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Entry
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- #254800 - MYOCLONIC EPILEPSY OF UNVERRICHT AND LUNDBORG
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- OMIM
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<p>
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<span class="h4">#254800</span>
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<br />
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<strong>Table of Contents</strong>
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<a href="#title"><strong>Title</strong></a>
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<a href="#phenotypeMap"><strong>Phenotype-Gene Relationships</strong></a>
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<a href="/clinicalSynopsis/254800"><strong>Clinical Synopsis</strong></a>
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<a href="/phenotypicSeries/PS254800"> <strong>Phenotypic Series</strong> </a>
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<a href="#text"><strong>Text</strong></a>
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<a href="#description">Description</a>
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<a href="#clinicalFeatures">Clinical Features</a>
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<a href="#inheritance">Inheritance</a>
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<a href="#clinicalManagement">Clinical Management</a>
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<a href="#mapping">Mapping</a>
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<a href="#heterogeneity">Heterogeneity</a>
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<a href="#molecularGenetics">Molecular Genetics</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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<a href="#references"><strong>References</strong></a>
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<a href="#contributors"><strong>Contributors</strong></a>
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<li role="presentation">
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<a href="#creationDate"><strong>Creation Date</strong></a>
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<a href="#editHistory"><strong>Edit History</strong></a>
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<div style="display: table-cell;">External Links</div>
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</h4>
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<div><a href="https://clinicaltrials.gov/search?cond=MYOCLONIC EPILEPSY OF UNVERRICHT AND LUNDBORG" class="mim-tip-hint" title="A registry of federally and privately supported clinical trials conducted in the United States and around the world." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Clinical Trials', 'domain': 'clinicaltrials.gov'})">Clinical Trials</a></div>
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<div><a href="https://www.orpha.net/consor/cgi-bin/ClinicalLabs_Search_Simple.php?lng=EN&LnkId=294&Typ=Pat" class="mim-tip-hint" title="A list of European laboratories that offer genetic testing." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'EuroGentest', 'domain': 'orpha.net'})">EuroGentest</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/books/NBK1142/" 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/5038" 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/progressive-myoclonic-epilepsy-type-1" 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=254800[mim]" class="mim-tip-hint" title="Genetic Testing Registry." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'GTR', 'domain': 'ncbi.nlm.nih.gov'})">GTR</a></div>
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<div><a href="https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=308" class="mim-tip-hint" title="European reference portal for information on rare diseases and orphan drugs." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'OrphaNet', 'domain': 'orpha.net'})">OrphaNet</a></div>
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<div class="panel-heading mim-panel-heading" role="tab" id="mimAnimalModels">
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<span class="panel-title">
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<span class="small">
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<a href="#mimAnimalModelsLinksFold" id="mimAnimalModelsLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimAnimalModelsLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Animal Models</div>
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</div>
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</a>
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</span>
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.alliancegenome.org/disease/DOID:0111452" 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/254800" 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/OMIA000344/" 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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<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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<a id="title" class="mim-anchor"></a>
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<a id="number" class="mim-anchor"></a>
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<a href="#" class="mim-tip-icd" qtip_title="<strong>ICD+</strong>" qtip_text="
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<strong>SNOMEDCT:</strong> 230423006<br />
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<strong>ORPHA:</strong> 308<br />
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<strong>DO:</strong> 0111452<br />
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">ICD+</a>
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<div>
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<span class="h3">
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<span class="mim-font mim-tip-hint" title="Phenotype description, molecular basis known">
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<span class="text-danger"><strong>#</strong></span>
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254800
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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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MYOCLONIC EPILEPSY OF UNVERRICHT AND LUNDBORG
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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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ULD<br />
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EPILEPSY, PROGRESSIVE MYOCLONIC, 1A; EPM1A<br />
|
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EPILEPSY, PROGRESSIVE MYOCLONIC, 1; EPM1<br />
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PROGRESSIVE MYOCLONIC EPILEPSY; PME<br />
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BALTIC MYOCLONIC EPILEPSY
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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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<a id="phenotypeMap" class="mim-anchor"></a>
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<h4>
|
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<span class="mim-font">
|
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<strong>Phenotype-Gene Relationships</strong>
|
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</span>
|
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</h4>
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<div>
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<table class="table table-bordered table-condensed table-hover small mim-table-padding">
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<thead>
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<tr class="active">
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<th>
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Location
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</th>
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<th>
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Phenotype
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</th>
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<th>
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Phenotype <br /> MIM number
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</th>
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<th>
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Inheritance
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</th>
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<th>
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Phenotype <br /> mapping key
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</th>
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<th>
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Gene/Locus
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</th>
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<th>
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Gene/Locus <br /> MIM number
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<span class="mim-font">
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|
<a href="/geneMap/21/149?start=-3&limit=10&highlight=149">
|
|
21q22.3
|
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</a>
|
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</span>
|
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</td>
|
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<td>
|
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<span class="mim-font">
|
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Epilepsy, progressive myoclonic 1A (Unverricht and Lundborg)
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</span>
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</td>
|
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<td>
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<span class="mim-font">
|
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<a href="/entry/254800"> 254800 </a>
|
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</span>
|
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</td>
|
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<td>
|
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<span class="mim-font">
|
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<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
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</span>
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</td>
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<td>
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<span class="mim-font">
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<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
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</span>
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</td>
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<td>
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<span class="mim-font">
|
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CSTB
|
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</span>
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</td>
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<td>
|
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<span class="mim-font">
|
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<a href="/entry/601145"> 601145 </a>
|
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</span>
|
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</td>
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</tr>
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</tbody>
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</table>
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</div>
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</div>
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<div>
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<div class="btn-group ">
|
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<a href="/clinicalSynopsis/254800" class="btn btn-warning" role="button"> Clinical Synopsis </a>
|
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<button type="button" id="mimPhenotypicSeriesToggle" class="btn btn-warning dropdown-toggle mimSingletonFoldToggle" data-toggle="collapse" href="#mimClinicalSynopsisFold" onclick="ga('send', 'event', 'Unfurl', 'ClinicalSynopsis', 'omim.org')">
|
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<span class="caret"></span>
|
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<span class="sr-only">Toggle Dropdown</span>
|
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</button>
|
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</div>
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<div class="btn-group">
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<a href="/phenotypicSeries/PS254800" class="btn btn-info" role="button"> Phenotypic Series </a>
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<button type="button" id="mimPhenotypicSeriesToggle" class="btn btn-info dropdown-toggle mimSingletonFoldToggle" data-toggle="collapse" href="#mimPhenotypicSeriesFold" onclick="ga('send', 'event', 'Unfurl', 'PhenotypicSeries', 'omim.org')">
|
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<span class="caret"></span>
|
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<span class="sr-only">Toggle Dropdown</span>
|
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</button>
|
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</div>
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<div class="btn-group">
|
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<button type="button" class="btn btn-success dropdown-toggle" data-toggle="dropdown" aria-haspopup="true" aria-expanded="false">
|
|
PheneGene Graphics <span class="caret"></span>
|
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</button>
|
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<ul class="dropdown-menu" style="width: 17em;">
|
|
<li><a href="/graph/linear/254800" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Linear'})"> Linear </a></li>
|
|
<li><a href="/graph/radial/254800" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Radial'})"> Radial </a></li>
|
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</ul>
|
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</div>
|
|
<span class="glyphicon glyphicon-question-sign mim-tip-hint" title="OMIM PheneGene graphics depict relationships between phenotypes, groups of related phenotypes (Phenotypic Series), and genes.<br /><a href='/static/omim/pdf/OMIM_Graphics.pdf' target='_blank'>A quick reference overview and guide (PDF)</a>"></span>
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<div>
|
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<p />
|
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</div>
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<div id="mimClinicalSynopsisFold" class="well well-sm collapse mimSingletonToggleFold">
|
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<div class="small" style="margin: 5px">
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<div>
|
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<div>
|
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<span class="h5 mim-font">
|
|
<strong> INHERITANCE </strong>
|
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</span>
|
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</div>
|
|
<div style="margin-left: 2em;">
|
|
|
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<div>
|
|
<span class="mim-font">
|
|
|
|
- Autosomal recessive <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/258211005" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">258211005</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0441748&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0441748</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000007" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000007</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000007" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000007</a>]</span><br />
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</span>
|
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</div>
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</div>
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</div>
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<div>
|
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<div>
|
|
<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">
|
|
|
|
- Visual blackouts (stage 1) <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1850748&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1850748</a>]</span><br /> -
|
|
EEG - polyspike on photic stimulation (stage 1) <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1850749&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1850749</a>]</span><br /> -
|
|
Stimulation sensitive segmental myoclonus (stage 2) <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1850750&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1850750</a>]</span><br /> -
|
|
Stimulation sensitive generalized myoclonus (stage 3) <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1850751&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1850751</a>]</span><br /> -
|
|
