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Entry
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- #253400 - SPINAL MUSCULAR ATROPHY, TYPE III; SMA3
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- OMIM
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<p>
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<span class="h4">#253400</span>
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<br />
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<strong>Table of Contents</strong>
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</p>
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<a href="#title"><strong>Title</strong></a>
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<a href="#phenotypeMap"><strong>Phenotype-Gene Relationships</strong></a>
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<li role="presentation">
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<a href="/clinicalSynopsis/253400"><strong>Clinical Synopsis</strong></a>
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<a href="#text"><strong>Text</strong></a>
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<a href="#description">Description</a>
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<a href="#clinicalFeatures">Clinical Features</a>
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<a href="#inheritance">Inheritance</a>
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<a href="#clinicalManagement">Clinical Management</a>
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<a href="#cytogenetics">Cytogenetics</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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<a href="#seeAlso"><strong>See Also</strong></a>
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<li role="presentation">
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<a href="#references"><strong>References</strong></a>
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<a href="#contributors"><strong>Contributors</strong></a>
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<a href="#creationDate"><strong>Creation Date</strong></a>
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<li role="presentation">
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<a href="#editHistory"><strong>Edit History</strong></a>
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<div style="display: table-cell;">External Links</div>
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</div>
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</a>
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</h4>
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</div>
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<div style="display: table-row">
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<div id="mimClinicalResourcesLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">▼</div>
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<div style="display: table-cell;">Clinical Resources</div>
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<div id="mimClinicalResourcesLinksFold" class="panel-collapse collapse in mimLinksFold" role="tabpanel" aria-labelledby="clinicalResources">
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<div><a href="https://clinicaltrials.gov/search?cond=SPINAL MUSCULAR ATROPHY, TYPE III" class="mim-tip-hint" title="A registry of federally and privately supported clinical trials conducted in the United States and around the world." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Clinical Trials', 'domain': 'clinicaltrials.gov'})">Clinical Trials</a></div>
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<div><a href="#mimEuroGentestFold" id="mimEuroGentestToggle" data-toggle="collapse" class="mim-tip-hint mimTriangleToggle" title="A list of European laboratories that offer genetic testing."><span id="mimEuroGentestToggleTriangle" class="small" style="margin-left: -0.8em;">►</span>EuroGentest</div>
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<div id="mimEuroGentestFold" class="collapse">
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<div style="margin-left: 0.5em;"><a href="https://www.orpha.net/consor/cgi-bin/ClinicalLabs_Search_Simple.php?lng=EN&LnkId=633&Typ=Pat" title="Proximal spinal muscular atrophy" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'EuroGentest', 'domain': 'orpha.net'})">Proximal spinal muscular a… </a></div><div style="margin-left: 0.5em;"><a href="https://www.orpha.net/consor/cgi-bin/ClinicalLabs_Search_Simple.php?lng=EN&LnkId=11566&Typ=Pat" title="Proximal spinal muscular atrophy type 3" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'EuroGentest', 'domain': 'orpha.net'})">Proximal spinal muscular a… </a></div>
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</div>
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<div><a href="https://www.ncbi.nlm.nih.gov/books/NBK1352/" 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/6736" 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://www.ncbi.nlm.nih.gov/gtr/all/tests/?term=253400[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.acmg.net/PDFLibrary/SMA-ACT-Sheet.pdf" class="mim-tip-hint" title="Information and resources for newborn screening and genetics." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Newborn Screening', 'domain': 'www.acmg.net'})">Newborn Screening</a></div>
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<div><a href="#mimOrphanetFold" id="mimOrphanetToggle" data-toggle="collapse" class="mim-tip-hint mimTriangleToggle" title="European reference portal for information on rare diseases and orphan drugs."><span id="mimOrphanetToggleTriangle" class="small" style="margin-left: -0.8em;">►</span>Orphanet</div>
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<div id="mimOrphanetFold" class="collapse">
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<div style="margin-left: 0.5em;"><a href="https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=70" title="Proximal spinal muscular atrophy" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'OrphaNet', 'domain': 'orpha.net'})">Proximal spinal muscular a…</a></div><div style="margin-left: 0.5em;"><a href="https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=83419" title="Proximal spinal muscular atrophy type 3" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'OrphaNet', 'domain': 'orpha.net'})">Proximal spinal muscular a…</a></div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimAnimalModels">
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<span class="panel-title">
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<span class="small">
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<a href="#mimAnimalModelsLinksFold" id="mimAnimalModelsLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimAnimalModelsLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Animal Models</div>
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</div>
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</a>
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<div id="mimAnimalModelsLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.alliancegenome.org/disease/DOID:12376" 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/253400" 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/OMIA000939/" class="mim-tip-hint" title="Online Mendelian Inheritance in Animals (OMIA) is a database of genes, inherited disorders and traits in 191 animal species (other than human and mouse.)" target="_blank">OMIA</a></div>
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<div><a href="https://wormbase.org/resources/disease/DOID:12376" class="mim-tip-hint" title="Database of the biology and genome of Caenorhabditis elegans and related nematodes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Wormbase Disease Ontology', 'domain': 'wormbase.org'})">Wormbase Disease Ontology</a></div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimCellLines">
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<span class="panel-title">
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<span class="small">
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<a href="#mimCellLinesLinksFold" id="mimCellLinesLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimCellLinesLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Cell Lines</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimCellLinesLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://catalog.coriell.org/Search?q=OmimNum:253400" class="definition" title="Coriell Cell Repositories; cell cultures and DNA derived from cell cultures." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'CCR', 'domain': 'ccr.coriell.org'})">Coriell</a></div>
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</div>
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</div>
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</div>
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<span>
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<span class="mim-tip-bottom" qtip_title="<strong>Looking for this gene or this phenotype in other resources?</strong>" qtip_text="Select a related resource from the dropdown menu and click for a targeted link to information directly relevant.">
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<a id="title" class="mim-anchor"></a>
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<div>
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<a id="number" class="mim-anchor"></a>
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<div class="text-right">
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<a href="#" class="mim-tip-icd" qtip_title="<strong>ICD+</strong>" qtip_text="
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<strong>SNOMEDCT:</strong> 54280009<br />
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<strong>ICD9CM:</strong> 335.11<br />
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<strong>ORPHA:</strong> 70, 83419<br />
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<strong>DO:</strong> 12376<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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253400
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</span>
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SPINAL MUSCULAR ATROPHY, TYPE III; SMA3
|
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|
|
</span>
|
|
</h3>
|
|
</div>
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<a id="alternativeTitles" class="mim-anchor"></a>
|
|
<div>
|
|
<p>
|
|
<span class="mim-font">
|
|
<em>Alternative titles; symbols</em>
|
|
</span>
|
|
</p>
|
|
</div>
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
SMA III<br />
|
|
MUSCULAR ATROPHY, JUVENILE<br />
|
|
KUGELBERG-WELANDER SYNDROME; KWS<br />
|
|
SPINAL MUSCULAR ATROPHY, MILD CHILDHOOD AND ADOLESCENT FORM
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
</div>
|
|
<div>
|
|
<br />
|
|
</div>
|
|
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|
|
|
|
</div>
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|
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|
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|
|
|
|
|
|
<div>
|
|
<a id="phenotypeMap" class="mim-anchor"></a>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>Phenotype-Gene Relationships</strong>
|
|
</span>
|
|
</h4>
|
|
<div>
|
|
<table class="table table-bordered table-condensed table-hover small mim-table-padding">
|
|
<thead>
|
|
<tr class="active">
|
|
<th>
|
|
Location
|
|
</th>
|
|
<th>
|
|
Phenotype
|
|
</th>
|
|
<th>
|
|
Phenotype <br /> MIM number
|
|
</th>
|
|
<th>
|
|
Inheritance
|
|
</th>
|
|
<th>
|
|
Phenotype <br /> mapping key
|
|
</th>
|
|
<th>
|
|
Gene/Locus
|
|
</th>
|
|
<th>
|
|
Gene/Locus <br /> MIM number
|
|
</th>
|
|
</tr>
|
|
</thead>
|
|
<tbody>
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/geneMap/5/230?start=-3&limit=10&highlight=230">
|
|
5q13.2
|
|
</a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
{Spinal muscular atrophy, type III, modifier of}
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/253400"> 253400 </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">
|
|
SMN2
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/601627"> 601627 </a>
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/geneMap/5/232?start=-3&limit=10&highlight=232">
|
|
5q13.2
|
|
</a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
Spinal muscular atrophy-3
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/253400"> 253400 </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">
|
|
SMN1
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/600354"> 600354 </a>
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
</tbody>
|
|
</table>
|
|
</div>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
|
|
|
|
<div class="btn-group ">
|
|
<a href="/clinicalSynopsis/253400" class="btn btn-warning" role="button"> Clinical Synopsis </a>
|
|
<button type="button" id="mimPhenotypicSeriesToggle" class="btn btn-warning dropdown-toggle mimSingletonFoldToggle" data-toggle="collapse" href="#mimClinicalSynopsisFold" onclick="ga('send', 'event', 'Unfurl', 'ClinicalSynopsis', 'omim.org')">
|
|
<span class="caret"></span>
|
|
<span class="sr-only">Toggle Dropdown</span>
|
|
</button>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
<div class="btn-group">
|
|
<button type="button" class="btn btn-success dropdown-toggle" data-toggle="dropdown" aria-haspopup="true" aria-expanded="false">
|
|
PheneGene Graphics <span class="caret"></span>
|
|
</button>
|
|
<ul class="dropdown-menu" style="width: 17em;">
|
|
<li><a href="/graph/linear/253400" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Linear'})"> Linear </a></li>
|
|
<li><a href="/graph/radial/253400" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Radial'})"> Radial </a></li>
|
|
</ul>
|
|
</div>
|
|
<span class="glyphicon glyphicon-question-sign mim-tip-hint" title="OMIM PheneGene graphics depict relationships between phenotypes, groups of related phenotypes (Phenotypic Series), and genes.<br /><a href='/static/omim/pdf/OMIM_Graphics.pdf' target='_blank'>A quick reference overview and guide (PDF)</a>"></span>
|
|
|
|
|
|
|
|
<div>
|
|
<p />
|
|
</div>
|
|
|
|
|
|
<div id="mimClinicalSynopsisFold" class="well well-sm collapse mimSingletonToggleFold">
|
|
<div class="small" style="margin: 5px">
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<strong> INHERITANCE </strong>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
|
|
<div>
|
|
<span class="mim-font">
|
|
|
|
- Autosomal recessive <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/258211005" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">258211005</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0441748&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0441748</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000007" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000007</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000007" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000007</a>]</span><br />
|
|
|
|
</span>
|
|
</div>
|
|
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<strong> MUSCLE, SOFT TISSUES </strong>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
|
|
<div>
|
|
<span class="mim-font">
|
|
|
|
- Proximal muscle weakness and atrophy <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C2676670&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C2676670</a>]</span><br /> -
|
|
Muscle cramps <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/45352006" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">45352006</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/55300003" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">55300003</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/M62.83" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">M62.83</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/728.85" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">728.85</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0037763&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0037763</a>, <a href="https://bioportal.bioontology.org/search?q=C0026821&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0026821</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003394" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003394</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003394" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003394</a>]</span><br /> -
