielsen, K., Gross, A., Maguire, A., Carl, S., Johnson, S., Fernau, D., Diffie, E., Cuddon, P., Corado, C., Chandra, S., Sena-Esteves, M., Kolodny, E., Jiang, X., Martin, D., Gray-Edwards, H. <strong>Natural history of Tay-Sachs disease in sheep.</strong> Molec. Genet. Metab. 134: 164-174, 2021.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/34456134/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">34456134</a>] [<a href="https://doi.org/10.1016/j.ymgme.2021.08.009" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="34456134">Story et al. (2021)</a> characterized the neurologic phenotype of the naturally occurring Jacob sheep model of Tay-Sachs disease with deficient hexosaminidase A. The phenotypes were evaluated at 3 months (when the sheep are mildly affected), 6 months, and 9 months of life (or at the humane endpoint, when the sheep are severely affected and lose the ability to walk). Brain MRIs showed that the mutant sheep had demyelination evident at the borders of white and gray matter at 3 months of age and loss of normal white matter hypointensity due to demyelination at 9 months of age. MR spectroscopy of brain metabolites in mutant sheep demonstrated a progressive increase in glutamine and a decrease in glutamate from 3 to 9 months, and a progressive increase in taurine, glycerophosphocholine, and creatine from 3 to 9 months of age. Histopathology demonstrated widespread microglial activation starting at 6 months and reactive astrocytosis starting at 3 months in brain tissue. <a href="#94" class="mim-tip-reference" title="Story, B., Taghian, T., Gallagher, J., Koehler, J., Taylor, A., Randle, A., Nielsen, K., Gross, A., Maguire, A., Carl, S., Johnson, S., Fernau, D., Diffie, E., Cuddon, P., Corado, C., Chandra, S., Sena-Esteves, M., Kolodny, E., Jiang, X., Martin, D., Gray-Edwards, H. <strong>Natural history of Tay-Sachs disease in sheep.</strong> Molec. Genet. Metab. 134: 164-174, 2021.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/34456134/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">34456134</a>] [<a href="https://doi.org/10.1016/j.ymgme.2021.08.009" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="34456134">Story et al. (2021)</a> concluded that this sheep model most closely represents juvenile or late-onset Tay-Sachs disease. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=34456134" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a href="#Aronson1960" class="mim-tip-reference" title="Aronson, S. M., Valsamis, M. P., Volk, B. W. <strong>Infantile amaurotic family idiocy: occurrence, genetic considerations and pathophysiology in the non-Jewish infant.</strong> Pediatrics 26: 229-242, 1960.">Aronson et al. (1960)</a>; <a href="#Ben-Yoseph1985" class="mim-tip-reference" title="Ben-Yoseph, Y., Reid, J. E., Shapiro, B., Nadler, H. L. <strong>Diagnosis and carrier detection of Tay-Sachs disease: direct determination of hexosaminidase A using 4-methylumbelliferyl derivatives of beta-N-acetylglucosamine-6-sulfate and beta-N-acetylgalactosamine-6-sulfate.</strong> Am. J. Hum. Genet. 37: 733-748, 1985.">Ben-Yoseph et al. (1985)</a>; <a href="#Brady1970" class="mim-tip-reference" title="Brady, R. O. <strong>Cerebral lipidoses.</strong> Ann. Rev. Med. 21: 317-334, 1970.">Brady (1970)</a>; <a href="#Charrow1985" class="mim-tip-reference" title="Charrow, J., Inui, K., Wenger, D. A. <strong>Late onset GM(2) gangliosidosis: an alpha-locus genetic compound with near normal hexosaminidase activity.</strong> Clin. Genet. 27: 78-84, 1985.">Charrow et al. (1985)</a>; <a href="#Dreyfus1975" class="mim-tip-reference" title="Dreyfus, J.-C., Poenaru, L., Svennerholm, L. <strong>Absence of hexosaminidase A and B in a normal adult.</strong> New Eng. J. Med. 292: 61-63, 1975.">Dreyfus et al. (1975)</a>; <a href="#Greenberg1982" class="mim-tip-reference" title="Greenberg, D. A., Kaback, M. M. <strong>Estimation of the frequency of hexosaminidase A variant alleles in the American Jewish population.</strong> Am. J. Hum. Genet. 34: 444-451, 1982.">Greenberg and Kaback
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<strong>REFERENCES</strong>
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[<a href="https://doi.org/10.1172/JCI105876" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1016/s0009-8981(02)00002-5" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1073/pnas.73.10.3637" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1007/BF00292433" target="_blank">Full Text</a>]
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/936207/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">936207</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=936207" 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/10.1620/tjem.118.323" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1016/s0140-6736(69)92520-3" target="_blank">Full Text</a>]
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<strong>Juvenile GM2 gangliosidosis (A(M)B variant): inability to activate hexosaminidase A by activator protein.</strong>
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[<a href="https://doi.org/10.1002/ana.410110103" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1002/ana.410240316" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1111/j.1469-1809.1984.tb01025.x" target="_blank">Full Text</a>]
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</li>
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<li>
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<a id="107" class="mim-anchor"></a>
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<a id="Willner1981" class="mim-anchor"></a>
|
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<div class="">
|
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<p class="mim-text-font">
|
|
Willner, J. P., Grabowski, G. A., Gordon, R. E., Bender, A. N., Desnick, R. J.
|
|
<strong>Chronic GM(2) gangliosidosis masquerading as atypical Friedreich ataxia: clinical morphologic and biochemical studies of nine cases.</strong>
|
|
Neurology 31: 787-798, 1981.
|
|
|
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|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/6454083/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">6454083</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=6454083" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1212/wnl.31.7.787" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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<li>
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<a id="108" class="mim-anchor"></a>
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<a id="Yaffe1979" class="mim-anchor"></a>
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<div class="">
|
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<p class="mim-text-font">
|
|
Yaffe, M. G., Kaback, M., Goldberg, M., Miles, J., Itabashi, H., McIntyre, H., Mohandas, T.
|
|
<strong>An amyotrophic lateral sclerosis-like syndrome with hexosaminidase-A deficiency: a new type of GM(2) gangliosidosis. (Abstract)</strong>
|
|
Neurology 29: 611, 1979.
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</p>
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</div>
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</li>
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<li>
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<a id="109" class="mim-anchor"></a>
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<a id="Yokoyama1979" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Yokoyama, S.
|
|
<strong>Role of genetic drift in the high frequency of Tay-Sachs disease among Ashkenazic Jews.</strong>
|
|
Ann. Hum. Genet. 43: 133-136, 1979.