Generalized tonic-clonic seizures (stage 2 and 3) <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1850752&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1850752</a>]</span> <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/1217136003" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">1217136003</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/G40.4" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">G40.4</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0025190" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0025190</a>]</span><br /> -
|
|
Absence seizures (stage 2 and 3) <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1850753&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1850753</a>]</span> <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/79631006" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">79631006</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002121" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002121</a>]</span><br /> -
|
|
Minor motor impairment (stage 2) <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1850754&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1850754</a>]</span><br /> -
|
|
Intermittent wheelchair dependence (stage 3) <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1850755&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1850755</a>]</span><br /> -
|
|
EEG - alpha slowing, 4-6 Hz spike waves, myoclonus on photic stimulation (stage 2) <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1850756&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1850756</a>]</span><br /> -
|
|
EEG - alpha abolished, continuous spike waves, intense myoclonus on photic stimulation (stage 3) <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1850757&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1850757</a>]</span><br /> -
|
|
Action myoclonus (triggered by voluntary movements) <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1850758&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1850758</a>]</span> <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/27572006" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">27572006</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0034360" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0034360</a>]</span><br /> -
|
|
Ataxia <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/20262006" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">20262006</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/39384006" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">39384006</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/85102008" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">85102008</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/R27.0" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">R27.0</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/438.84" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">438.84</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0004134&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0004134</a>, <a href="https://bioportal.bioontology.org/search?q=C1135207&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1135207</a>, <a href="https://bioportal.bioontology.org/search?q=C0007758&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0007758</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001251" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001251</a>, <a href="https://hpo.jax.org/app/browse/term/HP:0010867" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0010867</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001251" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001251</a>]</span><br /> -
|
|
Mild mental deterioration <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1850759&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1850759</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001268" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001268</a>]</span><br /> -
|
|
Dysarthria <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/8011004" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">8011004</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/438.13" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">438.13</a>, <a href="https://purl.bioontology.org/ontology/ICD9CM/784.51" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">784.51</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0013362&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0013362</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001260" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001260</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001260" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001260</a>]</span><br />
|
|
|
|
</span>
|
|
</div>
|
|
</div>
|
|
|
|
|
|
|
|
</div>
|
|
|
|
</div>
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|
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<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<strong> MISCELLANEOUS </strong>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
|
|
<div>
|
|
<span class="mim-font">
|
|
|
|
- Onset 6-13 years<br /> -
|
|
Three stages of disease progression - Stage 1 (subclinical), Stage 2 (early myoclonic), Stage 3 (disabling myoclonic)<br /> -
|
|
Incidence of 1 in 20,000 live births<br /> -
|
|
High frequency in Finnish population<br />
|
|
|
|
</span>
|
|
</div>
|
|
|
|
</div>
|
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|
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</div>
|
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|
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|
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|
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|
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<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<strong> MOLECULAR BASIS </strong>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
|
|
<div>
|
|
<span class="mim-font">
|
|
|
|
- Caused by mutation in the cystatin B gene (CSTB, <a href="/entry/601145#0001">601145.0001</a>)<br />
|
|
|
|
</span>
|
|
</div>
|
|
|
|
</div>
|
|
|
|
</div>
|
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|
|
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|
|
<div class="text-right">
|
|
<a href="#mimClinicalSynopsisFold" data-toggle="collapse">▲ Close</a>
|
|
</div>
|
|
</div>
|
|
</div>
|
|
|
|
|
|
|
|
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|
|
<div id="mimPhenotypicSeriesFold" class="well well-sm collapse mimSingletonToggleFold">
|
|
<div class="small">
|
|
|
|
|
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|
|
<div class="row">
|
|
<div class="col-lg-12 col-md-12 col-sm-12 col-xs-12">
|
|
<h5>
|
|
Epilepsy, progressive myoclonic
|
|
- <a href="/phenotypicSeries/PS254800">PS254800</a>
|
|
- 13 Entries
|
|
</h5>
|
|
</div>
|
|
</div>
|
|
|
|
<div class="row" style="margin-left: 0.125em; margin-right: 0.125em;">
|
|
<table class="table table-bordered table-condensed table-hover mim-table-padding">
|
|
<thead>
|
|
<tr>
|
|
<th class="col-lg-1 col-md-1 col-sm-1 col-xs-1 text-nowrap">
|
|
<strong>Location</strong>
|
|
</th>
|
|
<th class="col-lg-5 col-md-5 col-sm-5 col-xs-6 text-nowrap">
|
|
<strong>Phenotype</strong>
|
|
</th>
|
|
<th class="col-lg-1 col-md-1 col-sm-1 col-xs-1 text-nowrap">
|
|
<strong>Inheritance</strong>
|
|
</th>
|
|
<th class="col-lg-1 col-md-1 col-sm-1 col-xs-1 text-nowrap">
|
|
<strong>Phenotype<br />mapping key</strong>
|
|
</th>
|
|
<th class="col-lg-1 col-md-1 col-sm-1 col-xs-1 text-nowrap">
|
|
<strong>Phenotype<br />MIM number</strong>
|
|
</th>
|
|
<th class="col-lg-1 col-md-1 col-sm-1 col-xs-1 text-nowrap">
|
|
<strong>Gene/Locus</strong>
|
|
</th>
|
|
<th class="col-lg-1 col-md-1 col-sm-1 col-xs-1 text-nowrap">
|
|
<strong>Gene/Locus<br />MIM number</strong>
|
|
</th>
|
|
</tr>
|
|
</thead>
|
|
<tbody>
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/geneMap/4/340?start=-3&limit=10&highlight=340"> 4q21.1 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/254900"> Epilepsy, progressive myoclonic 4, with or without renal failure </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/254900"> 254900 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/602257"> SCARB2 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/602257"> 602257 </a>
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/geneMap/4/357?start=-3&limit=10&highlight=357"> 4q21.21 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/616640"> ?Epilepsy, progressive myoclonic, 10 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/616640"> 616640 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/616639"> PRDM8 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/616639"> 616639 </a>
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/geneMap/6/96?start=-3&limit=10&highlight=96"> 6p22.3 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/620681"> Myoclonic epilepsy of Lafora 2 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/620681"> 620681 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/608072"> NHLRC1 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/608072"> 608072 </a>
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/geneMap/6/925?start=-3&limit=10&highlight=925"> 6q24.3 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/254780"> Myoclonic epilepsy of Lafora 1 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/254780"> 254780 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/607566"> EPM2A </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/607566"> 607566 </a>
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/geneMap/7/301?start=-3&limit=10&highlight=301"> 7q11.21 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/611726"> Epilepsy, progressive myoclonic 3, with or without intracellular inclusions </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/611726"> 611726 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/611725"> KCTD7 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/611725"> 611725 </a>
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/geneMap/11/213?start=-3&limit=10&highlight=213"> 11p15.1 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/616187"> Epilepsy, progressive myoclonic 7 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/616187"> 616187 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/176258"> KCNC1 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/176258"> 176258 </a>
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/geneMap/12/298?start=-3&limit=10&highlight=298"> 12q12 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/612437"> Epilepsy, progressive myoclonic 1B </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/612437"> 612437 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/608500"> PRICKLE1 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/608500"> 608500 </a>
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/geneMap/16/576?start=-3&limit=10&highlight=576"> 16q22.1 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/619191"> Epilepsy, progressive myoclonic, 12 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/619191"> 619191 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/619192"> SLC7A6OS </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/619192"> 619192 </a>
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/geneMap/17/671?start=-3&limit=10&highlight=671"> 17q21.32 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/614018"> Epilepsy, progressive myoclonic 6 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/614018"> 614018 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/604027"> GOSR2 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/604027"> 604027 </a>
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/geneMap/19/89?start=-3&limit=10&highlight=89"> 19p13.3 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/616540"> ?Epilepsy, progressive myoclonic, 9 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/616540"> 616540 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/150341"> LMNB2 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/150341"> 150341 </a>
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/geneMap/19/142?start=-3&limit=10&highlight=142"> 19p13.3 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/618876"> Epilepsy, progressive myoclonic, 11 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/618876"> 618876 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/608873"> SEMA6B </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/608873"> 608873 </a>
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/geneMap/19/475?start=-3&limit=10&highlight=475"> 19p13.11 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/616230"> Epilepsy, progressive myoclonic, 8 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/616230"> 616230 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/606919"> CERS1 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/606919"> 606919 </a>
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/geneMap/21/149?start=-3&limit=10&highlight=149"> 21q22.3 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/254800"> Epilepsy, progressive myoclonic 1A (Unverricht and Lundborg) </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/254800"> 254800 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
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<p>A number sign (#) is used with this entry because myoclonic epilepsy of Unverricht and Lundborg (ULD), also known as progressive myoclonic epilepsy-1A (EPM1A), is caused by mutation in the cystatin B gene (CSTB; <a href="/entry/601145">601145</a>) on chromosome 21q22.</p>
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<p>Myoclonic epilepsy of Unverricht and Lundborg, also known as progressive myoclonic epilepsy-1A (EPM1A), is an autosomal recessive disorder characterized by onset of neurodegeneration between 6 and 13 years of age. Although it is considered a progressive myoclonic epilepsy, it differs from other forms in that it appears to be progressive only in adolescence, with dramatic worsening of myoclonus and ataxia in the first 6 years after onset. The disease stabilizes in early adulthood, and myoclonus and ataxia may even improve, and there is minimal to no cognitive decline (summary by <a href="#43" class="mim-tip-reference" title="Ramachandran, N., Girard, J.-M., Turnbull, J., Minassian, B. A. <strong>The autosomal recessively inherited progressive myoclonus epilepsies and their genes.</strong> Epilepsia 50 (suppl.): 29-36, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19469843/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19469843</a>] [<a href="https://doi.org/10.1111/j.1528-1167.2009.02117.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19469843">Ramachandran et al., 2009</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19469843" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Genetic Heterogeneity of Progressive Myoclonic Epilepsy</em></strong></p><p>
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Progressive myoclonic epilepsy refers to a clinically and genetically heterogeneous group of neurodegenerative disorders, usually with debilitating symptoms, although severity varies. See also EPM1B (<a href="/entry/612437">612437</a>), caused by mutation in the PRICKLE1 gene (<a href="/entry/608500">608500</a>); Lafora disease-1 (EPM2A; <a href="/entry/254780">254780</a>), caused by mutation in the EPM2A gene (<a href="/entry/607566">607566</a>); Lafora disease-2 (EPM2B; <a href="/entry/620681">620681</a>), caused by mutation in the NHLRC1 (<a href="/entry/608072">608072</a>) gene; EPM3 (<a href="/entry/611726">611726</a>), caused by mutation in the KCTD7 gene (611725); EPM4 (<a href="/entry/254900">254900</a>), caused by mutation in the SCARB2 gene (<a href="/entry/602257">602257</a>); EPM6 (<a href="/entry/614018">614018</a>), caused by mutation in the GOSR2 gene (<a href="/entry/604027">604027</a>); EPM7 (<a href="/entry/616187">616187</a>), caused by mutation in the KCNC1 gene (<a href="/entry/176258">176258</a>); EPM8 (<a href="/entry/616230">616230</a>), caused by mutation in the CERS1 gene (<a href="/entry/606919">606919</a>); EPM9 (<a href="/entry/616540">616540</a>), caused by mutation in the LMNB2 gene (<a href="/entry/150341">150341</a>); EPM10 (<a href="/entry/616640">616640</a>), caused by mutation in the PRDM8 gene (<a href="/entry/616639">616639</a>); EPM11 (<a href="/entry/618876">618876</a>), caused by mutation in the SEMA6B gene (<a href="/entry/608873">608873</a>); and EPM12 (<a href="/entry/619191">619191</a>), caused by mutation in the SLC7A6OS gene (<a href="/entry/619192">619192</a>).</p><p>A form of progressive myoclonic epilepsy, formerly designated EPM5, is included in <a href="/entry/607459">607459</a> with the primary designation of spinocerebellar ataxia with epilepsy (SCAE).</p><p>Other disorders characterized by progressive myoclonic epilepsy include the neuronal ceroid lipofuscinoses (see, e.g., CLN1 (<a href="/entry/256730">256730</a>); sialidosis (<a href="/entry/256550">256550</a>); MERFF (<a href="/entry/545000">545000</a>); and DRPLA (<a href="/entry/125370">125370</a>), among others (reviews by <a href="#43" class="mim-tip-reference" title="Ramachandran, N., Girard, J.-M., Turnbull, J., Minassian, B. A. <strong>The autosomal recessively inherited progressive myoclonus epilepsies and their genes.</strong> Epilepsia 50 (suppl.): 29-36, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19469843/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19469843</a>] [<a href="https://doi.org/10.1111/j.1528-1167.2009.02117.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19469843">Ramachandran et al., 2009</a> and <a href="#7" class="mim-tip-reference" title="de Siqueira, L. F. M. <strong>Progressive myoclonic epilepsies: review of clinical, molecular and therapeutic aspects.