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Entry
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- #614575 - CEREBELLAR ATAXIA, NEUROPATHY, AND VESTIBULAR AREFLEXIA SYNDROME; CANVAS
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- OMIM
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<span class="h4">#614575</span>
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<br />
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<strong>Table of Contents</strong>
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<a href="#title"><strong>Title</strong></a>
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<a href="#phenotypeMap"><strong>Phenotype-Gene Relationships</strong></a>
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<a href="/clinicalSynopsis/614575"><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="#pathogenesis">Pathogenesis</a>
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<a href="#molecularGenetics">Molecular Genetics</a>
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<a href="#references"><strong>References</strong></a>
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<a href="#contributors"><strong>Contributors</strong></a>
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<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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</a>
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</h4>
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<div id="mimClinicalResourcesLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">▼</div>
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<div style="display: table-cell;">Clinical Resources</div>
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</div>
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<div><a href="https://clinicaltrials.gov/search?cond=CEREBELLAR ATAXIA, NEUROPATHY, AND VESTIBULAR AREFLEXIA SYNDROME" class="mim-tip-hint" title="A registry of federally and privately supported clinical trials conducted in the United States and around the world." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Clinical Trials', 'domain': 'clinicaltrials.gov'})">Clinical Trials</a></div>
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<div><a href="https://www.orpha.net/consor/cgi-bin/ClinicalLabs_Search_Simple.php?lng=EN&LnkId=26292&Typ=Pat" class="mim-tip-hint" title="A list of European laboratories that offer genetic testing." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'EuroGentest', 'domain': 'orpha.net'})">EuroGentest</a></div>
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<div><a href="#mimGeneReviewsFold" id="mimGeneReviewsToggle" data-toggle="collapse" class="mim-tip-hint mimTriangleToggle" title="Expert-authored, peer-reviewed descriptions of inherited disorders including the uses of genetic testing in diagnosis, management, and genetic counseling."><span id="mimGeneReviewsToggleTriangle" class="small" style="margin-left: -0.8em;">►</span>Gene Reviews</div>
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<div id="mimGeneReviewsFold" class="collapse">
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<div style="margin-left: 0.5em;"><a href="https://www.ncbi.nlm.nih.gov/books/NBK1138/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Gene Reviews', 'domain': 'ncbi.nlm.nih.gov'})">Hereditary Ataxia Overview</a></div><div style="margin-left: 0.5em;"><a href="https://www.ncbi.nlm.nih.gov/books/NBK564656/" title="RFC1 CANVAS / Spectrum Disorder" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Gene Reviews', 'domain': 'ncbi.nlm.nih.gov'})">RFC1 CANVAS / Spectrum Dis…</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/gtr/all/tests/?term=614575[mim]" class="mim-tip-hint" title="Genetic Testing Registry." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'GTR', 'domain': 'ncbi.nlm.nih.gov'})">GTR</a></div>
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<div><a href="https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=504476" class="mim-tip-hint" title="European reference portal for information on rare diseases and orphan drugs." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'OrphaNet', 'domain': 'orpha.net'})">OrphaNet</a></div>
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<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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<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> 1236804009<br />
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<strong>ORPHA:</strong> 504476<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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614575
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</span>
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</span>
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</div>
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</div>
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<div>
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<a id="preferredTitle" class="mim-anchor"></a>
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<h3>
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<span class="mim-font">
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CEREBELLAR ATAXIA, NEUROPATHY, AND VESTIBULAR AREFLEXIA SYNDROME; CANVAS
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</span>
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</h3>
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</div>
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<div>
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<br />
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<div>
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<a id="phenotypeMap" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<strong>Phenotype-Gene Relationships</strong>
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</span>
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</h4>
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<div>
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<table class="table table-bordered table-condensed table-hover small mim-table-padding">
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<thead>
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<tr class="active">
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<th>
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Location
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</th>
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<th>
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Phenotype
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</th>
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<th>
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Phenotype <br /> MIM number
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</th>
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<th>
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Inheritance
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</th>
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<th>
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Phenotype <br /> mapping key
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</th>
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<th>
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Gene/Locus
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</th>
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<th>
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Gene/Locus <br /> MIM number
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<tbody>
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<td>
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<span class="mim-font">
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<a href="/geneMap/4/158?start=-3&limit=10&highlight=158">
|
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4p14
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</a>
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</span>
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</td>
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<td>
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<span class="mim-font">
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Cerebellar ataxia, neuropathy, and vestibular areflexia syndrome
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</span>
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</td>
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<td>
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<span class="mim-font">
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<a href="/entry/614575"> 614575 </a>
|
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</span>
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</td>
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<td>
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<span class="mim-font">
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<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
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</span>
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</td>
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<td>
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<span class="mim-font">
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<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
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</td>
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<td>
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<span class="mim-font">
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RFC1
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</span>
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</td>
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<td>
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<span class="mim-font">
|
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<a href="/entry/102579"> 102579 </a>
|
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</span>
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</td>
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</tr>
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</tbody>
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</table>
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<div class="btn-group mim-changed mim-change">
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<a href="/clinicalSynopsis/614575" class="btn btn-warning" role="button"> Clinical Synopsis </a>
|
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<button type="button" id="mimPhenotypicSeriesToggle" class="btn btn-warning dropdown-toggle mimSingletonFoldToggle" data-toggle="collapse" href="#mimClinicalSynopsisFold" onclick="ga('send', 'event', 'Unfurl', 'ClinicalSynopsis', 'omim.org')">
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<span class="caret"></span>
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<span class="sr-only">Toggle Dropdown</span>
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</button>
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<button type="button" class="btn btn-success dropdown-toggle" data-toggle="dropdown" aria-haspopup="true" aria-expanded="false">
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PheneGene Graphics <span class="caret"></span>
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</button>
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<ul class="dropdown-menu" style="width: 17em;">
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<li><a href="/graph/linear/614575" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Linear'})"> Linear </a></li>
|
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<li><a href="/graph/radial/614575" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Radial'})"> Radial </a></li>
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</ul>
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</div>
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<span class="glyphicon glyphicon-question-sign mim-tip-hint" title="OMIM PheneGene graphics depict relationships between phenotypes, groups of related phenotypes (Phenotypic Series), and genes.<br /><a href='/static/omim/pdf/OMIM_Graphics.pdf' target='_blank'>A quick reference overview and guide (PDF)</a>"></span>
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<p />
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<div id="mimClinicalSynopsisFold" class="well well-sm collapse mimSingletonToggleFold">
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<span class="h5 mim-font">
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<strong> INHERITANCE </strong>
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</span>
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<div style="margin-left: 2em;">
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<div>
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<span class="mim-font">
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- Autosomal recessive <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/258211005" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">258211005</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0441748&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0441748</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000007" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000007</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000007" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000007</a>]</span><br />
|
|
|
|
</span>
|
|
</div>
|
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|
|
</div>
|
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|
|
</div>
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<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<strong> HEAD & NECK </strong>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
|
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<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<em> Ears </em>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
<span class="mim-font">
|
|
|
|
