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- #164400 - SPINOCEREBELLAR ATAXIA 1; SCA1
- OMIM
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<span class="h4">#164400</span>
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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/164400"><strong>Clinical Synopsis</strong></a>
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<a href="/phenotypicSeries/PS164400"> <strong>Phenotypic Series</strong> </a>
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<a href="#biochemicalFeatures">Biochemical Features</a>
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<a href="#diagnosis">Diagnosis</a>
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<a href="#heterogeneity">Heterogeneity</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="#genotypePhenotypeCorrelations">Genotype/Phenotype Correlations</a>
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<div><a href="https://clinicaltrials.gov/search?cond=SPINOCEREBELLAR ATAXIA" 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 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/NBK1184/" title="Spinocerebellar Ataxia Type 1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Gene Reviews', 'domain': 'ncbi.nlm.nih.gov'})">Spinocerebellar Ataxia Typ…</a></div>
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<div><a href="https://medlineplus.gov/genetics/condition/spinocerebellar-ataxia-type-1" class="mim-tip-hint" title="Consumer-friendly information about the effects of genetic variation on human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MedlinePlus Genetics', 'domain': 'medlineplus.gov'})">MedlinePlus Genetics</a></div>
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<div><a href="https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=98755" 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>
</div>
</div>
</div>
<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
<div class="panel-heading mim-panel-heading" role="tab" id="mimAnimalModels">
<span class="panel-title">
<span class="small">
<a href="#mimAnimalModelsLinksFold" id="mimAnimalModelsLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
<div style="display: table-row">
<div id="mimAnimalModelsLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">&#9658;</div>
&nbsp;
<div style="display: table-cell;">Animal Models</div>
</div>
</a>
</span>
</span>
</div>
<div id="mimAnimalModelsLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
<div class="panel-body small mim-panel-body">
<div><a href="https://www.alliancegenome.org/disease/DOID:0050954" class="mim-tip-hint" title="Search Across Species; explore model organism and human comparative genomics." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Alliance Genome', 'domain': 'alliancegenome.org'})">Alliance Genome</a></div>
<div><a href="http://www.informatics.jax.org/disease/164400" class="mim-tip-hint" title="Phenotypes, alleles, and disease models from Mouse Genome Informatics." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MGI Mouse Phenotype', 'domain': 'informatics.jax.org'})">MGI Mouse Phenotype</a></div>
<div><a href="https://omia.org/OMIA000740/" class="mim-tip-hint" title="Online Mendelian Inheritance in Animals (OMIA) is a database of genes, inherited disorders and traits in 191 animal species (other than human and mouse.)" target="_blank">OMIA</a></div>
<div><a href="https://wormbase.org/resources/disease/DOID:0050954" class="mim-tip-hint" title="Database of the biology and genome of Caenorhabditis elegans and related nematodes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Wormbase Disease Ontology', 'domain': 'wormbase.org'})">Wormbase Disease Ontology</a></div>
</div>
</div>
</div>
<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
<div class="panel-heading mim-panel-heading" role="tab" id="mimCellLines">
<span class="panel-title">
<span class="small">
<a href="#mimCellLinesLinksFold" id="mimCellLinesLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
<div style="display: table-row">
<div id="mimCellLinesLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">&#9658;</div>
&nbsp;
<div style="display: table-cell;">Cell Lines</div>
</div>
</a>
</span>
</span>
</div>
<div id="mimCellLinesLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
<div class="panel-body small mim-panel-body">
<div><a href="https://catalog.coriell.org/Search?q=OmimNum:164400" class="definition" title="Coriell Cell Repositories; cell cultures and DNA derived from cell cultures." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'CCR', 'domain': 'ccr.coriell.org'})">Coriell</a></div>
</div>
</div>
</div>
</div>
</div>
</div>
<span>
<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.">
&nbsp;
</span>
</span>
</div>
<div class="col-lg-8 col-lg-pull-2 col-md-8 col-md-pull-2 col-sm-8 col-sm-pull-2 col-xs-12">
<div>
<a id="title" class="mim-anchor"></a>
<div>
<a id="number" class="mim-anchor"></a>
<div class="text-right">
<a href="#" class="mim-tip-icd" qtip_title="<strong>ICD+</strong>" qtip_text="
<strong>SNOMEDCT:</strong> 715748006<br />
<strong>ORPHA:</strong> 98755<br />
<strong>DO:</strong> 0050954<br />
">ICD+</a>
</div>
<div>
<span class="h3">
<span class="mim-font mim-tip-hint" title="Phenotype description, molecular basis known">
<span class="text-danger"><strong>#</strong></span>
164400
</span>
</span>
</div>
</div>
<div>
<a id="preferredTitle" class="mim-anchor"></a>
<h3>
<span class="mim-font">
SPINOCEREBELLAR ATAXIA 1; SCA1
</span>
</h3>
</div>
<div>
<br />
</div>
<div>
<a id="alternativeTitles" class="mim-anchor"></a>
<div>
<p>
<span class="mim-font">
<em>Alternative titles; symbols</em>
</span>
</p>
</div>
<div>
<h4>
<span class="mim-font">
SPINOCEREBELLAR ATROPHY I<br />
OLIVOPONTOCEREBELLAR ATROPHY I; OPCA1<br />
OPCA I<br />
OLIVOPONTOCEREBELLAR ATROPHY IV; OPCA4<br />
OPCA IV<br />
CEREBELLOPARENCHYMAL DISORDER I; CPD1<br />
MENZEL TYPE OPCA<br />
SCHUT-HAYMAKER TYPE OPCA
</span>
</h4>
</div>
</div>
<div>
<br />
</div>
</div>
<div>
<a id="phenotypeMap" class="mim-anchor"></a>
<h4>
<span class="mim-font">
<strong>Phenotype-Gene Relationships</strong>
</span>
</h4>
<div>
<table class="table table-bordered table-condensed table-hover small mim-table-padding">
<thead>
<tr class="active">
<th>
Location
</th>
<th>
Phenotype
</th>
<th>
Phenotype <br /> MIM number
</th>
<th>
Inheritance
</th>
<th>
Phenotype <br /> mapping key
</th>
<th>
Gene/Locus
</th>
<th>
Gene/Locus <br /> MIM number
</th>
</tr>
</thead>
<tbody>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/6/90?start=-3&limit=10&highlight=90">
6p22.3
</a>
</span>
</td>
<td>
<span class="mim-font">
Spinocerebellar ataxia 1
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/164400"> 164400 </a>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
</span>
</td>
<td>
<span class="mim-font">
ATXN1
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/601556"> 601556 </a>
</span>
</td>
</tr>
</tbody>
</table>
</div>
</div>
<div>
<div class="btn-group ">
<a href="/clinicalSynopsis/164400" class="btn btn-warning" role="button"> Clinical Synopsis </a>
<button type="button" id="mimPhenotypicSeriesToggle" class="btn btn-warning dropdown-toggle mimSingletonFoldToggle" data-toggle="collapse" href="#mimClinicalSynopsisFold" onclick="ga('send', 'event', 'Unfurl', 'ClinicalSynopsis', 'omim.org')">
<span class="caret"></span>
<span class="sr-only">Toggle Dropdown</span>
</button>
</div>
&nbsp;
<div class="btn-group">
<a href="/phenotypicSeries/PS164400" class="btn btn-info" role="button"> Phenotypic Series </a>
<button type="button" id="mimPhenotypicSeriesToggle" class="btn btn-info dropdown-toggle mimSingletonFoldToggle" data-toggle="collapse" href="#mimPhenotypicSeriesFold" onclick="ga('send', 'event', 'Unfurl', 'PhenotypicSeries', 'omim.org')">
<span class="caret"></span>
<span class="sr-only">Toggle Dropdown</span>
</button>
</div>
&nbsp;
<div class="btn-group">
<button type="button" class="btn btn-success dropdown-toggle" data-toggle="dropdown" aria-haspopup="true" aria-expanded="false">
PheneGene Graphics <span class="caret"></span>
</button>
<ul class="dropdown-menu" style="width: 17em;">
<li><a href="/graph/linear/164400" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Linear'})"> Linear </a></li>
<li><a href="/graph/radial/164400" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Radial'})"> Radial </a></li>
</ul>
</div>
<span class="glyphicon glyphicon-question-sign mim-tip-hint" title="OMIM PheneGene graphics depict relationships between phenotypes, groups of related phenotypes (Phenotypic Series), and genes.<br /><a href='/static/omim/pdf/OMIM_Graphics.pdf' target='_blank'>A quick reference overview and guide (PDF)</a>"></span>
<div>
<p />
</div>
<div id="mimClinicalSynopsisFold" class="well well-sm collapse mimSingletonToggleFold">
<div class="small" style="margin: 5px">
<div>
<div>
<span class="h5 mim-font">
<strong> INHERITANCE </strong>
</span>
</div>
<div style="margin-left: 2em;">
<div>
<span class="mim-font">
- Autosomal dominant <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/263681008" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">263681008</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/771269000" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">771269000</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0443147&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0443147</a>, <a href="https://bioportal.bioontology.org/search?q=C1867440&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1867440</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000006" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000006</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000006" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000006</a>]</span><br />
</span>
</div>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<strong> HEAD & NECK </strong>
</span>
</div>
<div style="margin-left: 2em;">
<div>
<div>
<span class="h5 mim-font">
<em> Eyes </em>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