</strong> J. Neurol. 257: 1612-1619, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20593193/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20593193</a>] [<a href="https://doi.org/10.1007/s00415-010-5641-1" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20593193">de Siqueira, 2010</a>).) <a href="https://pubmed.ncbi.nlm.nih.gov/?term=19469843+20593193" 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>Unverricht (<a href="#46" class="mim-tip-reference" title="Unverricht, H. <strong>Die Myoclonie.</strong> Berlin: Franz Deuticke (pub.) 1891."None>1891</a>, <a href="#47" class="mim-tip-reference" title="Unverricht, H. <strong>Ueber familiaere Myoclonie.</strong> Dtsch. Z. Nervenheilk. 7: 32-67, 1895."None>1895</a>) and <a href="#31" class="mim-tip-reference" title="Lundborg, H. B. <strong>Die progressive Myoklonusepilepsie (Unverricht's Myoklonie). Vol. 8.</strong> Uppsala: Almqvist and Wiksell (pub.) 1903. Pp. 567-570."None>Lundborg (1903)</a> first reported a type of progressive myoclonic epilepsy common in Finland. Onset of the disorder occurred around age 10 years, and was characterized by progressive myoclonus resulting in incapacitation, but only mild mental deterioration. Histological studies of the brain showed 'degenerative' changes without inclusion bodies. Severity and survival were variable (<a href="#40" class="mim-tip-reference" title="Norio, R., Koskiniemi, M. <strong>Progressive myoclonus epilepsy: genetic and nosological aspects with special reference to 107 Finnish patients.</strong> Clin. Genet. 15: 382-398, 1979.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/109240/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">109240</a>] [<a href="https://doi.org/10.1111/j.1399-0004.1979.tb01770.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="109240">Norio and Koskiniemi, 1979</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=109240" 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>Eldridge et al. (<a href="#11" class="mim-tip-reference" title="Eldridge, R., Iivanainen, M., Stern, R., Koerber, T., Wilder, B. J. <strong>'Baltic' myoclonus epilepsy: a treatable hereditary disorder of childhood. (Abstract)</strong> Sixth International Congress of Human Genetics, Jerusalem 1981. P. 256."None>1981</a>, <a href="#12" class="mim-tip-reference" title="Eldridge, R., Iivanainen, M., Stern, R., Koerber, T., Wilder, B. J. <strong>'Baltic' myoclonus epilepsy: hereditary disorder of childhood made worse by phenytoin.</strong> Lancet 322: 838-842, 1983. Note: Originally Volume II.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/6137660/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">6137660</a>] [<a href="https://doi.org/10.1016/s0140-6736(83)90749-3" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="6137660">1983</a>) referred to this disorder as the 'Baltic type' of myoclonic epilepsy because the descriptions first by Unverricht and then by Lundborg were in families from Estonia and Eastern Sweden and subsequent patients were found in Finland. <a href="#12" class="mim-tip-reference" title="Eldridge, R., Iivanainen, M., Stern, R., Koerber, T., Wilder, B. J. <strong>'Baltic' myoclonus epilepsy: hereditary disorder of childhood made worse by phenytoin.</strong> Lancet 322: 838-842, 1983. Note: Originally Volume II.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/6137660/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">6137660</a>] [<a href="https://doi.org/10.1016/s0140-6736(83)90749-3" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="6137660">Eldridge et al. (1983)</a> found 15 families in the United States. The 27 affected members had the following features starting at about age 10 years: stimulus- and photo-sensitive and occasionally violent myoclonus, usually worse upon waking; generalized tonic-clonic seizures, sometimes associated with absence attacks; and light-sensitive, generally synchronous, spike-and-wave discharges on EEG that preceded clinical manifestations. Necropsy showed marked loss of Purkinje cells of the cerebellum, but no inclusion bodies. Phenytoin was associated with progressive motor and intellectual deterioration, marked ataxia, and even death. Treatment with valproic acid was associated with marked improvement. Contrary to myoclonic epilepsy with Lafora bodies, intelligence in this form was only slightly affected and psychotic symptoms were not found. In addition, Lafora body disease is invariably fatal. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=6137660" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#21" class="mim-tip-reference" title="Kyllerman, M., Sommerfelt, K., Hedstrom, A., Wennergren, G., Holmgren, D. <strong>Clinical and neurophysiological development of Unverricht-Lundborg disease in four Swedish siblings.</strong> Epilepsia 32: 900-909, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1743164/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1743164</a>] [<a href="https://doi.org/10.1111/j.1528-1157.1991.tb05549.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1743164">Kyllerman et al. (1991)</a> described 4 sibs who demonstrated a subclinical stage of this disorder at the age of 9 to 11 years, with visual blackouts and polyspike electroencephalographic (EEG) activity on photic stimulation; an early myoclonic stage at the age of 12 to 15 years, with increasing segmental, stimulus-sensitive myoclonus, occasional nocturnal buildup myoclonic 'cascade' seizures, slowing of EEG alpha-activity, episodic 4-6 Hz bilateral sharp waves and polyspikes with myoclonus on photic stimulation; and a disabling myoclonic stage at the age of 16 to 18 years, with periodic generalized myoclonus, nocturnal myoclonic 'cascade' seizures, ataxia, dysarthria, mental changes, intermittent wheelchair dependency, and continuous EEG slow waves with polyspikes and intense myoclonus on photic stimulation. One of the sibs died at the age of 18 years with no apparent cause of death. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1743164" 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>As pointed out by the <a href="#34" class="mim-tip-reference" title="Marseille Consensus Group. <strong>Classification of progressive myoclonus epilepsies and related disorders.</strong> Ann. Neurol. 28: 113-116, 1990.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2115761/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2115761</a>] [<a href="https://doi.org/10.1002/ana.410280129" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2115761">Marseille Consensus Group (1990)</a>, patients with Ramsay Hunt syndrome (<a href="/entry/213400">213400</a>) cannot be distinguished clinically from patients with Unverricht-Lundborg disease. Linkage studies may help determine whether that disorder is caused by mutation at the same locus. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2115761" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#6" class="mim-tip-reference" title="Cochius, J., Carpenter, S., Andermann, E., Rouleau, G., Nousiainen, U., Kalviainen, R., Farrell, K., Andermann, F. <strong>Sweat gland vacuoles in Unverricht-Lundborg disease: a clue to diagnosis?</strong> Neurology 44: 2372-2375, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7991128/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7991128</a>] [<a href="https://doi.org/10.1212/wnl.44.12.2372" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7991128">Cochius et al. (1994)</a> reported for the first time a pathologic abnormality outside the central nervous system in patients with Unverricht-Lundborg disease. They found membrane-bound vacuoles with clear contents in eccrine clear cells and dark cells in 5 of 7 patients, as well as in 1 clinically unaffected sib. Sweat gland vacuoles were not seen in the biopsies of 8 patients with Lafora disease. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7991128" 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>Photosensitivity, i.e., precipitation of myoclonic jerks by intermittent photic stimulation, is a characteristic feature of progressive myoclonic epilepsies. <a href="#36" class="mim-tip-reference" title="Mazarib, A., Xiong, L., Neufeld, M. Y., Birnbaum, M., Korczyn, A. D., Pandolfo, M., Berkovic, S. F. <strong>Unverricht-Lundborg disease in a five-generation Arab family: instability of dodecamer repeats.</strong> Neurology 57: 1050-1054, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11571333/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11571333</a>] [<a href="https://doi.org/10.1212/wnl.57.6.1050" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11571333">Mazarib et al. (2001)</a> described an affected Arab family in which photosensitivity was absent. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11571333" 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="#35" class="mim-tip-reference" title="Mascalchi, M., Michelucci, R., Cosottini, M., Tessa, C., Lolli, F., Riguzzi, P., Lehesjoki, A. E., Tosetti, M., Villari, N., Tassinari, C. A. <strong>Brainstem involvement in Unverricht-Lundborg disease (EPM1): an MRI and 1-H MRS study.</strong> Neurology 58: 1686-1689, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12058102/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12058102</a>] [<a href="https://doi.org/10.1212/wnl.58.11.1686" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12058102">Mascalchi et al. (2002)</a> performed MRI and proton MRS on 10 patients with genetically confirmed EPM1 and found significant loss of bulk of the basis pontis, medulla, and cerebellar hemispheres as well as mild cerebral atrophy, compared to 20 healthy controls. The findings differed in some critical features from those in olivopontocerebellar atrophy. <a href="#35" class="mim-tip-reference" title="Mascalchi, M., Michelucci, R., Cosottini, M., Tessa, C., Lolli, F., Riguzzi, P., Lehesjoki, A. E., Tosetti, M., Villari, N., Tassinari, C. A. <strong>Brainstem involvement in Unverricht-Lundborg disease (EPM1): an MRI and 1-H MRS study.</strong> Neurology 58: 1686-1689, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12058102/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12058102</a>] [<a href="https://doi.org/10.1212/wnl.58.11.1686" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12058102">Mascalchi et al. (2002)</a> concluded that their findings support the hypothesis that the disease results from a decreased inhibitory control of the cerebral cortex by the brainstem and cerebellum via the thalamocortical loop. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12058102" 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="Canafoglia, L., Ciano, C., Panzica, F., Scaioli, V., Zucca, C., Agazzi, P., Visani, E., Avanzini, G., Franceschetti, S. <strong>Sensorimotor cortex excitability in Unverricht-Lundborg disease and Lafora body disease.</strong> Neurology 63: 2309-2315, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15623692/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15623692</a>] [<a href="https://doi.org/10.1212/01.wnl.0000147475.71345.aa" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15623692">Canafoglia et al. (2004)</a> found different electrophysiologic profiles representing sensorimotor cortex hyperexcitability in 8 patients with Lafora disease (age range, 14 to 27 years) and 10 patients with Unverricht-Lundborg disease (age range, 25 to 62 years). In general, the ULD patients had a quasistationary disease course, rare seizures, and little or no mental impairment, whereas the Lafora disease patients had recurrent seizures and worsening mental status. Patients with ULD had prominent action myoclonus clearly triggered by voluntary movements. Lafora disease patients experienced spontaneous myoclonic jerks associated with clear EEG paroxysms with only minor action myoclonus. Although both groups had enlarged or giant somatosensory evoked potentials, the pattern in the Lafora group was consistent with a distortion of cortical circuitry. Patients with ULD had enhanced long-loop reflexes with extremely brief cortical relay times. The findings were consistent with an aberrant subcortical or cortical loop, possibly short-cutting the somatosensory cortex, that may be involved in generating the prominent action myoclonus that characterizes ULD. Patients with Lafora disease had varied cortical relay times and delayed and prolonged facilitation as evidenced by sustained hyperexcitability of the sensorimotor cortex in response to afferent stimuli. The findings were consistent with an impairment of inhibitory mechanisms in Lafora disease. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15623692" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#39" class="mim-tip-reference" title="Noad, K. B., Lance, J. W. <strong>Familial myoclonic epilepsy and its association with cerebellar disturbance.</strong> Brain 83: 618-630, 1960.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/13729348/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">13729348</a>] [<a href="https://doi.org/10.1093/brain/83.4.618" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="13729348">Noad and Lance (1960)</a> described myoclonic epilepsy with cerebellar ataxia in several offspring of a mating of first cousins once removed, indicating autosomal recessive inheritance. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=13729348" 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="#42" class="mim-tip-reference" title="Pennacchio, L. A., Lehesjoki, A.-E., Stone, N. E., Willour, V. L., Virtaneva, K., Miao, J., D'Amato, E., Ramirez, L., Faham, M., Koskiniemi, M., Warrington, J. A., Norio, R., de la Chapelle, A., Cox, D. R., Myers, R. M. <strong>Mutations in the gene encoding cystatin B in progressive myoclonus epilepsy (EPM1).</strong> Science 271: 1731-1734, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8596935/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8596935</a>] [<a href="https://doi.org/10.1126/science.271.5256.1731" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8596935">Pennacchio et al. (1996)</a> stated that, even in chronic and severe cases, patients with EPM1 show marked improvement when treated with the antiepileptic drug sodium valproate; however, phenytoin, another drug that is effective against some other forms of epilepsy, does not improve the condition of EPM1 patients, often shows toxic effects, and, in some cases, is fatal. They stated that the identification of mutant genes encoding cystatin B in patients with EPM1 may help understanding of the differential response to these 2 drugs. Furthermore, this knowledge provides a biochemical pathway and molecular target for the treatment of EPM1 and perhaps other forms of epilepsy. <a href="#44" class="mim-tip-reference" title="Selwa, L. M. <strong>N-acetylcysteine therapy for Unverricht-Lundborg disease.</strong> Neurology 52: 426-427, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9932979/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9932979</a>] [<a href="https://doi.org/10.1212/wnl.52.2.426" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9932979">Selwa (1999)</a> reported significant improvement in seizures, tremors, speech and ambulation in a 40-year-old patient with Unverricht-Lundborg disease who was given N-acetylcysteine as well as other vitamin preparations containing antioxidants. The patient relapsed when medication was discontinued, but improvement was sustained during a 10-month follow-up after resumption of treatment. Improvement had previously been reported in 4 similarly treated sibs (<a href="#17" class="mim-tip-reference" title="Hurd, R. W., Wilder, B. J., Helveston, W. R., Uthman, B. M. <strong>Treatment of four siblings with progressive myoclonus epilepsy of the Unverricht-Lundborg type with N-acetylcysteine.</strong> Neurology 47: 1264-1268, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8909441/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8909441</a>] [<a href="https://doi.org/10.1212/wnl.47.5.1264" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8909441">Hurd et al., 1996</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=9932979+8596935+8909441" 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="#9" class="mim-tip-reference" title="Edwards, M. J. J., Hargreaves, I. P., Heales, S. J. R., Jones, S. J., Ramachandran, V., Bhatia, K. P., Sisodiya, S. <strong>N-acetylcysteine and Unverricht-Lundborg disease.</strong> Neurology 59: 1447-1449, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12427904/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12427904</a>] [<a href="https://doi.org/10.1212/wnl.59.9.1447" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12427904">Edwards et al. (2002)</a> found low glutathione levels in a patient with Unverricht-Lundborg disease proven by DNA studies. Glutathione levels increased during treatment with N-acetylcysteine (NAC). This increase was mirrored by an improvement in seizures, but not in myoclonus or ataxia. Three other patients with clinically determined Unverricht-Lundborg disease showed a variable response and some notable side effects during treatment with NAC, including sensorineural deafness. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12427904" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#18" class="mim-tip-reference" title="Kinrions, P., Ibrahim, N., Murphy, K., Lehesjoki, A.-E., Jarvela, I., Delanty, N. <strong>Efficacy of levetiracetam in a patient with Unverricht-Lundborg progressive myoclonic epilepsy.