<div class="mim-changed mim-change"> - Hearing impairment (in some patients) <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/103276001" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">103276001</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/15188001" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">15188001</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/H91.9" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">H91.9</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/389.9" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">389.9</a>, <a href="https://purl.bioontology.org/ontology/ICD9CM/389" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">389</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1384666&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1384666</a>, <a href="https://bioportal.bioontology.org/search?q=C1550444&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1550444</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000365" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000365</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000365" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000365</a>]</span><br /></div>
|
|
- Loss of vestibular reflexes <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C3281227&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C3281227</a>]</span><br />
|
|
- Atrophy of vestibular nerves and ganglion cells (ascertained in 1 patient) <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C3281228&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C3281228</a>]</span><br />
|
|
|
|
</span>
|
|
</div>
|
|
</div>
|
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<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<em> Eyes </em>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
<span class="mim-font">
|
|
|
|
- Impairment of compensatory eye movement reflexes <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C3281229&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C3281229</a>]</span><br /> -
|
|
Impaired visually enhanced vestibuloocular reflex (VVOR) <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C3281230&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C3281230</a>]</span><br /> -
|
|
Impaired vestibuloocular reflex (VOR) <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C3281231&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C3281231</a>]</span><br /> -
|
|
Impaired horizontal smooth pursuit <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1866753&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1866753</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001151" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001151</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001151" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001151</a>]</span><br /> -
|
|
Oscillopsia <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/246650003" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">246650003</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0422980&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0422980</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0034773" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0034773</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0034773" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0034773</a>]</span><br /> -
|
|
Saccadic movements <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C3281232&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C3281232</a>]</span><br /> -
|
|
Gaze-evoked nystagmus <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/1220537002" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">1220537002</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C5574666&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C5574666</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000640" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000640</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000640" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000640</a>]</span><br />
|
|
|
|
</span>
|
|
</div>
|
|
</div>
|
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|
|
|
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|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<strong> CARDIOVASCULAR </strong>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
|
|
|
|
|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<em> Vascular </em>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
<span class="mim-font">
|
|
|
|
- Orthostatic hypotension <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/28651003" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">28651003</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/I95.1" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">I95.1</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/458.0" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">458.0</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0020651&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0020651</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001278" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001278</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001278" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001278</a>]</span><br />
|
|
|
|
</span>
|
|
</div>
|
|
</div>
|
|
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<strong> RESPIRATORY </strong>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
|
|
<div>
|
|
<span class="mim-font">
|
|
|
|
- Chronic cough (in some patients) <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/68154008" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">68154008</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/R05.3" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">R05.3</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0010201&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0010201</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0034315" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0034315</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0034315" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0034315</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">
|
|
|
|
<div class="mim-changed mim-change"> - Muscle cramps (in some patients) <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 /> -
|
|
Distal muscle weakness (in some patients) <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/249942005" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">249942005</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0427065&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0427065</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002460" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002460</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002460" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002460</a>]</span><br /> -
|
|
Distal muscle atrophy (in some patients) <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1848736&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1848736</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003693" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003693</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003693" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003693</a>]</span><br /> -
|
|
Fasciculations (in some patients) <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/82470000" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">82470000</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/R25.3" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">R25.3</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0015644&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0015644</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002380" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002380</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002380" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002380</a>]</span><br /> -
|
|
EMG shows chronic neurogenic atrophy (in some patients)<br /></div>
|
|
|
|
</span>
|
|
</div>
|
|
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
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|
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|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<strong> NEUROLOGIC </strong>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
|
|
|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<em> Central Nervous System </em>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
<span class="mim-font">
|
|
|
|
- Imbalance <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/282299006" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">282299006</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/387603000" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">387603000</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C5848678&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C5848678</a>, <a href="https://bioportal.bioontology.org/search?q=C0241981&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0241981</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002172" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002172</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002172" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002172</a>]</span><br />
|
|
- Dizziness <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/404640003" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">404640003</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/399153001" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">399153001</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/399090003" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">399090003</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/R42" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">R42</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0012833&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0012833</a>, <a href="https://bioportal.bioontology.org/search?q=C0042571&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0042571</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002321" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002321</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002321" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002321</a>]</span><br />
|
|
- Cerebellar ataxia <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/85102008" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">85102008</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0007758&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0007758</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001251" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001251</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001251" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001251</a>]</span><br />
|
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- Gait ataxia <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/25136009" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">25136009</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/R26.0" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">R26.0</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0751837&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0751837</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002066" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002066</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002066" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002066</a>]</span><br />
|
|
- Appendicular ataxia <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0750937&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0750937</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002070" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002070</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002070" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002070</a>]</span><br />
|
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- Positive Romberg sign <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/298310004" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">298310004</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0240914&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0240914</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002403" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002403</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002403" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002403</a>]</span><br />
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- Dysarthria <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/8011004" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">8011004</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/438.13" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">438.13</a>, <a href="https://purl.bioontology.org/ontology/ICD9CM/784.51" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">784.51</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0013362&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0013362</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001260" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001260</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001260" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001260</a>]</span><br />
|
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<div class="mim-changed mim-change"> - Extensor plantar responses (in some patients) <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/246586009" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">246586009</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/366575004" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">366575004</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0034935&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0034935</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003487" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003487</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003487" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003487</a>]</span><br /></div>
|
|
- Sleep disorder <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/39898005" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">39898005</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/G47" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">G47</a>, <a href="https://purl.bioontology.org/ontology/ICD10CM/G47.9" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">G47.9</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0851578&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0851578</a>]</span><br />