- Supranuclear ophthalmoplegia <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1408507&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1408507</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000623" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000623</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000623" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000623</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 /> -
Slow saccades (less common) <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/404686001" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">404686001</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1321329&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1321329</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000514" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000514</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000514" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000514</a>]</span><br /> -
Dysmetric saccades <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1836392&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1836392</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000641" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000641</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000641" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000641</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 /> -
Optic atrophy <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/76976005" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">76976005</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/H47.2" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">H47.2</a>, <a href="https://purl.bioontology.org/ontology/ICD10CM/H47.20" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">H47.20</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/377.10" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">377.10</a>, <a href="https://purl.bioontology.org/ontology/ICD9CM/377.1" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">377.1</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0029124&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0029124</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000648" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000648</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000648" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000648</a>]</span><br /> -
Pale optic discs <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/302200001" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">302200001</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0554970&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0554970</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000543" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000543</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000543" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000543</a>]</span><br />
</span>
</div>
</div>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<strong> ABDOMEN </strong>
</span>
</div>
<div style="margin-left: 2em;">
<div>
<div>
<span class="h5 mim-font">
<em> Gastrointestinal </em>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
- Dysphagia <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/288939007" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">288939007</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/40739000" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">40739000</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/R13.1" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">R13.1</a>, <a href="https://purl.bioontology.org/ontology/ICD10CM/R13.10" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">R13.10</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/787.2" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">787.2</a>, <a href="https://purl.bioontology.org/ontology/ICD9CM/787.20" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">787.20</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0011168&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0011168</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002015" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002015</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002015" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002015</a>]</span><br />
</span>
</div>
</div>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<strong> GENITOURINARY </strong>
</span>
</div>
<div style="margin-left: 2em;">
<div>
<div>
<span class="h5 mim-font">
<em> Bladder </em>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
- Sphincter disturbances <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1843663&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1843663</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002839" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002839</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002839" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002839</a>]</span><br />
</span>
</div>
</div>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<strong> NEUROLOGIC </strong>
</span>
</div>
<div style="margin-left: 2em;">
<div>
<div>
<span class="h5 mim-font">
<em> Central Nervous System </em>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
- Cerebellar ataxia, progressive <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/230233000" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">230233000</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0393525&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0393525</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002073" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002073</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002073" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002073</a>]</span><br /> -
Hyperreflexia (early) <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1834003&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1834003</a>]</span> <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/86854008" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">86854008</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001347" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001347</a>]</span><br /> -
Spasticity <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/221360009" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">221360009</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/397790002" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">397790002</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0026838&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0026838</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001257" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001257</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001257" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001257</a>]</span><br /> -
Scanning speech <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/77420001" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">77420001</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0240952&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0240952</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002168" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002168</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002168" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002168</a>]</span><br /> -
Limb 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 /> -
Truncal ataxia <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/250067008" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">250067008</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0427190&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0427190</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002078" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002078</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002078" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002078</a>]</span><br /> -
Dysarthria <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/8011004" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">8011004</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/438.13" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">438.13</a>, <a href="https://purl.bioontology.org/ontology/ICD9CM/784.51" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">784.51</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0013362&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0013362</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001260" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001260</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001260" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001260</a>]</span><br /> -
Dysmetria <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/32566006" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">32566006</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0234162&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0234162</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001310" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001310</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001310" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001310</a>]</span><br /> -
Hypotonia <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/398151007" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">398151007</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/398152000" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">398152000</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0026827&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0026827</a>, <a href="https://bioportal.bioontology.org/search?q=C1858120&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1858120</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001290" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001290</a>, <a href="https://hpo.jax.org/app/browse/term/HP:0001252" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001252</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001252" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001252</a>]</span><br /> -