|
|
Chronic denervation seen on EMG <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C3550584&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C3550584</a>]</span><br /> -
|
|
Neuropathic process seen on muscle biopsy <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C3550585&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C3550585</a>]</span><br />
|
|
|
|
</span>
|
|
</div>
|
|
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<strong> NEUROLOGIC </strong>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
|
|
|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<em> Central Nervous System </em>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
<span class="mim-font">
|
|
|
|
- Muscle weakness, symmetric, proximal (lower limbs more affected than upper limbs) due to motor neuronopathy <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1854665&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1854665</a>]</span><br /> -
|
|
Tongue fasciculation/fibrillation <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/249878001" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">249878001</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0239548&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0239548</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001308" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001308</a>]</span><br /> -
|
|
Limb fasciculation <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1854657&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1854657</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0007289" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0007289</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0007289" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0007289</a>]</span><br /> -
|
|
Degeneration of anterior horn cells <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1843505&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1843505</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002398" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002398</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002398" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002398</a>]</span><br /> -
|
|
Hand tremor <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0239842&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0239842</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002378" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002378</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002378" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002378</a>]</span><br />
|
|
|
|
</span>
|
|
</div>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<em> Peripheral Nervous System </em>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
<span class="mim-font">
|
|
|
|
- Hyporeflexia <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/835279003" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">835279003</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/405946002" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">405946002</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0700078&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0700078</a>, <a href="https://bioportal.bioontology.org/search?q=C0151888&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0151888</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001265" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001265</a>, <a href="https://hpo.jax.org/app/browse/term/HP:0001315" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001315</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001265" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001265</a>]</span><br /> -
|
|
Areflexia of the lower limbs <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1856694&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1856694</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002522" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002522</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002522" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002522</a>]</span><br />
|
|
|
|
</span>
|
|
</div>
|
|
</div>
|
|
|
|
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
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|
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|
|
|
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|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<strong> MISCELLANEOUS </strong>
|
|
</span>
|
|
</div>
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Onset usually in childhood or adolescence<br /> -
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Progressive disorder <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1864985&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1864985</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003676" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003676</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003676" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003676</a>]</span><br /> -
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Deletions in NAIP gene (<a href="/entry/600355">600355</a>) found in 18% of SMA2 patients<br />
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- Caused by mutation in the survival of motor neuron 1 gene (SMN1, <a href="/entry/600354#0003">600354.0003</a>)<br />
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<span class="mim-tip-floating" qtip_title="<strong>Looking For More References?</strong>" qtip_text="Click the 'reference plus' icon <span class='glyphicon glyphicon-plus-sign'></span> at the end of each OMIM text paragraph to see more references related to the content of the preceding paragraph.">
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<strong>TEXT</strong>
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<p>A number sign (#) is used with this entry because spinal muscular atrophy type III (SMA3) is caused by homozygous or compound heterozygous mutation in the SMN1 gene (<a href="/entry/600354">600354</a>) on chromosome 5q13.</p>
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<p>Spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disorder characterized by progressive proximal muscle weakness and atrophy affecting the upper and lower limbs. By convention, SMA is classified into 4 types: I (SMA1; <a href="/entry/253300">253300</a>), II (SMA2; <a href="/entry/253550">253550</a>), III (SMA3), and IV (<a href="/entry/271150">271150</a>), by increasing age at onset and decreasing clinical severity. SMA1 is the most severe form of the disorder and often results in death in early childhood. SMA3, known as the juvenile form, tends to show onset in childhood or adolescence (summary by <a href="#13" class="mim-tip-reference" title="Fraidakis, M. J., Drunat, S., Maisonobe, T., Gerard, B., Pradat, P. F., Meininger, V., Salachas, F. <strong>Genotype-phenotype relationship in 2 SMA III patients with novel mutations in the Tudor domain.</strong> Neurology 78: 551-556, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22323744/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22323744</a>] [<a href="https://doi.org/10.1212/WNL.0b013e318247ca69" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22323744">Fraidakis et al., 2012</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22323744" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#26" class="mim-tip-reference" title="Kugelberg, E., Welander, L. <strong>Heredofamilial juvenile muscular atrophy simulating muscular dystrophy.</strong> Arch. Neurol. Psychiat. 75: 500-509, 1956.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/13312732/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">13312732</a>] [<a href="https://doi.org/10.1001/archneurpsyc.1956.02330230050005" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="13312732">Kugelberg and Welander (1956)</a> described 12 patients from 6 families with a juvenile type of hereditary muscular atrophy. All of the patients had earlier been considered to have a form of limb-girdle muscular dystrophy. Twitchings (fasciculations) were an important differentiating sign. Muscular biopsy and electromyography showed the true nature of the process as a lower motor neuron disease. Onset occurred between 2 and 17 years of age. Atrophy and weakness of proximal limb muscles, primarily in the legs, was followed by distal involvement. The course was slowly progressive. The ability to walk was lost at the earliest 8 to 9 years after the onset of symptoms. Seven patients were able to walk 20 years or more after onset, and 1 patient after 40 years. The ability to sit up was preserved. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=13312732" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#27" class="mim-tip-reference" title="Levy, J. A., Wittig, E. O. <strong>Familial proximal muscular atrophy.</strong> Arq. Neuropsiquiatr. 20: 233-237, 1962.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/13930266/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">13930266</a>] [<a href="https://doi.org/10.1590/s0004-282x1962000300006" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="13930266">Levy and Wittig (1962)</a> described similar features in 2 half brothers, with onset at 13 and 16 years. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=13930266" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#34" class="mim-tip-reference" title="Samaha, F. J., Buncher, C. R., Russman, B. S., White, M. L., Iannaccone, S. T., Barker, L., Burhans, K., Smith, C., Perkins, B., Zimmerman, L. <strong>Pulmonary function in spinal muscular atrophy.</strong> J. Child Neurol. 9: 326-329, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7930415/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7930415</a>] [<a href="https://doi.org/10.1177/088307389400900321" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7930415">Samaha et al. (1994)</a> studied forced vital capacity longitudinally in 40 SMA patients ranging in age from 5 to 18 years. Although the majority of the patients grew in height, only 35% showed an increase in height-adjusted forced vital capacity. In the most seriously affected patients, all lost height-adjusted forced vital capacity over time. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7930415" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#14" class="mim-tip-reference" title="Furukawa, T., Nakao, K., Sugita, H., Tsukagoshi, H. <strong>Kugelberg-Welander disease, with particular reference to sex-influenced manifestations.</strong> Arch. Neurol. 19: 156-162, 1968.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/5675302/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">5675302</a>] [<a href="https://doi.org/10.1001/archneur.1968.00480020042004" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="5675302">Furukawa et al. (1968)</a> reported 2 families, each with affected brother and sister. The parents in one family were first cousins. The authors pointed out that in their cases, as well as in those in the literature, the symptoms of female patients were mild and the clinical course slow whereas male sibs were severely affected. They interpreted this as sex-influence. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=5675302" 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="Bundey, S. E., Filomeno, A. R. <strong>Proximal spinal muscular atrophy.</strong> Birth Defects Orig. Art. Ser. X(4): 336-338, 1974."None>Bundey and Filomeno (1974)</a> described a black sibship in which 5 sibs out of 10 had this disorder.</p><p><a href="#30" class="mim-tip-reference" title="Pearn, J., Bundey, S., Carter, C. O., Wilson, J., Gardner-Medwin, D., Walton, J. N. <strong>A genetic study of subacute and chronic spinal muscular atrophy in childhood: a nosological analysis of 124 index patients.</strong> J. Neurol. Sci. 37: 227-248, 1978.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/681978/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">681978</a>] [<a href="https://doi.org/10.1016/0022-510x(78)90206-x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="681978">Pearn et al. (1978)</a> reported a spinal muscular atrophy syndrome characterized by adolescent onset, gross hypertrophy of the calves, and a slowly progressive clinical course. One of their families with 2 affected brothers and 2 affected maternal uncles probably had Kennedy disease (<a href="/entry/313200">313200</a>), an X-linked form of SMA in which calf hypertrophy has been observed. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=681978" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#13" class="mim-tip-reference" title="Fraidakis, M. J., Drunat, S., Maisonobe, T., Gerard, B., Pradat, P. F., Meininger, V., Salachas, F. <strong>Genotype-phenotype relationship in 2 SMA III patients with novel mutations in the Tudor domain.</strong> Neurology 78: 551-556, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22323744/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22323744</a>] [<a href="https://doi.org/10.1212/WNL.0b013e318247ca69" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22323744">Fraidakis et al. (2012)</a> reported 2 unrelated French men, aged 44 and 50 years, with SMA type III. Both had onset of slowly progressive proximal lower limb weakness beginning in adolescence, followed by proximal upper limb weakness. At age 44, the first patient patient had proximal lower limb amyotrophy, proximal upper and lower limb weakness, and absence of lower limb reflexes; he used a cane to walk. Muscle biopsy and EMG showed a chronic neuropathic process. The second patient developed muscle cramps and was wheelchair-bound at age 48. Physical examination showed severe motor deficit and amyotrophy in the pelvic and shoulder girdles, as well as severe motor deficit and amyotrophy in the distal limb muscles. EMG was consistent with severe chronic denervation at all extremities. <a href="#13" class="mim-tip-reference" title="Fraidakis, M. J., Drunat, S., Maisonobe, T., Gerard, B., Pradat, P. F., Meininger, V., Salachas, F. <strong>Genotype-phenotype relationship in 2 SMA III patients with novel mutations in the Tudor domain.</strong> Neurology 78: 551-556, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22323744/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22323744</a>] [<a href="https://doi.org/10.1212/WNL.0b013e318247ca69" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22323744">Fraidakis et al. (2012)</a> commented on the relatively mild disease course in these patients and suggested that there were likely compensatory factors affecting expression of the SMN genes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22323744" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#10" class="mim-tip-reference" title="Coratti, G., Messina, S., Lucibello, S., Pera, M. C., Montes, J., Pasternak, A., Bovis, F., Escudero, J. E., Mazzone, E. S., Mayhew, A., Glanzman, A.. M., Young, S. D. <strong>Clinical variability in spinal muscular atrophy type III.</strong> Ann. Neurol. 88: 1109-1117, 2020.