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- Cerebellar atrophy <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0740279&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0740279</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001272" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001272</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001272" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001272</a>]</span><br />
|
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- Loss of cerebellar Purkinje cells <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C3281224&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C3281224</a>]</span><br />
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</span>
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</div>
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</div>
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<div>
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<div>
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<span class="h5 mim-font">
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<em> Peripheral Nervous System </em>
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</span>
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</div>
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<div style="margin-left: 2em;">
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<span class="mim-font">
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- Peripheral neuropathy, sensory <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/95662005" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">95662005</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/789588003" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">789588003</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0151313&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0151313</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000763" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000763</a>]</span><br /> -
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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 /> -
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Dysesthesia <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/279079003" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">279079003</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/762397008" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">762397008</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0241057&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0241057</a>, <a href="https://bioportal.bioontology.org/search?q=C0392699&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0392699</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0012534" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0012534</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0012534" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0012534</a>]</span><br /> -
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Sensory impairment, non length-dependent <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C3281225&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C3281225</a>]</span><br /> -
|
|
Decreased or absent sensory nerve action potentials, upper and lower limbs <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C3281226&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C3281226</a>]</span><br /> -
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Loss of myelinated fibers seen on sural nerve biopsy <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C4014944&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C4014944</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003380" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003380</a>]</span><br />
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</span>
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</div>
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</div>
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</div>
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</div>
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<div>
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<div>
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<span class="h5 mim-font">
|
|
<strong> LABORATORY ABNORMALITIES </strong>
|
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</span>
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</div>
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<div style="margin-left: 2em;">
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<div>
|
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<span class="mim-font">
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<div class="mim-changed mim-change"> - Increased serum creatine kinase (in some patients) <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0241005&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0241005</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003236" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003236</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003236" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003236</a>]</span><br /></div>
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</span>
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</div>
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</div>
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</div>
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<div>
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<div>
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<span class="h5 mim-font">
|
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<strong> MISCELLANEOUS </strong>
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</span>
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</div>
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<div style="margin-left: 2em;">
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<div>
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<span class="mim-font">
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- Adult onset (mean 54 years) <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1853562&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1853562</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003581" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003581</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003581" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003581</a>]</span><br /> -
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Slowly progressive <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1854494&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1854494</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003677" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003677</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003677" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003677</a>]</span><br />
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- Caused by a repeat expansion AAGGG(n) in the replication factor C, subunit 1, gene (RFC1, <a href="/entry/102579#0001">102579.0001</a>)<br />
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<p>A number sign (#) is used with this entry because of evidence that cerebellar ataxia, neuropathy, and vestibular areflexia syndrome (CANVAS) is caused by homozygous or compound heterozygous pentanucleotide repeat expansions or truncation mutations in the RFC1 gene on chromosome 4p14. The repeat expansions include AAGGG(n), (AAAGG)10-25(AAGGG)n, (AAAGG)10-25(AAGGG)n(AAAGG)4-6, and ACAGG(n). The reference allele for AAAAG(n) is a simple tandem pentanucleotide repeat of 11, (AAAAG)11.</p>
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<p>Cerebellar ataxia, neuropathy, and vestibular areflexia syndrome (CANVAS) is an autosomal recessive slowly progressive neurologic disorder characterized by imbalance due to cerebellar gait and limb ataxia with cerebellar atrophy on brain imaging, nystagmus, dysarthria, and peripheral sensory neuropathy with decreased or absent deep tendon reflexes. More variable features include vestibular dysfunction, chronic cough, autonomic dysfunction, saccadic pursuit, and pyramidal signs (extensor plantar responses). Most patients have onset in late adulthood, although earlier onset has been reported. Rare patients have features suggestive of lower motor neuron involvement (<a href="#7" class="mim-tip-reference" title="Szmulewicz, D. J., Waterston, J. A., MacDougall, H. G., Mossman, S., Chancellor, A. M., McLean, C. A., Merchant, S., Patrikios, P., Halmagyi, G. M., Storey, E. <strong>Cerebellar ataxia, neuropathy, vestibular areflexia syndrome (CANVAS): a review of the clinical features and video-oculographic diagnosis.</strong> Ann. N.Y. Acad. Sci. 1233: 139-147, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21950986/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21950986</a>] [<a href="https://doi.org/10.1111/j.1749-6632.2011.06158.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21950986">Szmulewicz et al., 2011</a>, <a href="#5" class="mim-tip-reference" title="Miyatake, S., Yoshida, K., Koshimizu, E., Doi, H., Yamada, M., Miyaji, Y., Ueda, N., Tsuyuzaki, J., Kodaira, M., Onoue, H., Taguri, M., Imamura, S., and 24 others. <strong>Repeat conformation heterogeneity in cerebellar ataxia, neuropathy, vestibular areflexia syndrome.</strong> Brain 145: 1139-1150, 2022.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/35355059/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">35355059</a>] [<a href="https://doi.org/10.1093/brain/awab363" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="35355059">Miyatake et al., 2022</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=21950986+35355059" 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="Migliaccio, A. A., Halmagyi, G. M., McGarvie, L. A., Cremer, P. D. <strong>Cerebellar ataxia with bilateral vestibulopathy: description of a syndrome and its characteristic clinical sign.</strong> Brain 127: 280-293, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14607788/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14607788</a>] [<a href="https://doi.org/10.1093/brain/awh030" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14607788">Migliaccio et al. (2004)</a> reported 4 unrelated patients, 2 males and 2 females, with a syndrome comprising cerebellar ataxia and bilateral vestibulopathy with impaired ability of the eye velocity to match head velocity. All had a characteristic sign on clinical examination: impairment of the visually enhanced vestibuloocular reflex (VVOR), or 'doll's head reflex,' in which a normal individual shows compensatory saccades when the head is slowly and smoothly oscillated from side to side while trying to view an earth-fixed target straight ahead. None of the patients had a family history of a similar disorder. Each patient presented between 50 and 60 years of age with slowly increasing gait ataxia and later developed dysarthria. All had problems standing and showed a positive Romberg test. Limb ataxia was less prominent. Detailed vestibuloocular testing showed impaired smooth pursuit, impaired vestibuloocular reflex, and impaired optokinetic reflex. Gaze-evoked nystagmus was present under certain conditions. Three patients had clinical and electrophysiologic evidence of a sensory peripheral neuropathy. Sural nerve biopsy of 1 patient showed a severe axonal neuropathy. None had extrapyramidal features. Brain MRI showed cerebellar atrophy. Genetic testing for several common spinocerebellar ataxias (see, e.g., SCA1, <a href="/entry/164400">164400</a>) was negative. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14607788" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#7" class="mim-tip-reference" title="Szmulewicz, D. J., Waterston, J. A., MacDougall, H. G., Mossman, S., Chancellor, A. M., McLean, C. A., Merchant, S., Patrikios, P., Halmagyi, G. M., Storey, E. <strong>Cerebellar ataxia, neuropathy, vestibular areflexia syndrome (CANVAS): a review of the clinical features and video-oculographic diagnosis.</strong> Ann. N.Y. Acad. Sci. 1233: 139-147, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21950986/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21950986</a>] [<a href="https://doi.org/10.1111/j.1749-6632.2011.06158.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21950986">Szmulewicz et al. (2011)</a> reported retrospective data on 27 patients, including the 4 reported by <a href="#4" class="mim-tip-reference" title="Migliaccio, A. A., Halmagyi, G. M., McGarvie, L. A., Cremer, P. D. <strong>Cerebellar ataxia with bilateral vestibulopathy: description of a syndrome and its characteristic clinical sign.</strong> Brain 127: 280-293, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14607788/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14607788</a>] [<a href="https://doi.org/10.1093/brain/awh030" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14607788">Migliaccio et al. (2004)</a>, with a syndrome including cerebellar ataxia, neuropathy, and vestibular areflexia, which they termed 'CANVAS.' The median age at onset was 60 years (range, 33-71), and most (20 patients) presented with gait imbalance. Other presenting features included dysesthesia (8), oscillopsia (5), dizziness (2), and intrinsic falls (1). All patients had saccadic smooth pursuit, gaze-evoked nystagmus, gait and limb ataxia, and dysarthria. Brain MRI showed cerebellar atrophy in 22 patients. Detailed vestibular function testing showed that all had bilateral vestibulopathy manifest as decreased visual acuity on vertical head shaking, absent or reduced horizontal nystagmus on caloric stimulation, and absent or reduced nystagmus in response to constant acceleration rotational testing. VVOR deficit was demonstrated by videooculography. Hearing was unaffected. Temporal bone and brain pathology of 1 patient showed atrophy of the vestibular nerves and vestibular, trigeminal, and facial ganglion cells, but not of the cochlear ganglion cells. There was also a loss of cerebellar Purkinje cells. There was a non-length-dependent neuropathy with areflexia and decreased vibration and pinprick sensation in the upper and lower limbs associated with absence of sensory nerve action potentials. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=21950986+14607788" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#3" class="mim-tip-reference" title="Cortese, A., Simone, R., Sullivan, R., Vandrovcova, J., Tariq, H., Yau, W. Y., Humphrey, J., Jaunmuktane, Z., Sivakumar, P., Polke, J., Ilyas, M., Tribollet, E., and 18 others. <strong>Biallelic expansion of an intronic repeat in RFC1 is a common cause of late-onset ataxia.