Loss of deep tendon reflexes (later) <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1834004&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1834004</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001284" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001284</a>]</span><br /> -
Extensor plantar response <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 /> -
Extrapyramidal signs <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/43378000" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">43378000</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0234133&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0234133</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002071" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002071</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002071" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002071</a>]</span><br /> -
Corticospinal signs <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/14648003" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">14648003</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0234132&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0234132</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0007256" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0007256</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0007256" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0007256</a>]</span><br /> -
Chorea <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/271700006" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">271700006</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/G25.5" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">G25.5</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0008489&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0008489</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002072" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002072</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002072" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002072</a>]</span><br /> -
Bulbar palsies <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C4082299&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C4082299</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001283" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001283</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001283" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001283</a>]</span><br /> -
Dysphagia <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/288939007" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">288939007</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/40739000" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">40739000</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/R13.1" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">R13.1</a>, <a href="https://purl.bioontology.org/ontology/ICD10CM/R13.10" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">R13.10</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/787.2" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">787.2</a>, <a href="https://purl.bioontology.org/ontology/ICD9CM/787.20" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">787.20</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0011168&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0011168</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002015" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002015</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002015" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002015</a>]</span><br /> -
Dysdiadochokinesis <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/23133003" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">23133003</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0234979&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0234979</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002075" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002075</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002075" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002075</a>]</span><br /> -
Fasciculation-like movements <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1866748&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1866748</a>]</span><br /> -
Cognitive impairment, mild <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/386805003" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">386805003</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/G31.84" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">G31.84</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1270972&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1270972</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0100543" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0100543</a>]</span><br /> -
Olivopontocerebellar atrophy <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/67761004" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">67761004</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0028968&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0028968</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002542" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002542</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002542" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002542</a>]</span><br /> -
Enlarged fourth ventricle <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1847117&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1847117</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002198" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002198</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002198" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002198</a>]</span><br /> -
Spinocerebellar tract degeneration <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1866751&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1866751</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002503" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002503</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002503" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002503</a>]</span><br /> -
Posterior column degeneration <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1866750&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1866750</a>]</span><br />
</span>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<em> Peripheral Nervous System </em>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
- Peripheral neuropathy <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/42658009" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">42658009</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/302226006" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">302226006</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/G64" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">G64</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/350-359.99" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">350-359.99</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C4721453&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C4721453</a>, <a href="https://bioportal.bioontology.org/search?q=C0031117&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0031117</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0009830" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0009830</a>, <a href="https://hpo.jax.org/app/browse/term/HP:0000759" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000759</a>, <a href="https://hpo.jax.org/app/browse/term/HP:0001271" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001271</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0009830" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0009830</a>]</span><br /> -
Decreased vibration sense <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/130980003" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">130980003</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1295585&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1295585</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002495" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002495</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002495" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002495</a>]</span><br /> -
Distal muscle atrophy <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 />
</span>
</div>
</div>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<strong> MISCELLANEOUS </strong>
</span>
</div>
<div style="margin-left: 2em;">
<div>
<span class="mim-font">
- Onset in third or fourth decade<br /> -
Genetic anticipation <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0600498&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0600498</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003743" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003743</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003743" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003743</a>]</span><br /> -
Paternal anticipation bias <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1834002&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1834002</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003744" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003744</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003744" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003744</a>]</span><br />
</span>
</div>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<strong> MOLECULAR BASIS </strong>
</span>
</div>
<div style="margin-left: 2em;">
<div>
<span class="mim-font">