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/32926458/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">32926458</a>] [<a href="https://doi.org/10.1002/ana.25900" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="32926458">Coratti et al. (2020)</a> reported the clinical features of a cohort of 199 patients, aged 30 months to 30 years, with SMA type III. The patients were divided into 2 groups: type IIIA, those with onset between 18 months and 3 years (147 patients), and type IIIB, those with onset after 3 years (52 patients). Twenty-six of the patients lost ambulation during follow-up (22 with SMA type IIIA and 4 with SMA type IIIB), 11 had spinal surgery at the first visit (7 with SMA type IIIA and 4 with SMA type IIIB), and 9 had scoliosis surgery after the first visit. Of the 199 patients, 17 were excluded for further analysis due to lack of follow-up. The median age of the remaining 182 patients at baseline was 10.46 years, and the patients were followed for 0.46 to 13.34 years. The functional status of the patients was measured with the Hammersmith Functional Motor Scale Expanded (HFMSE). Across the entire cohort, there was relative functional stability with some modest improvement until age 7 years, followed by a decline. Within just the SMA type IIIB cohort, the HFMSE scores remained stable for 10 years; most patients had HFMSE scores above 40 and were still ambulatory by the end of the second decade of life. Age, SMA type, and ambulatory status were found to be significantly associated with changes in HFMSE scores, whereas gender and number of SMN2 copies were not. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=32926458" 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="Habets, L. E., Bartels, B., Asselman, F.-L., Hooijmans, M. T., van den Berg, S., Nederveen, A. J., van der Pol, W. L., Jeneson, J. A. L. <strong>Magnetic resonance reveals mitochondrial dysfunction and muscle remodelling in spinal muscular atrophy.</strong> Brain 145: 1422-1435, 2022.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/34788410/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">34788410</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=34788410[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1093/brain/awab411" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="34788410">Habets et al. (2022)</a> evaluated the bioenergetic and structural characteristics of the biceps and triceps muscles in 14 patients with SMA type III (6 with type IIIA and 8 with type IIIB) and 1 patient with SMA type IV (<a href="/entry/271150">271150</a>). MRIs demonstrated fatty infiltration in both triceps and biceps, which was greater in the triceps, and atrophy of the triceps muscles. Maximal voluntary contraction of force was reduced in both triceps and biceps muscles, and blood lactate increases after exercise were lower in patients compared to controls. 31P MR spectroscopy studies identified white-to-red shift of muscle fiber types and slow metabolic recovery after exercise in white myofibers due to ATP synthetic dysfunction. <a href="#18" class="mim-tip-reference" title="Habets, L. E., Bartels, B., Asselman, F.-L., Hooijmans, M. T., van den Berg, S., Nederveen, A. J., van der Pol, W. L., Jeneson, J. A. L. <strong>Magnetic resonance reveals mitochondrial dysfunction and muscle remodelling in spinal muscular atrophy.</strong> Brain 145: 1422-1435, 2022.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/34788410/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">34788410</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=34788410[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1093/brain/awab411" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="34788410">Habets et al. (2022)</a> concluded that these findings demonstrated the disproportionate vulnerability of white myofibers to SMN protein depletion. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=34788410" 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="#37" class="mim-tip-reference" title="Spira, R. <strong>Neurogenic, familial, girdle type muscular atrophy (clinical electromyographic and pathological study).</strong> Confin. Neurol. 23: 245-255, 1963.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/13990174/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">13990174</a>] [<a href="https://doi.org/10.1159/000104301" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="13990174">Spira (1963)</a> described 7 affected members in 2 sibships of a family with proximal spinal muscular atrophy. In each case the affected persons were offspring of a first-cousin marriage, consistent with autosomal recessive inheritance. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=13990174" 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="Pearn, J., Bundey, S., Carter, C. O., Wilson, J., Gardner-Medwin, D., Walton, J. N. <strong>A genetic study of subacute and chronic spinal muscular atrophy in childhood: a nosological analysis of 124 index patients.</strong> J. Neurol. Sci. 37: 227-248, 1978.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/681978/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">681978</a>] [<a href="https://doi.org/10.1016/0022-510x(78)90206-x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="681978">Pearn et al. (1978)</a> reviewed 141 cases of SMA with onset before age 14 years (excluding SMA type I, or Werdnig-Hoffmann disease). Autosomal recessive inheritance could account for over 90% of cases. In these, onset was before age 5 and usually before age 2 years. The disorder was compatible with life into the third decade. A small group of cases appeared to be either new dominant mutations or phenocopies. <a href="#22" class="mim-tip-reference" title="Hausmanowa-Petrusewicz, I., Zaremba, J., Borkowska, J. <strong>Chronic proximal spinal muscular atrophy of childhood and adolescence: problems of classification and genetic counselling.</strong> J. Med. Genet. 22: 350-353, 1985.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2370051/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2370051</a>] [<a href="https://doi.org/10.1007/BF00193198" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2370051">Hausmanowa-Petrusewicz et al. (1985)</a> called this the mild childhood and adolescent type of spinal muscular atrophy and emphasized the significance of sex influence (<a href="#21" class="mim-tip-reference" title="Hausmanowa-Petrusewicz, I., Zaremba, J., Borkowska, J., Szirkowiec, W. <strong>Chronic proximal spinal muscular atrophy of childhood and adolescence: sex influence.</strong> J. Med. Genet. 21: 447-450, 1984.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/6512833/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">6512833</a>] [<a href="https://doi.org/10.1136/jmg.21.6.447" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="6512833">Hausmanowa-Petrusewicz et al., 1984</a>). <a href="#42" class="mim-tip-reference" title="Zerres, K., Stephan, M., Kehren, U., Grimm, T. <strong>Becker's allelic model to explain unusual pedigrees with spinal muscular atrophy. (Letter)</strong> Clin. Genet. 31: 276-277, 1987.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3594936/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3594936</a>] [<a href="https://doi.org/10.1111/j.1399-0004.1987.tb02807.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3594936">Zerres et al. (1987)</a> advanced Becker's allelic model as a possible explanation for unusual pedigrees with spinal muscular atrophy. Because of the finding of linkage of SMA I, II (SMA2; <a href="/entry/253550">253550</a>), and III to the same region, 5q11.2-q13.3 (<a href="#5" class="mim-tip-reference" title="Brzustowicz, L. M., Lehner, T., Castilla, L. H., Penchaszadeh, G. K., Wilhelmsen, K. C., Daniels, R., Davies, K. E., Leppert, M., Ziter, F., Wood, D., Dubowitz, V., Zerres, K., Hausmanowa-Petrusewicz, I., Ott, J., Munsat, T. L., Gilliam, T. C. <strong>Genetic mapping of chronic childhood-onset spinal muscular atrophy to chromosome 5q11.2-13.3.</strong> Nature 344: 540-541, 1990.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2320125/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2320125</a>] [<a href="https://doi.org/10.1038/344540a0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2320125">Brzustowicz et al., 1990</a>), it is likely that these are allelic disorders. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=681978+3594936+2370051+6512833+2320125" 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>In fibroblast cultures from patients with SMA1, SMA2, or SMA3, <a href="#1" class="mim-tip-reference" title="Andreassi, C., Angelozzi, C., Tiziano, F. D., Vitali, T., De Vincenzi, E., Boninsegna, A., Villanova, M., Bertini, E., Pini, A., Neri, G., Brahe, C. <strong>Phenylbutyrate increases SMN expression in vitro: relevance for treatment of spinal muscular atrophy.</strong> Europ. J. Hum. Genet. 12: 59-65, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14560316/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14560316</a>] [<a href="https://doi.org/10.1038/sj.ejhg.5201102" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14560316">Andreassi et al. (2004)</a> found a significant increase in SMN2 gene (<a href="/entry/601627">601627</a>) expression (increase in SMN2 transcripts of 50 to 160% in SMA1, and of 80 to 400% in SMA2 and SMA3) and a more moderate increase in SMN protein expression in response to treatment with 4-phenylbutyrate (PBA). PBA treatment also resulted in an increase in the number of SMN-containing nuclear structures (GEMS). The authors suggested a potential use for PBA in treatment of various types of SMA. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14560316" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#17" class="mim-tip-reference" title="Grzeschik, S. M., Ganta, M., Prior, T. W., Heavlin, W. D., Wang, C. H. <strong>Hydroxyurea enhances SMN2 gene expression in spinal muscular atrophy cells.</strong> Ann. Neurol. 58: 194-202, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16049920/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16049920</a>] [<a href="https://doi.org/10.1002/ana.20548" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16049920">Grzeschik et al. (2005)</a> reported that cultured lymphocytes from patients with SMA showed increased production of the full-length SMN mRNA and protein in response to treatment with hydroxyurea. The findings suggested that hydroxyurea promoted inclusion of exon 7 during SMN2 transcription. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16049920" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#40" class="mim-tip-reference" title="Weihl, C. C., Connolly, A. M., Pestronk, A. <strong>Valproate may improve strength and function in patients with type III/IV spinal muscle atrophy.</strong> Neurology 67: 500-501, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16775228/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16775228</a>] [<a href="https://doi.org/10.1212/01.wnl.0000231139.26253.d0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16775228">Weihl et al. (2006)</a> reported increased quantitative muscle strength and subjective function in 7 adult patients with SMA3/SMA4 who were treated with oral valproate for a mean duration of 8 months. Most patients reported improvement within a few months of beginning treatment. The authors noted that previous studies (see <a href="#2" class="mim-tip-reference" title="Brichta, L., Hofmann, Y., Hahnen, E., Siebzehnrubl, F. A., Raschke, H., Blumcke, I., Eyupoglu, I. Y., Wirth, B. <strong>Valproic acid increases the SMN2 protein level: a well-known drug as a potential therapy for spinal muscular atrophy.</strong> Hum. Molec. Genet. 12: 2481-2489, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12915451/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12915451</a>] [<a href="https://doi.org/10.1093/hmg/ddg256" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12915451">Brichta et al., 2003</a>) had suggested that inhibitors of histone deacetylase, such as valproate, may increase SMN2 gene transcription and result in increased production of full-length SMN protein. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=16775228+12915451" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In a study of valproic acid (VPA) treatment in 10 SMA carriers and 20 patients with SMA1, SMA2, or SMA3, <a href="#3" class="mim-tip-reference" title="Brichta, L., Holker, I., Haug, K., Klockgether, T., Wirth, B. <strong>In vivo activation of SMN in spinal muscular atrophy carriers and patients treated with valproate.</strong> Ann. Neurol. 59: 970-975, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16607616/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16607616</a>] [<a href="https://doi.org/10.1002/ana.20836" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16607616">Brichta et al. (2006)</a> found that VPA increased peripheral blood full-length SMN mRNA and protein levels in 7 carriers, increased full-length SMN2 mRNA in 7 patients, and left full-length SMN2 mRNA levels unchanged or decreased in 13 patients. The effect on protein levels in carriers was more pronounced than on mRNA levels, and the variability in augmentation among carriers and patients suggested to the authors that VPA interferes with transcription of genes encoding translation factors or regulates translation or SMN protein stability. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16607616" 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="#4" class="mim-tip-reference" title="Brzustowicz, L. M., Allitto, B. A., Matseoane, D., Theve, R., Michaud, L., Chatkupt, S., Sugarman, E., Penchaszadeh, G. K., Suslak, L., Koenigsberger, M. R., Gilliam, T. C., Handelin, B. L. <strong>Paternal isodisomy for chromosome 5 in a child with spinal muscular atrophy.</strong> Am. J. Hum. Genet. 54: 482-488, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8116617/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8116617</a>]" pmid="8116617">Brzustowicz et al. (1994)</a> detected paternal isodisomy for chromosome 5 in a 2-year-old boy with type III SMA. Examination of 17 short-sequence repeat polymorphisms spanning a large part of the chromosome produced no evidence of maternally inherited alleles. Cytogenetic analysis showed a normal male karyotype, and fluorescence in situ hybridization with probes closely flanking the SMA locus confirmed the presence of 2 copies of chromosome 5. No developmental abnormalities other than those attributable to classic childhood-onset SMA were present. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8116617" 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 analysis of uniparental disomy cases, <a href="#25" class="mim-tip-reference" title="Kotzot, D. <strong>Abnormal phenotypes in uniparental disomy (UPD): fundamental aspects and a critical review with bibliography of UPD other than 15.</strong> Am. J. Med. Genet. 82: 265-274, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10215553/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10215553</a>]" pmid="10215553">Kotzot (1999)</a> found only one example of uniparental disomy involving chromosome 5, that of <a href="#4" class="mim-tip-reference" title="Brzustowicz, L. M., Allitto, B. A., Matseoane, D., Theve, R., Michaud, L., Chatkupt, S., Sugarman, E., Penchaszadeh, G. K., Suslak, L., Koenigsberger, M. R., Gilliam, T. C., Handelin, B. L. <strong>Paternal isodisomy for chromosome 5 in a child with spinal muscular atrophy.</strong> Am. J. Hum. Genet. 54: 482-488, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8116617/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8116617</a>]" pmid="8116617">Brzustowicz et al. (1994)</a>. No reports were found of uniparental disomy of chromosomes 12, 17, 18, and 19. On the other hand, 33 examples of chromosome 16 UPD were found, all of them maternal except 1. The bases of UPD are always 2 events: 2 meiotic; 1 meiotic and 1 mitotic; or 2 mitotic. Abnormal phenotypes result from an aberrant imprint, homozygosity of autosomal recessive gene mutations, homozygosity of X-chromosomal mutations in females, and father-to-son transmission of X-linked traits. The most frequent mechanism of UPD appears to be fertilization of a disomic gamete by a gamete monosomic for the same chromosome and subsequent loss of the normally inherited chromosome (trisomy rescue). This mechanism might result in mosaicism in the placenta or even in a subset of fetal tissues. This low level mosaicism can remain undetected and renders the delineation of a phenotype difficult. In general, the phenotype of cases with UPD is determined by mosaicism, genomic imprinting, nonmendelian inheritance of monogenic disorders, or a combination of these factors. <a href="#25" class="mim-tip-reference" title="Kotzot, D. <strong>Abnormal phenotypes in uniparental disomy (UPD): fundamental aspects and a critical review with bibliography of UPD other than 15.