</strong> Neurology 60: 1394-1395, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12707458/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12707458</a>] [<a href="https://doi.org/10.1212/01.wnl.0000058755.38892.80" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12707458">Kinrions et al. (2003)</a> reported that levetiracetam, a piracetam analog, markedly improved myoclonus and quality of life in a 38-year-old woman with genetically confirmed Unverricht-Lundborg disease. Her illness began at age 13 and had progressed to leave her wheelchair-bound, dysarthric, and with multifocal myoclonus. Treatment with multiple medications had been unsuccessful. The authors cited previous reports of the effectiveness of levetiracetam in symptomatic myoclonus of various etiologies. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12707458" 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="#28" class="mim-tip-reference" title="Lehesjoki, A.-E., Koskiniemi, M., Sistonen, P., Miao, J., Hastbacka, J., Norio, R., de la Chapelle, A. <strong>Localization of a gene for progressive myoclonus epilepsy to chromosome 21q22.</strong> Proc. Nat. Acad. Sci. 88: 3696-3699, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1673790/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1673790</a>] [<a href="https://doi.org/10.1073/pnas.88.9.3696" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1673790">Lehesjoki et al. (1991)</a> demonstrated close linkage between the EPM1 locus and 3 markers on distal chromosome 21. The loci BCEI (<a href="/entry/113710">113710</a>) and D21S154 gave the highest positive lod scores of 5.49 and 4.25, respectively, at zero recombination. The third locus, D21S112, gave a lod score of 6.91 at a recombination fraction of 0.034. No evidence of heterogeneity was found in the 12 families studied. Multipoint lod scores calculated against a fixed map of the 3 marker loci gave a maximum 4-point lod score of 10.08 at a location of the disease gene at 6.0 cM distal to locus BCEI and 0.8 cM proximal to D21S154. Both of these markers had previously been localized to 21q22.3. <a href="#27" class="mim-tip-reference" title="Lehesjoki, A.-E., Koskiniemi, M., Pandolfo, M., Antonelli, A., Kyllerman, M., Wahlstrom, J., Nergardh, A., Burmeister, M., Sistonen, P., Norio, R., de la Chapelle, A. <strong>Linkage studies in progressive myoclonus epilepsy: Unverricht-Lundborg and Lafora's diseases.</strong> Neurology 42: 1545-1550, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1641151/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1641151</a>] [<a href="https://doi.org/10.1212/wnl.42.8.1545" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1641151">Lehesjoki et al. (1992)</a> refined the localization of EPM1 by linkage analysis between the disease phenotype and 9 DNA markers in 13 Finnish families. A maximum multipoint lod score of 11.04 was reached at loci D21S154/PFKL (<a href="/entry/171860">171860</a>), which had previously been mapped to 21q22.3. <a href="#26" class="mim-tip-reference" title="Lehesjoki, A.-E., Koskiniemi, M., Norio, R., Tirrito, S., Sistonen, P., Lander, E., de la Chapelle, A. <strong>Localization of the EPM1 gene for progressive myoclonus epilepsy on chromosome 21: linkage disequilibrium allows high resolution mapping.</strong> Hum. Molec. Genet. 2: 1229-1234, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8104628/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8104628</a>] [<a href="https://doi.org/10.1093/hmg/2.8.1229" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8104628">Lehesjoki et al. (1993)</a> narrowed the assignment of EPM1 to an interval of approximately 7 cM, between loci D21S212 and CD18, by analyzing crossover events in multiplex families. They refined the localization further by applying linkage disequilibrium mapping in 38 Finnish families, consisting of 12 with multiple affected children and 26 with a single affected child. In this way, they were able to conclude that EPM1 resides within 0.3 cM of PFKL, D21S25, and D21S154. This represents a likely physical distance of 300 kb or less. In a family reported by <a href="#12" class="mim-tip-reference" title="Eldridge, R., Iivanainen, M., Stern, R., Koerber, T., Wilder, B. J. <strong>'Baltic' myoclonus epilepsy: hereditary disorder of childhood made worse by phenytoin.</strong> Lancet 322: 838-842, 1983. Note: Originally Volume II.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/6137660/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">6137660</a>] [<a href="https://doi.org/10.1016/s0140-6736(83)90749-3" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="6137660">Eldridge et al. (1983)</a>, of mixed Italian and Irish ancestry, living in the United States, <a href="#25" class="mim-tip-reference" title="Lehesjoki, A.-E., Eldridge, R., Eldridge, J., Wilder, B. J., de la Chapelle, A. <strong>Progressive myoclonus epilepsy of Unverricht-Lundborg type: a clinical and molecular genetic study of a family from the United States with four affected sibs.</strong> Neurology 43: 2384-2386, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8232963/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8232963</a>] [<a href="https://doi.org/10.1212/wnl.43.11.2384" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8232963">Lehesjoki et al. (1993)</a> again found linkage to markers in the distal part of chromosome 21. Crossover events in the family helped refine the gene localization by placing EPM1 between CBS (<a href="/entry/613381">613381</a>) and D21S112. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=1673790+8232963+1641151+8104628+6137660" 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>Uncertainty has existed about the relationship between Unverricht-Lundborg disease, also referred to as Baltic myoclonus, and Mediterranean myoclonus, formerly considered to be a subgroup of the Ramsay Hunt syndrome. <a href="#29" class="mim-tip-reference" title="Lehesjoki, A.-E., Tassinari, C. A., Avanzini, G., Michelucci, R., Franceschetti, S., Antonelli, A., Rubboli, G., de la Chapelle, A. <strong>PME of Unverricht-Lundborg type in the Mediterranean region: linkage and linkage disequilibrium confirm the assignment to the EPM1 locus.</strong> Hum. Genet. 93: 668-674, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8005591/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8005591</a>] [<a href="https://doi.org/10.1007/BF00201568" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8005591">Lehesjoki et al. (1994)</a> studied 7 phenotypically homogeneous Mediterranean myoclonus families, using DNA markers from the genetically defined EPM1 region on chromosome 21. No recombination between the disease phenotype and the markers studied was detected. Within the EPM1 region, the highest lod score was 5.07 (at theta = 0.00) for PFKL. Significant allelic association between the disease mutation and PFKL was detected, suggesting a founder effect in Mediterranean myoclonus. However, haplotype data from 4 marker loci residing within 300 kb of each other and of EPM1 suggested the occurrence of more than 1 mutation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8005591" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Using linkage disequilibrium and recombination breakpoint mapping with Finnish EPM1 patients, <a href="#42" class="mim-tip-reference" title="Pennacchio, L. A., Lehesjoki, A.-E., Stone, N. E., Willour, V. L., Virtaneva, K., Miao, J., D'Amato, E., Ramirez, L., Faham, M., Koskiniemi, M., Warrington, J. A., Norio, R., de la Chapelle, A., Cox, D. R., Myers, R. M. <strong>Mutations in the gene encoding cystatin B in progressive myoclonus epilepsy (EPM1).</strong> Science 271: 1731-1734, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8596935/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8596935</a>] [<a href="https://doi.org/10.1126/science.271.5256.1731" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8596935">Pennacchio et al. (1996)</a> refined the location of the EPM1 gene to a region between markers D21S2040 and D21S1259. This region was entirely encompassed in a 750-kb bacterial clone contig generated by sequence tagged site content mapping and walking. A detailed restriction map of the contig determined that the distance between the DNA markers defining the boundaries of EPM1 was about 175 kb. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8596935" 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="Carr, J. A., van der Walt, P. E., Nakayama, J., Fu, Y.-H., Corfield, V., Brink, P., Ptacek, L. <strong>FAME3: a novel form of progressive myoclonus and epilepsy.</strong> Neurology 68: 1382-1389, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17452583/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17452583</a>] [<a href="https://doi.org/10.1212/01.wnl.0000260063.46425.7e" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17452583">Carr et al. (2007)</a> reported 2 large families from the Western Cape province of South Africa with generalized tonic-clonic seizures and myoclonus. The mean age at onset was 20 years (range 13 to 31). Myoclonus predominantly affected the trunk and upper limbs but was also observed in the lower limbs. Hand tremor became apparent on posture holding. Additional features included nystagmus, abnormal pursuit, dysarthria, hyperreflexia, cerebellar ataxia, and cerebellar atrophy. A number of patients also had progressive cognitive impairment, resulting in dementia in some. EEG studies were abnormal in the majority of patients, with polyspike and wave activity and/or clear epileptogenic activity. Postmortem examination of 1 patient showed cerebellar atrophy and cerebellar neuronal loss. Several patients died in their thirties and forties. The families were of mixed ancestry, predominantly resulting from intermarriage between the original inhabitants of the area, the Khoi-San, and early settlers of European origin. <a href="#5" class="mim-tip-reference" title="Carr, J. A., van der Walt, P. E., Nakayama, J., Fu, Y.-H., Corfield, V., Brink, P., Ptacek, L. <strong>FAME3: a novel form of progressive myoclonus and epilepsy.</strong> Neurology 68: 1382-1389, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17452583/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17452583</a>] [<a href="https://doi.org/10.1212/01.wnl.0000260063.46425.7e" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17452583">Carr et al. (2007)</a> noted that the phenotype was more severe and showed earlier onset than typical familial adult myoclonic epilepsy (FAME1; <a href="/entry/601068">601068</a>). The phenotype was also progressive, falling within the spectrum of progressive myoclonic epilepsies. Linkage analysis excluded FAME1 and FAME2 (<a href="/entry/607876">607876</a>). <a href="#45" class="mim-tip-reference" title="Striano, P., Striano, S., Zara, F. <strong>FAME3: a novel form of progressive myoclonus and epilepsy. (Letter)</strong> Neurology 70: 85 only, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18166714/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18166714</a>] [<a href="https://doi.org/10.1212/01.wnl.0000295707.90283.e6" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18166714">Striano et al. (2008)</a> commented that the phenotype described by <a href="#5" class="mim-tip-reference" title="Carr, J. A., van der Walt, P. E., Nakayama, J., Fu, Y.-H., Corfield, V., Brink, P., Ptacek, L. <strong>FAME3: a novel form of progressive myoclonus and epilepsy.</strong> Neurology 68: 1382-1389, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17452583/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17452583</a>] [<a href="https://doi.org/10.1212/01.wnl.0000260063.46425.7e" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17452583">Carr et al. (2007)</a> was more severe than typically seen for FAME, and suggested that the disorder described by <a href="#5" class="mim-tip-reference" title="Carr, J. A., van der Walt, P. E., Nakayama, J., Fu, Y.-H., Corfield, V., Brink, P., Ptacek, L. <strong>FAME3: a novel form of progressive myoclonus and epilepsy.</strong> Neurology 68: 1382-1389, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17452583/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17452583</a>] [<a href="https://doi.org/10.1212/01.wnl.0000260063.46425.7e" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17452583">Carr et al. (2007)</a> as 'FAME3,' should be placed within the group of progressive myoclonic epilepsies. <a href="#45" class="mim-tip-reference" title="Striano, P., Striano, S., Zara, F. <strong>FAME3: a novel form of progressive myoclonus and epilepsy. (Letter)</strong> Neurology 70: 85 only, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18166714/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18166714</a>] [<a href="https://doi.org/10.1212/01.wnl.0000295707.90283.e6" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18166714">Striano et al. (2008)</a> suggested that the designation FAME be reserved for familial nonprogressive cortical tremor and epilepsy. In a large French family with FAME, a locus designated FAME3 (<a href="/entry/613608">613608</a>) was mapped to chromosome 5p15 by <a href="#8" class="mim-tip-reference" title="Depienne, C., Magnin, E., Bouteiller, D., Stevanin, G., Saint-Martin, C., Vidailhet, M., Apartis, E., Hirsch, E., LeGuern, E., Labauge, P., Rumbach, L. <strong>Familial cortical myoclonic tremor with epilepsy: the third locus (FCMTE3) maps to 5p.</strong> Neurology 74: 2000-2003, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20548044/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20548044</a>] [<a href="https://doi.org/10.1212/WNL.0b013e3181e396a8" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20548044">Depienne et al. (2010)</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=17452583+18166714+20548044" 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="#42" class="mim-tip-reference" title="Pennacchio, L. A., Lehesjoki, A.-E., Stone, N. E., Willour, V. L., Virtaneva, K., Miao, J., D'Amato, E., Ramirez, L., Faham, M., Koskiniemi, M., Warrington, J. A., Norio, R., de la Chapelle, A., Cox, D. R., Myers, R. M. <strong>Mutations in the gene encoding cystatin B in progressive myoclonus epilepsy (EPM1).</strong> Science 271: 1731-1734, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8596935/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8596935</a>] [<a href="https://doi.org/10.1126/science.271.5256.1731" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8596935">Pennacchio et al. (1996)</a> used a combination of genetic and physical mapping information to search systematically for the causative gene for EPM1. Several cDNAs identified with a bacterial artificial chromosome (BAC) clone encoded a previously described protein, cystatin B (<a href="/entry/601145">601145</a>), a cysteine protease inhibitor. Because of the wide expression of the cystatin B gene in normal individuals and the finding of reduced expression in lymphoblastoid cells from affected individuals, <a href="#42" class="mim-tip-reference" title="Pennacchio, L. A., Lehesjoki, A.-E., Stone, N. E., Willour, V. L., Virtaneva, K., Miao, J., D'Amato, E., Ramirez, L., Faham, M., Koskiniemi, M., Warrington, J. A., Norio, R., de la Chapelle, A., Cox, D. R., Myers, R. M. <strong>Mutations in the gene encoding cystatin B in progressive myoclonus epilepsy (EPM1).</strong> Science 271: 1731-1734, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8596935/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8596935</a>] [<a href="https://doi.org/10.1126/science.271.5256.1731" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8596935">Pennacchio et al. (1996)</a> sequenced the cystatin B gene (also known as stefin B) from affected individuals and identified 2 different mutations in the gene. Cystatin C (CST3; <a href="/entry/604312">604312</a>) is the site of heterozygous mutations causing hereditary cerebral amyloid angiopathy. This dominantly inherited disorder is characterized by the deposition of cystatin C-rich amyloid fibrils in affected brain arteries. EPM1 is inherited as a recessive and appears to be the result of decreased amounts of cystatin B, suggesting different mechanisms for the 2 diseases. The genes responsible for Lafora disease (<a href="/entry/254780">254780</a>) (EPM2A; <a href="/entry/607566">607566</a>) and juvenile myoclonic epilepsy (<a href="/entry/254770">254770</a>) mapped to 6q and 6p, respectively. The identification of cystatin B defects in EPM1 suggested that other members of the cystatin superfamily or their substrates may be defective in these related epilepsies. See <a href="/entry/601145">601145</a> for point mutations identified in the stefin B gene in patients with EPM1. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8596935" 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="#22" class="mim-tip-reference" title="Lafreniere, R. G., Rochefort, D. L., Chretien, N., Rommens, J. M., Cochius, J. I., Kalviainen, R., Nousiainen, U., Patry, G., Farrell, K., Soderfeldt, B., Federico, A., Hale, B. R., Cossio, O. H., Sorensen, T., Pouliot, M. A., Kmiec, T., Uldall, P., Janszky, J., Pranzatelli, M. R., Andermann, F., Andermann, E., Rouleau, G. A. <strong>Unstable insertion of the 5-prime flanking region of the cystatin B gene is the most common mutation in progressive myoclonus epilepsy type 1, EPM1.</strong> Nature Genet. 15: 298-302, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9054946/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9054946</a>] [<a href="https://doi.org/10.1038/ng0397-298" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9054946">Lafreniere et al. (1997)</a> and <a href="#48" class="mim-tip-reference" title="Virtaneva, K., D'Amato, E., Miao, J., Koskiniemi, M., Norio, R., Avanzini, G., Franceschetti, S., Michelucci, R., Tassinari, C. A., Omer, S., Pennacchio, L. A., Myers, R. M., Dieguez-Lucena, J. L., Krahe, R., de la Chapelle, A., Lehesjoki, A.