</strong> Nature Genet. 51: 649-658, 2019. Note: Erratum: Nature Genet. 51: 920 only, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30926972/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30926972</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=30926972[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/s41588-019-0372-4" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30926972">Cortese et al. (2019)</a> reported 23 affected individuals, either sib pairs or first cousins, from 11 unrelated families with CANVAS. They subsequently identified 33 additional patients with sporadic occurrence of the disorder. All patients were of European descent. The mean age at onset was 54 (range, 35-73 years), and most patients presented with unsteadiness or dizziness, particularly in the dark, and/or distal numbness. Patients had peripheral neuropathy and cerebellar dysfunction, usually associated with cerebellar atrophy on brain imaging, and most also had vestibular dysfunction. Nerve conduction studies showed a nonlength-dependent sensory neuropathy with no motor abnormalities, and sural nerve biopsies showed loss of myelinated fibers. Less common features included cough and autonomic abnormalities, such as urinary urgency, erectile dysfunction, and blood pressure dysregulation. Neuropathologic examination of 1 patient showed severe widespread loss of Purkinje cells and gliosis in the cerebellum. There were no pathologic cytoplasmic or intranuclear inclusions or abnormal RNAi foci in the cerebellar cortex. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30926972" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#1" class="mim-tip-reference" title="Beecroft, S. J., Cortese, A. Sullivan, R., Yau, W. Y., Dyer, Z., Wu, T. Y., Mulroy, E., Pelosi, L., Rodrigues, M., Taylor, R., Mossman, S., Leadbetter, R., Cleland, J., Anderson, T., Ravenscroft, G., Laing, N. G., Houlden, H., Reilly, M. M., Roxburgh, R. H. <strong>A Maori specific RFC1 pathogenic repeat configuration in CANVAS, likely due to a founder allele.</strong> Brain 143: 2673-2680, 2020.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/32851396/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">32851396</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=32851396[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/awaa203" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="32851396">Beecroft et al. (2020)</a> reported 13 Maori patients with CANVAS, 2 from Cook Island and 11 from New Zealand. The mean age of symptom onset, excluding patient M2 V:1, was 55 years. Ten of 13 patients had dysarthria, 7 of 13 had sensory symptoms, and 3 of 9 had vestibular symptoms. Eight of 10 patients had a cough, 8 of 12 had autonomic dysfunction, 12 of 12 had an ataxic gait, 7 of 12 had nystagmus, 7 of 12 had reduced reflexes, and 9 of 11 had limb ataxia. Brain MRI or CT findings showed vermal atrophy in 9 of 10 patients, and a video head impulse test (vHIT) was abnormal in 9 of 10 patients. Two of 5 patients had an REM sleep behavior disorder. Patient M2 V:1, aged 20 years, had symptom onset at age 6 years, was wheelchair-dependent at age 8, and had profound limb ataxia at age 20. Brain MRI at age 6 years showed increased signal in the cerebellar peduncles and dorsal brainstem. It was thought that she had an early onset form of the disorder. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=32851396" 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="Scriba, C. K., Beecroft, S. J., Clayton, J. S., Cortese, A., Sullivan, R., Yau, W. Y., Dominik, N., Rodrigues, M., Walker, E., Dyer, Z., Wu, T. Y., Davis, M. R., Chandler, D. C., Weisburd, B., Houlden, H., Reilly, M. M., Laing, N. G., Lamont, P. J., Roxburgh, R. H., Ravenscroft, G. <strong>A novel RFC1 repeat motif (ACAGG) in two Asia-Pacific CANVAS families.</strong> Brain 143: 2904-2910, 2020. Note: Erratum: Brain 144: e51, 2021.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/33103729/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">33103729</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=33103729[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/awaa263" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="33103729">Scriba et al. (2020)</a> reported 3 patients from 2 unrelated families from the Asian Pacific region with CANVAS associated with a ACAGG(n) repeat expansion in the RFC1 gene (<a href="/entry/102579#0007">102579.0007</a>). Two brothers (family Indo1) presented in their mid-50's with distal weakness and atrophy of the lower limbs with later involvement of the upper limbs, poor balance, chronic cough, abnormal vestibuloocular reflex, severe sensorimotor peripheral neuropathy, and decreased or absent deep tendon reflexes. Cerebellar signs included saccadic pursuit, gait ataxia, and dysarthria associated with progressive cerebellar atrophy on brain imaging. They also had fasciculations and increased serum creatine kinase; muscle biopsy showed atrophic muscle fibers and group atrophy, consistent with a neurogenic cause. Electron microscopy showed subsarcolemmal accumulation of pleomorphic mitochondria with electron-dense inclusions. An unrelated female patient (N1) presented at age 57 with syncope, dysarthria, dysphagia, nystagmus, broken smooth pursuit, abnormal vestibular ocular reflex, sensory neuropathy, ataxia, and cerebellar atrophy. Additional features included autonomic dysfunction, muscle cramps, fasciculations, absent reflexes, and mild intention tremor. Serum creatine kinase was elevated, and EMG showed chronic denervation. The disorder was progressive and she died at age 71. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=33103729" 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="Weber, S., Coarelli, G., Heinzmann, A., Monin, M. L., Richard, N., Gerard, M., Durr, A., Huin, V. <strong>Two RFC1 splicing variants in CANVAS.</strong> Brain 146: e14-e16, 2023.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/36478048/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">36478048</a>] [<a href="https://doi.org/10.1093/brain/awac466" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="36478048">Weber et al. (2023)</a> reported 2 unrelated patients with CANVAS. Case 1, a 62-year-old man, presented with progressive ataxia, cerebellar signs, and hand myotonia. He developed gait problems at 37 years of age and had a chronic cough since age 20 years. On examination, he had proprioceptive ataxia, absent deep tendon reflexes, and sensory abnormalities. Other findings included action tremor, dysarthria, and vertical nystagmus. He had symptoms of dysautonomia, including orthostatic hypotension, tachycardia, and abnormal temperature regulation. Brain MRI showed mild cerebellar atrophy involving the vermis. Case 2, a 38-year-old man, presented with cerebellar and proprioceptive ataxia, which started at age 32 with gait abnormalities. On examination, he had decreased vibration sense at the ankles, cerebellar ataxia, dysarthria, and brisk deep tendon reflexes and fasciculations of the lower limbs. He had a chronic cough since age 18 years. EMG showed generalized sensory neuronopathy. Brain MRI showed cerebellar atrophy of the vermis and cerebellar hemispheres. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=36478048" 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="#5" class="mim-tip-reference" title="Miyatake, S., Yoshida, K., Koshimizu, E., Doi, H., Yamada, M., Miyaji, Y., Ueda, N., Tsuyuzaki, J., Kodaira, M., Onoue, H., Taguri, M., Imamura, S., and 24 others. <strong>Repeat conformation heterogeneity in cerebellar ataxia, neuropathy, vestibular areflexia syndrome.</strong> Brain 145: 1139-1150, 2022.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/35355059/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">35355059</a>] [<a href="https://doi.org/10.1093/brain/awab363" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="35355059">Miyatake et al. (2022)</a> reported 16 Japanese adults from 11 unrelated families with onset of CANVAS in late adulthood (mean age of disease onset was 62 years). Patients 1-6 came from the same consanguineous family (family A), whereas patients 7-16 came from unrelated families and were identified through a cohort of 210 patients with unsolved ataxia who underwent genetic screening. Four patients died in their mid-70's. The patients had typical features of the disorder, including unsteady or ataxic gait disturbances, sometimes resulting in loss of ambulation, cerebellar impairment, usually with cerebellar atrophy on brain imaging, nystagmus, peripheral sensory neuropathy, and decreased or absent deep tendon reflexes. More variable features included dysarthria, vestibular impairment, autonomic involvement, sensorineural hearing loss, saccadic eye movements, pyramidal signs (hyperreflexia or extensor plantar responses), chronic cough, and mild cognitive impairment. Three patients had evidence of lower motor neuron involvement, including muscle atrophy, fasciculations, slightly increased serum creatine kinase, and chronic neurogenic atrophy on EMG. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=35355059" 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="#7" class="mim-tip-reference" title="Szmulewicz, D. J., Waterston, J. A., MacDougall, H. G., Mossman, S., Chancellor, A. M., McLean, C. A., Merchant, S., Patrikios, P., Halmagyi, G. M., Storey, E. <strong>Cerebellar ataxia, neuropathy, vestibular areflexia syndrome (CANVAS): a review of the clinical features and video-oculographic diagnosis.</strong> Ann. N.Y. Acad. Sci. 1233: 139-147, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21950986/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21950986</a>] [<a href="https://doi.org/10.1111/j.1749-6632.2011.06158.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21950986">Szmulewicz et al. (2011)</a> reported 2 sets of affected sib pairs with CANVAS, consistent with autosomal recessive inheritance. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21950986" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>The transmission pattern of CANVAS in the families reported by <a href="#3" class="mim-tip-reference" title="Cortese, A., Simone, R., Sullivan, R., Vandrovcova, J., Tariq, H., Yau, W. Y., Humphrey, J., Jaunmuktane, Z., Sivakumar, P., Polke, J., Ilyas, M., Tribollet, E., and 18 others. <strong>Biallelic expansion of an intronic repeat in RFC1 is a common cause of late-onset ataxia.</strong> Nature Genet. 51: 649-658, 2019. Note: Erratum: Nature Genet. 51: 920 only, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30926972/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30926972</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=30926972[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/s41588-019-0372-4" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30926972">Cortese et al. (2019)</a> and <a href="#5" class="mim-tip-reference" title="Miyatake, S., Yoshida, K., Koshimizu, E., Doi, H., Yamada, M., Miyaji, Y., Ueda, N., Tsuyuzaki, J., Kodaira, M., Onoue, H., Taguri, M., Imamura, S., and 24 others. <strong>Repeat conformation heterogeneity in cerebellar ataxia, neuropathy, vestibular areflexia syndrome.</strong> Brain 145: 1139-1150, 2022.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/35355059/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">35355059</a>] [<a href="https://doi.org/10.1093/brain/awab363" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="35355059">Miyatake et al. (2022)</a> was consistent with autosomal recessive inheritance. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=30926972+35355059" 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="#9" class="mim-tip-reference" title="Wada, T., Doi, H., Okubo, M., Tada, M., Ueda, N., Suzuki, H., Tominaga, W., Koike, H., Komiya, H., Kubota, S., Hashiguchi, S., Nakamura, H., and 13 others. <strong>RNA foci in two bi-allelic RFC1 expansion carriers.</strong> Ann. Neurol. 95: 607-613, 2024.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/38062616/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">38062616</a>] [<a href="https://doi.org/10.1002/ana.26848" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="38062616">Wada et al. (2024)</a> examined autopsy material from 2 unrelated Japanese women with CANVAS who carried different homozygous repeat expansions in the RFC1 gene. P1, who was 83 years old, had a homozygous (ACAGG)n repeat expansion (<a href="/entry/102579#0007">102579.0007</a>) with 697/605 repeats, and P2, who was 86 years old, had a homozygous (AAGGG)n repeat expansion (<a href="/entry/102579#0001">102579.0001</a>) with 758/431 repeats. Both cases showed pathologic findings consistent with the essential clinical features of CANVAS, including severe loss of myelinated fibers in the sural nerve, neuronal loss in dorsal root ganglia, degeneration of the posterior columns of the spinal cord, neuronal loss and gliosis in the vestibular nucleus, and loss of Purkinje cells with Bergmann gliosis in the cerebellum. There were some differences between the patients: P2 had better preserved number of neurons/fibers in the cerebellar cortex, inferior olivary nucleus, anterior horn, and ventral root compared to P1, whereas degenerative changes in the vestibular nucleus were more severe in P2. The degeneration of Purkinje cells and motor neurons was more severe in P1. Lewy body pathology in the brainstem was apparent only in P2, who had a history consistent with Lewy body dementia. CCTGT- and CCCTT-containing RNA foci were detected in neuronal nuclei of tissues with neuronal loss, and the size of the RNA foci correlated with the degree of neurodegenerative changes in various affected regions. In P1, there was no colocalization of RNA-binding proteins with the RNA foci, suggesting that the RNA foci did not sequester these proteins. Overall, the findings suggested that RNA toxicity may be involved in the pathogenesis of CANVAS. <a href="#9" class="mim-tip-reference" title="Wada, T., Doi, H., Okubo, M., Tada, M., Ueda, N., Suzuki, H., Tominaga, W., Koike, H., Komiya, H., Kubota, S., Hashiguchi, S., Nakamura, H., and 13 others. <strong>RNA foci in two bi-allelic RFC1 expansion carriers.</strong> Ann. Neurol. 95: 607-613, 2024.