</strong> Am. J. Med. Genet. 82: 265-274, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10215553/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10215553</a>]" pmid="10215553">Kotzot (1999)</a> reviewed the entire bibliography of UPD other than that involving chromosome 15 and found a predominance of maternal versus paternal UPD (approximately 3 in 1) and a nonuniform chromosomal distribution. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=8116617+10215553" 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="Matthijs, G., Schollen, E., Legius, E., Devriendt, K., Goemans, N., Kayserili, H., Apak, M. Y., Cassiman, J.-J. <strong>Unusual molecular findings in autosomal recessive spinal muscular atrophy.</strong> J. Med. Genet. 33: 469-474, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8782046/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8782046</a>] [<a href="https://doi.org/10.1136/jmg.33.6.469" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8782046">Matthijs et al. (1996)</a> used an SSCP assay for the molecular diagnosis of 58 patients with SMA, including 8 patients (6 Belgian and 2 Turkish) with SMA III. The SSCP assay discriminates between the SMN gene (<a href="/entry/600354">600354</a>) and the almost identical centromeric BCD541 repeating unit. In 7 of the 8 SMA III patients, homozygous deletion of exon 7 of the SMN gene was detected. In 6 of the 7, the deletion was associated with homozygous deletion of exon 8, and in 1 it was associated with heterozygous deletion of exon 8. Deletion of the SMN gene was not found in 1 Belgian patient with typical manifestations of SMA III. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8782046" 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 families with proximal spinal muscular atrophy affecting individuals in 2 generations, <a href="#33" class="mim-tip-reference" title="Rudnik-Schoneborn, S., Zerres, K., Hahnen, E., Meng, G., Voit, T., Hanefeld, F., Wirth, B. <strong>Apparent autosomal recessive inheritance in families with proximal spinal muscular atrophy affecting individuals in two generations. (Letter)</strong> Am. J. Hum. Genet. 59: 1163-1165, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8900246/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8900246</a>]" pmid="8900246">Rudnik-Schoneborn et al. (1996)</a> examined whether there was pseudodominant inheritance of the regular autosomal recessive form or a dominant form of SMA which is not linked to 5q (see <a href="/entry/158590">158590</a>). Four families had affected members in 2 generations who showed SMN gene deletions. The range of variability in severity was striking. In family 4, the father had onset at age 16, whereas the son had onset in the first year; both had deletion of exons 7 and 8 of the SMN gene. Even more striking was family 3, in which the father had onset 'in youth' and the first son was asymptomatic thus far, whereas the second son had onset at 6 months of age (SMA I); all 3 had deletion of exons 7 and 8 of the SMN gene. Two sons had inherited different haplotypes from their affected father and shared identical maternal haplotypes. <a href="#33" class="mim-tip-reference" title="Rudnik-Schoneborn, S., Zerres, K., Hahnen, E., Meng, G., Voit, T., Hanefeld, F., Wirth, B. <strong>Apparent autosomal recessive inheritance in families with proximal spinal muscular atrophy affecting individuals in two generations. (Letter)</strong> Am. J. Hum. Genet. 59: 1163-1165, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8900246/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8900246</a>]" pmid="8900246">Rudnik-Schoneborn et al. (1996)</a> noted that, although homozygous deletions in the telomeric copy of the SMN gene can be detected in 95% to 98% of patients with early-onset SMA types I and II (<a href="#19" class="mim-tip-reference" title="Hahnen, E., Forkert, R., Marke, C., Rudnik-Schoneborn, S., Schonling, J., Zerres, K., Wirth, B. <strong>Molecular analysis of candidate genes on chromosome 5q13 in autosomal recessive spinal muscular atrophy: evidence of homozygous deletions of the SMN gene in unaffected individuals.</strong> Hum. Molec. Genet. 4: 1927-1933, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8595417/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8595417</a>] [<a href="https://doi.org/10.1093/hmg/4.10.1927" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8595417">Hahnen et al., 1995</a>), as many as 10% to 20% of patients with type III SMA do not show deletions. Since no molecular genetic test was available to support a locus other than that on 5q, the question of heterogeneity remained an important issue in proximal SMA. Given an incidence of more than 1/10,000 for autosomal recessive SMA (what <a href="#33" class="mim-tip-reference" title="Rudnik-Schoneborn, S., Zerres, K., Hahnen, E., Meng, G., Voit, T., Hanefeld, F., Wirth, B. <strong>Apparent autosomal recessive inheritance in families with proximal spinal muscular atrophy affecting individuals in two generations. (Letter)</strong> Am. J. Hum. Genet. 59: 1163-1165, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8900246/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8900246</a>]" pmid="8900246">Rudnik-Schoneborn et al. (1996)</a> referred to as 'SMA 5q'), patients with autosomal recessive SMA have a recurrence risk of approximately 1% to their offspring. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=8900246+8595417" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In 2 unrelated French men with onset of SMA type III in adolescence, <a href="#13" class="mim-tip-reference" title="Fraidakis, M. J., Drunat, S., Maisonobe, T., Gerard, B., Pradat, P. F., Meininger, V., Salachas, F. <strong>Genotype-phenotype relationship in 2 SMA III patients with novel mutations in the Tudor domain.</strong> Neurology 78: 551-556, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22323744/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22323744</a>] [<a href="https://doi.org/10.1212/WNL.0b013e318247ca69" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22323744">Fraidakis et al. (2012)</a> identified compound heterozygosity for a deletion of the SMN1 gene (<a href="/entry/600354#0021">600354.0021</a>) and a missense mutation affecting the same codon in exon 3 (Y130C, <a href="/entry/600354#0019">600354.0019</a> and Y130H, <a href="/entry/600354#0020">600354.0020</a>, respectively). Both missense mutations affected highly conserved residues in the Tudor domain, but the patients had a relatively mild form of the disorder. One patient had 1 copy of SMN2 and the other had 2 copies of SMN2. <a href="#13" class="mim-tip-reference" title="Fraidakis, M. J., Drunat, S., Maisonobe, T., Gerard, B., Pradat, P. F., Meininger, V., Salachas, F. <strong>Genotype-phenotype relationship in 2 SMA III patients with novel mutations in the Tudor domain.</strong> Neurology 78: 551-556, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22323744/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22323744</a>] [<a href="https://doi.org/10.1212/WNL.0b013e318247ca69" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22323744">Fraidakis et al. (2012)</a> commented on the relatively mild disease course in these patients and suggested that there were likely compensatory factors affecting expression of the SMN genes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22323744" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In a 50-year-old man with SMA type III, <a href="#39" class="mim-tip-reference" title="Vezain, M., Thauvin-Robinet, C., Vial, Y., Coutant, S., Drunat, S., Urtizberea, J. A., Rolland, A., Jacquin-Piques, A., Fehrenbach, S., Nicolas, G., Lecoquierre, F., Saugier-Veber, P. <strong>Retrotransposon insertion as a novel mutational cause of spinal muscular atrophy.</strong> Hum. Genet. 142: 125-138, 2023.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/36138164/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">36138164</a>] [<a href="https://doi.org/10.1007/s00439-022-02473-6" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="36138164">Vezain et al. (2023)</a> identified compound heterozygosity for 2 mutations in the SMN1 gene, an SVA retrotransposon insertion in intron 7 (<a href="/entry/600354#0022">600354.0022</a>) and a deletion of one copy of SMN1. The insertion was approximately 1,090 basepairs long and was flanked by 13-bp target site duplications. Transcript analysis in patient lymphoblastoid cells demonstrated decreased expression of the full-length SMN1 transcript. Although the patient was also found to have 1 copy of SMN2, his phenotype was relatively mild SMA type III, which <a href="#39" class="mim-tip-reference" title="Vezain, M., Thauvin-Robinet, C., Vial, Y., Coutant, S., Drunat, S., Urtizberea, J. A., Rolland, A., Jacquin-Piques, A., Fehrenbach, S., Nicolas, G., Lecoquierre, F., Saugier-Veber, P. <strong>Retrotransposon insertion as a novel mutational cause of spinal muscular atrophy.</strong> Hum. Genet. 142: 125-138, 2023.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/36138164/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">36138164</a>] [<a href="https://doi.org/10.1007/s00439-022-02473-6" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="36138164">Vezain et al. (2023)</a> hypothesized could be due to a full-length SMN1-SVA transcript with some residual function. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=36138164" 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>Modifying Factors</em></strong></p><p>
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<a href="#11" class="mim-tip-reference" title="Feldkotter, M., Schwarzer, V., Wirth, R., Wienker, T. F., Wirth, B. <strong>Quantitative analyses of SMN1 and SMN2 based on real-time lightCycler PCR: fast and highly reliable carrier testing and prediction of severity of spinal muscular atrophy.</strong> Am. J. Hum. Genet. 70: 358-368, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11791208/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11791208</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11791208[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1086/338627" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11791208">Feldkotter et al. (2002)</a> developed a quantitative test for either SMN1 or SMN2 to analyze SMA patients for their SMN2 copy number and to correlate the SMN2 copy number with type of SMA and duration of survival. The quantitative analysis of SMN2 copies in 375 patients with type I, type II, or type III SMA showed a significant correlation between SMN2 copy number and type of SMA as well as duration of survival. Thus, 80% of patients with type I SMA carried 1 or 2 SMN2 copies and 82% of patients with type II SMA carried 3 SMN2 copies, whereas 96% of patients with type III SMA carried 3 or 4 SMN2 copies. Among 113 patients with type I SMA, 9 with 1 SMN2 copy lived less than 11 months, 88 of 94 with 2 SMN2 copies lived less than 21 months, and 8 of 10 with 3 SMN2 copies lived 33 to 66 months. On the basis of SMN2 copy number, <a href="#11" class="mim-tip-reference" title="Feldkotter, M., Schwarzer, V., Wirth, R., Wienker, T. F., Wirth, B. <strong>Quantitative analyses of SMN1 and SMN2 based on real-time lightCycler PCR: fast and highly reliable carrier testing and prediction of severity of spinal muscular atrophy.</strong> Am. J. Hum. Genet. 70: 358-368, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11791208/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11791208</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11791208[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1086/338627" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11791208">Feldkotter et al. (2002)</a> calculated the posterior probability that a child with homozygous absence of SMN1 will develop type I, type II, or type III SMA. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11791208" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#41" class="mim-tip-reference" title="Wirth, B., Brichta, L., Schrank, B., Lochmuller, H., Blick, S., Baasner, A., Heller, R. <strong>Mildly affected patients with spinal muscular atrophy are partially protected by an increased SMN2 copy number.</strong> Hum. Genet. 119: 422-428, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16508748/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16508748</a>] [<a href="https://doi.org/10.1007/s00439-006-0156-7" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16508748">Wirth et al. (2006)</a> analyzed SMN2 copy number in 115 patients with SMA3 or SMA4 (<a href="/entry/271150">271150</a>) who had confirmed homozygous absence of SMN1 and found that 62% of SMA3 patients with age of onset less than 3 years had 2 or 3 SMN2 copies, whereas 65% of SMA3 patients with age of onset greater than 3 years had 4 to 5 SMN2 copies. Of the 4 adult-onset (SMA4) patients, 3 had 4 SMN2 copies and 1 had 6 copies. <a href="#41" class="mim-tip-reference" title="Wirth, B., Brichta, L., Schrank, B., Lochmuller, H., Blick, S., Baasner, A., Heller, R. <strong>Mildly affected patients with spinal muscular atrophy are partially protected by an increased SMN2 copy number.</strong> Hum. Genet. 119: 422-428, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16508748/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16508748</a>] [<a href="https://doi.org/10.1007/s00439-006-0156-7" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16508748">Wirth et al. (2006)</a> concluded that SMN2 may have a disease-modifying role in SMA, with a greater SMN2 copy number associated with later onset and better prognosis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16508748" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#24" class="mim-tip-reference" title="Jedrzejowska, M., Borkowska, J., Zimowski, J., Kostera-Pruszczyk, A., Milewski, M., Jurek, M., Sielska, D., Kostyk, E., Nyka, W., Zaremba, J., Hausmanowa-Petrusewicz, I. <strong>Unaffected patients with a homozygous absence of the SMN1 gene.</strong> Europ. J. Hum. Genet. 16: 930-934, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18337729/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18337729</a>] [<a href="https://doi.org/10.1038/ejhg.2008.41" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18337729">Jedrzejowska et al. (2008)</a> reported 3 unrelated families with asymptomatic carriers of a biallelic deletion of the SMN1 gene. In the first family, the biallelic deletion was found in 3 sibs: 2 affected brothers with SMA3 and a 25-year-old asymptomatic sister. All of them had 4 copies of the SMN2 gene. In the second family, 4 sibs were affected, 3 with SMA2 and 1 with SMA3, and each had 3 copies of SMN2. The clinically asymptomatic 47-year-old father had the biallelic deletion and 4 copies of SMN2. In the third family, the biallelic SMN1 deletion was found in a girl affected with SMA1 and in her healthy 53-year-old father who had 5 copies of SMN2. The findings again confirmed that an increased number of SMN2 copies in healthy carriers of the biallelic SMN1 deletion is an important SMA phenotype modifier, but also suggested that other factors play a role in disease modification. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18337729" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In a 42-year-old woman with a mild form of SMA type III, despite a homozygous absence of SMN1 exon 7, <a href="#31" class="mim-tip-reference" title="Prior, T. W., Krainer, A. R., Hua, Y., Swoboda, K. J., Snyder, P. C., Bridgeman, S. J., Burghes, A. H. M., Kissel, J. T. <strong>A positive modifier of spinal muscular atrophy in the SMN2 gene.</strong> Am. J. Hum. Genet. 85: 408-413, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19716110/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19716110</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19716110[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2009.08.002" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19716110">Prior et al. (2009)</a> identified a homozygous variant (G287R; <a href="/entry/601627#0001">601627.0001</a>) in the SMN2 gene. In vitro functional expression studies showed that the variant resulted in the creation of an exonic splicing enhancer element and increased the amount of full-length SMN2 transcripts compared to wildtype. The SMN1 genotype (0 SMN1, 0 SMN2) predicted a more severe disorder (SMA1; <a href="/entry/253300">253300</a>), but the SMN2 variant increased SMN2 transcripts, resulting in a less severe phenotype. The same G287R variant was identified in heterozygosity in 2 additional unrelated patients with mild forms of SMA, who were predicted to have a more severe form of the disorder from their genotypes (0 SMN1/1 SMN2 and 0 SMN1, 2 SMN2). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19716110" 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="#38" class="mim-tip-reference" title="Stratigopoulos, G., Lanzano, P., Deng, L., Guo, J., Kaufmann, P., Darras, B., Finkel, R., Tawil, R., McDermott, M. P., Martens, W., Devivo, D. C., Chung, W. K. <strong>Association of plastin 3 expression with disease severity in spinal muscular atrophy only in postpubertal females.</strong> Arch. Neurol. 67: 1252-1256, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20937953/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20937953</a>] [<a href="https://doi.org/10.1001/archneurol.2010.239" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20937953">Stratigopoulos et al. (2010)</a> evaluated blood levels of PLS3 (<a href="/entry/300131">300131</a>) mRNA transcripts in 88 patients with SMA, including 29 males under age 11 years, 12 males over age 11, 29 prepubertal girls, and 18 postpubertal girls in an attempt to examine whether PLS3 was a modifier of the phenotype. PLS3 expression was decreased in the older patients of both sexes. However, expression correlated with phenotype only in postpubertal girls: expression was greatest in those with SMA type III, intermediate in those with SMA type II, and lowest in those with SMA type I, and correlated with residual motor function as well as SMN2 copy number. <a href="#38" class="mim-tip-reference" title="Stratigopoulos, G., Lanzano, P., Deng, L., Guo, J., Kaufmann, P., Darras, B., Finkel, R., Tawil, R., McDermott, M. P., Martens, W., Devivo, D. C., Chung, W. K. <strong>Association of plastin 3 expression with disease severity in spinal muscular atrophy only in postpubertal females.</strong> Arch. Neurol. 67: 1252-1256, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20937953/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20937953</a>] [<a href="https://doi.org/10.1001/archneurol.2010.239" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20937953">Stratigopoulos et al. (2010)</a> concluded that the PLS3 gene may be an age- and/or puberty-specific and sex-specific modifier of SMA. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20937953" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#32" class="mim-tip-reference" title="Riessland, M., Kaczmarek, A., Schneider, S., Swoboda, K. J., Lohr, H., Bradler, C., Grysko, V., Dimitriadi, M., Hosseinibarkooie, S., Torres-Benito, L., Peters, M., and 17 others. <strong>Neurocalcin delta suppression protects against spinal muscular atrophy in humans and across species by restoring impaired endocytosis.</strong> Am. J. Hum. Genet. 100: 297-315, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28132687/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28132687</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=28132687[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2017.01.005" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="28132687">Riessland et al. (2017)</a> identified NCALD (<a href="/entry/606722">606722</a>), a negative regulator of endocytosis, as a modifying factor in SMA. They identified 5 asymptomatic members of a 4-generation Mormon family from Utah who were homozygous for SMN1 deletions and had 4 SMN2 copies, resembling a genotype associated with type 3 SMA. Linkage analysis combined with transcriptome-wide expression analysis identified significant downregulation of NCALD in these individuals compared to controls. The decreased expression of NCALD was associated with 2 polymorphisms on chromosome 8q: a 2-bp insertion (<a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs147264092;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs147264092</a>) in intron 1 of the NCALD gene and a 17-bp deletion (<a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs150254064;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs150254064</a>) located 600-kb upstream of NCALD. These 2 variants were also found in an unrelated patient with a homozygous SMN1 deletion and only 1 copy of SMN2: this genotype would have been predicted to result in perinatal lethality, but the patient survived for 9 months. Cellular studies in SMN-deficient cells showed that knockdown of Ncald triggered motor neuron differentiation and restored neurite and axonal growth. Knockdown of Ncald in several SMA animal models ameliorated SMA-associated pathologic defects and improved endocytosis and synaptic function. The findings suggested that decreased levels of NCALD may act as a protective modifier in SMA, and that perturbed synaptic vesicle endocytosis plays a role in the pathogenesis of the disease. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=28132687" 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>In a carrier screening of autosomal recessive mutations involving 1,644 Schmiedeleut (S-leut) Hutterites in the United States, <a href="#9" class="mim-tip-reference" title="Chong, J. X., Ouwenga, R., Anderson, R. L., Waggoner, D. J., Ober, C. <strong>A population-based study of autosomal-recessive disease-causing mutations in a founder population.</strong> Am. J. Hum. Genet. 91: 608-620, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22981120/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22981120</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22981120[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2012.08.007" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22981120">Chong et al. (2012)</a> identified deletion of SMN1 exon 7 in heterozygous state in 179 individuals among 1,415 screened and in homozygous state in 2, giving a carrier frequency of 0.127 (1 in 8). The carrier frequency in other populations is 1 in 35 (<a href="#23" class="mim-tip-reference" title="Hendrickson, B. C., Donohoe, C., Akmaev, V. R., Sugarman, E. A., Labrousse, P., Boguslavskiy, L., Flynn, K., Rohlfs, E. M., Walker, A., Allitto, B., Sears, C., Scholl, T. <strong>Differences in SMN1 allele frequencies among ethnic groups within North America. (Letter)</strong> J. Med. Genet. 46: 641-644, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19625283/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19625283</a>] [<a href="https://doi.org/10.1136/jmg.2009.066969" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19625283">Hendrickson et al., 2009</a>). One adult was homozygous for the SMA-causing deletion. She was previously reported by <a href="#8" class="mim-tip-reference" title="Chong, J. X., Oktay, A. A., Dai, Z., Swoboda, K .J., Prior, T. W., Ober, C. <strong>A common spinal muscular atrophy deletion mutation is present on a single founder haplotype in the US Hutterites.</strong> Europ. J. Hum. Genet. 19: 1045-1051, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21610747/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21610747</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21610747[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/ejhg.2011.85" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21610747">Chong et al. (2011)</a>. At the time of the initial evaluation she was 41 years old and asymptomatic. She subsequently died of cancer at the age of 50 without any symptoms related to SMA, according to her close relatives. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=21610747+22981120+19625283" 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 dominant form represented by the mother and 2 children described by <a href="#12" class="mim-tip-reference" title="Ford, F. R. <strong>Diseases of the Nervous System in Infancy, Childhood and Adolescence.</strong> Springfield, Ill.: Charles C Thomas (pub.) 1961. P. 390."None>Ford (1961)</a> may also exist and this may be the same as what has been termed scapuloperoneal amyotrophy (<a href="/entry/181400">181400</a>).</p>
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<p><a href="#35" class="mim-tip-reference" title="Simon, C. M., Jablonka, S., Ruiz, R., Tabares, L., Sendtner, M. <strong>Ciliary neurotrophic factor-induced sprouting preserves motor function in a mouse model of mild spinal muscular atrophy.</strong> Hum. Molec. Genet. 19: 973-986, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20022887/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20022887</a>] [<a href="https://doi.org/10.1093/hmg/ddp562" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20022887">Simon et al. (2010)</a> analyzed Smn +/- mice, a model of type III/IV SMA, electrophysiologically and histologically to characterize single motor units. Smn +/- mice exhibit progressive loss of motor neurons and denervation of motor endplates starting at 4 weeks of age. Confocal analysis revealed pronounced sprouting of innervating motor axons. As ciliary neurotrophic factor (CNTF; <a href="/entry/118945">118945</a>) is highly expressed in Schwann cells, <a href="#35" class="mim-tip-reference" title="Simon, C. M., Jablonka, S., Ruiz, R., Tabares, L., Sendtner, M. <strong>Ciliary neurotrophic factor-induced sprouting preserves motor function in a mouse model of mild spinal muscular atrophy.</strong> Hum. Molec. Genet. 19: 973-986, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20022887/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20022887</a>] [<a href="https://doi.org/10.1093/hmg/ddp562" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20022887">Simon et al. (2010)</a> investigated its role in a compensatory sprouting response and maintenance of muscle strength in this mouse model. Genetic ablation of CNTF resulted in reduced sprouting and decline of muscle strength in Smn +/- mice. The authors concluded that CNTF is necessary for a sprouting response and thus may enhance the size of motor units in skeletal muscles of Smn +/- mice. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20022887" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Although human SMN1 and SMN2 both encode the SMN protein, the SMN2 gene is unable to compensate for the loss of SMN1 protein in SMA patients. A translationally silent T at nucleotide +6 of SMN2 exon 7 instead of SMN1's C causes the final RNA product to be improperly regulated, with the majority of SMN2 pre-mRNA transcripts lacking exon 7. While humans have both SMN1 and SMN2 genes, mice and other mammals have only a single Smn gene. Using mouse and human SMN minigenes and homologous recombination, <a href="#16" class="mim-tip-reference" title="Gladman, J. T., Bebee, T. W., Edwards, C., Wang, X., Sahenk, Z., Rich, M. M., Chandler, D. S. <strong>A humanized Smn gene containing the SMN2 nucleotide alteration in exon 7 mimics SMN2 splicing and the SMA disease phenotype.</strong> Hum. Molec. Genet. 19: 4239-4252, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20705738/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20705738</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20705738[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1093/hmg/ddq343" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20705738">Gladman et al. (2010)</a> created a mouse model of SMA by inserting the SMN2 C-to-T nucleotide alteration into the endogenous mouse Smn gene. The C-to-T mutation was sufficient to induce exon 7 skipping in the mouse minigene as in the human SMN2. When the mouse Smn gene was humanized to carry the C-to-T mutation, keeping it under the control of the endogenous promoter, and in the natural genomic context, the resulting mice exhibited exon 7 skipping and mild adult-onset SMA characterized by muscle weakness, decreased activity, and an alteration of muscle fiber size. <a href="#16" class="mim-tip-reference" title="Gladman, J. T., Bebee, T. W., Edwards, C., Wang, X., Sahenk, Z., Rich, M. M., Chandler, D. S. <strong>A humanized Smn gene containing the SMN2 nucleotide alteration in exon 7 mimics SMN2 splicing and the SMA disease phenotype.</strong> Hum. Molec. Genet. 19: 4239-4252, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20705738/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20705738</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20705738[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1093/hmg/ddq343" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20705738">Gladman et al. (2010)</a> proposed that the Smn C-to-T mouse is a model for the adult-onset form of SMA (type III/IV) known as Kugelberg-Welander disease. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20705738" 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="#Bundey1975" class="mim-tip-reference" title="Bundey, S., Lovelace, R. E. <strong>A clinical and genetic study of chronic proximal spinal muscular atrophy.</strong> Brain 98: 455-472, 1975.">Bundey and Lovelace (1975)</a>; <a href="#Furukawa1966" class="mim-tip-reference" title="Furukawa, T., Tsukagoshi, H., Sugita, H., Kondo, K., Tsubaki, T. <strong>Clinical and genetic considerations on Kugelberg-Welander's disease.</strong> Clin. Neurol. 6: 148-155, 1966.">Furukawa et al. (1966)</a>; <a href="#Hausmanowa-Petrusewicz1962" class="mim-tip-reference" title="Hausmanowa-Petrusewicz, I., Sobkowicz, H., Zielinska, S., Dobosz, I. <strong>Apropos of heredofamilial juvenile muscular atrophy.</strong> Schweiz. Arch. Neurol. Psychiat. 90: 255-267, 1962.">Hausmanowa-Petrusewicz et al. (1962)</a>; <a href="#Meadows1969" class="mim-tip-reference" title="Meadows, J. C., Marsden, C. D., Harriman, D. G. F. <strong>Chronic spinal muscular atrophy in adults. I. The Kugelberg-Welander syndrome.</strong> J. Neurol. Sci. 9: 527-550, 1969.">Meadows et al. (1969)</a>; <a href="#Smith1965" class="mim-tip-reference" title="Smith, J. B., Patel, A. <strong>The Wohlfart-Kugelberg-Welander disease. Review of the literature and report of a case.</strong> Neurology 15: 469-473, 1965.">Smith
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Andreassi, C., Angelozzi, C., Tiziano, F. D., Vitali, T., De Vincenzi, E., Boninsegna, A., Villanova, M., Bertini, E., Pini, A., Neri, G., Brahe, C.
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<strong>Phenylbutyrate increases SMN expression in vitro: relevance for treatment of spinal muscular atrophy.</strong>
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Europ. J. Hum. Genet. 12: 59-65, 2004.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14560316/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14560316</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14560316" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1038/sj.ejhg.5201102" target="_blank">Full Text</a>]
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Brichta, L., Hofmann, Y., Hahnen, E., Siebzehnrubl, F. A., Raschke, H., Blumcke, I., Eyupoglu, I. Y., Wirth, B.