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|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/525971/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">525971</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=525971" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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|
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[<a href="https://doi.org/10.1111/j.1469-1809.1979.tb02005.x" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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<li>
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<a id="110" class="mim-anchor"></a>
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<a id="Zlotogora2003" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Zlotogora, J., Bach, G.
|
|
<strong>The possibility of a selection process in the Ashkenazi Jewish population. (Letter)</strong>
|
|
Am. J. Hum. Genet. 73: 438-440, 2003.
|
|
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|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12868052/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12868052</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12868052" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1086/377008" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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</ol>
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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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<div>
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<a id="contributors" class="mim-anchor"></a>
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<div class="row">
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
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<span class="mim-text-font">
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<a href="#mimCollapseContributors" role="button" data-toggle="collapse"> Contributors: </a>
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</span>
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</div>
|
|
<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
|
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<span class="mim-text-font">
|
|
Hilary J. Vernon - updated : 06/23/2022
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</span>
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</div>
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</div>
|
|
<div class="row collapse" id="mimCollapseContributors">
|
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<div class="col-lg-offset-2 col-md-offset-4 col-sm-offset-4 col-xs-offset-2 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 : 10/08/2021<br>Hilary J. Vernon - updated : 09/09/2021<br>Ada Hamosh - updated : 5/30/2013<br>Ada Hamosh - updated : 1/6/2012<br>Cassandra L. Kniffin - updated : 1/4/2010<br>Cassandra L. Kniffin - updated : 4/6/2005<br>Cassandra L. Kniffin - updated : 12/15/2004<br>Marla J. F. O'Neill - updated : 6/30/2004<br>Victor A. McKusick - updated : 8/11/2003<br>George E. Tiller - updated : 2/24/2003<br>Victor A. McKusick - updated : 1/22/2003<br>Cassandra L. Kniffin - reorganized : 5/7/2002<br>Cassandra L. Kniffin - updated : 5/7/2002<br>Victor A. McKusick - updated : 2/21/2001<br>Victor A. McKusick - updated : 5/18/1999<br>Victor A. McKusick - updated : 9/9/1998<br>Victor A. McKusick - updated : 9/4/1998<br>Victor A. McKusick - edited : 2/24/1998<br>Victor A. McKusick - updated : 10/10/1997<br>Victor A. McKusick - updated : 8/27/1997<br>Victor A. McKusick - updated : 6/16/1997<br>Victor A. McKusick - updated : 5/8/1997<br>Victor A. McKusick - updated : 4/17/1997<br>Perseveranda M. Cagas - updated : 11/6/1996<br>Orest Hurko - updated : 11/6/1996<br>Stylianos E. Antonarakis - updated : 6/29/1996<br>Orest Hurko - updated : 6/13/1995
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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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<a id="creationDate" class="mim-anchor"></a>
|
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<div class="row">
|
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
|
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<span class="text-nowrap mim-text-font">
|
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Creation Date:
|
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</span>
|
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</div>
|
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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">
|
|
Victor A. McKusick : 6/4/1986
|
|
</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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<a id="editHistory" class="mim-anchor"></a>
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<div class="row">
|
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
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<span class="text-nowrap mim-text-font">
|
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<a href="#mimCollapseEditHistory" role="button" data-toggle="collapse"> Edit History: </a>
|
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</span>
|
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</div>
|
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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">
|
|
carol : 06/24/2022
|
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</span>
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</div>
|
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</div>
|
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<div class="row collapse" id="mimCollapseEditHistory">
|
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<div class="col-lg-offset-2 col-md-offset-2 col-sm-offset-4 col-xs-offset-4 col-lg-6 col-md-6 col-sm-6 col-xs-6">
|
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<span class="mim-text-font">
|
|
carol : 06/23/2022<br>carol : 10/08/2021<br>carol : 09/11/2021<br>carol : 09/10/2021<br>carol : 09/09/2021<br>carol : 07/23/2021<br>carol : 07/05/2017<br>carol : 10/17/2016<br>carol : 07/09/2016<br>carol : 5/12/2015<br>alopez : 5/30/2013<br>alopez : 11/29/2012<br>alopez : 11/29/2012<br>alopez : 11/27/2012<br>terry : 10/2/2012<br>carol : 5/30/2012<br>carol : 5/10/2012<br>carol : 1/9/2012<br>terry : 1/6/2012<br>wwang : 2/16/2010<br>ckniffin : 1/4/2010<br>carol : 11/4/2009<br>carol : 11/4/2009<br>carol : 11/2/2009<br>terry : 3/25/2009<br>carol : 11/20/2008<br>terry : 8/26/2008<br>terry : 8/26/2008<br>terry : 8/26/2008<br>carol : 10/1/2007<br>carol : 11/18/2005<br>wwang : 4/20/2005<br>wwang : 4/15/2005<br>ckniffin : 4/6/2005<br>carol : 3/3/2005<br>tkritzer : 12/21/2004<br>ckniffin : 12/15/2004<br>carol : 7/1/2004<br>terry : 6/30/2004<br>tkritzer : 8/18/2003<br>terry : 8/11/2003<br>carol : 8/1/2003<br>carol : 2/27/2003<br>cwells : 2/24/2003<br>cwells : 1/29/2003<br>tkritzer : 1/22/2003<br>carol : 5/7/2002<br>carol : 5/7/2002<br>carol : 5/7/2002<br>ckniffin : 5/6/2002<br>carol : 5/6/2002<br>ckniffin : 4/30/2002<br>carol : 3/2/2001<br>cwells : 2/27/2001<br>terry : 2/21/2001<br>mcapotos : 8/4/2000<br>mgross : 5/25/1999<br>terry : 5/18/1999<br>carol : 10/14/1998<br>dkim : 9/10/1998<br>alopez : 9/10/1998<br>terry : 9/9/1998<br>carol : 9/8/1998<br>terry : 9/4/1998<br>terry : 8/13/1998<br>terry : 7/24/1998<br>terry : 6/4/1998<br>mark : 3/3/1998<br>terry : 2/24/1998<br>mark : 2/11/1998<br>alopez : 1/13/1998<br>jenny : 10/17/1997<br>terry : 10/10/1997<br>jenny : 9/5/1997<br>terry : 8/27/1997<br>terry : 6/23/1997<br>terry : 6/16/1997<br>mark : 6/10/1997<br>mark : 5/8/1997<br>alopez : 5/6/1997<br>mark : 4/17/1997<br>terry : 4/14/1997<br>mark : 4/2/1997<br>terry : 3/31/1997<br>terry : 1/17/1997<br>mark : 11/6/1996<br>mark : 11/6/1996<br>terry : 10/23/1996<br>carol : 6/29/1996<br>carol : 6/27/1996<br>carol : 5/29/1996<br>mark : 2/14/1996<br>mark : 2/9/1996<br>terry : 2/9/1996<br>terry : 1/31/1996<br>mark : 12/20/1995<br>mark : 10/30/1995<br>carol : 9/21/1994<br>davew : 8/31/1994<br>jason : 7/12/1994<br>warfield : 4/20/1994
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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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<div class="container visible-print-block">
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<div class="row">
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<div class="col-md-8 col-md-offset-1">