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/38062616/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">38062616</a>] [<a href="https://doi.org/10.1002/ana.26848" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="38062616">Wada et al. (2024)</a> hypothesized that there may be a loss of RFC1 function caused by the RFC1 repeat expansions and RNA foci formation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=38062616" 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 25 affected individuals from 11 unrelated families with CANVAS, <a href="#3" class="mim-tip-reference" title="Cortese, A., Simone, R., Sullivan, R., Vandrovcova, J., Tariq, H., Yau, W. Y., Humphrey, J., Jaunmuktane, Z., Sivakumar, P., Polke, J., Ilyas, M., Tribollet, E., and 18 others. <strong>Biallelic expansion of an intronic repeat in RFC1 is a common cause of late-onset ataxia.</strong> Nature Genet. 51: 649-658, 2019. Note: Erratum: Nature Genet. 51: 920 only, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30926972/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30926972</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=30926972[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/s41588-019-0372-4" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30926972">Cortese et al. (2019)</a> identified a homozygous expanded 5-bp intronic repeat, AAGGG(n), in the RFC1 gene (<a href="/entry/102579#0001">102579.0001</a>). The variant, which was found by a combination of linkage analysis and whole-genome and whole-exome sequencing, was confirmed by Sanger sequencing. Screening of an additional cohort of 150 patients with sporadic late-onset ataxia identified the recessive AAGGG(n) expansion in 33 patients (22%). Haplotype analysis showed that all affected individuals from the 11 families and 32 of the sporadic cases shared the same haplotype. The reference allele, a simple tandem pentanucleotide AAAAG repeat of 11, (AAAAG)11, was replaced by a variable number of expanded pentanucleotide AAGGG repeated units. The expansion size varied across different families, ranging from about 400 to 2,000 repeats, but the majority of cases had about 1,000 repeats. Repeat size was relatively stable in sibs, and there was no association between age at onset and repeat size. There were no instances of vertical transmission; all families studied consisted of affected sibs or first cousins in the same generation. Patient cells showed normal expression levels of RFC1 mRNA and protein, and postmortem brain tissue from 1 CANVAS patients had normal levels of RFC1 and FXN (<a href="/entry/606829">606829</a>) compared to controls. However, patient cells showed some evidence of altered pre-mRNA processing with an increase in the retention of intron 2 compared to controls. Patient fibroblasts did not show increased susceptibility to DNA damage. <a href="#3" class="mim-tip-reference" title="Cortese, A., Simone, R., Sullivan, R., Vandrovcova, J., Tariq, H., Yau, W. Y., Humphrey, J., Jaunmuktane, Z., Sivakumar, P., Polke, J., Ilyas, M., Tribollet, E., and 18 others. <strong>Biallelic expansion of an intronic repeat in RFC1 is a common cause of late-onset ataxia.</strong> Nature Genet. 51: 649-658, 2019. Note: Erratum: Nature Genet. 51: 920 only, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30926972/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30926972</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=30926972[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/s41588-019-0372-4" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30926972">Cortese et al. (2019)</a> noted that their studies did not show evidence of a loss-of-function effect. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30926972" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#1" class="mim-tip-reference" title="Beecroft, S. J., Cortese, A. Sullivan, R., Yau, W. Y., Dyer, Z., Wu, T. Y., Mulroy, E., Pelosi, L., Rodrigues, M., Taylor, R., Mossman, S., Leadbetter, R., Cleland, J., Anderson, T., Ravenscroft, G., Laing, N. G., Houlden, H., Reilly, M. M., Roxburgh, R. H. <strong>A Maori specific RFC1 pathogenic repeat configuration in CANVAS, likely due to a founder allele.</strong> Brain 143: 2673-2680, 2020.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/32851396/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">32851396</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=32851396[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/awaa203" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="32851396">Beecroft et al. (2020)</a> identified a biallelic (AAAGG)10-25(AAGGG)n intronic repeat expansion of the RFC1 gene (<a href="/entry/102579#0002">102579.0002</a>) in 13 patients with CANVAS: 2 from a Cook Island Maori family, 6 from a New Zealand Maori family, and 5 from unrelated New Zealand Maori families. Two of the affected individuals also had an additional repeat sequence, (AAAGG)4-6, at the distal end of the repeat sequence. A common haplotype was identified in these patients, suggesting a founder effect, with the most recent common ancestor estimated to date to 1369-1499 CE. There were no apparent phenotypic differences between this patient cohort and patients with the (AAGGG)n repeat expansion (<a href="/entry/102579#0001">102579.0001</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=32851396" 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 3 patients from 2 unrelated families in the Asian Pacific (consanguineous family Indo1 of Chinese descent and patient N1 from the island of Niue) with CANVAS, <a href="#6" class="mim-tip-reference" title="Scriba, C. K., Beecroft, S. J., Clayton, J. S., Cortese, A., Sullivan, R., Yau, W. Y., Dominik, N., Rodrigues, M., Walker, E., Dyer, Z., Wu, T. Y., Davis, M. R., Chandler, D. C., Weisburd, B., Houlden, H., Reilly, M. M., Laing, N. G., Lamont, P. J., Roxburgh, R. H., Ravenscroft, G. <strong>A novel RFC1 repeat motif (ACAGG) in two Asia-Pacific CANVAS families.</strong> Brain 143: 2904-2910, 2020. Note: Erratum: Brain 144: e51, 2021.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/33103729/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">33103729</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=33103729[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/awaa263" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="33103729">Scriba et al. (2020)</a> identified a homozygous expanded 5-bp repeat, (ACAGG)n, in intron 2 of the RFC1 gene (<a href="/entry/102579#0007">102579.0007</a>). The variant, which was found by PCR analysis and confirmed by Sanger sequencing, segregated with the disorder in family Indo1. Southern blot analysis in family Indo1 showed that the pathogenic allele was about 10,000 kb (the control allele being about 5,000 kb) and contained about 1,015 repeated units. Haplotype analysis showed that the ACAGG and AAGGG motifs share the same core haplotype, suggesting a single ancient origin of the disease. The RFC1 ACAGG motif was present in 7 of 26,745 samples in gnomAD (v.3), including individuals of African, South Asian, and East Asian origin. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=33103729" 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 72-year-old Japanese man with sporadic CANVAS, <a href="#8" class="mim-tip-reference" title="Tsuchiya, M., Nan, H., Koh, K., Ichinose, Y., Gao, L., Shimozono, K., Hata, T., Kim, Y.-J., Ohtsuka, T., Cortese, A., Takiyama, Y. <strong>RFC1 repeat expansion in Japanese patients with late-onset cerebellar ataxia.</strong> J. Hum. Genet. 65: 1143-1147, 2020.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/32694621/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">32694621</a>] [<a href="https://doi.org/10.1038/s10038-020-0807-x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="32694621">Tsuchiya et al. (2020)</a> identified a homozygous (ACAGG)n repeat expansion in the RFC1 gene. The patient was part of a cohort of 37 Japanese patients with late-onset cerebellar ataxia who underwent genetic studies. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=32694621" 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 patients with CANVAS, <a href="#2" class="mim-tip-reference" title="Benkirane, M., Da Cunha, D., Marelli, C., Larrieu, L., Renaud, M., Varilh, J., Pointaux, M., Baux, D., Ardouin, O., Vangoethem, C., Taulan, M., Daumas Duport, B., Bergougnoux, A., Corbille, A. G., Cossee, M., Juntas Morales, R., Tuffery-Giraud, S., Koenig, M., Isidor, B., Vincent, M. C. <strong>RFC1 nonsense and frameshift variants cause CANVAS: clues for an unsolved pathophysiology.</strong> Brain 145: 3770-3775, 2022.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/35883251/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">35883251</a>] [<a href="https://doi.org/10.1093/brain/awac280" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="35883251">Benkirane et al. (2022)</a> identified compound heterozygous mutations in the RFC1 gene, an AAGGG repeat expansion on one allele in both patients and a nonsense mutation (R388X; <a href="/entry/102579#0003">102579.0003</a>) in patient 1 and a frameshift mutation (c.575delA; <a href="/entry/102579#0004">102579.0004</a>) in patient 2. In both patients, RFC1 expression was reduced from the allele with the truncating mutation. <a href="#2" class="mim-tip-reference" title="Benkirane, M., Da Cunha, D., Marelli, C., Larrieu, L., Renaud, M., Varilh, J., Pointaux, M., Baux, D., Ardouin, O., Vangoethem, C., Taulan, M., Daumas Duport, B., Bergougnoux, A., Corbille, A. G., Cossee, M., Juntas Morales, R., Tuffery-Giraud, S., Koenig, M., Isidor, B., Vincent, M. C. <strong>RFC1 nonsense and frameshift variants cause CANVAS: clues for an unsolved pathophysiology.</strong> Brain 145: 3770-3775, 2022.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/35883251/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">35883251</a>] [<a href="https://doi.org/10.1093/brain/awac280" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="35883251">Benkirane et al. (2022)</a> concluded that CANVAS likely results from a loss-of-function of RFC1. Clinical features in these 2 patients did not differ from what had been reported in patients with homozygosity for repeat expansion mutations in RFC1. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=35883251" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Among 16 Japanese patients from 11 unrelated families with CANVAS, <a href="#5" class="mim-tip-reference" title="Miyatake, S., Yoshida, K., Koshimizu, E., Doi, H., Yamada, M., Miyaji, Y., Ueda, N., Tsuyuzaki, J., Kodaira, M., Onoue, H., Taguri, M., Imamura, S., and 24 others. <strong>Repeat conformation heterogeneity in cerebellar ataxia, neuropathy, vestibular areflexia syndrome.</strong> Brain 145: 1139-1150, 2022.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/35355059/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">35355059</a>] [<a href="https://doi.org/10.1093/brain/awab363" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="35355059">Miyatake et al. (2022)</a> found heterogeneity for RFC1 repeat expansions. Seven patients had homozygous ACAGG expansions (<a href="/entry/102579#0007">102579.0007</a>), 7 had homozygous AAGGG expansions (<a href="/entry/102579#0001">102579.0001</a>), and 2 were compound heterozygous for ACAGG and AAGGG expansions. There were no interrupting sequences. Of note, of 6 affected sibs in consanguineous family A, 5 (P2-P6) were homozygous for ACAGG, whereas 1 (P1) was compound heterozygous for ACAGG and AAGGG. The number of repeats varied between 310 and 1,615. The authors found some evidence for a genotype/phenotype correlation: patients homozygous for the AAGGG repeat expansion tended to have a higher frequency of chronic cough, hearing impairment, vestibular dysfunction, autonomic dysfunction, and mild cognitive impairment compared to those with a homozygous ACAGG repeat expansion. Homozygosity for the ACAGG expansion was associated with lower motor neuron involvement, including muscle atrophy, fasciculations, slightly increased serum creatine kinase, and neurogenic atrophy on EMG. Compound heterozygosity for these expansions was associated with a slightly later age at onset and slower disease progression, although the authors noted that this observation was difficult to explain from a functional point of view. Functional studies and studies of patient cells were not performed. In the Japanese population, the carrier frequency of the AAGGG expanded allele was 7.8%, and that of the ACAGG expanded allele was 0%; however, the authors noted that gnomAD had reported a carrier frequency of 0.26% for ACAGG in the South Asian population. The overall detection rate of RFC1 repeat expansions in the cohort studied was 5.2% (11 of 212 families). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=35355059" 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="Weber, S., Coarelli, G., Heinzmann, A., Monin, M. L., Richard, N., Gerard, M., Durr, A., Huin, V. <strong>Two RFC1 splicing variants in CANVAS.</strong> Brain 146: e14-e16, 2023.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/36478048/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">36478048</a>] [<a href="https://doi.org/10.1093/brain/awac466" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="36478048">Weber et al. (2023)</a> identified compound heterozygous mutations in the RFC1 gene in 2 unrelated patients with CANVAS; both patients had an AAGGG repeat expansion on one allele with a different mutation on the other allele, c.2535+2T-C (<a href="/entry/102579#0005">102579.0005</a>) or c.2690+1G-A (<a href="/entry/102579#0006">102579.0006</a>). Both patients had an earlier onset of disease than that reported for classical CANVAS. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=36478048" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Associations Pending Confirmation</em></strong></p><p>
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For discussion of a possible association between an autosomal dominant form of cerebellar ataxia, neuropathy, and vestibular areflexia syndrome (CANVAS) and variation in the ELF2 gene, see <a href="/entry/619798#0001">619798.0001</a>.</p>
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<strong>REFERENCES</strong>
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<a id="Beecroft2020" class="mim-anchor"></a>
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Beecroft, S. J., Cortese, A. Sullivan, R., Yau, W. Y., Dyer, Z., Wu, T. Y., Mulroy, E., Pelosi, L., Rodrigues, M., Taylor, R., Mossman, S., Leadbetter, R., Cleland, J., Anderson, T., Ravenscroft, G., Laing, N. G., Houlden, H., Reilly, M. M., Roxburgh, R. H.