- Caused by expanded CAG trinucleotide repeats in the ataxin-1 gene (ATX1, <a href="/entry/601556#0001">601556.0001</a>)<br />
</span>
</div>
</div>
</div>
<div class="text-right">
<a href="#mimClinicalSynopsisFold" data-toggle="collapse">&#9650;&nbsp;Close</a>
</div>
</div>
</div>
<div id="mimPhenotypicSeriesFold" class="well well-sm collapse mimSingletonToggleFold">
<div class="small">
<div class="row">
<div class="col-lg-12 col-md-12 col-sm-12 col-xs-12">
<h5>
Spinocerebellar ataxia
- <a href="/phenotypicSeries/PS164400">PS164400</a>
- 49 Entries
</h5>
</div>
</div>
<div class="row" style="margin-left: 0.125em; margin-right: 0.125em;">
<table class="table table-bordered table-condensed table-hover mim-table-padding">
<thead>
<tr>
<th class="col-lg-1 col-md-1 col-sm-1 col-xs-1 text-nowrap">
<strong>Location</strong>
</th>
<th class="col-lg-5 col-md-5 col-sm-5 col-xs-6 text-nowrap">
<strong>Phenotype</strong>
</th>
<th class="col-lg-1 col-md-1 col-sm-1 col-xs-1 text-nowrap">
<strong>Inheritance</strong>
</th>
<th class="col-lg-1 col-md-1 col-sm-1 col-xs-1 text-nowrap">
<strong>Phenotype<br />mapping key</strong>
</th>
<th class="col-lg-1 col-md-1 col-sm-1 col-xs-1 text-nowrap">
<strong>Phenotype<br />MIM number</strong>
</th>
<th class="col-lg-1 col-md-1 col-sm-1 col-xs-1 text-nowrap">
<strong>Gene/Locus</strong>
</th>
<th class="col-lg-1 col-md-1 col-sm-1 col-xs-1 text-nowrap">
<strong>Gene/Locus<br />MIM number</strong>
</th>
</tr>
</thead>
<tbody>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/1/49?start=-3&limit=10&highlight=49"> 1p36.33 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/607454"> Spinocerebellar ataxia 21 </a>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/607454"> 607454 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/616101"> TMEM240 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/616101"> 616101 </a>
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/1/378?start=-3&limit=10&highlight=378"> 1p35.2 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/617931"> Spinocerebellar ataxia 47 </a>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/617931"> 617931 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/607204"> PUM1 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/607204"> 607204 </a>
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/1/653?start=-3&limit=10&highlight=653"> 1p32.2-p32.1 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/615945"> Spinocerebellar ataxia 37 </a>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/615945"> 615945 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/603448"> DAB1 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/603448"> 603448 </a>
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/1/919?start=-3&limit=10&highlight=919"> 1p13.2 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/607346"> Spinocerebellar ataxia 19 </a>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/607346"> 607346 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/605411"> KCND3 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/605411"> 605411 </a>
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/2/269?start=-3&limit=10&highlight=269"> 2p16.1 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/608703"> Spinocerebellar ataxia 25 </a>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/608703"> 608703 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/610316"> PNPT1 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/610316"> 610316 </a>
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/3/17?start=-3&limit=10&highlight=17"> 3p26.1 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/117360"> Spinocerebellar ataxia 29, congenital nonprogressive </a>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/117360"> 117360 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/147265"> ITPR1 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/147265"> 147265 </a>
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/3/17?start=-3&limit=10&highlight=17"> 3p26.1 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/606658"> Spinocerebellar ataxia 15 </a>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/606658"> 606658 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/147265"> ITPR1 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/147265"> 147265 </a>
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/3/436?start=-3&limit=10&highlight=436"> 3p14.1 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/164500"> Spinocerebellar ataxia 7 </a>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/164500"> 164500 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/607640"> ATXN7 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/607640"> 607640 </a>
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/3/798?start=-3&limit=10&highlight=798"> 3q25.2 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/617018"> ?Spinocerebellar ataxia 43 </a>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/617018"> 617018 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/120520"> MME </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/120520"> 120520 </a>
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/4/531?start=-3&limit=10&highlight=531"> 4q27 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/616410"> ?Spinocerebellar ataxia 41 </a>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/616410"> 616410 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/602345"> TRPC3 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/602345"> 602345 </a>
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/4/691?start=-3&limit=10&highlight=691"> 4q34.3-q35.1 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/613371"> ?Spinocerebellar ataxia 30 </a>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="2 - The disorder was placed on the map by statistical methods"> 2 </abbr>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/613371"> 613371 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/613371"> SCA30 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/613371"> 613371 </a>
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/5/633?start=-3&limit=10&highlight=633"> 5q32 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/604326"> Spinocerebellar ataxia 12 </a>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/604326"> 604326 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/604325"> PPP2R2B </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/604325"> 604325 </a>
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/5/687?start=-3&limit=10&highlight=687"> 5q33.1 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/617769"> Spinocerebellar ataxia 45 </a>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/617769"> 617769 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/604269"> FAT2 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/604269"> 604269 </a>
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/6/90?start=-3&limit=10&highlight=90"> 6p22.3 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/164400"> Spinocerebellar ataxia 1 </a>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/164400"> 164400 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/601556"> ATXN1 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/601556"> 601556 </a>
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/6/600?start=-3&limit=10&highlight=600"> 6p12.1 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/615957"> Spinocerebellar ataxia 38 </a>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/615957"> 615957 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/611805"> ELOVL5 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/611805"> 611805 </a>
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/6/667?start=-3&limit=10&highlight=667"> 6q14.1 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/133190"> Spinocerebellar ataxia 34 </a>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/133190"> 133190 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/605512"> ELOVL4 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/605512"> 605512 </a>
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/6/928?start=-3&limit=10&highlight=928"> 6q24.3 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/617691"> Spinocerebellar ataxia 44 </a>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/617691"> 617691 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/604473"> GRM1 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/604473"> 604473 </a>
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/6/1041?start=-3&limit=10&highlight=1041"> 6q27 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/607136"> Spinocerebellar ataxia 17 </a>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/607136"> 607136 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/600075"> TBP </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/600075"> 600075 </a>
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/7/414?start=-3&limit=10&highlight=414"> 7q21.2 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/619806"> ?Spinocerebellar ataxia 49 </a>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/619806"> 619806 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/611170"> SAMD9L </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/611170"> 611170 </a>
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/7/454?start=-3&limit=10&highlight=454"> 7q22-q32 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/607458"> Spinocerebellar ataxia 18 </a>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="2 - The disorder was placed on the map by statistical methods"> 2 </abbr>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/607458"> 607458 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/607458"> SCA18 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/607458"> 607458 </a>