-E. <strong>Unstable minisatellite expansion causing recessively inherited myoclonus epilepsy, EPM1.</strong> Nature Genet. 15: 393-396, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9090386/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9090386</a>] [<a href="https://doi.org/10.1038/ng0497-393" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9090386">Virtaneva et al. (1997)</a> reported a novel type of disease-causing mutation, an unstable minisatellite repeat expansion in the putative promoter region of the gene (<a href="/entry/601145#0003">601145.0003</a>). The mutation accounted for most EPM1 patients worldwide. <a href="#48" class="mim-tip-reference" title="Virtaneva, K., D'Amato, E., Miao, J., Koskiniemi, M., Norio, R., Avanzini, G., Franceschetti, S., Michelucci, R., Tassinari, C. A., Omer, S., Pennacchio, L. A., Myers, R. M., Dieguez-Lucena, J. L., Krahe, R., de la Chapelle, A., Lehesjoki, A.-E. <strong>Unstable minisatellite expansion causing recessively inherited myoclonus epilepsy, EPM1.</strong> Nature Genet. 15: 393-396, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9090386/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9090386</a>] [<a href="https://doi.org/10.1038/ng0497-393" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9090386">Virtaneva et al. (1997)</a> noted that haplotype data from their study were compatible with a single ancestral founder mutation. The length of the repeat array differed between chromosomes and families, but changes in repeat number seemed to be comparatively rare events. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=9054946+9090386" 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="Lalioti, M. D., Mirotsou, M., Buresi, C., Peitsch, M. C., Rossier, C., Ouazzani, R., Baldy-Moulinier, M., Bottani, A., Malafosse, A., Antonarakis, S. E. <strong>Identification of mutations in cystatin B, the gene responsible for the Unverricht-Lundborg type of progressive myoclonus epilepsy (EPM1).</strong> Am. J. Hum. Genet. 60: 342-351, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9012407/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9012407</a>]" pmid="9012407">Lalioti et al. (1997)</a> identified 6 nucleotide changes in the CSTB gene in non-Finnish EPM1 families from northern Africa and Europe. One of these, a homozygous G-to-C transversion at nucleotide 426 in exon 1, resulted in a gly4-to-arg substitution (G4R; <a href="/entry/601145#0004">601145.0004</a>) and was the first missense mutation described in association with EPM1. Molecular modeling predicted that this substitution would severely affect the contact of cystatin B with papain. The 6 mutations were found in 7 of the 29 unrelated EPM1 patients analyzed, in homozygosity in 1, and in heterozygosity in the others. They also found a tandem repeat of a dodecamer (CCCCGCCCCGCG) in the 5-prime untranslated region as a polymorphism (<a href="/entry/601145#0003">601145.0003</a>). They identified 2 allelic variants with 2 or 3 tandem copies. The frequency of the 3-copy allele was 66% in the normal Caucasian population. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9012407" 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 an elaboration on their previous work, <a href="#24" class="mim-tip-reference" title="Lalioti, M. D., Scott, H. S., Buresi, C., Rossier, C., Bottani, A., Morris, M. A., Malafosse, A., Antonarakis, S. E. <strong>Dodecamer repeat expansion in cystatin B gene in progressive myoclonus epilepsy.</strong> Nature 386: 847-851, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9126745/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9126745</a>] [<a href="https://doi.org/10.1038/386847a0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9126745">Lalioti et al. (1997)</a> stated that the common mutation mechanism in EPM1 is the expansion of the dodecamer repeat (<a href="/entry/601145#0003">601145.0003</a>), and considered this mutation to be the most likely source of the disorder. An examination of 58 EPM1 alleles revealed that 50 of these contained the dodecamer repeat expansion. In addition to the expanded repeat mutation and the 2 or 3 repeats found in alleles considered to be normal, <a href="#23" class="mim-tip-reference" title="Lalioti, M. D., Mirotsou, M., Buresi, C., Peitsch, M. C., Rossier, C., Ouazzani, R., Baldy-Moulinier, M., Bottani, A., Malafosse, A., Antonarakis, S. E. <strong>Identification of mutations in cystatin B, the gene responsible for the Unverricht-Lundborg type of progressive myoclonus epilepsy (EPM1).</strong> Am. J. Hum. Genet. 60: 342-351, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9012407/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9012407</a>]" pmid="9012407">Lalioti et al. (1997)</a> identified alleles with 12 to 17 repeats, which they termed 'premutational,' that were transmitted unstably to offspring. These 'premutational' alleles were not connected with a clinical phenotype of EPM1. <a href="#23" class="mim-tip-reference" title="Lalioti, M. D., Mirotsou, M., Buresi, C., Peitsch, M. C., Rossier, C., Ouazzani, R., Baldy-Moulinier, M., Bottani, A., Malafosse, A., Antonarakis, S. E. <strong>Identification of mutations in cystatin B, the gene responsible for the Unverricht-Lundborg type of progressive myoclonus epilepsy (EPM1).</strong> Am. J. Hum. Genet. 60: 342-351, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9012407/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9012407</a>]" pmid="9012407">Lalioti et al. (1997)</a> stated that no correlation between number of repeat expansions and age of onset or severity had been found. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=9012407+9126745" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#1" class="mim-tip-reference" title="Antonarakis, S. <strong>Personal Communication.</strong> Geneva, Switzerland 4/8/1997."None>Antonarakis (1997)</a> confirmed that the only EPM1-related point mutation in the cystatin B gene found in homozygous state was the G4R amino acid substitution. All other point mutations identified in EPM1 patients were found as compound heterozygotes with the 12-bp repeat expansion allele. The repeat expansion allele was also homozygous in some patients. <a href="#1" class="mim-tip-reference" title="Antonarakis, S. <strong>Personal Communication.</strong> Geneva, Switzerland 4/8/1997."None>Antonarakis (1997)</a> found no patients with null point mutations (e.g., nonsense, frameshift, or splice site) in homozygous state; all EPM1 patients had residual gene activity. He proposed that homozygosity for null alleles was either nonviable or presented a different phenotype.</p><p><strong><em>Associations Pending Confirmation</em></strong></p><p>
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For discussion of a possible association between progressive myoclonic epilepsy and variation in the GPR37L1 gene, see <a href="/entry/617630#0001">617630.0001</a>.</p>
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<p><a href="#19" class="mim-tip-reference" title="Koskiniemi, M., Donner, M., Toivakka, E., Norio, R. <strong>Progressive myoclonus epilepsy (PME). In: Eriksson, A. W.; Forsius, H. R.; Nevanlinna, H. R.; Workman, P. L.; Norio, R. K.: Population Structure and Genetic Disorders.</strong> New York: Academic Press (pub.) 1980. Pp. 669-672."None>Koskiniemi et al. (1980)</a> estimated that over 100 cases in 70 sibships had been identified in Finland. Fewer cases had been found in all the rest of the world. The incidence in Finland is about 1 in 20,000.</p><p><a href="#38" class="mim-tip-reference" title="Moulard, B., Genton, P., Grid, D., Jeanpierre, M., Ouazzani, R., Mrabet, A., Morris, M., LeGuern, E., Dravet, C., Mauguiere, F., Utermann, B., Baldy-Moulinier, M., and 13 others. <strong>Haplotype study of West European and north African Unverricht-Lundborg chromosomes: evidence for a few founder mutations.</strong> Hum. Genet. 111: 255-262, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12215838/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12215838</a>] [<a href="https://doi.org/10.1007/s00439-002-0755-x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12215838">Moulard et al. (2002)</a> stated that Unverricht-Lundborg disease is also common North Africa but less common in western Europe. They performed a haplotype study of Unverricht-Lundborg disease chromosomes with a dodecamer repeat expansion in the CSTB gene (<a href="/entry/601145#0003">601145.0003</a>), the most frequent cause of the disorder. They found that 29 (61.7%) of 47 patients from North Africa shared the same haplotype, thus establishing a founder effect in this population. The haplotypes from 48 Caucasian patients from western Europe were heterogeneous. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12215838" 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>Stevenson pointed out, in a discussion of genetic aspects of the study by <a href="#16" class="mim-tip-reference" title="Harriman, D. G. F., Millar, J. H. D. <strong>Progressive familial myoclonic epilepsy in 3 families: its clinical features and pathological basis.</strong> Brain 78: 325-349, 1955.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/13269595/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">13269595</a>] [<a href="https://doi.org/10.1093/brain/78.3.325" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="13269595">Harriman and Millar (1955)</a>, that Lundborg's study is 'of considerable historic interest in human genetics.' Lundborg's data were used to test statistically the recessive hypothesis, the first such analysis in man. The statistical analysis was done first by <a href="#50" class="mim-tip-reference" title="Weinberg, W. <strong>Weitere Beitrage zur Theorie der Vererbung. 4. Ueber Methode und Fehlerquellen der Untersuchung auf Mendelsche Zahlen beim Menschen.</strong> Arch. Rass. Ges. Biol. 9: 165-174, 1912."None>Weinberg (1912)</a> and later by <a href="#2" class="mim-tip-reference" title="Bernstein, F. <strong>Variations-und Erblichkeitsstatistik.</strong> Berlin: Borntraeger (pub.) 1929."None>Bernstein (1929)</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=13269595" 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>Lundborg's report was one of the earliest of recessive inheritance. He published the names of those affected. When <a href="#3" class="mim-tip-reference" title="Book, J. A. <strong>Personal Communication.</strong> Uppsala, Sweden 1978."None>Book (1978)</a> later attempted a follow-up, he found that marriage of relatives had been carefully avoided in the group and no more cases had occurred. <a href="#3" class="mim-tip-reference" title="Book, J. A. <strong>Personal Communication.</strong> Uppsala, Sweden 1978."None>Book (1978)</a> suggested that this was one of the earliest and largest instances of group genetic counseling.</p>
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<p>A possibly homologous disorder in Poll Hereford cattle was shown by <a href="#15" class="mim-tip-reference" title="Gundlach, A. L., Dodd, P. R., Grabara, C. S. G., Watson, W. E. J., Johnston, G. A. R., Harper, P. A. W., Dennis, J. A., Healy, P. J. <strong>Deficit of spinal cord glycine/strychnine receptors in inherited myoclonus of Poll Hereford calves.</strong> Science 241: 1807-1810, 1988.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2845573/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2845573</a>] [<a href="https://doi.org/10.1126/science.2845573" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2845573">Gundlach et al. (1988)</a> to have a defect in glycine/strychnine receptors. The symptoms of the disorder suggested a failure of spinal interneuron inhibition and are similar to those in subconvulsive strychnine poisoning. Strychnine blocks the synaptic action of the inhibitory amino acid transmitter glycine by interacting with the postsynaptic glycine receptor. The mouse mutant 'spastic' may have a similar defect. The gene for the 'spastic' mutant maps to mouse chromosome 3 (<a href="#10" class="mim-tip-reference" title="Eicher, E. M., Lane, P. W. <strong>Assignment of LH XVI to chromosome 3 in the mouse.</strong> J. Hered. 71: 315-318, 1980.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/6160178/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">6160178</a>] [<a href="https://doi.org/10.1093/oxfordjournals.jhered.a109378" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="6160178">Eicher and Lane, 1980</a>). <a href="#14" class="mim-tip-reference" title="Grenningloh, G., Schmieden, V., Schofield, P. R., Seeburg, P. H., Siddique, T., Mohandas, T. K., Becker, C.-M., Betz, H. <strong>Alpha subunit variants of the human glycine receptor: primary structures, functional expression and chromosomal localization of the corresponding genes.</strong> EMBO J. 9: 771-776, 1990.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2155780/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2155780</a>] [<a href="https://doi.org/10.1002/j.1460-2075.1990.tb08172.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2155780">Grenningloh et al. (1990)</a> indicated that it is the alpha-1 form of the glycine receptor (<a href="/entry/138491">138491</a>) that is coded by an autosome, whereas the alpha-2 receptor (<a href="/entry/305990">305990</a>) is X-linked. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=6160178+2845573+2155780" 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 features of EPM1 were reproduced by targeted disruption of the cystatin B gene in mice (<a href="#41" class="mim-tip-reference" title="Pennacchio, L. A., Bouley, D. M., Higgins, K. M., Scott, M. P., Noebels, J. L., Myers, R. M. <strong>Progressive ataxia, myoclonic epilepsy and cerebellar apoptosis in cystatin B-deficient mice.</strong> Nature Genet. 20: 251-258, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9806543/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9806543</a>] [<a href="https://doi.org/10.1038/3059" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9806543">Pennacchio et al., 1998</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9806543" 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="Lieuallen, K., Pennacchio, L. A., Park, M., Myers, R. M., Lennon, G. G. <strong>Cystatin B-deficient mice have increased expression of apoptosis and glial activation genes.</strong> Hum. Molec. Genet. 10: 1867-1871, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11555622/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11555622</a>] [<a href="https://doi.org/10.1093/hmg/10.18.1867" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11555622">Lieuallen et al. (2001)</a> identified 7 genes with consistently increased transcript levels in neurologic tissues from Cstb-deficient knockout mice: cathepsin S (<a href="/entry/116845">116845</a>), C1q B-chain of complement (<a href="/entry/120570">120570</a>), beta-2-microglobulin (<a href="/entry/109700">109700</a>), glial fibrillary acidic protein (<a href="/entry/137780">137780</a>), apolipoprotein D (<a href="/entry/107740">107740</a>), fibronectin-1 (<a href="/entry/135600">135600</a>), and metallothionein II (<a href="/entry/156360">156360</a>). These proteins are expected to be involved in increased proteolysis, apoptosis, and glial activation. The molecular changes in Cstb-deficient mice were consistent with the pathology found in the mouse model. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11555622" 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="#Ford1951" class="mim-tip-reference" title="Ford, F. R., Livingston, S., Pryles, C. V. <strong>Familial degeneration of cerebral gray matter in childhood, with convulsions, myoclonus, spasticity, cerebellar ataxia, choreoathetosis, dementia, and death in status epilepticus: differentiation of infantile and juvenile types.</strong> J. Pediat. 39: 33-43, 1951.">Ford et al. (1951)</a>; <a href="#Kraus-Ruppert1970" class="mim-tip-reference" title="Kraus-Ruppert, R., Ostertag, B., Hafner, H. <strong>A study of the late form (type Lundborg) of progressive myoclonic epilepsy.</strong> J. Neurol. Sci. 11: 1-15, 1970.">Kraus-Ruppert et al. (1970)</a>; <a href="#Lundborg1912" class="mim-tip-reference" title="Lundborg, H. B. <strong>Der Erbgang der progressiven Myoklonusepilepsie. (Myoklonie-Epilepsie, Unverricht's familiaere Myoklonie).</strong> Z. Ges. Neurol. Psychiat. 9: 353-358, 1912.">Lundborg (1912)</a>; <a href="#Lundborg1913" class="mim-tip-reference" title="Lundborg, H. B. <strong>Medizinisch-biologische Familienforschungen innerhalb eines 2232 koepfigen Bauerngeschlechtes in Schweden.</strong> Jena: Fischer (pub.) 1913.">Lundborg (1913)</a>; <a href="#Morse1949" class="mim-tip-reference" title="Morse, W. I. <strong>Hereditary myoclonus epilepsy: two cases with pathological findings.</strong> Bull. Johns Hopkins Hosp. 84: 116-134, 1949.">Morse (1949)</a>; <a href="#Vogel1965" class="mim-tip-reference" title="Vogel, F., Hafner, H., Diebold, K. <strong>Zur Genetik der progressiven Myoklonusepilepsien (Unverricht-Lundborg).</strong> Humangenetik 1: 437-475, 1965.">Vogel et al. (1965)</a>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15623692/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15623692</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15623692" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1212/01.wnl.0000147475.71345.aa" target="_blank">Full Text</a>]
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Carr, J. A., van der Walt, P. E., Nakayama, J., Fu, Y.-H., Corfield, V., Brink, P., Ptacek, L.