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<div>
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<div>
|
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<h3>
|
|
<span class="mim-font">
|
|
<strong>#</strong> 272800
|
|
</span>
|
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</h3>
|
|
</div>
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|
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<div>
|
|
<h3>
|
|
<span class="mim-font">
|
|
|
|
TAY-SACHS DISEASE; TSD
|
|
|
|
</span>
|
|
</h3>
|
|
</div>
|
|
<div>
|
|
<br />
|
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</div>
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<div>
|
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<div >
|
|
<p>
|
|
<span class="mim-font">
|
|
<em>Alternative titles; symbols</em>
|
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</span>
|
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</p>
|
|
</div>
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
GM2-GANGLIOSIDOSIS, TYPE I<br />
|
|
B VARIANT GM2-GANGLIOSIDOSIS<br />
|
|
HEXOSAMINIDASE A DEFICIENCY<br />
|
|
HEXA DEFICIENCY
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
</div>
|
|
<div>
|
|
<br />
|
|
</div>
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<div>
|
|
<div>
|
|
<p>
|
|
<span class="mim-font">
|
|
Other entities represented in this entry:
|
|
</span>
|
|
</p>
|
|
</div>
|
|
<div>
|
|
<span class="h3 mim-font">
|
|
TAY-SACHS DISEASE, JUVENILE, INCLUDED
|
|
</span>
|
|
</div>
|
|
|
|
<div>
|
|
<span class="h4 mim-font">
|
|
|
|
HEXOSAMINIDASE A DEFICIENCY, ADULT TYPE, INCLUDED<br />
|
|
GM2-GANGLIOSIDOSIS, ADULT CHRONIC TYPE, INCLUDED<br />
|
|
GM2-GANGLIOSIDOSIS, VARIANT B1, INCLUDED<br />
|
|
TAY-SACHS DISEASE, VARIANT B1, INCLUDED<br />
|
|
TAY-SACHS DISEASE, PSEUDO-AB VARIANT, INCLUDED
|
|
</span>
|
|
</div>
|
|
|
|
</div>
|
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<div>
|
|
<br />
|
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</div>
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</div>
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<div>
|
|
<p>
|
|
<span class="mim-text-font">
|
|
|
|
<strong>SNOMEDCT:</strong> 111385000;
|
|
|
|
|
|
<strong>ICD10CM:</strong> E75.02;
|
|
|
|
|
|
|
|
<strong>ORPHA:</strong> 309178, 309185, 309192, 845;
|
|
|
|
|
|
<strong>DO:</strong> 3320;
|
|
|
|
|
|
</span>
|
|
</p>
|
|
</div>
|
|
<div>
|
|
<br />
|
|
</div>
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|
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|
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<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>Phenotype-Gene Relationships</strong>
|
|
</span>
|
|
</h4>
|
|
<div>
|
|
<table class="table table-bordered table-condensed small mim-table-padding">
|
|
<thead>
|
|
<tr class="active">
|
|
<th>
|
|
Location
|
|
</th>
|
|
<th>
|
|
Phenotype
|
|
</th>
|
|
<th>
|
|
Phenotype <br /> MIM number
|
|
</th>
|
|
<th>
|
|
Inheritance
|
|
</th>
|
|
<th>
|
|
Phenotype <br /> mapping key
|
|
</th>
|
|
<th>
|
|
Gene/Locus
|
|
</th>
|
|
<th>
|
|
Gene/Locus <br /> MIM number
|
|
</th>
|
|
</tr>
|
|
</thead>
|
|
<tbody>
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
15q23
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
Tay-Sachs disease
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
272800
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
Autosomal recessive
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
3
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
HEXA
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
606869
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
15q23
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
GM2-gangliosidosis, several forms
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
272800
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
Autosomal recessive
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
3
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
HEXA
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
606869
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
15q23
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
[Hex A pseudodeficiency]
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
272800
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
Autosomal recessive
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
3
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
HEXA
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
606869
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
</tbody>
|
|
</table>
|
|
</div>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>TEXT</strong>
|
|
</span>
|
|
</h4>
|
|
|
|
|
|
|
|
|
|
|
|
<span class="mim-text-font">
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<p>A number sign (#) is used with this entry because Tay-Sachs disease (TSD) is caused by homozygous or compound heterozygous mutation in the alpha subunit of the hexosaminidase A gene (HEXA; 606869) on chromosome 15q23.</p>
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<strong>Description</strong>
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<p>Tay-Sachs disease is an autosomal recessive, progressive neurodegenerative disorder which, in the classic infantile form, is usually fatal by age 2 or 3 years.</p>
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<strong>Clinical Features</strong>
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<p>Classic Tay-Sachs disease is characterized by the onset in infancy of developmental retardation, followed by paralysis, dementia and blindness, with death in the second or third year of life. A gray-white area around the retinal fovea centralis, due to lipid-laden ganglion cells, leaving a central 'cherry-red' spot is a typical funduscopic finding. Pathologic verification is provided by the finding of the typically ballooned neurons in the central nervous system. An early and persistent extension response to sound ('startle reaction') is useful for recognizing the disorder.</p><p>Kolodny (1972), who studied the proband described by Okada et al. (1971), stated that visual function was retained and optic atrophy was not present at age 20 months. At death at 32 months, microscopic findings in the central nervous system were similar to those in Tay-Sachs disease. The patients showed normal results in tests that usually demonstrate the Tay-Sachs heterozygote. </p><p>Suzuki et al. (1970) and O'Brien (1972) reported non-Jewish patients with the Tay-Sachs variant of juvenile-onset GM2-gangliosidosis. Onset occurred with ataxia between ages 2 and 6 years. Thereafter deterioration to decerebrate rigidity took place. Blindness occurred late in the course in only some patients, unlike the situation in classic Tay-Sachs disease in which blindness is an invariable and early development. Death occurred between ages 5 and 15 years. The defect is a partial deficiency of hexosaminidase A. </p><p>Rapin et al. (1976) described a brother and 2 sisters of Ashkenazi extraction who had slowly progressive deterioration of gait and posture beginning in early childhood, muscle atrophy beginning distally, pes cavus, foot drop, spasticity, mild ataxia of limbs and trunk, dystonia, and dysarthria. Intelligence was little affected, vision and optic fundi were normal, and no seizures had occurred. One sister died at age 16 following a drug reaction. Autopsy showed diffuse neuronal storage with zebra bodies and increased GM2-ganglioside. Hexosaminidase A was decreased in the serum and leukocytes of the 2 living patients, and in their parents was in the range of carriers of Tay-Sachs disease. The 2 living sibs were 31 and 34 years old at the time of the report. This may be an allelic variety of Tay-Sachs disease. Kaback et al. (1978) described a similar but possibly distinct case. The son of an Ashkenazi couple was entirely normal until age 16 when slight leg muscle cramps began. Hex-A deficiency was found in a screening program at age 20. Both parents and a sister were heterozygotes. Heterokaryon complementation showed the development of Hex-A when the proband's cells were fused with Sandhoff cells, but showed no complementation with Tay-Sachs cells. Between ages 20 and 22, the patient showed dramatically progressive proximal muscle wasting, weakness, fasciculations, EMG abnormality, and elevated CPK. Ophthalmologic, audiologic