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/7/642?start=-3&limit=10&highlight=642"> 7q32-q33 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/613909"> Spinocerebellar ataxia 32 </a>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="2 - The disorder was placed on the map by statistical methods"> 2 </abbr>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/613909"> 613909 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/613909"> SCA32 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/613909"> 613909 </a>
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/11/380?start=-3&limit=10&highlight=380"> 11q12 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/608687"> Spinocerebellar ataxia 20 </a>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="4 - A contiguous gene duplication or deletion syndrome in which multiple genes are involved"> 4 </abbr>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/608687"> 608687 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/608687"> SCA20 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/608687"> 608687 </a>
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/11/646?start=-3&limit=10&highlight=646"> 11q13.2 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/600224"> Spinocerebellar ataxia 5 </a>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/600224"> 600224 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/604985"> SPTBN2 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/604985"> 604985 </a>
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/12/813?start=-3&limit=10&highlight=813"> 12q24.12 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/183090"> Spinocerebellar ataxia 2 </a>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/183090"> 183090 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/601517"> ATXN2 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/601517"> 601517 </a>
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/12/813?start=-3&limit=10&highlight=813"> 12q24.12 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/183090"> {Amyotrophic lateral sclerosis, susceptibility to, 13} </a>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/183090"> 183090 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/601517"> ATXN2 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/601517"> 601517 </a>
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/13/204?start=-3&limit=10&highlight=204"> 13q21 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/608768"> Spinocerebellar ataxia 8 </a>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/608768"> 608768 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/613289"> ATXN8 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/613289"> 613289 </a>
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/13/213?start=-3&limit=10&highlight=213"> 13q21.33 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/608768"> Spinocerebellar ataxia 8 </a>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/608768"> 608768 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/603680"> ATXN8OS </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/603680"> 603680 </a>
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/13/293?start=-3&limit=10&highlight=293"> 13q33.1 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/193003"> Spinocerebellar ataxia 27A </a>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/193003"> 193003 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/601515"> FGF14 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/601515"> 601515 </a>
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/13/293?start=-3&limit=10&highlight=293"> 13q33.1 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/620174"> Spinocerebellar ataxia 27B, late-onset </a>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/620174"> 620174 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/601515"> FGF14 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/601515"> 601515 </a>
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/14/460?start=-3&limit=10&highlight=460"> 14q32.11-q32.12 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/616053"> ?Spinocerebellar ataxia 40 </a>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/616053"> 616053 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/611204"> CCDC88C </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/611204"> 611204 </a>
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/14/466?start=-3&limit=10&highlight=466"> 14q32.12 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/109150"> Machado-Joseph disease </a>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/109150"> 109150 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/607047"> ATXN3 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/607047"> 607047 </a>
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/15/139?start=-3&limit=10&highlight=139"> 15q15.2 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/604432"> Spinocerebellar ataxia 11 </a>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/604432"> 604432 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/611695"> TTBK2 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/611695"> 611695 </a>
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/16/37?start=-3&limit=10&highlight=37"> 16p13.3 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/618093"> Spinocerebellar ataxia 48 </a>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/618093"> 618093 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/607207"> STUB1 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/607207"> 607207 </a>
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/16/510?start=-3&limit=10&highlight=510"> 16q21 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/117210"> Spinocerebellar ataxia 31 </a>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/117210"> 117210 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/612051"> BEAN1 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/612051"> 612051 </a>
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/16/561?start=-3&limit=10&highlight=561"> 16q22.1 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/620947"> Spinocerebellar ataxia 51 </a>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/620947"> 620947 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/609119"> THAP11 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/609119"> 609119 </a>
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/16/630?start=-3&limit=10&highlight=630"> 16q22.2-q22.3 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/600223"> Spinocerebellar ataxia 4 </a>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/600223"> 600223 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/104155"> ZFHX3 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/104155"> 104155 </a>
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/17/747?start=-3&limit=10&highlight=747"> 17q21.33 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/616795"> Spinocerebellar ataxia 42 </a>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/616795"> 616795 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/604065"> CACNA1G </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/604065"> 604065 </a>
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/17/1021?start=-3&limit=10&highlight=1021"> 17q25.3 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/620158"> Spinocerebellar ataxia 50 </a>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/620158"> 620158 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/602367"> NPTX1 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/602367"> 602367 </a>
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/18/63?start=-3&limit=10&highlight=63"> 18p11.21 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/610246"> Spinocerebellar ataxia 28 </a>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/610246"> 610246 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/604581"> AFG3L2 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/604581"> 604581 </a>
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/19/123?start=-3&limit=10&highlight=123"> 19p13.3 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/609306"> ?Spinocerebellar ataxia 26 </a>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/609306"> 609306 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/130610"> EEF2 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/130610"> 130610 </a>
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/19/355?start=-3&limit=10&highlight=355"> 19p13.13 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/183086"> Spinocerebellar ataxia 6 </a>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/183086"> 183086 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/601011"> CACNA1A </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/601011"> 601011 </a>
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/19/700?start=-3&limit=10&highlight=700"> 19q13.2 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/617770"> ?Spinocerebellar ataxia 46 </a>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/617770"> 617770 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/615698"> PLD3 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/615698"> 615698 </a>
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/19/978?start=-3&limit=10&highlight=978"> 19q13.33 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/605259"> Spinocerebellar ataxia 13 </a>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/605259"> 605259 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/176264"> KCNC3 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/176264"> 176264 </a>
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/19/1111?start=-3&limit=10&highlight=1111"> 19q13.42 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/605361"> Spinocerebellar ataxia 14 </a>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/605361"> 605361 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/176980"> PRKCG </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/176980"> 176980 </a>