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Neurology 68: 1382-1389, 2007.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17452583/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17452583</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17452583" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1212/01.wnl.0000260063.46425.7e" target="_blank">Full Text</a>]
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Cochius, J., Carpenter, S., Andermann, E., Rouleau, G., Nousiainen, U., Kalviainen, R., Farrell, K., Andermann, F.
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Neurology 44: 2372-2375, 1994.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7991128/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7991128</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7991128" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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de Siqueira, L. F. M.
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Depienne, C., Magnin, E., Bouteiller, D., Stevanin, G., Saint-Martin, C., Vidailhet, M., Apartis, E., Hirsch, E., LeGuern, E., Labauge, P., Rumbach, L.
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<strong>Familial cortical myoclonic tremor with epilepsy: the third locus (FCMTE3) maps to 5p.</strong>
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Neurology 74: 2000-2003, 2010.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20548044/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20548044</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20548044" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12427904/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12427904</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12427904" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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Eicher, E. M., Lane, P. W.
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<strong>Assignment of LH XVI to chromosome 3 in the mouse.</strong>
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J. Hered. 71: 315-318, 1980.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/6160178/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">6160178</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=6160178" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1093/oxfordjournals.jhered.a109378" target="_blank">Full Text</a>]
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Eldridge, R., Iivanainen, M., Stern, R., Koerber, T., Wilder, B. J.
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<strong>'Baltic' myoclonus epilepsy: a treatable hereditary disorder of childhood. (Abstract)</strong>
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Sixth International Congress of Human Genetics, Jerusalem 1981. P. 256.
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Eldridge, R., Iivanainen, M., Stern, R., Koerber, T., Wilder, B. J.
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<strong>'Baltic' myoclonus epilepsy: hereditary disorder of childhood made worse by phenytoin.</strong>
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Lancet 322: 838-842, 1983. Note: Originally Volume II.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/6137660/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">6137660</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=6137660" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/5868699/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">5868699</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=5868699" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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Weinberg, W.
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<strong>Weitere Beitrage zur Theorie der Vererbung. 4. Ueber Methode und Fehlerquellen der Untersuchung auf Mendelsche Zahlen beim Menschen.</strong>
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Arch. Rass. Ges. Biol. 9: 165-174, 1912.
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Cassandra L. Kniffin - updated : 1/21/2011
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Cassandra L. Kniffin - updated : 2/4/2008<br>Cassandra L. Kniffin - updated : 4/6/2005<br>Cassandra L. Kniffin - updated : 6/11/2003<br>Victor A. McKusick - updated : 1/22/2003<br>Victor A. McKusick - updated : 10/10/2002<br>Cassandra L. Kniffin - updated : 9/3/2002<br>George E. Tiller - updated : 1/28/2002<br>Carol A. Bocchini - reorganized : 11/8/2001<br>Victor A. McKusick - updated : 11/2/2001<br>Orest Hurko - updated : 3/24/1999<br>Victor A. McKusick - updated : 10/23/1998<br>Stylianos E. Antonarakis - updated : 9/22/1997<br>Mark H. Paalman - updated : 4/9/1997<br>Victor A. McKusick - updated : 3/31/1997
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<span class="mim-text-font">
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Victor A. McKusick : 6/4/1986
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carol : 01/24/2024
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alopez : 03/17/2023<br>carol : 05/06/2021<br>alopez : 02/24/2021<br>ckniffin : 02/18/2021<br>alopez : 05/12/2020<br>ckniffin : 05/06/2020<br>carol : 04/21/2018<br>carol : 04/20/2018<br>ckniffin : 04/18/2018<br>carol : 10/14/2016<br>carol : 03/28/2016<br>carol : 3/25/2016<br>carol : 3/24/2016<br>carol : 11/13/2015<br>ckniffin : 11/11/2015<br>alopez : 9/17/2015<br>ckniffin : 9/16/2015<br>ckniffin : 2/18/2015<br>carol : 1/20/2015<br>ckniffin : 1/15/2015<br>wwang : 6/10/2011<br>ckniffin : 5/31/2011<br>terry : 4/28/2011<br>wwang : 3/29/2011<br>ckniffin : 3/25/2011<br>alopez : 3/11/2011<br>wwang : 2/21/2011<br>ckniffin : 1/21/2011<br>wwang : 10/26/2010<br>ckniffin : 10/20/2010<br>carol : 5/4/2010<br>terry : 3/13/2009<br>wwang : 12/5/2008<br>ckniffin : 11/24/2008<br>wwang : 4/23/2008<br>ckniffin : 4/17/2008<br>wwang : 2/25/2008<br>wwang : 2/22/2008<br>wwang : 2/4/2008<br>ckniffin : 2/4/2008<br>carol : 4/20/2005<br>wwang : 4/15/2005<br>ckniffin : 4/6/2005<br>terry : 3/3/2005<br>tkritzer : 1/15/2004<br>carol : 6/16/2003<br>ckniffin : 6/11/2003<br>ckniffin : 2/27/2003<br>carol : 2/27/2003<br>cwells : 1/29/2003<br>tkritzer : 1/22/2003<br>carol : 10/17/2002<br>carol : 10/17/2002<br>tkritzer : 10/16/2002<br>terry : 10/10/2002<br>carol : 9/10/2002<br>carol : 9/10/2002<br>ckniffin : 9/3/2002<br>carol : 2/21/2002<br>cwells : 2/14/2002<br>cwells : 1/28/2002<br>carol : 11/8/2001<br>carol : 11/8/2001<br>mcapotos : 11/2/2001<br>carol : 11/24/1999<br>terry : 4/29/1999<br>mgross : 4/8/1999<br>carol : 3/24/1999<br>dkim : 11/6/1998<br>carol : 10/23/1998<br>dkim : 9/10/1998<br>alopez : 5/20/1998<br>dholmes : 12/4/1997<br>alopez : 9/22/1997<br>alopez : 9/22/1997<br>alopez : 9/22/1997<br>terry : 8/27/1997<br>mark : 4/9/1997<br>mark : 4/9/1997<br>mark : 3/31/1997<br>terry : 3/28/1997<br>mark : 3/21/1996<br>terry : 3/18/1996<br>mimman : 2/8/1996<br>mark : 6/13/1995<br>terry : 2/9/1995<br>carol : 2/1/1995<br>pfoster : 8/16/1994<br>warfield : 4/15/1994<br>mimadm : 4/12/1994
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<strong>#</strong> 254800
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MYOCLONIC EPILEPSY OF UNVERRICHT AND LUNDBORG
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<em>Alternative titles; symbols</em>
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ULD<br />
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EPILEPSY, PROGRESSIVE MYOCLONIC, 1A; EPM1A<br />
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EPILEPSY, PROGRESSIVE MYOCLONIC, 1; EPM1<br />
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PROGRESSIVE MYOCLONIC EPILEPSY; PME<br />
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BALTIC MYOCLONIC EPILEPSY
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<strong>SNOMEDCT:</strong> 230423006;
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<strong>ORPHA:</strong> 308;
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<strong>DO:</strong> 0111452;
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<strong>Phenotype-Gene Relationships</strong>
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Location
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Phenotype
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Inheritance
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Phenotype <br /> mapping key
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21q22.3
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<span class="mim-font">
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Epilepsy, progressive myoclonic 1A (Unverricht and Lundborg)
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<span class="mim-font">
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254800
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<span class="mim-font">
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Autosomal recessive
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3
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CSTB
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601145
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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 myoclonic epilepsy of Unverricht and Lundborg (ULD), also known as progressive myoclonic epilepsy-1A (EPM1A), is caused by mutation in the cystatin B gene (CSTB; 601145) on chromosome 21q22.</p>
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<strong>Description</strong>
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<span class="mim-text-font">
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<p>Myoclonic epilepsy of Unverricht and Lundborg, also known as progressive myoclonic epilepsy-1A (EPM1A), is an autosomal recessive disorder characterized by onset of neurodegeneration between 6 and 13 years of age. Although it is considered a progressive myoclonic epilepsy, it differs from other forms in that it appears to be progressive only in adolescence, with dramatic worsening of myoclonus and ataxia in the first 6 years after onset. The disease stabilizes in early adulthood, and myoclonus and ataxia may even improve, and there is minimal to no cognitive decline (summary by Ramachandran et al., 2009). </p><p><strong><em>Genetic Heterogeneity of Progressive Myoclonic Epilepsy</em></strong></p><p>
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Progressive myoclonic epilepsy refers to a clinically and genetically heterogeneous group of neurodegenerative disorders, usually with debilitating symptoms, although severity varies. See also EPM1B (612437), caused by mutation in the PRICKLE1 gene (608500); Lafora disease-1 (EPM2A; 254780), caused by mutation in the EPM2A gene (607566); Lafora disease-2 (EPM2B; 620681), caused by mutation in the NHLRC1 (608072) gene; EPM3 (611726), caused by mutation in the KCTD7 gene (611725); EPM4 (254900), caused by mutation in the SCARB2 gene (602257); EPM6 (614018), caused by mutation in the GOSR2 gene (604027); EPM7 (616187), caused by mutation in the KCNC1 gene (176258); EPM8 (616230), caused by mutation in the CERS1 gene (606919); EPM9 (616540), caused by mutation in the LMNB2 gene (150341); EPM10 (616640), caused by mutation in the PRDM8 gene (616639); EPM11 (618876), caused by mutation in the SEMA6B gene (608873); and EPM12 (619191), caused by mutation in the SLC7A6OS gene (619192).</p><p>A form of progressive myoclonic epilepsy, formerly designated EPM5, is included in 607459 with the primary designation of spinocerebellar ataxia with epilepsy (SCAE).</p><p>Other disorders characterized by progressive myoclonic epilepsy include the neuronal ceroid lipofuscinoses (see, e.g., CLN1 (256730); sialidosis (256550); MERFF (545000); and DRPLA (125370), among others (reviews by Ramachandran et al., 2009 and de Siqueira, 2010).) </p>
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<h4>
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<strong>Clinical Features</strong>
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<span class="mim-text-font">
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<p>Unverricht (1891, 1895) and Lundborg (1903) first reported a type of progressive myoclonic epilepsy common in Finland. Onset of the disorder occurred around age 10 years, and was characterized by progressive myoclonus resulting in incapacitation, but only mild mental deterioration. Histological studies of the brain showed 'degenerative' changes without inclusion bodies. Severity and survival were variable (Norio and Koskiniemi, 1979). </p><p>Eldridge et al. (1981, 1983) referred to this disorder as the 'Baltic type' of myoclonic epilepsy because the descriptions first by Unverricht and then by Lundborg were in families from Estonia and Eastern Sweden and subsequent patients were found in Finland. Eldridge et al. (1983) found 15 families in the United States. The 27 affected members had the following features starting at about age 10 years: stimulus- and photo-sensitive and occasionally violent myoclonus, usually worse upon waking; generalized tonic-clonic seizures, sometimes associated with absence attacks; and light-sensitive, generally synchronous, spike-and-wave discharges on EEG that preceded clinical manifestations. Necropsy showed marked loss of Purkinje cells of the cerebellum, but no inclusion bodies. Phenytoin was associated with progressive motor and intellectual deterioration, marked ataxia, and even death. Treatment with valproic acid was associated with marked improvement. Contrary to myoclonic epilepsy with Lafora bodies, intelligence in this form was only slightly affected and psychotic symptoms were not found. In addition, Lafora body disease is invariably fatal. </p><p>Kyllerman et al. (1991) described 4 sibs who demonstrated a subclinical stage of this disorder at the age of 9 to 11 years, with visual blackouts and polyspike electroencephalographic (EEG) activity on photic stimulation; an early myoclonic stage at the age of 12 to 15 years, with increasing segmental, stimulus-sensitive myoclonus, occasional nocturnal buildup myoclonic 'cascade' seizures, slowing of EEG alpha-activity, episodic 4-6 Hz bilateral sharp waves and polyspikes with myoclonus on photic stimulation; and a disabling myoclonic stage at the age of 16 to 18 years, with periodic generalized myoclonus, nocturnal myoclonic 'cascade' seizures, ataxia, dysarthria, mental changes, intermittent wheelchair dependency, and continuous EEG slow waves with polyspikes and intense myoclonus on photic stimulation. One of the sibs died at the age of 18 years with no apparent cause of death. </p><p>As pointed out by the Marseille Consensus Group (1990), patients with Ramsay Hunt syndrome (213400) cannot be distinguished clinically from patients with Unverricht-Lundborg disease. Linkage studies may help determine whether that disorder is caused by mutation at the same locus. </p><p>Cochius et al. (1994) reported for the first time a pathologic abnormality outside the central nervous system in patients with Unverricht-Lundborg disease. They found membrane-bound vacuoles with clear contents in eccrine clear cells and dark cells in 5 of 7 patients, as well as in 1 clinically unaffected sib. Sweat gland vacuoles were not seen in the biopsies of 8 patients with Lafora disease. </p><p>Photosensitivity, i.e., precipitation of myoclonic jerks by intermittent photic stimulation, is a characteristic feature of progressive myoclonic epilepsies. Mazarib et al. (2001) described an affected Arab family in which photosensitivity was absent. </p><p>Mascalchi et al. (2002) performed MRI and proton MRS on 10 patients with genetically confirmed EPM1 and found significant loss of bulk of the basis pontis, medulla, and cerebellar hemispheres as well as mild cerebral atrophy, compared to 20 healthy controls. The findings differed in some critical features from those in olivopontocerebellar atrophy. Mascalchi et al. (2002) concluded that their findings support the hypothesis that the disease results from a decreased inhibitory control of the cerebral cortex by the brainstem and cerebellum via the thalamocortical loop. </p><p>Canafoglia et al. (2004) found different electrophysiologic profiles representing sensorimotor cortex hyperexcitability in 8 patients with Lafora disease (age range, 14 to 27 years) and 10 patients with Unverricht-Lundborg disease (age range, 25 to 62 years). In general, the ULD patients had a quasistationary disease course, rare seizures, and little or no mental impairment, whereas the Lafora disease patients had recurrent seizures and worsening mental status. Patients with ULD had prominent action myoclonus clearly triggered by voluntary movements. Lafora disease patients experienced spontaneous myoclonic jerks associated with clear EEG paroxysms with only minor action myoclonus. Although both groups had enlarged or giant somatosensory evoked potentials, the pattern in the Lafora group was consistent with a distortion of cortical circuitry. Patients with ULD had enhanced long-loop reflexes with extremely brief cortical relay times. The findings were consistent with an aberrant subcortical or cortical loop, possibly short-cutting the somatosensory cortex, that may be involved in generating the prominent action myoclonus that characterizes ULD. Patients with Lafora disease had varied cortical relay times and delayed and prolonged facilitation as evidenced by sustained hyperexcitability of the sensorimotor cortex in response to afferent stimuli. The findings were consistent with an impairment of inhibitory mechanisms in Lafora disease. </p>