and intellectual function remained normal. Muscle biopsy suggested anterior horn disease. Rectal ganglion cells showed ballooning and onion-skin cytoplasmic bodies. </p><p>Willner et al. (1981) reported 9 patients from 4 unrelated Ashkenazi Jewish families with a variant form of Hex-A deficiency masquerading as atypical Friedreich ataxia. They proposed that the affected individuals may be genetic compounds for the Tay-Sachs allele and another distinctive allele. </p><p>Johnson et al. (1982) observed a 24-year-old Ashkenazi man with a 9-year history of progressive leg weakness and fasciculations. Other data were consistent with anterior horn cell disease. Hex-A was markedly decreased in the patient and partially decreased in both parents and a brother. A paternal relative had classic Tay-Sachs disease. The clinical picture, which suggested the Kugelberg-Welander phenotype, may have resulted, according to the suggestion of the authors, from a genetic compound state of the classic allele and a mild allele. </p><p>Griffin (1984) had a 31-year-old patient with hexosaminidase deficiency and marked cerebellar atrophy, dementia, and denervation motor neuron disease. Both parents showed a partial deficiency. In 3 patients in 2 unrelated families, Mitsumoto et al. (1985) described adult variants of hexosaminidase A deficiency. A 30-year-old non-Jewish proband in the first family had juvenile amyotrophic lateral sclerosis beginning at age 16 years and evolving to mild dementia, ataxia, and axonal (neuronal) motor-sensory peripheral neuropathy. A supposedly healthy brother, aged 32, had difficulty with memory in college but had obtained 2 degrees in 8 years and worked in an electronics company. He was dismissed from his job for poor memory and comprehension. He showed mild spasticity and ataxia but no evidence of motor neuron disease. In the second family, a 36-year-old man with Ashkenazi mother and Syrian Sephardic father had 'pure' spinal muscular atrophy; he had lifelong physical limitation with inability to run or throw a ball as a child. All 3 had marked cerebellar atrophy. Against artificial substrates, Hex-A activity was in the range of Tay-Sachs disease homozygotes but was higher when GM2 substrates were used. Hex-A activity in the parents was in the heterozygous range. </p><p>In a 34-year-old English Canadian man described by Parnes et al. (1985), the clinical picture was that of juvenile-onset spinal muscular atrophy. Atypical features were prominent muscle cramps, postural and action tremor, recurrent psychosis, incoordination, corticospinal and corticobulbar involvement, and dysarthria. With the report of a 24-year-old, non-Jewish man with dystonia, dementia, amyotrophy, choreoathetosis, and ataxia, Oates et al. (1986) emphasized that presumably allelic forms of Hex-A deficiency can take unusual clinical forms. </p><p>In Israel, Navon et al. (1986) identified 18 Hex-A-deficient adults by the end of 1985. All were Ashkenazi. The clinical picture varied between and within families and included spinocerebellar, various motor neuron, and cerebellar syndromes. The possibility exists that many of the affected persons are compound heterozygotes of the TSD allele with another rare allele. The relatively high frequency of the atypical adult disorder(s) in Ashkenazim is the result of the high frequency of the TSD allele to create genetic compounds. </p><p>Grebner et al. (1986) studied 3 clinically normal persons, aged 6 to 30 years, with absent serum Hex-A activity against artificial substrates and concluded that they were probably genetic compounds of the usual Tay-Sachs allele and a different mutant allele that in combination with it gave the abnormal phenotype. Karni et al. (1988) described a 39-year-old Israeli woman with proximal lower limb weakness and fasciculations as the only manifestations of Hex-A deficiency. </p><p>Bayleran et al. (1987) characterized the defective enzyme in 2 patients with Tay-Sachs disease and a high residual Hex-A activity. Clinical presentation was identical to that found among Ashkenazi patients. Both patients appeared to be heterozygous for the B1 phenotype, having virtually no capacity for hydrolysis of the sulfated HEXA substrate 4-methylumbelliferyl-beta-D-N-acetylglucosamine-6-sulfate (4MUGS). </p><p>Barnes et al. (1991) described a 42-year-old man of non-Jewish ancestry who in his 20s and 30s had the onset of slowly progressive gait disturbance, generalized weakness, dysarthria, clumsiness and tremor of his hands, and involuntary jerks. Two previously unreported features were clinically evident sensory neuropathy and internuclear ophthalmoplegia. </p><p>Perlman (2002) commented on late-onset Tay-Sachs disease as a Friedreich ataxia phenocopy. </p><p>Rucker et al. (2004) evaluated eye movements in 14 patients with late-onset Tay-Sachs disease (average age, 39 years). The main clinical features included childhood clumsiness or incoordination, proximal muscle weakness, ataxia, dysarthria, and tremor. All patients had normal visual function and normal optic fundi without cherry red spots. Saccades were hypometric and multistep with transient decelerations. Peak acceleration values of the saccades were normal, but decelerations occurred sooner and faster than in controls. Smooth pursuit was also impaired. Rucker et al. (2004) postulated a disruption in a 'latch circuit' that normally inhibits pontine 'omnipause' neurons to allow completion of eye movement. Saccade measurements may be a means of evaluating responses to treatment in patients with late-onset Tay-Sachs disease. </p><p>Rowe et al. (2021) examined MRI and MR spectroscopy in 7 patients with late-onset Tay-Sachs disease and 3 patients with late-onset Sandhoff disease (268800). Compared to age-matched controls, patients with late-onset Tay-Sachs disease had decreased total cerebellar volume and cerebellar gray matter. On MR spectroscopy of the cerebellum, patients with late-onset Tay-Sachs disease had significantly decreased N-acetylaspartate, combined glutamine and glutamate, and creatine as well as significantly increased myo-inositol compared to controls. Rowe et al. (2021) concluded that the changes in these metabolites indicated widespread neuronal dysfunction, inflammation, and altered energy metabolism in late-onset Tay-Sachs disease. Among the 10 patients with late-onset Tay-Sachs or Sandhoff disease, there was a significant association between cerebellar volume and the Scale for the Assessment and Rating of Ataxia (SARA). </p><p><strong><em>Reviews</em></strong></p><p>
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Neufeld (1989) provided a review of the disorders related to mutations in the HEXA (606869) and HEXB genes (606873). </p>
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<strong>Biochemical Features</strong>
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<p>Balint and Kyriakides (1968) demonstrated accumulation of a glycoprotein in red cells of patients with Tay-Sachs disease. The basic enzyme defect was shown by Okada and O'Brien (1969) to concern one component of hexosaminidase. Total hexosaminidase activity was normal but when components A (HEXA; 606869) and B (HEXB; 606873) were separated, component A was found to be absent. Hultberg (1969) confirmed the findings of Okada and O'Brien (1969). Okada et al. (1971) compared the findings in regard to hexosaminidases A and B in 3 forms of ganglioside GM2 storage disease--Tay-Sachs disease, Sandhoff disease (268800), and juvenile GM2-gangliosidosis. </p><p>Galjaard et al. (1974), Thomas et al. (1974), and Rattazzi et al. (1975) showed that Hex-A activity appears after fusion of Tay-Sachs and Sandhoff cells, suggesting genetic (or at least metabolic) complementation. </p><p>Beutler et al. (1975) concluded that Hex-A has the structure alpha-beta, whereas Hex-B is beta-beta; Tay-Sachs disease is an alpha-minus mutation, whereas Sandhoff disease is a beta-minus mutation; in the absence of beta subunits there is increased polymerization of alpha units to form Hex-S, which is a normal constituent of plasma and probably has a structure of alpha-6. </p><p>O'Brien (1978) made suggestions for nomenclature of the various hexosaminidase A and B mutations. Three loci were postulated: alpha, responsible for the alpha subunit, mapped to chromosome 15; beta, responsible for the beta subunit, mapped to chromosome 5; and an activator locus or loci determining the structure of one or more proteins that stimulate Hex-A to cleave GM2 and GA2 gangliosides. </p><p>Conzelmann et al. (1983) used a sensitive assay to demonstrate a correlation between level of residual activity and clinical severity: Tay-Sachs disease, 0.1% of normal; late infantile, 0.5%; adult GM2-gangliosidosis, 2-4%; healthy persons with 'low hexosaminidase,' 11% and 20%. </p><p>Several patients with a chronic type of Tay-Sachs disease were found by d'Azzo et al. (1984) to produce alpha-hexosaminidase A. </p><p><strong><em>GM2-Gangliosidosis, B1 Variant</em></strong></p><p>