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/20/29?start=-3&limit=10&highlight=29"> 20p13 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/610245"> Spinocerebellar ataxia 23 </a>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/610245"> 610245 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/131340"> PDYN </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/131340"> 131340 </a>
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/20/32?start=-3&limit=10&highlight=32"> 20p13 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/613908"> Spinocerebellar ataxia 35 </a>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/613908"> 613908 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/613900"> TGM6 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/613900"> 613900 </a>
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/20/35?start=-3&limit=10&highlight=35"> 20p13 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/614153"> Spinocerebellar ataxia 36 </a>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/614153"> 614153 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/614154"> NOP56 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/614154"> 614154 </a>
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/22/380?start=-3&limit=10&highlight=380"> 22q13.31 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/603516"> Spinocerebellar ataxia 10 </a>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/603516"> 603516 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/611150"> ATXN10 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/611150"> 611150 </a>
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
Not Mapped
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/612876"> Spinocerebellar ataxia 9 </a>
</span>
</td>
<td>
<span class="mim-font">
</span>
</td>
<td>
<span class="mim-font">
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/612876"> 612876 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/612876"> SCA9 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/612876"> 612876 </a>
</span>
</td>
</tr>
</tbody>
</table>
</div>
<div class="text-right small">
<a href="#mimPhenotypicSeriesFold" data-toggle="collapse">&#9650;&nbsp;Close</a>
</div>
</div>
</div>
</div>
<div>
<br />
</div>
<div>
<a id="text" class="mim-anchor"></a>
<h4 href="#mimTextFold" id="mimTextToggle" class="mimTriangleToggle" style="cursor: pointer;" data-toggle="collapse">
<span id="mimTextToggleTriangle" class="small mimTextToggleTriangle">&#9660;</span>
<span class="mim-font">
<span class="mim-tip-floating" qtip_title="<strong>Looking For More References?</strong>" qtip_text="Click the 'reference plus' icon &lt;span class='glyphicon glyphicon-plus-sign'&gt;&lt;/span&gt at the end of each OMIM text paragraph to see more references related to the content of the preceding paragraph.">
<strong>TEXT</strong>
</span>
</span>
</h4>
<div id="mimTextFold" class="collapse in ">
<span class="mim-text-font">
<p>A number sign (#) is used with this entry because spinocerebellar ataxia-1 (SCA1) is caused by an expanded (CAG)n trinucleotide repeat in the ataxin-1 gene (ATXN1; <a href="/entry/601556">601556</a>) on chromosome 6p22.</p>
</span>
<div>
<br />
</div>
</div>
<div>
<a id="description" class="mim-anchor"></a>
<h4 href="#mimDescriptionFold" id="mimDescriptionToggle" class="mimTriangleToggle" style="cursor: pointer;" data-toggle="collapse">
<span id="mimDescriptionToggleTriangle" class="small mimTextToggleTriangle">&#9660;</span>
<span class="mim-font">
<strong>Description</strong>
</span>
</h4>
</div>
<div id="mimDescriptionFold" class="collapse in ">
<span class="mim-text-font">
<p>The autosomal dominant cerebellar degenerative disorders are generally referred to as 'spinocerebellar ataxias,' (SCAs) even though 'spinocerebellar' is a hybrid term, referring to both clinical signs and neuroanatomical regions (<a href="#55" class="mim-tip-reference" title="Margolis, R. L. &lt;strong&gt;Dominant spinocerebellar ataxias: a molecular approach to classification, diagnosis, pathogenesis and the future.&lt;/strong&gt; Expert Rev. Molec. Diagn. 3: 715-732, 2003.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/14628900/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;14628900&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1586/14737159.3.6.715&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="14628900">Margolis, 2003</a>). Neuropathologists have defined SCAs as cerebellar ataxias with variable involvement of the brainstem and spinal cord, and the clinical features of the disorders are caused by degeneration of the cerebellum and its afferent and efferent connections, which involve the brainstem and spinal cord (<a href="#87" class="mim-tip-reference" title="Schols, L., Bauer, P., Schmidt, T., Schulte, T., Riess, O. &lt;strong&gt;Autosomal dominant cerebellar ataxias: clinical features, genetics, and pathogenesis.&lt;/strong&gt; Lancet Neurol. 3: 291-304, 2004.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/15099544/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;15099544&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/S1474-4422(04)00737-9&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="15099544">Schols et al., 2004</a>; <a href="#99" class="mim-tip-reference" title="Taroni, F., DiDonato, S. &lt;strong&gt;Pathways to motor incoordination: the inherited ataxias.&lt;/strong&gt; Nature Rev. Neurosci. 5: 641-655, 2004.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/15263894/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;15263894&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1038/nrn1474&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="15263894">Taroni and DiDonato, 2004</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=14628900+15099544+15263894" 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>Historically, <a href="#30" class="mim-tip-reference" title="Harding, A. E. &lt;strong&gt;The clinical features and classification of the late onset autosomal dominant cerebellar ataxias: a study of 11 families, including descendants of &#x27;the Drew family of Walworth&#x27;.&lt;/strong&gt; Brain 105: 1-28, 1982.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/7066668/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;7066668&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1093/brain/105.1.1&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="7066668">Harding (1982)</a> proposed a clinical classification for autosomal dominant cerebellar ataxias (ADCAs). ADCA I was characterized by cerebellar ataxia in combination with various associated neurologic features, such as ophthalmoplegia, pyramidal and extrapyramidal signs, peripheral neuropathy, and dementia, among others. ADCA II was characterized by the cerebellar ataxia, associated neurologic features, and the additional findings of macular and retinal degeneration. ADCA III was a pure form of late-onset cerebellar ataxia without additional features. SCA1, SCA2 (<a href="/entry/183090">183090</a>), and SCA3, or Machado-Joseph disease (<a href="/entry/109150">109150</a>), are considered to be forms of ADCA I. These 3 disorders are characterized at the molecular level by CAG repeat expansions on 6p24-p23, 12q24.1, and 14q32.1, respectively. SCA7 (<a href="/entry/607640">607640</a>), caused by a CAG repeat expansion in the ATXN7 gene (<a href="/entry/607640">607640</a>) on chromosome 3p13-p12, is a form of ADCA II. SCA5 (<a href="/entry/600224">600224</a>), SCA31 (<a href="/entry/117210">117210</a>), SCA6 (<a href="/entry/183086">183086</a>), and SCA11 (<a href="/entry/600432">600432</a>) are associated with phenotypes most suggestive of ADCA III. However, <a href="#84" class="mim-tip-reference" title="Schelhaas, H. J., Ippel, P. F., Beemer, F. A., Hageman, G. &lt;strong&gt;Similarities and differences in the phenotype, genotype and pathogenesis of different spinocerebellar ataxias.&lt;/strong&gt; Europ. J. Neurol. 7: 309-314, 2000.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/10886315/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;10886315&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1046/j.1468-1331.2000.00067.x&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="10886315">Schelhaas et al. (2000)</a> noted that there is significant phenotypic overlap between different forms of SCA as well as significant phenotypic variability within each subtype. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=7066668+10886315" 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>Classic reviews of olivopontocerebellar atrophies and of inherited ataxias in general include those of <a href="#45" class="mim-tip-reference" title="Konigsmark, B. W., Weiner, L. P. &lt;strong&gt;The olivo-ponto-cerebellar atrophies: a review.&lt;/strong&gt; Medicine 49: 227-242, 1970.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/4910986/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;4910986&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1097/00005792-197005000-00003&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="4910986">Konigsmark and Weiner (1970)</a>, who identified 5 types of olivopontocerebellar atrophy, <a href="#5" class="mim-tip-reference" title="Berciano, J. &lt;strong&gt;Olivopontocerebellar atrophy: a review of 117 cases.&lt;/strong&gt; J. Neurol. Sci. 53: 253-272, 1982.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/7057212/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;7057212&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/0022-510x(82)90011-9&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="7057212">Berciano (1982)</a>, <a href="#32" class="mim-tip-reference" title="Harding, A. E. &lt;strong&gt;Clinical features and classification of inherited ataxias.&lt;/strong&gt; Adv. Neurol. 61: 1-14, 1993.