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<h4>
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<span class="mim-font">
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<strong>Inheritance</strong>
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</span>
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</div>
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<span class="mim-text-font">
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<p>Noad and Lance (1960) described myoclonic epilepsy with cerebellar ataxia in several offspring of a mating of first cousins once removed, indicating autosomal recessive inheritance. </p>
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<h4>
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<span class="mim-font">
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<strong>Clinical Management</strong>
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<span class="mim-text-font">
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<p>Pennacchio et al. (1996) stated that, even in chronic and severe cases, patients with EPM1 show marked improvement when treated with the antiepileptic drug sodium valproate; however, phenytoin, another drug that is effective against some other forms of epilepsy, does not improve the condition of EPM1 patients, often shows toxic effects, and, in some cases, is fatal. They stated that the identification of mutant genes encoding cystatin B in patients with EPM1 may help understanding of the differential response to these 2 drugs. Furthermore, this knowledge provides a biochemical pathway and molecular target for the treatment of EPM1 and perhaps other forms of epilepsy. Selwa (1999) reported significant improvement in seizures, tremors, speech and ambulation in a 40-year-old patient with Unverricht-Lundborg disease who was given N-acetylcysteine as well as other vitamin preparations containing antioxidants. The patient relapsed when medication was discontinued, but improvement was sustained during a 10-month follow-up after resumption of treatment. Improvement had previously been reported in 4 similarly treated sibs (Hurd et al., 1996). </p><p>Edwards et al. (2002) found low glutathione levels in a patient with Unverricht-Lundborg disease proven by DNA studies. Glutathione levels increased during treatment with N-acetylcysteine (NAC). This increase was mirrored by an improvement in seizures, but not in myoclonus or ataxia. Three other patients with clinically determined Unverricht-Lundborg disease showed a variable response and some notable side effects during treatment with NAC, including sensorineural deafness. </p><p>Kinrions et al. (2003) reported that levetiracetam, a piracetam analog, markedly improved myoclonus and quality of life in a 38-year-old woman with genetically confirmed Unverricht-Lundborg disease. Her illness began at age 13 and had progressed to leave her wheelchair-bound, dysarthric, and with multifocal myoclonus. Treatment with multiple medications had been unsuccessful. The authors cited previous reports of the effectiveness of levetiracetam in symptomatic myoclonus of various etiologies. </p>
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</span>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Mapping</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Lehesjoki et al. (1991) demonstrated close linkage between the EPM1 locus and 3 markers on distal chromosome 21. The loci BCEI (113710) and D21S154 gave the highest positive lod scores of 5.49 and 4.25, respectively, at zero recombination. The third locus, D21S112, gave a lod score of 6.91 at a recombination fraction of 0.034. No evidence of heterogeneity was found in the 12 families studied. Multipoint lod scores calculated against a fixed map of the 3 marker loci gave a maximum 4-point lod score of 10.08 at a location of the disease gene at 6.0 cM distal to locus BCEI and 0.8 cM proximal to D21S154. Both of these markers had previously been localized to 21q22.3. Lehesjoki et al. (1992) refined the localization of EPM1 by linkage analysis between the disease phenotype and 9 DNA markers in 13 Finnish families. A maximum multipoint lod score of 11.04 was reached at loci D21S154/PFKL (171860), which had previously been mapped to 21q22.3. Lehesjoki et al. (1993) narrowed the assignment of EPM1 to an interval of approximately 7 cM, between loci D21S212 and CD18, by analyzing crossover events in multiplex families. They refined the localization further by applying linkage disequilibrium mapping in 38 Finnish families, consisting of 12 with multiple affected children and 26 with a single affected child. In this way, they were able to conclude that EPM1 resides within 0.3 cM of PFKL, D21S25, and D21S154. This represents a likely physical distance of 300 kb or less. In a family reported by Eldridge et al. (1983), of mixed Italian and Irish ancestry, living in the United States, Lehesjoki et al. (1993) again found linkage to markers in the distal part of chromosome 21. Crossover events in the family helped refine the gene localization by placing EPM1 between CBS (613381) and D21S112. </p><p>Uncertainty has existed about the relationship between Unverricht-Lundborg disease, also referred to as Baltic myoclonus, and Mediterranean myoclonus, formerly considered to be a subgroup of the Ramsay Hunt syndrome. Lehesjoki et al. (1994) studied 7 phenotypically homogeneous Mediterranean myoclonus families, using DNA markers from the genetically defined EPM1 region on chromosome 21. No recombination between the disease phenotype and the markers studied was detected. Within the EPM1 region, the highest lod score was 5.07 (at theta = 0.00) for PFKL. Significant allelic association between the disease mutation and PFKL was detected, suggesting a founder effect in Mediterranean myoclonus. However, haplotype data from 4 marker loci residing within 300 kb of each other and of EPM1 suggested the occurrence of more than 1 mutation. </p><p>Using linkage disequilibrium and recombination breakpoint mapping with Finnish EPM1 patients, Pennacchio et al. (1996) refined the location of the EPM1 gene to a region between markers D21S2040 and D21S1259. This region was entirely encompassed in a 750-kb bacterial clone contig generated by sequence tagged site content mapping and walking. A detailed restriction map of the contig determined that the distance between the DNA markers defining the boundaries of EPM1 was about 175 kb. </p>
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</span>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Heterogeneity</strong>
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</span>
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</h4>
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<span class="mim-text-font">
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<p>Carr et al. (2007) reported 2 large families from the Western Cape province of South Africa with generalized tonic-clonic seizures and myoclonus. The mean age at onset was 20 years (range 13 to 31). Myoclonus predominantly affected the trunk and upper limbs but was also observed in the lower limbs. Hand tremor became apparent on posture holding. Additional features included nystagmus, abnormal pursuit, dysarthria, hyperreflexia, cerebellar ataxia, and cerebellar atrophy. A number of patients also had progressive cognitive impairment, resulting in dementia in some. EEG studies were abnormal in the majority of patients, with polyspike and wave activity and/or clear epileptogenic activity. Postmortem examination of 1 patient showed cerebellar atrophy and cerebellar neuronal loss. Several patients died in their thirties and forties. The families were of mixed ancestry, predominantly resulting from intermarriage between the original inhabitants of the area, the Khoi-San, and early settlers of European origin. Carr et al. (2007) noted that the phenotype was more severe and showed earlier onset than typical familial adult myoclonic epilepsy (FAME1; 601068). The phenotype was also progressive, falling within the spectrum of progressive myoclonic epilepsies. Linkage analysis excluded FAME1 and FAME2 (607876). Striano et al. (2008) commented that the phenotype described by Carr et al. (2007) was more severe than typically seen for FAME, and suggested that the disorder described by Carr et al. (2007) as 'FAME3,' should be placed within the group of progressive myoclonic epilepsies. Striano et al. (2008) suggested that the designation FAME be reserved for familial nonprogressive cortical tremor and epilepsy. In a large French family with FAME, a locus designated FAME3 (613608) was mapped to chromosome 5p15 by Depienne et al. (2010). </p>
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</span>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Molecular Genetics</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Pennacchio et al. (1996) used a combination of genetic and physical mapping information to search systematically for the causative gene for EPM1. Several cDNAs identified with a bacterial artificial chromosome (BAC) clone encoded a previously described protein, cystatin B (601145), a cysteine protease inhibitor. Because of the wide expression of the cystatin B gene in normal individuals and the finding of reduced expression in lymphoblastoid cells from affected individuals, Pennacchio et al. (1996) sequenced the cystatin B gene (also known as stefin B) from affected individuals and identified 2 different mutations in the gene. Cystatin C (CST3; 604312) is the site of heterozygous mutations causing hereditary cerebral amyloid angiopathy. This dominantly inherited disorder is characterized by the deposition of cystatin C-rich amyloid fibrils in affected brain arteries. EPM1 is inherited as a recessive and appears to be the result of decreased amounts of cystatin B, suggesting different mechanisms for the 2 diseases. The genes responsible for Lafora disease (254780) (EPM2A; 607566) and juvenile myoclonic epilepsy (254770) mapped to 6q and 6p, respectively. The identification of cystatin B defects in EPM1 suggested that other members of the cystatin superfamily or their substrates may be defective in these related epilepsies. See 601145 for point mutations identified in the stefin B gene in patients with EPM1. </p><p>Lafreniere et al. (1997) and Virtaneva et al. (1997) reported a novel type of disease-causing mutation, an unstable minisatellite repeat expansion in the putative promoter region of the gene (601145.0003). The mutation accounted for most EPM1 patients worldwide. Virtaneva et al. (1997) noted that haplotype data from their study were compatible with a single ancestral founder mutation. The length of the repeat array differed between chromosomes and families, but changes in repeat number seemed to be comparatively rare events. </p><p>Lalioti et al. (1997) identified 6 nucleotide changes in the CSTB gene in non-Finnish EPM1 families from northern Africa and Europe. One of these, a homozygous G-to-C transversion at nucleotide 426 in exon 1, resulted in a gly4-to-arg substitution (G4R; 601145.0004) and was the first missense mutation described in association with EPM1. Molecular modeling predicted that this substitution would severely affect the contact of cystatin B with papain. The 6 mutations were found in 7 of the 29 unrelated EPM1 patients analyzed, in homozygosity in 1, and in heterozygosity in the others. They also found a tandem repeat of a dodecamer (CCCCGCCCCGCG) in the 5-prime untranslated region as a polymorphism (601145.0003). They identified 2 allelic variants with 2 or 3 tandem copies. The frequency of the 3-copy allele was 66% in the normal Caucasian population. </p><p>In an elaboration on their previous work, Lalioti et al. (1997) stated that the common mutation mechanism in EPM1 is the expansion of the dodecamer repeat (601145.0003), and considered this mutation to be the most likely source of the disorder. An examination of 58 EPM1 alleles revealed that 50 of these contained the dodecamer repeat expansion. In addition to the expanded repeat mutation and the 2 or 3 repeats found in alleles considered to be normal, Lalioti et al. (1997) identified alleles with 12 to 17 repeats, which they termed 'premutational,' that were transmitted unstably to offspring. These 'premutational' alleles were not connected with a clinical phenotype of EPM1. Lalioti et al. (1997) stated that no correlation between number of repeat expansions and age of onset or severity had been found. </p><p>Antonarakis (1997) confirmed that the only EPM1-related point mutation in the cystatin B gene found in homozygous state was the G4R amino acid substitution. All other point mutations identified in EPM1 patients were found as compound heterozygotes with the 12-bp repeat expansion allele. The repeat expansion allele was also homozygous in some patients. Antonarakis (1997) found no patients with null point mutations (e.g., nonsense, frameshift, or splice site) in homozygous state; all EPM1 patients had residual gene activity. He proposed that homozygosity for null alleles was either nonviable or presented a different phenotype.</p><p><strong><em>Associations Pending Confirmation</em></strong></p><p>