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Patients with the GM2-gangliosidosis B1 variant produce hexosaminidase A, which appears catalytically normal when tested with substrates such as 4-methylumbelliferyl N-acetyl-glucosaminidase that are split by an active site of the beta subunit, but is catalytically defective against substrates that are hydrolyzed by the active site on the alpha subunit of normal hexosaminidase A, which is inactivated in patients' enzyme (Kytzia and Sandhoff, 1985). </p><p>Li et al. (1981) described a patient described as having a variant of type AB GM2-gangliosidosis but with a probable defect in beta-hexosaminidase A and not in the GM2 activator. </p><p>Inui et al. (1983) described a brother and sister from a consanguineous Puerto Rican marriage who had a juvenile-onset lipidosis first evident clinically at age 2.5 years by difficulties in motor function and delay in development. The sibs continued to deteriorate, showing muscle atrophy, spasticity, and loss of speech, and died at ages 7 and 8. Examination of the brains from these patients showed that the disorder was a GM2-gangliosidosis. HEXA and other lysosomal enzymes were normal and the GM2-activator protein was present in high normal concentrations in the liver. The defect in these patients appeared to reside in HEXA, which although normal in heat stability, electrophoretic mobility, and activity toward fluorogenic substrates, was resistant to activation, possibly because of defective binding to the activator. Inui et al. (1983) suggested that this be called the A(M)B variant of juvenile GM2-gangliosidosis to distinguish it from the disorder in patients missing the activator protein. (M = mutant.) </p><p>Sonderfeld et al. (1985) showed the expected complementation between the B (Tay-Sachs disease) and 0 (Sandhoff disease) variants and between the AB variant (activator deficiency) and any of the 3 variants: B, 0, and B1. Hex-A was shown to have 2 distinct catalytic sites. Complementation was demonstrated between B1 cells and variant 0 but not with variant B. Thus, the B1 cells must carry a mutation in the gene for the alpha subunit. Confirmation came from studies of the processing of immature enzyme in variant B1 cells showing the presence of alpha precursors and mature alpha chains but at a lower level than normal cells. </p>
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<strong>Pathogenesis</strong>
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<p>Through serial analysis of gene expression (SAGE), Myerowitz et al. (2002) determined gene expression profiles in cerebral cortex from a Tay-Sachs patient, a Sandhoff disease patient, and a pediatric control. Examination of genes that showed altered expression in both patients revealed molecular details of the pathophysiology of the disorders relating to neuronal dysfunction and loss. A large fraction of the elevated genes in the patients could be attributed to activated macrophages/microglia and astrocytes, and included class II histocompatibility antigens, the proinflammatory cytokine osteopontin (SPP1; 166490), complement components, proteinases and inhibitors, galectins, osteonectin (SPARC; 182120), and prostaglandin D2 synthase (PTGDS; 176803). The authors proposed a model of neurodegeneration that includes inflammation as a factor leading to the precipitous loss of neurons in individuals with these disorders. </p>
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<strong>Mapping</strong>
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<p>By study of somatic cell hybrids, Lalley et al. (1974) suggested that a locus determining hexosaminidase A is on chromosome 7. Subsequently, Van Heyningen et al. (1975) found that the MPI (154550) and PK3 (179050) loci are on chromosome 15, and Gilbert et al. (1975) concluded that MPI, PK3 and HEXA are syntenic. </p><p>Chern et al. (1976) studied heteropolymeric hexosaminidase A formed by human-mouse hybrid cells that contained an X-15 translocation chromosome but lacked human chromosome 5. Tests with specific antisera suggested that the hybrid molecule had human alpha units and mouse beta units. The findings are consistent with hexosaminidase A being composed of alpha and beta subunits coded by genes on chromosomes 15 and 5, respectively. </p><p>Formiga et al. (1988) reported 2 cases of interstitial deletion of chromosome 15. Assay of hexosaminidase A in 1 enabled them to confirm that the structural gene is located between 15q22 and 15q25 and is included in the deletion. By high resolution in situ hybridization, Takeda et al. (1990) narrowed the assignment to 15q23-q24. Using a cDNA clone for in situ hybridization, Nakai et al. (1991) assigned the HEXA gene to 15q23-q24. </p>
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<strong>Molecular Genetics</strong>
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<p>Myerowitz and Costigan (1988) demonstrated that the most frequent DNA lesion in Tay-Sachs disease in Ashkenazi Jews is a 4-bp insertion in exon 11 of the HEXA gene (606869.0001). </p><p>The gene responsible for the juvenile form has been shown by molecular analysis of the HEXA gene to be allelic to that responsible for the classic infantile form of Tay-Sachs disease (Paw et al., 1990). Whereas classic Tay-Sachs patients with complete deficiency of hexosaminidase A die before age 5 years, patients with the partial deficiency die by age 15 years. </p><p>Tanaka et al. (1990) studied 7 patients with the enzymologic characteristics of the B1 variant. All of the patients, except 1 from Czechoslovakia, carried the same arg178-to-his mutation referred to as DN (see 606869.0006). The Czechoslovakian patient had a mutation in the same codon: a change at nucleotide 532 from C to T resulting in an arg178-to-cys change in the protein (see 606869.0007). Site-directed mutagenesis and expression studies in COS-1 cells demonstrated that either of the point mutations abolished catalytic activity of the alpha subunit. The HEXA gene has 1 intron that is exceptionally large. Is it possible that it contains a sequence that codes for an unrelated protein, with an allelic form in linkage disequilibrium with the Tay-Sachs gene accounting for the high frequency of the gene in Ashkenazim? </p><p>Myerowitz (1997) stated that 78 mutations in the HEXA gene had been described, including 65 single-base substitutions, 1 large and 10 small deletions, and 2 small insertions. </p><p>Wicklow et al. (2004) described a child with severe subacute GM2-gangliosidosis who presented at age 22 months with classic cherry-red spots of the fundus but did not develop any neurologic deficit until almost age 4. They identified 3 mutations in the HEXA gene: 10T-C (S4P; 606869.0014) and 972T-A (V324V; 606869.0057) on the maternal allele, and 1A-T (M1L; 606869.0027) on the paternal allele. Because the delay in onset of neurologic symptoms indicated the presence of residual HEXA, Wicklow et al. (2004) analyzed the effects of the amino acid substitutions on HEXA expression in COS-7 cells and discovered that the 972T-A mutation created a new exon 8 donor site, causing a 17-bp deletion and destabilization of the resulting abnormal transcript. Wicklow et al. (2004) concluded that the remaining normal mRNA produced from the 972T-A allele must account for the delayed onset of symptoms in this child. </p><p>By homozygosity mapping followed by exon enrichment and next-generation sequencing in 136 consanguineous families (over 90% Iranian and less than 10% Turkish or Arab) segregating syndromic or nonsyndromic forms of autosomal recessive intellectual disability, Najmabadi et al. (2011) identified a missense mutation in the HEXA gene (606869.0058) in a family (M165) in which first-cousin parents had 5 healthy children and 3 children with moderate intellectual disability and seizures. </p>