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<strong>Valproic acid increases the SMN2 protein level: a well-known drug as a potential therapy for spinal muscular atrophy.</strong>
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Hum. Molec. Genet. 12: 2481-2489, 2003.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12915451/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12915451</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12915451" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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Brichta, L., Holker, I., Haug, K., Klockgether, T., Wirth, B.
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<strong>In vivo activation of SMN in spinal muscular atrophy carriers and patients treated with valproate.</strong>
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Ann. Neurol. 59: 970-975, 2006.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16607616/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16607616</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16607616" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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Brzustowicz, L. M., Allitto, B. A., Matseoane, D., Theve, R., Michaud, L., Chatkupt, S., Sugarman, E., Penchaszadeh, G. K., Suslak, L., Koenigsberger, M. R., Gilliam, T. C., Handelin, B. L.
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<strong>Paternal isodisomy for chromosome 5 in a child with spinal muscular atrophy.</strong>
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Am. J. Hum. Genet. 54: 482-488, 1994.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8116617/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8116617</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8116617" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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Brzustowicz, L. M., Lehner, T., Castilla, L. H., Penchaszadeh, G. K., Wilhelmsen, K. C., Daniels, R., Davies, K. E., Leppert, M., Ziter, F., Wood, D., Dubowitz, V., Zerres, K., Hausmanowa-Petrusewicz, I., Ott, J., Munsat, T. L., Gilliam, T. C.
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<strong>Genetic mapping of chronic childhood-onset spinal muscular atrophy to chromosome 5q11.2-13.3.</strong>
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Nature 344: 540-541, 1990.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2320125/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2320125</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2320125" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1038/344540a0" target="_blank">Full Text</a>]
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Bundey, S. E., Filomeno, A. R.
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<strong>Proximal spinal muscular atrophy.</strong>
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Birth Defects Orig. Art. Ser. X(4): 336-338, 1974.
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Bundey, S., Lovelace, R. E.
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<strong>A clinical and genetic study of chronic proximal spinal muscular atrophy.</strong>
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Brain 98: 455-472, 1975.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1182487/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1182487</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1182487" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1093/brain/98.3.455" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1136/jmg.33.6.469" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1016/0022-510x(69)90093-8" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1016/0022-510x(78)90206-x" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1001/archneurol.2010.239" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1212/01.wnl.0000231139.26253.d0" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1007/s00439-006-0156-7" target="_blank">Full Text</a>]
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<p class="mim-text-font">
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Zerres, K., Stephan, M., Kehren, U., Grimm, T.
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<strong>Becker's allelic model to explain unusual pedigrees with spinal muscular atrophy. (Letter)</strong>
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Clin. Genet. 31: 276-277, 1987.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3594936/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3594936</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=3594936" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1111/j.1399-0004.1987.tb02807.x" target="_blank">Full Text</a>]
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<span class="mim-text-font">
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Hilary J. Vernon - updated : 03/07/2023
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Hilary J. Vernon - updated : 08/25/2022<br>Hilary J. Vernon - updated : 02/03/2021<br>George E. Tiller - updated : 06/26/2017<br>Cassandra L. Kniffin - updated : 06/08/2017<br>Ada Hamosh - updated : 2/7/2013<br>Cassandra L. Kniffin - updated : 10/31/2012<br>George E. Tiller - updated : 11/10/2011<br>Cassandra L. Kniffin - updated : 7/21/2011<br>Cassandra L. Kniffin - updated : 10/6/2009<br>Cassandra L. Kniffin - updated : 8/19/2008<br>Cassandra L. Kniffin - updated : 8/3/2007<br>Marla J. F. O'Neill - updated : 8/11/2006<br>Cassandra L. Kniffin - updated : 12/5/2005<br>Cassandra L. Kniffin - updated : 5/7/2004<br>Victor A. McKusick - updated : 2/26/1999<br>Iosif W. Lurie - updated : 7/10/1996
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Creation Date:
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<span class="mim-text-font">
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Victor A. McKusick : 6/4/1986
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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carol : 10/22/2024
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carol : 10/21/2024<br>carol : 10/18/2024<br>carol : 03/07/2023<br>carol : 08/25/2022<br>carol : 02/03/2021<br>carol : 01/23/2018<br>alopez : 06/26/2017<br>carol : 06/08/2017<br>ckniffin : 06/08/2017<br>carol : 05/01/2017<br>alopez : 02/11/2013<br>terry : 2/7/2013<br>terry : 2/7/2013<br>terry : 12/5/2012<br>carol : 11/9/2012<br>carol : 11/9/2012<br>ckniffin : 10/31/2012<br>alopez : 11/15/2011<br>terry : 11/10/2011<br>wwang : 7/26/2011<br>ckniffin : 7/21/2011<br>terry : 5/12/2010<br>wwang : 10/8/2009<br>ckniffin : 10/6/2009<br>wwang : 8/28/2008<br>ckniffin : 8/19/2008<br>wwang : 8/21/2007<br>ckniffin : 8/6/2007<br>ckniffin : 8/3/2007<br>wwang : 8/15/2006<br>terry : 8/11/2006<br>wwang : 12/5/2005<br>tkritzer : 5/10/2004<br>ckniffin : 5/7/2004<br>ckniffin : 3/29/2004<br>carol : 11/14/2003<br>carol : 3/1/1999<br>terry : 2/26/1999<br>joanna : 9/23/1997<br>jenny : 1/7/1997<br>mark : 1/3/1997<br>terry : 12/20/1996<br>carol : 7/10/1996<br>mimman : 2/8/1996<br>carol : 1/13/1995<br>jason : 6/7/1994<br>supermim : 3/17/1992<br>carol : 2/23/1992<br>supermim : 8/22/1990<br>supermim : 5/16/1990
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<h3>
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<span class="mim-font">
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<strong>#</strong> 253400
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</span>
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</h3>
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</div>
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<div>
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<h3>
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<span class="mim-font">
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SPINAL MUSCULAR ATROPHY, TYPE III; SMA3
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</span>
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</h3>
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<span class="mim-font">
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<em>Alternative titles; symbols</em>
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<h4>
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<span class="mim-font">
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SMA III<br />
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MUSCULAR ATROPHY, JUVENILE<br />
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KUGELBERG-WELANDER SYNDROME; KWS<br />
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SPINAL MUSCULAR ATROPHY, MILD CHILDHOOD AND ADOLESCENT FORM
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<strong>SNOMEDCT:</strong> 54280009;
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<strong>ICD9CM:</strong> 335.11;
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<strong>ORPHA:</strong> 70, 83419;
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<strong>DO:</strong> 12376;
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<h4>
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<strong>Phenotype-Gene Relationships</strong>
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<table class="table table-bordered table-condensed small mim-table-padding">
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<thead>
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Location
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Phenotype
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</th>
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Phenotype <br /> MIM number
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Inheritance
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Phenotype <br /> mapping key
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Gene/Locus
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Gene/Locus <br /> MIM number
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<span class="mim-font">
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5q13.2
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<td>
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<span class="mim-font">
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{Spinal muscular atrophy, type III, modifier of}
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</td>
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<td>
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<span class="mim-font">
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253400
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<td>
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<span class="mim-font">
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Autosomal recessive
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<td>
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<span class="mim-font">
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3
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<td>
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<span class="mim-font">
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SMN2
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<td>
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<span class="mim-font">
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601627
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<span class="mim-font">
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5q13.2
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<td>
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<span class="mim-font">
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Spinal muscular atrophy-3
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<span class="mim-font">
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253400
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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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Autosomal recessive
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</td>
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<td>
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<span class="mim-font">
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3
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<td>
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<span class="mim-font">
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SMN1
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</td>
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<td>
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<span class="mim-font">
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600354
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</table>
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<h4>
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<span class="mim-font">
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<strong>TEXT</strong>
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</span>
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</h4>
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<span class="mim-text-font">
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<p>A number sign (#) is used with this entry because spinal muscular atrophy type III (SMA3) is caused by homozygous or compound heterozygous mutation in the SMN1 gene (600354) on chromosome 5q13.</p>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Description</strong>
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</h4>
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<span class="mim-text-font">
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<p>Spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disorder characterized by progressive proximal muscle weakness and atrophy affecting the upper and lower limbs. By convention, SMA is classified into 4 types: I (SMA1; 253300), II (SMA2; 253550), III (SMA3), and IV (271150), by increasing age at onset and decreasing clinical severity. SMA1 is the most severe form of the disorder and often results in death in early childhood. SMA3, known as the juvenile form, tends to show onset in childhood or adolescence (summary by Fraidakis et al., 2012). </p>
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<h4>
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<span class="mim-font">