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Brain 143: 2673-2680, 2020.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/32851396/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">32851396</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=32851396[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=32851396" 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/awaa203" target="_blank">Full Text</a>]
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Benkirane, M., Da Cunha, D., Marelli, C., Larrieu, L., Renaud, M., Varilh, J., Pointaux, M., Baux, D., Ardouin, O., Vangoethem, C., Taulan, M., Daumas Duport, B., Bergougnoux, A., Corbille, A. G., Cossee, M., Juntas Morales, R., Tuffery-Giraud, S., Koenig, M., Isidor, B., Vincent, M. C.
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Brain 145: 3770-3775, 2022.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/35883251/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">35883251</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=35883251" 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/awac280" target="_blank">Full Text</a>]
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Cortese, A., Simone, R., Sullivan, R., Vandrovcova, J., Tariq, H., Yau, W. Y., Humphrey, J., Jaunmuktane, Z., Sivakumar, P., Polke, J., Ilyas, M., Tribollet, E., and 18 others.
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<strong>Biallelic expansion of an intronic repeat in RFC1 is a common cause of late-onset ataxia.</strong>
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Nature Genet. 51: 649-658, 2019. Note: Erratum: Nature Genet. 51: 920 only, 2019.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30926972/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30926972</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=30926972[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30926972" 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/s41588-019-0372-4" target="_blank">Full Text</a>]
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Migliaccio, A. A., Halmagyi, G. M., McGarvie, L. A., Cremer, P. D.
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<strong>Cerebellar ataxia with bilateral vestibulopathy: description of a syndrome and its characteristic clinical sign.</strong>
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Brain 127: 280-293, 2004.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14607788/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14607788</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14607788" 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/awh030" target="_blank">Full Text</a>]
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Miyatake, S., Yoshida, K., Koshimizu, E., Doi, H., Yamada, M., Miyaji, Y., Ueda, N., Tsuyuzaki, J., Kodaira, M., Onoue, H., Taguri, M., Imamura, S., and 24 others.
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<strong>Repeat conformation heterogeneity in cerebellar ataxia, neuropathy, vestibular areflexia syndrome.</strong>
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Brain 145: 1139-1150, 2022.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/35355059/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">35355059</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=35355059" 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/awab363" target="_blank">Full Text</a>]
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Scriba, C. K., Beecroft, S. J., Clayton, J. S., Cortese, A., Sullivan, R., Yau, W. Y., Dominik, N., Rodrigues, M., Walker, E., Dyer, Z., Wu, T. Y., Davis, M. R., Chandler, D. C., Weisburd, B., Houlden, H., Reilly, M. M., Laing, N. G., Lamont, P. J., Roxburgh, R. H., Ravenscroft, G.
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<strong>A novel RFC1 repeat motif (ACAGG) in two Asia-Pacific CANVAS families.</strong>
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Brain 143: 2904-2910, 2020. Note: Erratum: Brain 144: e51, 2021.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/33103729/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">33103729</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=33103729[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=33103729" 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/awaa263" target="_blank">Full Text</a>]
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Szmulewicz, D. J., Waterston, J. A., MacDougall, H. G., Mossman, S., Chancellor, A. M., McLean, C. A., Merchant, S., Patrikios, P., Halmagyi, G. M., Storey, E.
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<strong>Cerebellar ataxia, neuropathy, vestibular areflexia syndrome (CANVAS): a review of the clinical features and video-oculographic diagnosis.</strong>
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Ann. N.Y. Acad. Sci. 1233: 139-147, 2011.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21950986/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21950986</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21950986" 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.1749-6632.2011.06158.x" target="_blank">Full Text</a>]
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Tsuchiya, M., Nan, H., Koh, K., Ichinose, Y., Gao, L., Shimozono, K., Hata, T., Kim, Y.-J., Ohtsuka, T., Cortese, A., Takiyama, Y.
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<strong>RFC1 repeat expansion in Japanese patients with late-onset cerebellar ataxia.</strong>
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J. Hum. Genet. 65: 1143-1147, 2020.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/32694621/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">32694621</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=32694621" 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/s10038-020-0807-x" target="_blank">Full Text</a>]
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Wada, T., Doi, H., Okubo, M., Tada, M., Ueda, N., Suzuki, H., Tominaga, W., Koike, H., Komiya, H., Kubota, S., Hashiguchi, S., Nakamura, H., and 13 others.
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<strong>RNA foci in two bi-allelic RFC1 expansion carriers.</strong>
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Ann. Neurol. 95: 607-613, 2024.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/38062616/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">38062616</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=38062616" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1002/ana.26848" target="_blank">Full Text</a>]
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Weber, S., Coarelli, G., Heinzmann, A., Monin, M. L., Richard, N., Gerard, M., Durr, A., Huin, V.
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<strong>Two RFC1 splicing variants in CANVAS.</strong>
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Brain 146: e14-e16, 2023.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/36478048/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">36478048</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=36478048" 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/awac466" target="_blank">Full Text</a>]
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Cassandra L. Kniffin - updated : 10/31/2024
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Hilary J. Vernon - updated : 11/18/2020<br>Cassandra L. Kniffin - updated : 04/17/2019
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Cassandra L. Kniffin : 4/17/2012
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alopez : 11/04/2024<br>ckniffin : 10/31/2024<br>carol : 08/28/2023<br>carol : 05/03/2022<br>ckniffin : 04/27/2022<br>carol : 11/19/2020<br>carol : 11/18/2020<br>alopez : 05/23/2019<br>carol : 04/18/2019<br>carol : 04/17/2019<br>ckniffin : 04/17/2019<br>carol : 04/18/2012<br>ckniffin : 4/18/2012
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<strong>#</strong> 614575
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CEREBELLAR ATAXIA, NEUROPATHY, AND VESTIBULAR AREFLEXIA SYNDROME; CANVAS
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<strong>SNOMEDCT:</strong> 1236804009;
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<strong>ORPHA:</strong> 504476;
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<strong>Phenotype-Gene Relationships</strong>
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Location
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Phenotype
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Phenotype <br /> MIM number
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Inheritance
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Phenotype <br /> mapping key
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Gene/Locus <br /> MIM number
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4p14
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Cerebellar ataxia, neuropathy, and vestibular areflexia syndrome
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614575
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Autosomal recessive
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3
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RFC1
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102579
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<strong>TEXT</strong>
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<p>A number sign (#) is used with this entry because of evidence that cerebellar ataxia, neuropathy, and vestibular areflexia syndrome (CANVAS) is caused by homozygous or compound heterozygous pentanucleotide repeat expansions or truncation mutations in the RFC1 gene on chromosome 4p14. The repeat expansions include AAGGG(n), (AAAGG)10-25(AAGGG)n, (AAAGG)10-25(AAGGG)n(AAAGG)4-6, and ACAGG(n). The reference allele for AAAAG(n) is a simple tandem pentanucleotide repeat of 11, (AAAAG)11.</p>
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<strong>Description</strong>
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<p>Cerebellar ataxia, neuropathy, and vestibular areflexia syndrome (CANVAS) is an autosomal recessive slowly progressive neurologic disorder characterized by imbalance due to cerebellar gait and limb ataxia with cerebellar atrophy on brain imaging, nystagmus, dysarthria, and peripheral sensory neuropathy with decreased or absent deep tendon reflexes. More variable features include vestibular dysfunction, chronic cough, autonomic dysfunction, saccadic pursuit, and pyramidal signs (extensor plantar responses). Most patients have onset in late adulthood, although earlier onset has been reported. Rare patients have features suggestive of lower motor neuron involvement (Szmulewicz et al., 2011, Miyatake et al., 2022). </p>
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<strong>Clinical Features</strong>