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<p>Balint et al. (1967) found that both homozygotes and heterozygotes show reduced sphingomyelin in red blood cells and suggested that this reduction is useful in carrier identification.</p><p>Triggs-Raine et al. (1990) compared DNA-based and enzyme-based screening tests for carriers of TSD among Ashkenazim. Among 62 Ashkenazi obligate carriers, 3 specific mutations, indicated as 606869.0001, 606869.0002, and 606869.0008 among the allelic variants, accounted for all but one of the mutant alleles (98%). In 216 Ashkenazi carriers identified by the enzyme tests, DNA analysis showed that 177 (82%) had 1 of the identified mutations. Of the 177, 79% had the exon 11 insertion mutation (606869.0001), 18% had the intron 12 splice junction mutation (606869.0002), and 3% had the less severe exon 7 mutation associated with adult-onset disease (606869.0008). The results of the enzyme tests in 39 subjects (18%) who were defined as carriers but in whom DNA analysis did not identify a mutant allele were probably false positive (although there remained some possibility of unidentified mutations). Of 152 persons defined as noncarriers by the enzyme-based test, 1 was identified as a carrier by DNA analysis (i.e., a false-negative enzyme-test result). </p><p>Tay-Sachs disease was one of the disorders used as a trial for preamplification DNA diagnosis of multiple disorders by Snabes et al. (1994). They applied single-cell whole-genome preamplification to PCR-based analysis of multiple disease loci from the same diploid cell. The method they described allowed diagnosis of multiple disease genes, analysis of multiple exons/introns within a gene, or corroborative embryo-sex assignment and specific mutation detection at sex-linked loci. </p><p>Although Tay-Sachs mutations are rare in the general population, non-Jewish individuals may be screened as spouses of Jewish carriers or as relatives of probands. To define a panel of alleles that might account for most mutations in non-Jewish carriers, Akerman et al. (1997) investigated 26 independent alleles from 20 obligate carriers and 3 affected individuals. Eighteen alleles were represented by 12 previously identified mutations, 7 that were newly identified and 1 that remained unidentified. They then investigated 46 enzyme-defined carrier alleles: 19 were pseudodeficiency alleles and 5 mutations accounted for 15 other alleles. An eighth new mutation was detected among enzyme-defined carriers. Eleven alleles remained unidentified, despite the testing for 23 alleles. Some may represent false positives for the enzyme test. The results indicated that predominant mutations, other than the 2 pseudodeficiency alleles (739C-T, 606869.0035 and 745C-T) and 1 disease allele (IVS9+1G-A; 606869.0033) do not occur in the general population. Thus, Akerman et al. (1997) concluded that determination of carrier status by DNA analysis alone is inefficient because of the large proportion of rare alleles. Notwithstanding the possibility of false positives inherent to enzyme screening, this method remains an essential component of carrier screening in non-Jews. DNA screening can be best used as an adjunct to enzyme testing to exclude known HEXA pseudodeficiency alleles, the IVS9+1G-A disease allele, and other mutations relevant to the subject's genetic heritage. </p><p>Bach et al. (2001) presented results strongly supporting the use of DNA testing alone as the most cost-effective and efficient approach to carrier screening for TSD in individuals of confirmed Ashkenazi Jewish ancestry. </p><p>Chamoles et al. (2002) described methods for the assay of hexosaminidase A activity in dried blood spots on filter paper for the screening of newborns. </p><p>Vallance et al. (2006) reported 2 clinically unaffected Ashkenazi Jewish brothers who had discrepant results on diagnosis of Tay-Sachs disease carrier status. Both had low-normal serum percent HexA enzyme activity above the cut-off for carrier detection, but leukocyte HexA activity was in the carrier range. DNA analysis showed that both brothers carried the common 4-bp insertion in the HEXA gene (1277_1278insTATC; 606869.0001) gene. Both also had 2 common polymorphisms in the HEXB gene: 619A-G (I207V) and a 2-bp deletion (delTG) in the 3-prime untranslated region. Genotyping of a larger sample of 72 Jewish and 104 non-Jewish alleles samples found that the HEXB variants were in strong linkage disequilibrium with haplotype frequencies of 9.7% and 7.7%, respectively. Three additional TSD carriers with the unusual biochemical phenotype (normal serum HexA activity and decreased leukocyte HexA activity) all carried the same HEXB I207V/delTG haplotype. Finally, analysis of a larger sample of 69 alleles found that the frequency of this HexB haplotype was significantly associated with low serum HexB activity. These findings indicated that this haplotype lowers HexB activity in serum, which has the effect of raising the percent of HexA activity as determined by heat inactivation methods of total Hex activity. This can result in masking of carrier status in carriers of TSD alleles that are measured solely by serum percentage of HexA activity. Vallance et al. (2006) noted that the high prevalence of this HexB haplotype may become clinically relevant in diagnosis of TSD carrier status, and that additional diagnostic methods should be used. </p><p><strong><em>Prenatal Diagnosis</em></strong></p><p>
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Conzelmann et al. (1985) performed prenatal diagnosis in a family with the pseudo-AB variant (B1 variant) of GM2-gangliosidosis. These patients have a late infantile form with nearly normal beta-hexosaminidase A levels when assayed with the usual synthetic substrate 4-methylumbelliferyl-N-acetyl-beta-D-glucosaminide. Since the enzyme is also inactive against another substrate that is thought to be hydrolyzed predominantly by Hex-A, the mutation is in the alpha subunit. </p>
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<p>Many aspects of Tay-Sachs disease and related disorders were discussed in the proceedings of a conference edited by Kaback et al. (1977). Tay-Sachs disease is approximately 100 times more common in infants of Ashkenazi Jewish ancestry (central-eastern Europe) than in non-Jewish infants (Kaback et al., 1977). Tay-Sachs disease and Sandhoff disease in French Canadians of Quebec was discussed by Andermann et al. (1977). Whether this represents an infusion of the Tay-Sachs gene from Jewish fur traders or an independent mutation was not known at that time, but was settled when the intragenic lesions were identified; see 606869.0003.</p><p>Petersen et al. (1983) concluded that proliferation of the TSD gene occurred among the antecedents of modern Ashkenazi Jewry after the second Diaspora (70 A.D.) and before the major migrations to regions of Poland and Russia (1100 A.D. and later). Among Moroccan Jews, the carriers of a Tay-Sachs mutation were estimated to have a frequency of 1 in 45 (Navon, 1990), a figure not greatly different from that found in North American Jews. </p><p>Petersen et al. (1983) found a TSD carrier frequency in 46,304 North American Jews to be 0.0324 (1 in 31). Jews with Polish and/or Russian ancestry constituted 88% of this sample and had a carrier frequency of 0.0327. No carrier was found among the 166 Jews of Near Eastern origins. Relative to Jews of Polish and Russian origins, there was a 2-fold increase in carrier frequency in Jews of Austrian, Hungarian, and Czechoslovakian origins. Among U.S. Jews originating from Austria, a carrier frequency of 0.1092 was observed. </p><p>Yokoyama (1979) concluded that it is unlikely that drift alone was responsible for the high frequency of Tay-Sachs disease in Ashkenazim. Heterozygote advantage was considered a likely additional factor. Spyropoulos et al. (1981) showed that proportionally the grandparents of Tay-Sachs disease carriers died from the same causes as grandparents of noncarriers. They suggested that the finding indirectly supports the notion that the high frequency of the TSD gene in Ashkenazim is 'caused by a combination of founder effect, genetic drift, and differential immigration patterns.' </p><p>Diamond (1988) defended selective advantage as the cause of the high frequency of the TS gene in Ashkenazi Jews.