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<strong>Clinical Features</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Kugelberg and Welander (1956) described 12 patients from 6 families with a juvenile type of hereditary muscular atrophy. All of the patients had earlier been considered to have a form of limb-girdle muscular dystrophy. Twitchings (fasciculations) were an important differentiating sign. Muscular biopsy and electromyography showed the true nature of the process as a lower motor neuron disease. Onset occurred between 2 and 17 years of age. Atrophy and weakness of proximal limb muscles, primarily in the legs, was followed by distal involvement. The course was slowly progressive. The ability to walk was lost at the earliest 8 to 9 years after the onset of symptoms. Seven patients were able to walk 20 years or more after onset, and 1 patient after 40 years. The ability to sit up was preserved. </p><p>Levy and Wittig (1962) described similar features in 2 half brothers, with onset at 13 and 16 years. </p><p>Samaha et al. (1994) studied forced vital capacity longitudinally in 40 SMA patients ranging in age from 5 to 18 years. Although the majority of the patients grew in height, only 35% showed an increase in height-adjusted forced vital capacity. In the most seriously affected patients, all lost height-adjusted forced vital capacity over time. </p><p>Furukawa et al. (1968) reported 2 families, each with affected brother and sister. The parents in one family were first cousins. The authors pointed out that in their cases, as well as in those in the literature, the symptoms of female patients were mild and the clinical course slow whereas male sibs were severely affected. They interpreted this as sex-influence. </p><p>Bundey and Filomeno (1974) described a black sibship in which 5 sibs out of 10 had this disorder.</p><p>Pearn et al. (1978) reported a spinal muscular atrophy syndrome characterized by adolescent onset, gross hypertrophy of the calves, and a slowly progressive clinical course. One of their families with 2 affected brothers and 2 affected maternal uncles probably had Kennedy disease (313200), an X-linked form of SMA in which calf hypertrophy has been observed. </p><p>Fraidakis et al. (2012) reported 2 unrelated French men, aged 44 and 50 years, with SMA type III. Both had onset of slowly progressive proximal lower limb weakness beginning in adolescence, followed by proximal upper limb weakness. At age 44, the first patient patient had proximal lower limb amyotrophy, proximal upper and lower limb weakness, and absence of lower limb reflexes; he used a cane to walk. Muscle biopsy and EMG showed a chronic neuropathic process. The second patient developed muscle cramps and was wheelchair-bound at age 48. Physical examination showed severe motor deficit and amyotrophy in the pelvic and shoulder girdles, as well as severe motor deficit and amyotrophy in the distal limb muscles. EMG was consistent with severe chronic denervation at all extremities. Fraidakis et al. (2012) commented on the relatively mild disease course in these patients and suggested that there were likely compensatory factors affecting expression of the SMN genes. </p><p>Coratti et al. (2020) reported the clinical features of a cohort of 199 patients, aged 30 months to 30 years, with SMA type III. The patients were divided into 2 groups: type IIIA, those with onset between 18 months and 3 years (147 patients), and type IIIB, those with onset after 3 years (52 patients). Twenty-six of the patients lost ambulation during follow-up (22 with SMA type IIIA and 4 with SMA type IIIB), 11 had spinal surgery at the first visit (7 with SMA type IIIA and 4 with SMA type IIIB), and 9 had scoliosis surgery after the first visit. Of the 199 patients, 17 were excluded for further analysis due to lack of follow-up. The median age of the remaining 182 patients at baseline was 10.46 years, and the patients were followed for 0.46 to 13.34 years. The functional status of the patients was measured with the Hammersmith Functional Motor Scale Expanded (HFMSE). Across the entire cohort, there was relative functional stability with some modest improvement until age 7 years, followed by a decline. Within just the SMA type IIIB cohort, the HFMSE scores remained stable for 10 years; most patients had HFMSE scores above 40 and were still ambulatory by the end of the second decade of life. Age, SMA type, and ambulatory status were found to be significantly associated with changes in HFMSE scores, whereas gender and number of SMN2 copies were not. </p><p>Habets et al. (2022) evaluated the bioenergetic and structural characteristics of the biceps and triceps muscles in 14 patients with SMA type III (6 with type IIIA and 8 with type IIIB) and 1 patient with SMA type IV (271150). MRIs demonstrated fatty infiltration in both triceps and biceps, which was greater in the triceps, and atrophy of the triceps muscles. Maximal voluntary contraction of force was reduced in both triceps and biceps muscles, and blood lactate increases after exercise were lower in patients compared to controls. 31P MR spectroscopy studies identified white-to-red shift of muscle fiber types and slow metabolic recovery after exercise in white myofibers due to ATP synthetic dysfunction. Habets et al. (2022) concluded that these findings demonstrated the disproportionate vulnerability of white myofibers to SMN protein depletion. </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>Inheritance</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>Spira (1963) described 7 affected members in 2 sibships of a family with proximal spinal muscular atrophy. In each case the affected persons were offspring of a first-cousin marriage, consistent with autosomal recessive inheritance. </p><p>Pearn et al. (1978) reviewed 141 cases of SMA with onset before age 14 years (excluding SMA type I, or Werdnig-Hoffmann disease). Autosomal recessive inheritance could account for over 90% of cases. In these, onset was before age 5 and usually before age 2 years. The disorder was compatible with life into the third decade. A small group of cases appeared to be either new dominant mutations or phenocopies. Hausmanowa-Petrusewicz et al. (1985) called this the mild childhood and adolescent type of spinal muscular atrophy and emphasized the significance of sex influence (Hausmanowa-Petrusewicz et al., 1984). Zerres et al. (1987) advanced Becker's allelic model as a possible explanation for unusual pedigrees with spinal muscular atrophy. Because of the finding of linkage of SMA I, II (SMA2; 253550), and III to the same region, 5q11.2-q13.3 (Brzustowicz et al., 1990), it is likely that these are allelic disorders. </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>Clinical Management</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>In fibroblast cultures from patients with SMA1, SMA2, or SMA3, Andreassi et al. (2004) found a significant increase in SMN2 gene (601627) expression (increase in SMN2 transcripts of 50 to 160% in SMA1, and of 80 to 400% in SMA2 and SMA3) and a more moderate increase in SMN protein expression in response to treatment with 4-phenylbutyrate (PBA). PBA treatment also resulted in an increase in the number of SMN-containing nuclear structures (GEMS). The authors suggested a potential use for PBA in treatment of various types of SMA. </p><p>Grzeschik et al. (2005) reported that cultured lymphocytes from patients with SMA showed increased production of the full-length SMN mRNA and protein in response to treatment with hydroxyurea. The findings suggested that hydroxyurea promoted inclusion of exon 7 during SMN2 transcription. </p><p>Weihl et al. (2006) reported increased quantitative muscle strength and subjective function in 7 adult patients with SMA3/SMA4 who were treated with oral valproate for a mean duration of 8 months. Most patients reported improvement within a few months of beginning treatment. The authors noted that previous studies (see Brichta et al., 2003) had suggested that inhibitors of histone deacetylase, such as valproate, may increase SMN2 gene transcription and result in increased production of full-length SMN protein. </p><p>In a study of valproic acid (VPA) treatment in 10 SMA carriers and 20 patients with SMA1, SMA2, or SMA3, Brichta et al. (2006) found that VPA increased peripheral blood full-length SMN mRNA and protein levels in 7 carriers, increased full-length SMN2 mRNA in 7 patients, and left full-length SMN2 mRNA levels unchanged or decreased in 13 patients. The effect on protein levels in carriers was more pronounced than on mRNA levels, and the variability in augmentation among carriers and patients suggested to the authors that VPA interferes with transcription of genes encoding translation factors or regulates translation or SMN protein stability. </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>Cytogenetics</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>Brzustowicz et al. (1994) detected paternal isodisomy for chromosome 5 in a 2-year-old boy with type III SMA. Examination of 17 short-sequence repeat polymorphisms spanning a large part of the chromosome produced no evidence of maternally inherited alleles. Cytogenetic analysis showed a normal male karyotype, and fluorescence in situ hybridization with probes closely flanking the SMA locus confirmed the presence of 2 copies of chromosome 5. No developmental abnormalities other than those attributable to classic childhood-onset SMA were present. </p><p>In an analysis of uniparental disomy cases, Kotzot (1999) found only one example of uniparental disomy involving chromosome 5, that of Brzustowicz et al. (1994). No reports were found of uniparental disomy of chromosomes 12, 17, 18, and 19. On the other hand, 33 examples of chromosome 16 UPD were found, all of them maternal except 1. The bases of UPD are always 2 events: 2 meiotic; 1 meiotic and 1 mitotic; or 2 mitotic. Abnormal phenotypes result from an aberrant imprint, homozygosity of autosomal recessive gene mutations, homozygosity of X-chromosomal mutations in females, and father-to-son transmission of X-linked traits. The most frequent mechanism of UPD appears to be fertilization of a disomic gamete by a gamete monosomic for the same chromosome and subsequent loss of the normally inherited chromosome (trisomy rescue). This mechanism might result in mosaicism in the placenta or even in a subset of fetal tissues. This low level mosaicism can remain undetected and renders the delineation of a phenotype difficult. In general, the phenotype of cases with UPD is determined by mosaicism, genomic imprinting, nonmendelian inheritance of monogenic disorders, or a combination of these factors. Kotzot (1999) reviewed the entire bibliography of UPD other than that involving chromosome 15 and found a predominance of maternal versus paternal UPD (approximately 3 in 1) and a nonuniform chromosomal distribution. </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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<span class="mim-text-font">
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<p>Matthijs et al. (1996) used an SSCP assay for the molecular diagnosis of 58 patients with SMA, including 8 patients (6 Belgian and 2 Turkish) with SMA III. The SSCP assay discriminates between the SMN gene (600354) and the almost identical centromeric BCD541 repeating unit. In 7 of the 8 SMA III patients, homozygous deletion of exon 7 of the SMN gene was detected. In 6 of the 7, the deletion was associated with homozygous deletion of exon 8, and in 1 it was associated with heterozygous deletion of exon 8. Deletion of the SMN gene was not found in 1 Belgian patient with typical manifestations of SMA III. </p><p>In families with proximal spinal muscular atrophy affecting individuals in 2 generations, Rudnik-Schoneborn et al. (1996) examined whether there was pseudodominant inheritance of the regular autosomal recessive form or a dominant form of SMA which is not linked to 5q (see 158590). Four families had affected members in 2 generations who showed SMN gene deletions. The range of variability in severity was striking. In family 4, the father had onset at age 16, whereas the son had onset in the first year; both had deletion of exons 7 and 8 of the SMN gene. Even more striking was family 3, in which the father had onset 'in youth' and the first son was asymptomatic thus far, whereas the second son had onset at 6 months of age (SMA I); all 3 had deletion of exons 7 and 8 of the SMN gene. Two sons had inherited different haplotypes from their affected father and shared identical maternal haplotypes. Rudnik-Schoneborn et al. (1996) noted that, although homozygous deletions in the telomeric copy of the SMN gene can be detected in 95% to 98% of patients with early-onset SMA types I and II (Hahnen et al., 1995), as many as 10% to 20% of patients with type III SMA do not show deletions. Since no molecular genetic test was available to support a locus other than that on 5q, the question of heterogeneity remained an important issue in proximal SMA. Given an incidence of more than 1/10,000 for autosomal recessive SMA (what Rudnik-Schoneborn et al. (1996) referred to as 'SMA 5q'), patients with autosomal recessive SMA have a recurrence risk of approximately 1% to their offspring. </p><p>In 2 unrelated French men with onset of SMA type III in adolescence, Fraidakis et al. (2012) identified compound heterozygosity for a deletion of the SMN1 gene (600354.0021) and a missense mutation affecting the same codon in exon 3 (Y130C, 600354.0019 and Y130H, 600354.0020, respectively). Both missense mutations affected highly conserved residues in the Tudor domain, but the patients had a relatively mild form of the disorder. One patient had 1 copy of SMN2 and the other had 2 copies of SMN2. Fraidakis et al. (2012) commented on the relatively mild disease course in these patients and suggested that there were likely compensatory factors affecting expression of the SMN genes. </p><p>In a 50-year-old man with SMA type III, Vezain et al. (2023) identified compound heterozygosity for 2 mutations in the SMN1 gene, an SVA retrotransposon insertion in intron 7 (600354.0022) and a deletion of one copy of SMN1. The insertion was approximately 1,090 basepairs long and was flanked by 13-bp target site duplications. Transcript analysis in patient lymphoblastoid cells demonstrated decreased expression of the full-length SMN1 transcript. Although the patient was also found to have 1 copy of SMN2, his phenotype was relatively mild SMA type III, which Vezain et al. (2023) hypothesized could be due to a full-length SMN1-SVA transcript with some residual function. </p><p><strong><em>Modifying Factors</em></strong></p><p>
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Feldkotter et al. (2002) developed a quantitative test for either SMN1 or SMN2 to analyze SMA patients for their SMN2 copy number and to correlate the SMN2 copy number with type of SMA and duration of survival. The quantitative analysis of SMN2 copies in 375 patients with type I, type II, or type III SMA showed a significant correlation between SMN2 copy number and type of SMA as well as duration of survival. Thus, 80% of patients with type I SMA carried 1 or 2 SMN2 copies and 82% of patients with type II SMA carried 3 SMN2 copies, whereas 96% of patients with type III SMA carried 3 or 4 SMN2 copies. Among 113 patients with type I SMA, 9 with 1 SMN2 copy lived less than 11 months, 88 of 94 with 2 SMN2 copies lived less than 21 months, and 8 of 10 with 3 SMN2 copies lived 33 to 66 months. On the basis of SMN2 copy number, Feldkotter et al. (2002) calculated the posterior probability that a child with homozygous absence of SMN1 will develop type I, type II, or type III SMA. </p><p>Wirth et al. (2006) analyzed SMN2 copy number in 115 patients with SMA3 or SMA4 (271150) who had confirmed homozygous absence of SMN1 and found that 62% of SMA3 patients with age of onset less than 3 years had 2 or 3 SMN2 copies, whereas 65% of SMA3 patients with age of onset greater than 3 years had 4 to 5 SMN2 copies. Of the 4 adult-onset (SMA4) patients, 3 had 4 SMN2 copies and 1 had 6 copies. Wirth et al. (2006) concluded that SMN2 may have a disease-modifying role in SMA, with a greater SMN2 copy number associated with later onset and better prognosis. </p><p>Jedrzejowska et al. (2008) reported 3 unrelated families with asymptomatic carriers of a biallelic deletion of the SMN1 gene. In the first family, the biallelic deletion was found in 3 sibs: 2 affected brothers with SMA3 and a 25-year-old asymptomatic sister. All of them had 4 copies of the SMN2 gene. In the second family, 4 sibs were affected, 3 with SMA2 and 1 with SMA3, and each had 3 copies of SMN2. The clinically asymptomatic 47-year-old father had the biallelic deletion and 4 copies of SMN2. In the third family, the biallelic SMN1 deletion was found in a girl affected with SMA1 and in her healthy 53-year-old father who had 5 copies of SMN2. The findings again confirmed that an increased number of SMN2 copies in healthy carriers of the biallelic SMN1 deletion is an important SMA phenotype modifier, but also suggested that other factors play a role in disease modification. </p><p>In a 42-year-old woman with a mild form of SMA type III, despite a homozygous absence of SMN1 exon 7, Prior et al. (2009) identified a homozygous variant (G287R; 601627.0001) in the SMN2 gene. In vitro functional expression studies showed that the variant resulted in the creation of an exonic splicing enhancer element and increased the amount of full-length SMN2 transcripts compared to wildtype. The SMN1 genotype (0 SMN1, 0 SMN2) predicted a more severe disorder (SMA1; 253300), but the SMN2 variant increased SMN2 transcripts, resulting in a less severe phenotype. The same G287R variant was identified in heterozygosity in 2 additional unrelated patients with mild forms of SMA, who were predicted to have a more severe form of the disorder from their genotypes (0 SMN1/1 SMN2 and 0 SMN1, 2 SMN2). </p><p>Stratigopoulos et al. (2010) evaluated blood levels of PLS3 (300131) mRNA transcripts in 88 patients with SMA, including 29 males under age 11 years, 12 males over age 11, 29 prepubertal girls, and 18 postpubertal girls in an attempt to examine whether PLS3 was a modifier of the phenotype. PLS3 expression was decreased in the older patients of both sexes. However, expression correlated with phenotype only in postpubertal girls: expression was greatest in those with SMA type III, intermediate in those with SMA type II, and lowest in those with SMA type I, and correlated with residual motor function as well as SMN2 copy number. Stratigopoulos et al. (2010) concluded that the PLS3 gene may be an age- and/or puberty-specific and sex-specific modifier of SMA. </p><p>Riessland et al. (2017) identified NCALD (606722), a negative regulator of endocytosis, as a modifying factor in SMA. They identified 5 asymptomatic members of a 4-generation Mormon family from Utah who were homozygous for SMN1 deletions and had 4 SMN2 copies, resembling a genotype associated with type 3 SMA. Linkage analysis combined with transcriptome-wide expression analysis identified significant downregulation of NCALD in these individuals compared to controls. The decreased expression of NCALD was associated with 2 polymorphisms on chromosome 8q: a 2-bp insertion (rs147264092) in intron 1 of the NCALD gene and a 17-bp deletion (rs150254064) located 600-kb upstream of NCALD. These 2 variants were also found in an unrelated patient with a homozygous SMN1 deletion and only 1 copy of SMN2: this genotype would have been predicted to result in perinatal lethality, but the patient survived for 9 months. Cellular studies in SMN-deficient cells showed that knockdown of Ncald triggered motor neuron differentiation and restored neurite and axonal growth. Knockdown of Ncald in several SMA animal models ameliorated SMA-associated pathologic defects and improved endocytosis and synaptic function. The findings suggested that decreased levels of NCALD may act as a protective modifier in SMA, and that perturbed synaptic vesicle endocytosis plays a role in the pathogenesis of the disease. </p>