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/8421960/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;8421960&lt;/a&gt;]" pmid="8421960">Harding (1993)</a>, <a href="#84" class="mim-tip-reference" title="Schelhaas, H. J., Ippel, P. F., Beemer, F. A., Hageman, G. &lt;strong&gt;Similarities and differences in the phenotype, genotype and pathogenesis of different spinocerebellar ataxias.&lt;/strong&gt; Europ. J. Neurol. 7: 309-314, 2000.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/10886315/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;10886315&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1046/j.1468-1331.2000.00067.x&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="10886315">Schelhaas et al. (2000)</a>, and <a href="#55" class="mim-tip-reference" title="Margolis, R. L. &lt;strong&gt;Dominant spinocerebellar ataxias: a molecular approach to classification, diagnosis, pathogenesis and the future.&lt;/strong&gt; Expert Rev. Molec. Diagn. 3: 715-732, 2003.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/14628900/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;14628900&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1586/14737159.3.6.715&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="14628900">Margolis (2003)</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=10886315+7057212+14628900+8421960+4910986" 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>Symptoms of SCA1 usually begin in the third or fourth decade of life, most often around age 30. In addition to cerebellar signs, there are upper motor neuron signs and extensor plantar responses. Involuntary choreiform movements may occur. Characteristic families with autosomal dominant spinocerebellar ataxia were reported by <a href="#58" class="mim-tip-reference" title="Menzel, P. &lt;strong&gt;Beitrag zur Kenntniss der hereditaeren Ataxie und Kleinhirnatrophie.&lt;/strong&gt; Arch. Psychiat. Nervenkr. 22: 160-190, 1891."None>Menzel (1891)</a>, <a href="#104" class="mim-tip-reference" title="Waggoner, R. W., Lowenberg, K., Speicher, K. G. &lt;strong&gt;Hereditary cerebellar ataxia: report of a case and genetic study.&lt;/strong&gt; Arch. Neurol. Psychiat. 39: 570-586, 1938."None>Waggoner et al. (1938)</a>, and <a href="#17" class="mim-tip-reference" title="Destunis, G. &lt;strong&gt;Die olivo-ponto-cerebellare Heredoataxie.&lt;/strong&gt; Z. Ges. Neurol. Psychiat. 177: 683-699, 1944."None>Destunis (1944)</a>.</p><p>Both the clinical and the pathologic pictures in the disorder described in a large kindred, known as Vandenberg, by <a href="#89" class="mim-tip-reference" title="Schut, J. W. &lt;strong&gt;Hereditary ataxia: clinical study through six generations.&lt;/strong&gt; Arch. Neurol. Psychiat. 63: 535-568, 1950."None>Schut (1950)</a> and by <a href="#88" class="mim-tip-reference" title="Schut, J. W., Haymaker, W. &lt;strong&gt;Hereditary ataxia: pathologic study of 5 cases of common ancestry.&lt;/strong&gt; J. Neuropath. Clin. Neurol. 1: 183-213, 1951.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/24541014/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;24541014&lt;/a&gt;]" pmid="24541014">Schut and Haymaker (1951)</a> were variable. Symptoms varied from those of spinocerebellar ataxia to spastic paraplegia. Identification as a form of OPCA was based on the presence of the major pathology in the inferior olivary nucleus and cerebellum with variable pontine involvement. The spinal cord showed variable loss of anterior motor horn cells and changes in the spinocerebellar tracts and posterior funiculus. Involvement of cranial nerves IX, X and XII was another distinguishing feature. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24541014" 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="#62" class="mim-tip-reference" title="Nino, H. E., Noreen, H. J., Dubey, D. P., Resch, J. A., Namboodiri, K., Elston, R. C., Yunis, E. J. &lt;strong&gt;A family with hereditary ataxia: HLA typing.&lt;/strong&gt; Neurology 30: 12-20, 1980.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/7188630/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;7188630&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1212/wnl.30.1.12&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="7188630">Nino et al. (1980)</a> reported a family in which the mean age of onset was 38.8 years. In addition to ataxia, affected persons showed lower bulbar palsies, hyperreflexia, scanning and explosive speech, incoordination, and, in some, slow motor-nerve conduction. Neuropathologic findings included atrophy of the cerebellum, pons and olives, degeneration of lower cranial nerve nuclei, and atrophy of the dorsal columns and spinocerebellar tracts. Deep tendon reflexes were increased and the Babinski sign was present. <a href="#69" class="mim-tip-reference" title="Pedersen, L. &lt;strong&gt;Hereditary ataxia in a large Danish pedigree.&lt;/strong&gt; Clin. Genet. 17: 385-393, 1980.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/7398110/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;7398110&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1111/j.1399-0004.1980.tb00168.x&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="7398110">Pedersen (1980)</a> reported an extensively affected Danish kindred. Clinical expression was highly variable so that different types of cerebellar ataxia had been diagnosed in individual members of the family. In at least 10, multiple sclerosis had been diagnosed. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=7398110+7188630" 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="#82" class="mim-tip-reference" title="Robitaille, Y., Schut, L., Kish, S. J. &lt;strong&gt;Structural and immunocytochemical features of olivopontocerebellar atrophy caused by the spinocerebellar ataxia type 1 (SCA-1) mutation define a unique phenotype.&lt;/strong&gt; Acta Neuropath. 90: 572-581, 1995.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/8615077/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;8615077&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1007/BF00318569&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="8615077">Robitaille et al. (1995)</a> compared the neuropathologic features of SCA1 with those reported for SCA2 and SCA3. Unlike the findings in SCA2 and SCA3, brains in SCA1 show almost no neuronal loss from the pars compacta of the substantia nigra or from the locus ceruleus, whereas there is severe atrophy of the dentatorubral pathways. Both SCA1 and SCA2 show severe loss of Purkinje cell and degeneration of the olivocerebellar pathways, which is not seen in SCA3. All 3 disorders share severe atrophy of the nucleus pontis, sparing of the retina and optic nerve, and marked atrophy of Clarke columns and the spinocerebellar tracts. Argyrophilic glial inclusions have not been reported in any of these disorders. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8615077" 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 19 (70%) of 27 patients with confirmed SCA type 1, 2, 3, 6, or 7, <a href="#101" class="mim-tip-reference" title="van de Warrenburg, B. P. C., Notermans, N. C., Schelhaas, H. J., van Alfen, N., Sinke, R. J., Knoers, N. V. A. M., Zwarts, M. J., Kremer, B. P. H. &lt;strong&gt;Peripheral nerve involvement in spinocerebellar ataxias.&lt;/strong&gt; Arch. Neurol. 61: 257-261, 2004.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/14967775/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;14967775&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1001/archneur.61.2.257&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="14967775">van de Warrenburg et al. (2004)</a> found electrophysiologic evidence of peripheral nerve involvement. Eight patients (30%) had findings compatible with a dying-back axonopathy, whereas 11 patients (40%) had findings consistent with a primary neuronopathy involving dorsal root ganglion and/or anterior horn cells; the 2 types were clinically almost indistinguishable. Four of 5 patients with SCA1 had a neuronopathy and 1 had a sensorimotor axonopathy. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14967775" 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 autopsied brain from 2 patients with autosomal dominant OPCA, <a href="#70" class="mim-tip-reference" title="Perry, T. L., Currier, R. D., Hansen, S., MacLean, J. &lt;strong&gt;Aspartate-taurine imbalance in dominantly inherited olivopontocerebellar atrophy.&lt;/strong&gt; Neurology 27: 257-261, 1977.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/557761/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;557761&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1212/wnl.27.3.257&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="557761">Perry et al. (1977)</a> found markedly reduced aspartic acid and markedly elevated taurine content. The patients were from the family reported by <a href="#15" class="mim-tip-reference" title="Currier, R. D., Glover, G., Jackson, J. F., Tipton, A. C. &lt;strong&gt;Spinocerebellar ataxia: study of a large kindred. I. General information and genetics.&lt;/strong&gt; Neurology 22: 1040-1043, 1972.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/4673259/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;4673259&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1212/wnl.22.9.1040&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="4673259">Currier et al. (1972)</a>, in which linkage to HLA was discovered by <a href="#34" class="mim-tip-reference" title="Jackson, J. F., Currier, R. D., Terasaki, P. I., Morton, N. E. &lt;strong&gt;Spinocerebellar ataxia and HLA linkage: risk prediction by HLA typing.&lt;/strong&gt; New Eng. J. Med. 296: 1138-1141, 1977.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/857157/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;857157&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1056/NEJM197705192962003&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="857157">Jackson et al. (1977)</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=4673259+557761+857157" 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="#71" class="mim-tip-reference" title="Plaitakis, A., Nicklas, W. J., Desnick, R. J. &lt;strong&gt;Glutamate dehydrogenase deficiency in three patients with spinocerebellar syndrome.