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<p>Migliaccio et al. (2004) reported 4 unrelated patients, 2 males and 2 females, with a syndrome comprising cerebellar ataxia and bilateral vestibulopathy with impaired ability of the eye velocity to match head velocity. All had a characteristic sign on clinical examination: impairment of the visually enhanced vestibuloocular reflex (VVOR), or 'doll's head reflex,' in which a normal individual shows compensatory saccades when the head is slowly and smoothly oscillated from side to side while trying to view an earth-fixed target straight ahead. None of the patients had a family history of a similar disorder. Each patient presented between 50 and 60 years of age with slowly increasing gait ataxia and later developed dysarthria. All had problems standing and showed a positive Romberg test. Limb ataxia was less prominent. Detailed vestibuloocular testing showed impaired smooth pursuit, impaired vestibuloocular reflex, and impaired optokinetic reflex. Gaze-evoked nystagmus was present under certain conditions. Three patients had clinical and electrophysiologic evidence of a sensory peripheral neuropathy. Sural nerve biopsy of 1 patient showed a severe axonal neuropathy. None had extrapyramidal features. Brain MRI showed cerebellar atrophy. Genetic testing for several common spinocerebellar ataxias (see, e.g., SCA1, 164400) was negative. </p><p>Szmulewicz et al. (2011) reported retrospective data on 27 patients, including the 4 reported by Migliaccio et al. (2004), with a syndrome including cerebellar ataxia, neuropathy, and vestibular areflexia, which they termed 'CANVAS.' The median age at onset was 60 years (range, 33-71), and most (20 patients) presented with gait imbalance. Other presenting features included dysesthesia (8), oscillopsia (5), dizziness (2), and intrinsic falls (1). All patients had saccadic smooth pursuit, gaze-evoked nystagmus, gait and limb ataxia, and dysarthria. Brain MRI showed cerebellar atrophy in 22 patients. Detailed vestibular function testing showed that all had bilateral vestibulopathy manifest as decreased visual acuity on vertical head shaking, absent or reduced horizontal nystagmus on caloric stimulation, and absent or reduced nystagmus in response to constant acceleration rotational testing. VVOR deficit was demonstrated by videooculography. Hearing was unaffected. Temporal bone and brain pathology of 1 patient showed atrophy of the vestibular nerves and vestibular, trigeminal, and facial ganglion cells, but not of the cochlear ganglion cells. There was also a loss of cerebellar Purkinje cells. There was a non-length-dependent neuropathy with areflexia and decreased vibration and pinprick sensation in the upper and lower limbs associated with absence of sensory nerve action potentials. </p><p>Cortese et al. (2019) reported 23 affected individuals, either sib pairs or first cousins, from 11 unrelated families with CANVAS. They subsequently identified 33 additional patients with sporadic occurrence of the disorder. All patients were of European descent. The mean age at onset was 54 (range, 35-73 years), and most patients presented with unsteadiness or dizziness, particularly in the dark, and/or distal numbness. Patients had peripheral neuropathy and cerebellar dysfunction, usually associated with cerebellar atrophy on brain imaging, and most also had vestibular dysfunction. Nerve conduction studies showed a nonlength-dependent sensory neuropathy with no motor abnormalities, and sural nerve biopsies showed loss of myelinated fibers. Less common features included cough and autonomic abnormalities, such as urinary urgency, erectile dysfunction, and blood pressure dysregulation. Neuropathologic examination of 1 patient showed severe widespread loss of Purkinje cells and gliosis in the cerebellum. There were no pathologic cytoplasmic or intranuclear inclusions or abnormal RNAi foci in the cerebellar cortex. </p><p>Beecroft et al. (2020) reported 13 Maori patients with CANVAS, 2 from Cook Island and 11 from New Zealand. The mean age of symptom onset, excluding patient M2 V:1, was 55 years. Ten of 13 patients had dysarthria, 7 of 13 had sensory symptoms, and 3 of 9 had vestibular symptoms. Eight of 10 patients had a cough, 8 of 12 had autonomic dysfunction, 12 of 12 had an ataxic gait, 7 of 12 had nystagmus, 7 of 12 had reduced reflexes, and 9 of 11 had limb ataxia. Brain MRI or CT findings showed vermal atrophy in 9 of 10 patients, and a video head impulse test (vHIT) was abnormal in 9 of 10 patients. Two of 5 patients had an REM sleep behavior disorder. Patient M2 V:1, aged 20 years, had symptom onset at age 6 years, was wheelchair-dependent at age 8, and had profound limb ataxia at age 20. Brain MRI at age 6 years showed increased signal in the cerebellar peduncles and dorsal brainstem. It was thought that she had an early onset form of the disorder. </p><p>Scriba et al. (2020) reported 3 patients from 2 unrelated families from the Asian Pacific region with CANVAS associated with a ACAGG(n) repeat expansion in the RFC1 gene (102579.0007). Two brothers (family Indo1) presented in their mid-50's with distal weakness and atrophy of the lower limbs with later involvement of the upper limbs, poor balance, chronic cough, abnormal vestibuloocular reflex, severe sensorimotor peripheral neuropathy, and decreased or absent deep tendon reflexes. Cerebellar signs included saccadic pursuit, gait ataxia, and dysarthria associated with progressive cerebellar atrophy on brain imaging. They also had fasciculations and increased serum creatine kinase; muscle biopsy showed atrophic muscle fibers and group atrophy, consistent with a neurogenic cause. Electron microscopy showed subsarcolemmal accumulation of pleomorphic mitochondria with electron-dense inclusions. An unrelated female patient (N1) presented at age 57 with syncope, dysarthria, dysphagia, nystagmus, broken smooth pursuit, abnormal vestibular ocular reflex, sensory neuropathy, ataxia, and cerebellar atrophy. Additional features included autonomic dysfunction, muscle cramps, fasciculations, absent reflexes, and mild intention tremor. Serum creatine kinase was elevated, and EMG showed chronic denervation. The disorder was progressive and she died at age 71. </p><p>Weber et al. (2023) reported 2 unrelated patients with CANVAS. Case 1, a 62-year-old man, presented with progressive ataxia, cerebellar signs, and hand myotonia. He developed gait problems at 37 years of age and had a chronic cough since age 20 years. On examination, he had proprioceptive ataxia, absent deep tendon reflexes, and sensory abnormalities. Other findings included action tremor, dysarthria, and vertical nystagmus. He had symptoms of dysautonomia, including orthostatic hypotension, tachycardia, and abnormal temperature regulation. Brain MRI showed mild cerebellar atrophy involving the vermis. Case 2, a 38-year-old man, presented with cerebellar and proprioceptive ataxia, which started at age 32 with gait abnormalities. On examination, he had decreased vibration sense at the ankles, cerebellar ataxia, dysarthria, and brisk deep tendon reflexes and fasciculations of the lower limbs. He had a chronic cough since age 18 years. EMG showed generalized sensory neuronopathy. Brain MRI showed cerebellar atrophy of the vermis and cerebellar hemispheres. </p><p>Miyatake et al. (2022) reported 16 Japanese adults from 11 unrelated families with onset of CANVAS in late adulthood (mean age of disease onset was 62 years). Patients 1-6 came from the same consanguineous family (family A), whereas patients 7-16 came from unrelated families and were identified through a cohort of 210 patients with unsolved ataxia who underwent genetic screening. Four patients died in their mid-70's. The patients had typical features of the disorder, including unsteady or ataxic gait disturbances, sometimes resulting in loss of ambulation, cerebellar impairment, usually with cerebellar atrophy on brain imaging, nystagmus, peripheral sensory neuropathy, and decreased or absent deep tendon reflexes. More variable features included dysarthria, vestibular impairment, autonomic involvement, sensorineural hearing loss, saccadic eye movements, pyramidal signs (hyperreflexia or extensor plantar responses), chronic cough, and mild cognitive impairment. Three patients had evidence of lower motor neuron involvement, including muscle atrophy, fasciculations, slightly increased serum creatine kinase, and chronic neurogenic atrophy on EMG. </p>
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<strong>Inheritance</strong>
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<p>Szmulewicz et al. (2011) reported 2 sets of affected sib pairs with CANVAS, consistent with autosomal recessive inheritance. </p><p>The transmission pattern of CANVAS in the families reported by Cortese et al. (2019) and Miyatake et al. (2022) was consistent with autosomal recessive inheritance. </p>
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<strong>Pathogenesis</strong>
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<p>Wada et al. (2024) examined autopsy material from 2 unrelated Japanese women with CANVAS who carried different homozygous repeat expansions in the RFC1 gene. P1, who was 83 years old, had a homozygous (ACAGG)n repeat expansion (102579.0007) with 697/605 repeats, and P2, who was 86 years old, had a homozygous (AAGGG)n repeat expansion (102579.0001) with 758/431 repeats. Both cases showed pathologic findings consistent with the essential clinical features of CANVAS, including severe loss of myelinated fibers in the sural nerve, neuronal loss in dorsal root ganglia, degeneration of the posterior columns of the spinal cord, neuronal loss and gliosis in the vestibular nucleus, and loss of Purkinje cells with Bergmann gliosis in the cerebellum. There were some differences between the patients: P2 had better preserved number of neurons/fibers in the cerebellar cortex, inferior olivary nucleus, anterior horn, and ventral root compared to P1, whereas degenerative changes in the vestibular nucleus were more severe in P2. The degeneration of Purkinje cells and motor neurons was more severe in P1. Lewy body pathology in the brainstem was apparent only in P2, who had a history consistent with Lewy body dementia. CCTGT- and CCCTT-containing RNA foci were detected in neuronal nuclei of tissues with neuronal loss, and the size of the RNA foci correlated with the degree of neurodegenerative changes in various affected regions. In P1, there was no colocalization of RNA-binding proteins with the RNA foci, suggesting that the RNA foci did not sequester these proteins. Overall, the findings suggested that RNA toxicity may be involved in the pathogenesis of CANVAS. Wada et al. (2024) hypothesized that there may be a loss of RFC1 function caused by the RFC1 repeat expansions and RNA foci formation. </p>
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<strong>Molecular Genetics</strong>