</p><p>Paw et al. (1990) analyzed the frequency of 3 HEXA mutations among heterozygotes identified in a Tay-Sachs screening program: the 4-nucleotide insertion in exon 11 (606869.0001), the G-to-C transversion at the 5-prime splice site in intron 12 (606869.0002), and the gly269-to-ser mutation in exon 7 (606869.0008). Mutation analysis included PCR amplification of the relevant regions followed by allele-specific oligonucleotide (ASO) hybridization and, in the case of the exon 11 insertion, the formation of heteroduplex PCR fragments of low electrophoretic mobility. The percentage distribution of the exon 11, intron 12, exon 7, and unidentified mutant alleles was 73:15:4:8 among 156 Jewish carriers of HEXA deficiency and 16:0:3:81 among 51 non-Jewish carriers. Regardless of the mutation, the ancestral origin of the Jewish carriers was primarily eastern and (somewhat less often) central Europe, whereas for non-Jewish carriers it was western Europe. </p><p>Among 148 Ashkenazi Jews carrying the Tay-Sachs gene, Grebner and Tomczak (1991) found that 108 had the insertion mutation (606869.0001), 26 had the splice junction mutation (606869.0002), 5 had the adult mutation (606869.0008), and 9 had none of the 3. Among 28 non-Jewish carriers tested, most of whom were obligate carriers, 4 had the insertion mutation, 1 had the adult mutation, and the remaining 23 had none of the 3. The 2 patients with the asp258-to-his type of B1 allele (606869.0038) had infantile TSD with serum and fibroblasts containing heterozygote levels of HEXA. </p><p>Risch et al. (2003) postulated that geographic distribution of disease mutations in the Ashkenazi Jewish population supports genetic drift, rather than selection, as the mechanism of unusually high frequency of conditions such as TSD. Zlotogora and Bach (2003) provided a rebuttal in support of selection as the determining factor. They stated that the occurrence of several mutations in the same gene or mutations in different genes responsible for the high prevalence of some genetic diseases in relatively small populations is most easily explained by selection, and pointed out that Bardet-Biedl syndrome (209900) has a high frequency among the Bedouins of the Negev, owing to mutations in 3 different genes. They pointed to the occurrence of the high frequency of 4 lysosomal storage diseases among Ashkenazim--TSD, Gaucher disease type I (230800), Niemann-Pick disease (see 257200), and mucolipidosis type IV (252650)--in which the mutations are in genes that encode enzymes from a common biochemical pathway. In all 4, the main storage substances are sphingolipids. A further indication of a nonrandom process is the number of mutations responsible for each disorder. In almost all of the nonlysosomal disorders, 1 mutation is prevalent, and, if more than 1 mutation is found in a given population, its frequency is significantly less than 10% of the first mutation. This is true for almost all the nonlysosomal disorders, except cystic fibrosis (219700), in which a selection process had been suggested, and factor XI deficiency (612416). On the other hand, in all 4 lysosomal disorders among Ashkenazim, the second allele is more than 10% prevalent, when compared with the frequency of the major mutation. Risch and Tang (2003) presented counterarguments. </p><p>In Table 4 of their report, Lazarin et al. (2013) noted that among 21,985 ethnically diverse individuals screened for Tay-Sachs disease/HexA deficiency carrier status, they identified 151 carriers. These 151 carriers included 90 carriers of Ashkenazi Jewish ethnicity from a subset of 2,386 Ashkenazi Jewish individuals screened. </p>
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<strong>History</strong>
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<p>Fernandes Filho and Shapiro (2004) reviewed the early history of Tay-Sachs disease. </p>
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<strong>Animal Model</strong>
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<p>Taniike et al. (1995) produced a mouse model of Tay-Sachs disease by targeted disruption of the HEXA gene. The mice were devoid of beta-hexosaminidase A activity, accumulated GM2 ganglioside in the central nervous system, and displayed neurons with membranous cytoplasmic bodies identical to those of Tay-Sachs disease in humans. Unlike human Tay-Sachs disease in which all neurons store GM2 ganglioside, no storage was evident in the olfactory bulb, cerebellar cortex, or spinal anterior horn cells of these mice. Sango et al. (1995) likewise found that disruption of the Hexa gene in mouse embryonic stem cells resulted in mice that showed no neurologic abnormalities, although they exhibited biochemical and pathologic features of the disease. In contrast, mice in whom the Hexb gene was disrupted as a model of Sandhoff disease were severely affected. The authors suggested that the phenotypic differences between the 2 mouse models was the result of differences in the ganglioside degradation pathway between mice and humans. The authors postulated that alternative ganglioside degradative pathway revealed by the hexosaminidase-deficient mice may be significant in the analysis of other mouse models of the sphingolipidoses, as well as suggest novel therapies for Tay-Sachs disease. </p><p>Cohen-Tannoudji et al. (1995) used gene targeting in embryonic stem (ES) cells to disrupt the mouse Hexa gene. Mice homozygous for the disrupted allele mimicked some of the biochemical and histologic features of human Tay-Sachs disease. They displayed, for example, total deficiency of Hexa activity and membranous cytoplasmic inclusions typical of GM2-gangliosidoses found in the cytoplasm of their neurons. However, while the number of storage neurons increased with age, it remained low compared with that found in the human, and no apparent motor or behavioral disorders could be observed. This suggested that beta-hexosaminidase A is not an absolute requirement for ganglioside degradation in mice. Nonetheless, the authors stated that animal models should be useful for the testing of new forms of therapy. </p><p>Phaneuf et al. (1996) likewise found that mice with disruption of the Hexa gene suffered no obvious behavioral or neurologic deficit whereas those homozygous for a disruption of the Hexb gene developed a fatal neurodegenerative disease with spasticity, muscle weakness, rigidity, tremor, and ataxia. They proposed that homozygous Hexa-deficient mice escaped disease through particle catabolism of accumulated G(M2) via G(A2) through the combined action of sialidase and beta-hexosaminidase B. </p><p>In a mouse model of Tay-Sachs disease, Platt et al. (1997) evaluated a strategy for treatment of the disorder based on N-butyldeoxynojirimycin, an inhibitor of glycosphingolipid (GSL) biosynthesis. When Tay Sachs mice were treated with this agent, the accumulation of GM2 in the brain was prevented, with the number of storage neurons and the quantity of ganglioside stored per cell markedly reduced. Thus, the authors concluded that limiting the biosynthesis of the substrate for the defective Hexa enzyme prevented GSL accumulation and the neuropathology associated with its storage in lysosomes. </p><p>Guidotti et al. (1999) determined the in vivo strategy leading to the highest Hexa activity in the maximum number of tissues in Hexa-deficient knockout mice. They demonstrated that intravenous coadministration of adenoviral vectors coding for both alpha- and beta-subunits, resulting in preferential liver transduction, was essential to obtain the most successful results. Only the supply of both subunits allowed for Hexa overexpression, leading to massive secretion of the enzyme in serum, and full or partial restoration of enzymatic activity in all peripheral tissues tested. These results emphasized the need to overexpress both subunits of heterodimeric proteins in order to obtain a high level of secretion in animals defective in only 1 subunit. Otherwise, the endogenous nondefective subunit is limiting. </p><p>Bertani et al. (2021) described 2 captive-bred wild boar littermates with a homozygous arg499-to-cys (R499C) mutation in the HEXA gene that was homologous to the R499C mutation (606869.0028) present in compound heterozygous state in some patients with infantile or juvenile forms of Tay-Sachs disease. A third similarly affected littermate did not undergo gene sequencing, and an unaffected littermate did not