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For discussion of a possible association between progressive myoclonic epilepsy and variation in the GPR37L1 gene, see 617630.0001.</p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Population Genetics</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Koskiniemi et al. (1980) estimated that over 100 cases in 70 sibships had been identified in Finland. Fewer cases had been found in all the rest of the world. The incidence in Finland is about 1 in 20,000.</p><p>Moulard et al. (2002) stated that Unverricht-Lundborg disease is also common North Africa but less common in western Europe. They performed a haplotype study of Unverricht-Lundborg disease chromosomes with a dodecamer repeat expansion in the CSTB gene (601145.0003), the most frequent cause of the disorder. They found that 29 (61.7%) of 47 patients from North Africa shared the same haplotype, thus establishing a founder effect in this population. The haplotypes from 48 Caucasian patients from western Europe were heterogeneous. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>History</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Stevenson pointed out, in a discussion of genetic aspects of the study by Harriman and Millar (1955), that Lundborg's study is 'of considerable historic interest in human genetics.' Lundborg's data were used to test statistically the recessive hypothesis, the first such analysis in man. The statistical analysis was done first by Weinberg (1912) and later by Bernstein (1929). </p><p>Lundborg's report was one of the earliest of recessive inheritance. He published the names of those affected. When Book (1978) later attempted a follow-up, he found that marriage of relatives had been carefully avoided in the group and no more cases had occurred. Book (1978) suggested that this was one of the earliest and largest instances of group genetic counseling.</p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Animal Model</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>A possibly homologous disorder in Poll Hereford cattle was shown by Gundlach et al. (1988) to have a defect in glycine/strychnine receptors. The symptoms of the disorder suggested a failure of spinal interneuron inhibition and are similar to those in subconvulsive strychnine poisoning. Strychnine blocks the synaptic action of the inhibitory amino acid transmitter glycine by interacting with the postsynaptic glycine receptor. The mouse mutant 'spastic' may have a similar defect. The gene for the 'spastic' mutant maps to mouse chromosome 3 (Eicher and Lane, 1980). Grenningloh et al. (1990) indicated that it is the alpha-1 form of the glycine receptor (138491) that is coded by an autosome, whereas the alpha-2 receptor (305990) is X-linked. </p><p>The features of EPM1 were reproduced by targeted disruption of the cystatin B gene in mice (Pennacchio et al., 1998). </p><p>Lieuallen et al. (2001) identified 7 genes with consistently increased transcript levels in neurologic tissues from Cstb-deficient knockout mice: cathepsin S (116845), C1q B-chain of complement (120570), beta-2-microglobulin (109700), glial fibrillary acidic protein (137780), apolipoprotein D (107740), fibronectin-1 (135600), and metallothionein II (156360). These proteins are expected to be involved in increased proteolysis, apoptosis, and glial activation. The molecular changes in Cstb-deficient mice were consistent with the pathology found in the mouse model. </p>
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</span>
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<div>
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<br />
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</div>
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>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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Ford et al. (1951); Kraus-Ruppert et al. (1970); Lundborg (1912);
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Lundborg (1913); Morse (1949); Vogel et al. (1965)
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</span>
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<div>
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<br />
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</div>
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>REFERENCES</strong>
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</span>
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</h4>
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<div>
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<p />
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</div>
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<div>
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<ol>
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<li>
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<p class="mim-text-font">
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Antonarakis, S.
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<strong>Personal Communication.</strong>
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Geneva, Switzerland 4/8/1997.
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Bernstein, F.
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<strong>Variations-und Erblichkeitsstatistik.</strong>
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Berlin: Borntraeger (pub.) 1929.
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Book, J. A.
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<strong>Personal Communication.</strong>
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Uppsala, Sweden 1978.
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Canafoglia, L., Ciano, C., Panzica, F., Scaioli, V., Zucca, C., Agazzi, P., Visani, E., Avanzini, G., Franceschetti, S.
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<strong>Sensorimotor cortex excitability in Unverricht-Lundborg disease and Lafora body disease.</strong>
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Neurology 63: 2309-2315, 2004.
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[PubMed: 15623692]
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[Full Text: https://doi.org/10.1212/01.wnl.0000147475.71345.aa]
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</p>
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<p class="mim-text-font">
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Carr, J. A., van der Walt, P. E., Nakayama, J., Fu, Y.-H., Corfield, V., Brink, P., Ptacek, L.
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<strong>FAME3: a novel form of progressive myoclonus and epilepsy.</strong>
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Neurology 68: 1382-1389, 2007.
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[PubMed: 17452583]
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[Full Text: https://doi.org/10.1212/01.wnl.0000260063.46425.7e]
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</p>
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<p class="mim-text-font">
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Cochius, J., Carpenter, S., Andermann, E., Rouleau, G., Nousiainen, U., Kalviainen, R., Farrell, K., Andermann, F.
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<strong>Sweat gland vacuoles in Unverricht-Lundborg disease: a clue to diagnosis?</strong>
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Neurology 44: 2372-2375, 1994.
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[PubMed: 7991128]
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[Full Text: https://doi.org/10.1212/wnl.44.12.2372]
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</p>
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<p class="mim-text-font">
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de Siqueira, L. F. M.
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<strong>Progressive myoclonic epilepsies: review of clinical, molecular and therapeutic aspects.</strong>
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J. Neurol. 257: 1612-1619, 2010.
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[PubMed: 20593193]
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[Full Text: https://doi.org/10.1007/s00415-010-5641-1]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Depienne, C., Magnin, E., Bouteiller, D., Stevanin, G., Saint-Martin, C., Vidailhet, M., Apartis, E., Hirsch, E., LeGuern, E., Labauge, P., Rumbach, L.
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<strong>Familial cortical myoclonic tremor with epilepsy: the third locus (FCMTE3) maps to 5p.</strong>
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Neurology 74: 2000-2003, 2010.
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[PubMed: 20548044]
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[Full Text: https://doi.org/10.1212/WNL.0b013e3181e396a8]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Edwards, M. J. J., Hargreaves, I. P., Heales, S. J. R., Jones, S. J., Ramachandran, V., Bhatia, K. P., Sisodiya, S.
|
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<strong>N-acetylcysteine and Unverricht-Lundborg disease.</strong>
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Neurology 59: 1447-1449, 2002.
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[PubMed: 12427904]
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[Full Text: https://doi.org/10.1212/wnl.59.9.1447]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Eicher, E. M., Lane, P. W.
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<strong>Assignment of LH XVI to chromosome 3 in the mouse.</strong>
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J. Hered. 71: 315-318, 1980.
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[PubMed: 6160178]
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[Full Text: https://doi.org/10.1093/oxfordjournals.jhered.a109378]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Eldridge, R., Iivanainen, M., Stern, R., Koerber, T., Wilder, B. J.
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<strong>'Baltic' myoclonus epilepsy: a treatable hereditary disorder of childhood. (Abstract)</strong>
|
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Sixth International Congress of Human Genetics, Jerusalem 1981. P. 256.
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Eldridge, R., Iivanainen, M., Stern, R., Koerber, T., Wilder, B. J.
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<strong>'Baltic' myoclonus epilepsy: hereditary disorder of childhood made worse by phenytoin.</strong>
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Lancet 322: 838-842, 1983. Note: Originally Volume II.
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[PubMed: 6137660]
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[Full Text: https://doi.org/10.1016/s0140-6736(83)90749-3]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Ford, F. R., Livingston, S., Pryles, C. V.
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<strong>Familial degeneration of cerebral gray matter in childhood, with convulsions, myoclonus, spasticity, cerebellar ataxia, choreoathetosis, dementia, and death in status epilepticus: differentiation of infantile and juvenile types.</strong>
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J. Pediat. 39: 33-43, 1951.
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[PubMed: 14851183]
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[Full Text: https://doi.org/10.1016/s0022-3476(51)80278-6]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Grenningloh, G., Schmieden, V., Schofield, P. R., Seeburg, P. H., Siddique, T., Mohandas, T. K., Becker, C.-M., Betz, H.
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<strong>Alpha subunit variants of the human glycine receptor: primary structures, functional expression and chromosomal localization of the corresponding genes.</strong>
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EMBO J. 9: 771-776, 1990.
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[PubMed: 2155780]
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[Full Text: https://doi.org/10.1002/j.1460-2075.1990.tb08172.x]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Gundlach, A. L., Dodd, P. R., Grabara, C. S. G., Watson, W. E. J., Johnston, G. A. R., Harper, P. A. W., Dennis, J. A., Healy, P. J.
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Cassandra L. Kniffin - updated : 1/21/2011<br>Cassandra L. Kniffin - updated : 2/4/2008<br>Cassandra L. Kniffin - updated : 4/6/2005<br>Cassandra L. Kniffin - updated : 6/11/2003<br>Victor A. McKusick - updated : 1/22/2003<br>Victor A. McKusick - updated : 10/10/2002<br>Cassandra L. Kniffin - updated : 9/3/2002<br>George E. Tiller - updated : 1/28/2002<br>Carol A. Bocchini - reorganized : 11/8/2001<br>Victor A. McKusick - updated : 11/2/2001<br>Orest Hurko - updated : 3/24/1999<br>Victor A. McKusick - updated : 10/23/1998<br>Stylianos E. Antonarakis - updated : 9/22/1997<br>Mark H. Paalman - updated : 4/9/1997<br>Victor A. McKusick - updated : 3/31/1997
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Victor A. McKusick : 6/4/1986
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carol : 01/24/2024<br>alopez : 03/17/2023<br>carol : 05/06/2021<br>alopez : 02/24/2021<br>ckniffin : 02/18/2021<br>alopez : 05/12/2020<br>ckniffin : 05/06/2020<br>carol : 04/21/2018<br>carol : 04/20/2018<br>ckniffin : 04/18/2018<br>carol : 10/14/2016<br>carol : 03/28/2016<br>carol : 3/25/2016<br>carol : 3/24/2016<br>carol : 11/13/2015<br>ckniffin : 11/11/2015<br>alopez : 9/17/2015<br>ckniffin : 9/16/2015<br>ckniffin : 2/18/2015<br>carol : 1/20/2015<br>ckniffin : 1/15/2015<br>wwang : 6/10/2011<br>ckniffin : 5/31/2011<br>terry : 4/28/2011<br>wwang : 3/29/2011<br>ckniffin : 3/25/2011<br>alopez : 3/11/2011<br>wwang : 2/21/2011<br>ckniffin : 1/21/2011<br>wwang : 10/26/2010<br>ckniffin : 10/20/2010<br>carol : 5/4/2010<br>terry : 3/13/2009<br>wwang : 12/5/2008<br>ckniffin : 11/24/2008<br>wwang : 4/23/2008<br>ckniffin : 4/17/2008<br>wwang : 2/25/2008<br>wwang : 2/22/2008<br>wwang : 2/4/2008<br>ckniffin : 2/4/2008<br>carol : 4/20/2005<br>wwang : 4/15/2005<br>ckniffin : 4/6/2005<br>terry : 3/3/2005<br>tkritzer : 1/15/2004<br>carol : 6/16/2003<br>ckniffin : 6/11/2003<br>ckniffin : 2/27/2003<br>carol : 2/27/2003<br>cwells : 1/29/2003<br>tkritzer : 1/22/2003<br>carol : 10/17/2002<br>carol : 10/17/2002<br>tkritzer : 10/16/2002<br>terry : 10/10/2002<br>carol : 9/10/2002<br>carol : 9/10/2002<br>ckniffin : 9/3/2002<br>carol : 2/21/2002<br>cwells : 2/14/2002<br>cwells : 1/28/2002<br>carol : 11/8/2001<br>carol : 11/8/2001<br>mcapotos : 11/2/2001<br>carol : 11/24/1999<br>terry : 4/29/1999<br>mgross : 4/8/1999<br>carol : 3/24/1999<br>dkim : 11/6/1998<br>carol : 10/23/1998<br>dkim : 9/10/1998<br>alopez : 5/20/1998<br>dholmes : 12/4/1997<br>alopez : 9/22/1997<br>alopez : 9/22/1997<br>alopez : 9/22/1997<br>terry : 8/27/1997<br>mark : 4/9/1997<br>mark : 4/9/1997<br>mark : 3/31/1997<br>terry : 3/28/1997<br>mark : 3/21/1996<br>terry : 3/18/1996<br>mimman : 2/8/1996<br>mark : 6/13/1995<br>terry : 2/9/1995<br>carol : 2/1/1995<br>pfoster : 8/16/1994<br>warfield : 4/15/1994<br>mimadm : 4/12/1994
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