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<p>In 25 affected individuals from 11 unrelated families with CANVAS, Cortese et al. (2019) identified a homozygous expanded 5-bp intronic repeat, AAGGG(n), in the RFC1 gene (102579.0001). The variant, which was found by a combination of linkage analysis and whole-genome and whole-exome sequencing, was confirmed by Sanger sequencing. Screening of an additional cohort of 150 patients with sporadic late-onset ataxia identified the recessive AAGGG(n) expansion in 33 patients (22%). Haplotype analysis showed that all affected individuals from the 11 families and 32 of the sporadic cases shared the same haplotype. The reference allele, a simple tandem pentanucleotide AAAAG repeat of 11, (AAAAG)11, was replaced by a variable number of expanded pentanucleotide AAGGG repeated units. The expansion size varied across different families, ranging from about 400 to 2,000 repeats, but the majority of cases had about 1,000 repeats. Repeat size was relatively stable in sibs, and there was no association between age at onset and repeat size. There were no instances of vertical transmission; all families studied consisted of affected sibs or first cousins in the same generation. Patient cells showed normal expression levels of RFC1 mRNA and protein, and postmortem brain tissue from 1 CANVAS patients had normal levels of RFC1 and FXN (606829) compared to controls. However, patient cells showed some evidence of altered pre-mRNA processing with an increase in the retention of intron 2 compared to controls. Patient fibroblasts did not show increased susceptibility to DNA damage. Cortese et al. (2019) noted that their studies did not show evidence of a loss-of-function effect. </p><p>Beecroft et al. (2020) identified a biallelic (AAAGG)10-25(AAGGG)n intronic repeat expansion of the RFC1 gene (102579.0002) in 13 patients with CANVAS: 2 from a Cook Island Maori family, 6 from a New Zealand Maori family, and 5 from unrelated New Zealand Maori families. Two of the affected individuals also had an additional repeat sequence, (AAAGG)4-6, at the distal end of the repeat sequence. A common haplotype was identified in these patients, suggesting a founder effect, with the most recent common ancestor estimated to date to 1369-1499 CE. There were no apparent phenotypic differences between this patient cohort and patients with the (AAGGG)n repeat expansion (102579.0001). </p><p>In 3 patients from 2 unrelated families in the Asian Pacific (consanguineous family Indo1 of Chinese descent and patient N1 from the island of Niue) with CANVAS, Scriba et al. (2020) identified a homozygous expanded 5-bp repeat, (ACAGG)n, in intron 2 of the RFC1 gene (102579.0007). The variant, which was found by PCR analysis and confirmed by Sanger sequencing, segregated with the disorder in family Indo1. Southern blot analysis in family Indo1 showed that the pathogenic allele was about 10,000 kb (the control allele being about 5,000 kb) and contained about 1,015 repeated units. Haplotype analysis showed that the ACAGG and AAGGG motifs share the same core haplotype, suggesting a single ancient origin of the disease. The RFC1 ACAGG motif was present in 7 of 26,745 samples in gnomAD (v.3), including individuals of African, South Asian, and East Asian origin. </p><p>In a 72-year-old Japanese man with sporadic CANVAS, Tsuchiya et al. (2020) identified a homozygous (ACAGG)n repeat expansion in the RFC1 gene. The patient was part of a cohort of 37 Japanese patients with late-onset cerebellar ataxia who underwent genetic studies. </p><p>In 2 patients with CANVAS, Benkirane et al. (2022) identified compound heterozygous mutations in the RFC1 gene, an AAGGG repeat expansion on one allele in both patients and a nonsense mutation (R388X; 102579.0003) in patient 1 and a frameshift mutation (c.575delA; 102579.0004) in patient 2. In both patients, RFC1 expression was reduced from the allele with the truncating mutation. Benkirane et al. (2022) concluded that CANVAS likely results from a loss-of-function of RFC1. Clinical features in these 2 patients did not differ from what had been reported in patients with homozygosity for repeat expansion mutations in RFC1. </p><p>Among 16 Japanese patients from 11 unrelated families with CANVAS, Miyatake et al. (2022) found heterogeneity for RFC1 repeat expansions. Seven patients had homozygous ACAGG expansions (102579.0007), 7 had homozygous AAGGG expansions (102579.0001), and 2 were compound heterozygous for ACAGG and AAGGG expansions. There were no interrupting sequences. Of note, of 6 affected sibs in consanguineous family A, 5 (P2-P6) were homozygous for ACAGG, whereas 1 (P1) was compound heterozygous for ACAGG and AAGGG. The number of repeats varied between 310 and 1,615. The authors found some evidence for a genotype/phenotype correlation: patients homozygous for the AAGGG repeat expansion tended to have a higher frequency of chronic cough, hearing impairment, vestibular dysfunction, autonomic dysfunction, and mild cognitive impairment compared to those with a homozygous ACAGG repeat expansion. Homozygosity for the ACAGG expansion was associated with lower motor neuron involvement, including muscle atrophy, fasciculations, slightly increased serum creatine kinase, and neurogenic atrophy on EMG. Compound heterozygosity for these expansions was associated with a slightly later age at onset and slower disease progression, although the authors noted that this observation was difficult to explain from a functional point of view. Functional studies and studies of patient cells were not performed. In the Japanese population, the carrier frequency of the AAGGG expanded allele was 7.8%, and that of the ACAGG expanded allele was 0%; however, the authors noted that gnomAD had reported a carrier frequency of 0.26% for ACAGG in the South Asian population. The overall detection rate of RFC1 repeat expansions in the cohort studied was 5.2% (11 of 212 families). </p><p>Weber et al. (2023) identified compound heterozygous mutations in the RFC1 gene in 2 unrelated patients with CANVAS; both patients had an AAGGG repeat expansion on one allele with a different mutation on the other allele, c.2535+2T-C (102579.0005) or c.2690+1G-A (102579.0006). Both patients had an earlier onset of disease than that reported for classical CANVAS. </p><p><strong><em>Associations Pending Confirmation</em></strong></p><p>
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For discussion of a possible association between an autosomal dominant form of cerebellar ataxia, neuropathy, and vestibular areflexia syndrome (CANVAS) and variation in the ELF2 gene, see 619798.0001.</p>
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<span class="mim-font">
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<strong>REFERENCES</strong>
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Beecroft, S. J., Cortese, A. Sullivan, R., Yau, W. Y., Dyer, Z., Wu, T. Y., Mulroy, E., Pelosi, L., Rodrigues, M., Taylor, R., Mossman, S., Leadbetter, R., Cleland, J., Anderson, T., Ravenscroft, G., Laing, N. G., Houlden, H., Reilly, M. M., Roxburgh, R. H.
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<strong>A Maori specific RFC1 pathogenic repeat configuration in CANVAS, likely due to a founder allele.</strong>
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Brain 143: 2673-2680, 2020.
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[PubMed: 32851396]
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[Full Text: https://doi.org/10.1093/brain/awaa203]
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Benkirane, M., Da Cunha, D., Marelli, C., Larrieu, L., Renaud, M., Varilh, J., Pointaux, M., Baux, D., Ardouin, O., Vangoethem, C., Taulan, M., Daumas Duport, B., Bergougnoux, A., Corbille, A. G., Cossee, M., Juntas Morales, R., Tuffery-Giraud, S., Koenig, M., Isidor, B., Vincent, M. C.
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<strong>RFC1 nonsense and frameshift variants cause CANVAS: clues for an unsolved pathophysiology.</strong>
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Brain 145: 3770-3775, 2022.
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[PubMed: 35883251]
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[Full Text: https://doi.org/10.1093/brain/awac280]
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Cortese, A., Simone, R., Sullivan, R., Vandrovcova, J., Tariq, H., Yau, W. Y., Humphrey, J., Jaunmuktane, Z., Sivakumar, P., Polke, J., Ilyas, M., Tribollet, E., and 18 others.
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<strong>Biallelic expansion of an intronic repeat in RFC1 is a common cause of late-onset ataxia.</strong>
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Migliaccio, A. A., Halmagyi, G. M., McGarvie, L. A., Cremer, P. D.
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<strong>Cerebellar ataxia with bilateral vestibulopathy: description of a syndrome and its characteristic clinical sign.</strong>
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Brain 127: 280-293, 2004.
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Miyatake, S., Yoshida, K., Koshimizu, E., Doi, H., Yamada, M., Miyaji, Y., Ueda, N., Tsuyuzaki, J., Kodaira, M., Onoue, H., Taguri, M., Imamura, S., and 24 others.
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<strong>Repeat conformation heterogeneity in cerebellar ataxia, neuropathy, vestibular areflexia syndrome.</strong>
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[Full Text: https://doi.org/10.1093/brain/awab363]
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Scriba, C. K., Beecroft, S. J., Clayton, J. S., Cortese, A., Sullivan, R., Yau, W. Y., Dominik, N., Rodrigues, M., Walker, E., Dyer, Z., Wu, T. Y., Davis, M. R., Chandler, D. C., Weisburd, B., Houlden, H., Reilly, M. M., Laing, N. G., Lamont, P. J., Roxburgh, R. H., Ravenscroft, G.
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<strong>A novel RFC1 repeat motif (ACAGG) in two Asia-Pacific CANVAS families.</strong>
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Szmulewicz, D. J., Waterston, J. A., MacDougall, H. G., Mossman, S., Chancellor, A. M., McLean, C. A., Merchant, S., Patrikios, P., Halmagyi, G. M., Storey, E.
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<strong>Cerebellar ataxia, neuropathy, vestibular areflexia syndrome (CANVAS): a review of the clinical features and video-oculographic diagnosis.</strong>
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Tsuchiya, M., Nan, H., Koh, K., Ichinose, Y., Gao, L., Shimozono, K., Hata, T., Kim, Y.-J., Ohtsuka, T., Cortese, A., Takiyama, Y.
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<strong>RFC1 repeat expansion in Japanese patients with late-onset cerebellar ataxia.</strong>
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Wada, T., Doi, H., Okubo, M., Tada, M., Ueda, N., Suzuki, H., Tominaga, W., Koike, H., Komiya, H., Kubota, S., Hashiguchi, S., Nakamura, H., and 13 others.
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Weber, S., Coarelli, G., Heinzmann, A., Monin, M. L., Richard, N., Gerard, M., Durr, A., Huin, V.
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<strong>Two RFC1 splicing variants in CANVAS.</strong>
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[PubMed: 36478048]
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[Full Text: https://doi.org/10.1093/brain/awac466]
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Cassandra L. Kniffin - updated : 10/31/2024<br>Hilary J. Vernon - updated : 11/18/2020<br>Cassandra L. Kniffin - updated : 04/17/2019
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Cassandra L. Kniffin : 4/17/2012
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carol : 01/15/2025<br>alopez : 11/04/2024<br>ckniffin : 10/31/2024<br>carol : 08/28/2023<br>carol : 05/03/2022<br>ckniffin : 04/27/2022<br>carol : 11/19/2020<br>carol : 11/18/2020<br>alopez : 05/23/2019<br>carol : 04/18/2019<br>carol : 04/17/2019<br>ckniffin : 04/17/2019<br>carol : 04/18/2012<br>ckniffin : 4/18/2012
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