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</span>
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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>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>In a carrier screening of autosomal recessive mutations involving 1,644 Schmiedeleut (S-leut) Hutterites in the United States, Chong et al. (2012) identified deletion of SMN1 exon 7 in heterozygous state in 179 individuals among 1,415 screened and in homozygous state in 2, giving a carrier frequency of 0.127 (1 in 8). The carrier frequency in other populations is 1 in 35 (Hendrickson et al., 2009). One adult was homozygous for the SMA-causing deletion. She was previously reported by Chong et al. (2011). At the time of the initial evaluation she was 41 years old and asymptomatic. She subsequently died of cancer at the age of 50 without any symptoms related to SMA, according to her close relatives. </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>A dominant form represented by the mother and 2 children described by Ford (1961) may also exist and this may be the same as what has been termed scapuloperoneal amyotrophy (181400).</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>Simon et al. (2010) analyzed Smn +/- mice, a model of type III/IV SMA, electrophysiologically and histologically to characterize single motor units. Smn +/- mice exhibit progressive loss of motor neurons and denervation of motor endplates starting at 4 weeks of age. Confocal analysis revealed pronounced sprouting of innervating motor axons. As ciliary neurotrophic factor (CNTF; 118945) is highly expressed in Schwann cells, Simon et al. (2010) investigated its role in a compensatory sprouting response and maintenance of muscle strength in this mouse model. Genetic ablation of CNTF resulted in reduced sprouting and decline of muscle strength in Smn +/- mice. The authors concluded that CNTF is necessary for a sprouting response and thus may enhance the size of motor units in skeletal muscles of Smn +/- mice. </p><p>Although human SMN1 and SMN2 both encode the SMN protein, the SMN2 gene is unable to compensate for the loss of SMN1 protein in SMA patients. A translationally silent T at nucleotide +6 of SMN2 exon 7 instead of SMN1's C causes the final RNA product to be improperly regulated, with the majority of SMN2 pre-mRNA transcripts lacking exon 7. While humans have both SMN1 and SMN2 genes, mice and other mammals have only a single Smn gene. Using mouse and human SMN minigenes and homologous recombination, Gladman et al. (2010) created a mouse model of SMA by inserting the SMN2 C-to-T nucleotide alteration into the endogenous mouse Smn gene. The C-to-T mutation was sufficient to induce exon 7 skipping in the mouse minigene as in the human SMN2. When the mouse Smn gene was humanized to carry the C-to-T mutation, keeping it under the control of the endogenous promoter, and in the natural genomic context, the resulting mice exhibited exon 7 skipping and mild adult-onset SMA characterized by muscle weakness, decreased activity, and an alteration of muscle fiber size. Gladman et al. (2010) proposed that the Smn C-to-T mouse is a model for the adult-onset form of SMA (type III/IV) known as Kugelberg-Welander disease. </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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Bundey and Lovelace (1975); Furukawa et al. (1966);
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Hausmanowa-Petrusewicz et al. (1962); Meadows et al. (1969); Smith
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and Patel (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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Andreassi, C., Angelozzi, C., Tiziano, F. D., Vitali, T., De Vincenzi, E., Boninsegna, A., Villanova, M., Bertini, E., Pini, A., Neri, G., Brahe, C.
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<strong>Phenylbutyrate increases SMN expression in vitro: relevance for treatment of spinal muscular atrophy.</strong>
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Europ. J. Hum. Genet. 12: 59-65, 2004.
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[PubMed: 14560316]
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[Full Text: https://doi.org/10.1038/sj.ejhg.5201102]
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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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Brichta, L., Hofmann, Y., Hahnen, E., Siebzehnrubl, F. A., Raschke, H., Blumcke, I., Eyupoglu, I. Y., Wirth, B.
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<strong>Valproic acid increases the SMN2 protein level: a well-known drug as a potential therapy for spinal muscular atrophy.</strong>
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Hum. Molec. Genet. 12: 2481-2489, 2003.
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[PubMed: 12915451]
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[Full Text: https://doi.org/10.1093/hmg/ddg256]
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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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Brichta, L., Holker, I., Haug, K., Klockgether, T., Wirth, B.
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<strong>In vivo activation of SMN in spinal muscular atrophy carriers and patients treated with valproate.</strong>
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Ann. Neurol. 59: 970-975, 2006.
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[PubMed: 16607616]
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[Full Text: https://doi.org/10.1002/ana.20836]
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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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Brzustowicz, L. M., Allitto, B. A., Matseoane, D., Theve, R., Michaud, L., Chatkupt, S., Sugarman, E., Penchaszadeh, G. K., Suslak, L., Koenigsberger, M. R., Gilliam, T. C., Handelin, B. L.
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<strong>Paternal isodisomy for chromosome 5 in a child with spinal muscular atrophy.</strong>
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Am. J. Hum. Genet. 54: 482-488, 1994.
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[PubMed: 8116617]
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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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Brzustowicz, L. M., Lehner, T., Castilla, L. H., Penchaszadeh, G. K., Wilhelmsen, K. C., Daniels, R., Davies, K. E., Leppert, M., Ziter, F., Wood, D., Dubowitz, V., Zerres, K., Hausmanowa-Petrusewicz, I., Ott, J., Munsat, T. L., Gilliam, T. C.
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<strong>Genetic mapping of chronic childhood-onset spinal muscular atrophy to chromosome 5q11.2-13.3.</strong>
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Nature 344: 540-541, 1990.
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[PubMed: 2320125]
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[Full Text: https://doi.org/10.1038/344540a0]
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</li>
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<li>
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<p class="mim-text-font">
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Bundey, S. E., Filomeno, A. R.
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<strong>Proximal spinal muscular atrophy.</strong>
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Birth Defects Orig. Art. Ser. X(4): 336-338, 1974.
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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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Bundey, S., Lovelace, R. E.
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<strong>A clinical and genetic study of chronic proximal spinal muscular atrophy.</strong>
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Brain 98: 455-472, 1975.
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[PubMed: 1182487]
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[Full Text: https://doi.org/10.1093/brain/98.3.455]
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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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Chong, J. X., Oktay, A. A., Dai, Z., Swoboda, K .J., Prior, T. W., Ober, C.
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<strong>A common spinal muscular atrophy deletion mutation is present on a single founder haplotype in the US Hutterites.</strong>
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Europ. J. Hum. Genet. 19: 1045-1051, 2011.
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[PubMed: 21610747]
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[Full Text: https://doi.org/10.1038/ejhg.2011.85]
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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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Chong, J. X., Ouwenga, R., Anderson, R. L., Waggoner, D. J., Ober, C.
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<strong>A population-based study of autosomal-recessive disease-causing mutations in a founder population.</strong>
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Am. J. Hum. Genet. 91: 608-620, 2012.
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[PubMed: 22981120]
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[Full Text: https://doi.org/10.1016/j.ajhg.2012.08.007]
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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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Coratti, G., Messina, S., Lucibello, S., Pera, M. C., Montes, J., Pasternak, A., Bovis, F., Escudero, J. E., Mazzone, E. S., Mayhew, A., Glanzman, A.. M., Young, S. D.
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<strong>Clinical variability in spinal muscular atrophy type III.</strong>
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Ann. Neurol. 88: 1109-1117, 2020.
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[PubMed: 32926458]
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[Full Text: https://doi.org/10.1002/ana.25900]
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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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Feldkotter, M., Schwarzer, V., Wirth, R., Wienker, T. F., Wirth, B.
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<strong>Quantitative analyses of SMN1 and SMN2 based on real-time lightCycler PCR: fast and highly reliable carrier testing and prediction of severity of spinal muscular atrophy.</strong>
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Am. J. Hum. Genet. 70: 358-368, 2002.
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[PubMed: 11791208]
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[Full Text: https://doi.org/10.1086/338627]
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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.
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<strong>Diseases of the Nervous System in Infancy, Childhood and Adolescence.</strong>
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Springfield, Ill.: Charles C Thomas (pub.) 1961. P. 390.
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</p>
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<div class="col-lg-1 col-md-1 col-sm-2 col-xs-2">
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<span class="text-nowrap mim-text-font">
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Contributors:
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</span>
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</div>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Hilary J. Vernon - updated : 03/07/2023<br>Hilary J. Vernon - updated : 08/25/2022<br>Hilary J. Vernon - updated : 02/03/2021<br>George E. Tiller - updated : 06/26/2017<br>Cassandra L. Kniffin - updated : 06/08/2017<br>Ada Hamosh - updated : 2/7/2013<br>Cassandra L. Kniffin - updated : 10/31/2012<br>George E. Tiller - updated : 11/10/2011<br>Cassandra L. Kniffin - updated : 7/21/2011<br>Cassandra L. Kniffin - updated : 10/6/2009<br>Cassandra L. Kniffin - updated : 8/19/2008<br>Cassandra L. Kniffin - updated : 8/3/2007<br>Marla J. F. O'Neill - updated : 8/11/2006<br>Cassandra L. Kniffin - updated : 12/5/2005<br>Cassandra L. Kniffin - updated : 5/7/2004<br>Victor A. McKusick - updated : 2/26/1999<br>Iosif W. Lurie - updated : 7/10/1996
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</span>
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<span class="text-nowrap mim-text-font">
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Creation Date:
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</span>
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</div>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Victor A. McKusick : 6/4/1986
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</span>
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</div>
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carol : 10/22/2024<br>carol : 10/21/2024<br>carol : 10/18/2024<br>carol : 03/07/2023<br>carol : 08/25/2022<br>carol : 02/03/2021<br>carol : 01/23/2018<br>alopez : 06/26/2017<br>carol : 06/08/2017<br>ckniffin : 06/08/2017<br>carol : 05/01/2017<br>alopez : 02/11/2013<br>terry : 2/7/2013<br>terry : 2/7/2013<br>terry : 12/5/2012<br>carol : 11/9/2012<br>carol : 11/9/2012<br>ckniffin : 10/31/2012<br>alopez : 11/15/2011<br>terry : 11/10/2011<br>wwang : 7/26/2011<br>ckniffin : 7/21/2011<br>terry : 5/12/2010<br>wwang : 10/8/2009<br>ckniffin : 10/6/2009<br>wwang : 8/28/2008<br>ckniffin : 8/19/2008<br>wwang : 8/21/2007<br>ckniffin : 8/6/2007<br>ckniffin : 8/3/2007<br>wwang : 8/15/2006<br>terry : 8/11/2006<br>wwang : 12/5/2005<br>tkritzer : 5/10/2004<br>ckniffin : 5/7/2004<br>ckniffin : 3/29/2004<br>carol : 11/14/2003<br>carol : 3/1/1999<br>terry : 2/26/1999<br>joanna : 9/23/1997<br>jenny : 1/7/1997<br>mark : 1/3/1997<br>terry : 12/20/1996<br>carol : 7/10/1996<br>mimman : 2/8/1996<br>carol : 1/13/1995<br>jason : 6/7/1994<br>supermim : 3/17/1992<br>carol : 2/23/1992<br>supermim : 8/22/1990<br>supermim : 5/16/1990
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