have the mutation. The affected boars showed neurologic decline starting at 6 months of age with behavioral changes, twitching, and dysmetria, and progressing to seizures and quadriplegia. They were euthanized at 12 months of age. Analysis of CNS gangliosides demonstrated accumulation of GM2 ganglioside and reduction in sphingomyelin, sulfatides, and cerebrosides. Lysosomal HexA enzyme activity in lymphocytes was almost absent. Neurons in the central and peripheral nervous systems from the affected animals were enlarged and foamy, with diffuse cytoplasmic vacuolization. Transmission electron microscopy of CNS neurons showed lysosomes with membranous cytoplasmic bodies. Bertani et al. (2021) proposed that because brain growth, composition, and myelination during development in pigs is similar to humans, wild boars serve as a better large animal model for Tay-Sachs disease compared to other models. </p><p>Story et al. (2021) characterized the neurologic phenotype of the naturally occurring Jacob sheep model of Tay-Sachs disease with deficient hexosaminidase A. The phenotypes were evaluated at 3 months (when the sheep are mildly affected), 6 months, and 9 months of life (or at the humane endpoint, when the sheep are severely affected and lose the ability to walk). Brain MRIs showed that the mutant sheep had demyelination evident at the borders of white and gray matter at 3 months of age and loss of normal white matter hypointensity due to demyelination at 9 months of age. MR spectroscopy of brain metabolites in mutant sheep demonstrated a progressive increase in glutamine and a decrease in glutamate from 3 to 9 months, and a progressive increase in taurine, glycerophosphocholine, and creatine from 3 to 9 months of age. Histopathology demonstrated widespread microglial activation starting at 6 months and reactive astrocytosis starting at 3 months in brain tissue. Story et al. (2021) concluded that this sheep model most closely represents juvenile or late-onset Tay-Sachs disease. </p>
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<h4>
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<span class="mim-font">
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<strong>See Also:</strong>
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</span>
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</h4>
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<span class="mim-text-font">
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Aronson et al. (1960); Ben-Yoseph et al. (1985); Brady (1970);
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Charrow et al. (1985); Dreyfus et al. (1975); Greenberg and Kaback
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(1982); Hanhart (1954); Higami et al. (1976); Johnson et al. (1980);
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Koeslag and Schach (1984); Lane et al. (1980); Meek et al. (1984);
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Momoi et al. (1978); Mules et al. (1992); Myerowitz and Proia (1984);
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Navon et al. (1976); O'Brien and Geiger (1979); O'Brien et al.
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(1970); O'Brien et al. (1971); O'Brien et al. (1978); Ohman et al.
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(1971); Ohno and Suzuki (1988); Ohno and Suzuki (1988); Ohno and
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Suzuki (1988); Rattazzi et al. (1976); Schneck et al. (1964); Sloan
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and Fredrickson (1972); Suzuki and Suzuki (1970); Van Cong et al.
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(1975); Volk (1964); Yaffe et al. (1979)
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</span>
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<br />
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<div>
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<h4>
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<span class="mim-font">
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<strong>REFERENCES</strong>
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</span>
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</h4>
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<p />
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</div>
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<ol>
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<p class="mim-text-font">
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Akerman, B. R., Natowicz, M. R., Kaback, M. M., Loyer, M., Campeau, E., Gravel, R. A.
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<strong>Novel mutations and DNA-based screening in non-Jewish carriers of Tay-Sachs disease.</strong>
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Am. J. Hum. Genet. 60: 1099-1106, 1997.
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<strong>Genetic variants of Tay-Sachs disease and Sandhoff's disease in French-Canadians, juvenile Tay-Sachs disease in Lebanese Canadians, and a Tay-Sachs screening program in the French-Canadian population. In: Kaback, M. M.; Rimoin, D. L.; O'Brien, J. S.: Tay-Sachs Disease: Screening and Prevention.</strong>
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New York: Alan R. Liss (pub.) 1977. Pp. 161-168.
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Aronson, S. M., Valsamis, M. P., Volk, B. W.
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Bach, G., Tomczak, J., Risch, N., Ekstein, J.
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<strong>On the chemical changes in the red cell stroma in Tay-Sachs disease: their value as genetic tracers. In: Aronson, S. M.; Volk, B. W.: Inborn Disorders of Sphingolipid Metabolism.</strong>
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Oxford: Pergamon Press (pub.) 1967. Pp. 423-430.
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Barnes, D., Misra, V. P., Young, E. P., Thomas, P. K., Harding, A. E.
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Am. J. Hum. Genet. 37: 733-748, 1985.
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Bertani, V., Prioni, S., Di Lecce, R., Gazza, F., Ragionieri, L., Merialdi, G., Bonilauri, P., Jagannathan, V., Grassi, S., Cabitta, L., Paoli, A., Morrone, A., Sonnino, S., Drogemuller, C., Cantoni, A. M.
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<strong>A pathogenic HEXA missense variant in wild boars with Tay-Sachs disease.</strong>
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<strong>Disruption of murine Hexa gene leads to enzymatic deficiency and to neuronal lysosomal storage, similar to that observed in Tay-Sachs disease.</strong>
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Hilary J. Vernon - updated : 06/23/2022<br>Hilary J. Vernon - updated : 10/08/2021<br>Hilary J. Vernon - updated : 09/09/2021<br>Ada Hamosh - updated : 5/30/2013<br>Ada Hamosh - updated : 1/6/2012<br>Cassandra L. Kniffin - updated : 1/4/2010<br>Cassandra L. Kniffin - updated : 4/6/2005<br>Cassandra L. Kniffin - updated : 12/15/2004<br>Marla J. F. O'Neill - updated : 6/30/2004<br>Victor A. McKusick - updated : 8/11/2003<br>George E. Tiller - updated : 2/24/2003<br>Victor A. McKusick - updated : 1/22/2003<br>Cassandra L. Kniffin - reorganized : 5/7/2002<br>Cassandra L. Kniffin - updated : 5/7/2002<br>Victor A. McKusick - updated : 2/21/2001<br>Victor A. McKusick - updated : 5/18/1999<br>Victor A. McKusick - updated : 9/9/1998<br>Victor A. McKusick - updated : 9/4/1998<br>Victor A. McKusick - edited : 2/24/1998<br>Victor A. McKusick - updated : 10/10/1997<br>Victor A. McKusick - updated : 8/27/1997<br>Victor A. McKusick - updated : 6/16/1997<br>Victor A. McKusick - updated : 5/8/1997<br>Victor A. McKusick - updated : 4/17/1997<br>Perseveranda M. Cagas - updated : 11/6/1996<br>Orest Hurko - updated : 11/6/1996<br>Stylianos E. Antonarakis - updated : 6/29/1996<br>Orest Hurko - updated : 6/13/1995
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<button type="button" id="mimDonationPopupDonate" class="btn btn-success btn-block" data-dismiss="modal"> Donate To OMIM! </button>
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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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</body>
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</html>
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