&lt;/strong&gt; Ann. Neurol. 7: 297-303, 1980.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/7377755/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;7377755&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ana.410070403&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="7377755">Plaitakis et al. (1980)</a> found deficiency of glutamate dehydrogenase (GLUD1; <a href="/entry/138130">138130</a>) in 3 patients with a 'spinocerebellar syndrome.' One was a 19-year-old male with juvenile onset of spinocerebellar and extrapyramidal manifestations. The others were 2 sibs, aged 64 and 71, with adult onset of spinocerebellar symptoms. The authors were led to this work by the fact that the nicotinamide antagonist 3-acetylpyridine produces ataxia in rats and CNS changes like those of OPCA IV. Four nicotinamide-adenine dinucleotide phosphate-requiring enzymes were measured. GDH may have an important role in metabolism of glutamate, a putative neurotransmitter in cerebellum, brainstem and spinal cord. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7377755" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#94" class="mim-tip-reference" title="Sorbi, S., Tonini, S., Giannini, E., Piacentini, S., Marini, P., Amaducci, L. &lt;strong&gt;Abnormal platelet glutamate dehydrogenase activity and activation in dominant and nondominant olivopontocerebellar atrophy.&lt;/strong&gt; Ann. Neurol. 19: 239-245, 1986.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/3963768/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;3963768&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ana.410190304&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="3963768">Sorbi et al. (1986)</a> found a 50 to 60% reduction in platelet GLUD activity in 3 patients out of 4 with a so-called nondominant, i.e., sporadic or recessive, form of adult-onset OPCA and in father and son with a dominant form of OPCA. In another family, affected members (but not unaffected members), despite normal GDH activity, showed lack of activation of GDH by ADP in either the presence or the absence of Triton. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=3963768" 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="#52" class="mim-tip-reference" title="Lucotte, G., Semonin, O., Mercier, G. &lt;strong&gt;Presymptomatic testing for autosomal dominant spinocerebellar ataxia type 1 in a French family.&lt;/strong&gt; Genet. Counsel. 12: 173-175, 2001.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/11491315/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;11491315&lt;/a&gt;]" pmid="11491315">Lucotte et al. (2001)</a> demonstrated the feasibility of presymptomatic diagnosis in spinocerebellar ataxia-1. They studied a family in which the mean age of onset of the disorder was 38 years. Hitherto, presymptomatic testing for late-onset autosomal dominant disorders had largely been confined to Huntington disease, which is a genetically homogeneous entity. The same protocol could be applied to dominantly inherited ataxias, with the additional requirement that the SCA type of the disorder must be determined in the family at risk. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11491315" 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="#34" class="mim-tip-reference" title="Jackson, J. F., Currier, R. D., Terasaki, P. I., Morton, N. E. &lt;strong&gt;Spinocerebellar ataxia and HLA linkage: risk prediction by HLA typing.&lt;/strong&gt; New Eng. J. Med. 296: 1138-1141, 1977.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/857157/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;857157&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1056/NEJM197705192962003&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="857157">Jackson et al. (1977)</a> concluded that a form of spinocerebellar atrophy is linked with HLA on chromosome 6; the lod score was 3.15 for a recombination fraction of about 12. <a href="#60" class="mim-tip-reference" title="Moller, E., Hindfelt, B., Olsson, J. E. &lt;strong&gt;HLA-determination in families with hereditary ataxia.&lt;/strong&gt; Tissue Antigens 12: 357-366, 1978.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/85351/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;85351&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1111/j.1399-0039.1978.tb01345.x&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="85351">Moller et al. (1978)</a> found further evidence in support of this linkage. In an extensively affected Prussian family, <a href="#62" class="mim-tip-reference" title="Nino, H. E., Noreen, H. J., Dubey, D. P., Resch, J. A., Namboodiri, K., Elston, R. C., Yunis, E. J. &lt;strong&gt;A family with hereditary ataxia: HLA typing.&lt;/strong&gt; Neurology 30: 12-20, 1980.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/7188630/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;7188630&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1212/wnl.30.1.12&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="7188630">Nino et al. (1980)</a> also found linkage to HLA. The maximum lod score was 1.97 at a male recombination fraction of 0.18 and a female recombination fraction of 0.36. When combined with data from other families, these results yielded a lod score of 4.681 at a recombination frequency of 0.22. <a href="#61" class="mim-tip-reference" title="Morton, N. E., Lalouel, J.-M., Jackson, J. F., Currier, R. D., Yee, S. &lt;strong&gt;Linkage studies in spinocerebellar ataxia (SCA).&lt;/strong&gt; Am. J. Med. Genet. 6: 251-257, 1980.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/7424977/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;7424977&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ajmg.1320060309&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="7424977">Morton et al. (1980)</a> reviewed linkage data on 13 kindreds. For linkage with HLA, they found a lod score of 5.53 at recombination rates of 0.223 in males and 0.327 in females. Nine of the 13 pedigrees, which appeared to have typical OPCA I, showed recombination rates of 0.150 in males and 0.300 in females. The remaining 4 pedigrees were clinically atypical or included discrepant data and gave no evidence of linkage. They suggested that linkage evidence may be decisive in delineation of the confused category of ataxias. In addition to the typical OPCA I of Menzel, other allelic forms of ataxia may exist, e.g., that in the Danish pedigree with pyramidal lesions and dementia (<a href="#68" class="mim-tip-reference" title="Pedersen, L., Platz, P., Ryder, L. P., Lam, L., Dissing, J. &lt;strong&gt;A linkage study of hereditary ataxias and related disorders: evidence of heterogeneity of dominant cerebellar ataxia.&lt;/strong&gt; Hum. Genet. 54: 371-383, 1980.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/6772543/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;6772543&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1007/BF00291585&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="6772543">Pedersen et al., 1980</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=857157+7424977+6772543+7188630+85351" 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 connection with other studies of a large family, the Schut-Swier kindred (<a href="#89" class="mim-tip-reference" title="Schut, J. W. &lt;strong&gt;Hereditary ataxia: clinical study through six generations.&lt;/strong&gt; Arch. Neurol. Psychiat. 63: 535-568, 1950."None>Schut, 1950</a>), <a href="#27" class="mim-tip-reference" title="Haines, J. L., Schut, L. J., Weitkamp, L. R., Thayer, M., Anderson, V. E. &lt;strong&gt;Spinocerebellar ataxia in a large kindred: age at onset, reproduction, and genetic linkage studies.&lt;/strong&gt; Neurology 34: 1542-1548, 1984.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/6504324/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;6504324&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1212/wnl.34.12.1542&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="6504324">Haines et al. (1984)</a> concluded that there was linkage with HLA (maximum lod score = 3.71 at theta = 0.18). <a href="#28" class="mim-tip-reference" title="Haines, J. L., Trofatter, J. A. &lt;strong&gt;Multipoint linkage analysis of spinocerebellar ataxia and markers on chromosome 6.&lt;/strong&gt; Genet. Epidemiol. 3: 399-405, 1986.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/3468044/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;3468044&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/gepi.1370030604&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="3468044">Haines and Trofatter (1986)</a> placed ATXN1 telomeric to HLA-A. Using a DNA marker (D6S7) to study the Schut-Swier kindred, <a href="#78" class="mim-tip-reference" title="Rich, S. S., Wilkie, P., Schut, L., Vance, G., Orr, H. T. &lt;strong&gt;Spinocerebellar ataxia: localization of an autosomal dominant locus between 2 markers on human chromosome 6.&lt;/strong&gt; Am. J. Hum. Genet. 41: 524-531, 1987.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/3477955/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;3477955&lt;/a&gt;]" pmid="3477955">Rich et al. (1987)</a> demonstrated linkage between the SCA locus and HLA-A. The observed linkage indicated that the position of the gene was about 15 cM telomeric of HLA-A on 6p. <a href="#77" class="mim-tip-reference" title="Rich, S. S., Orr, H. T. &lt;strong&gt;A linkage map of the short arm of human chromosome 6: location of the gene for autosomal dominant ataxia (SCA1). (Abstract)&lt;/strong&gt; Cytogenet. Cell Genet. 51: 1066, 1989."None>Rich and Orr (1989)</a> and <a href="#65" class="mim-tip-reference" title="Orr, H. T., Rich, S. S. &lt;strong&gt;Localization of the autosomal dominant, HLA-linked spinocerebellar ataxia (SCA1) locus in two kindreds within a subregion of chromosome 6p. (Abstract)&lt;/strong&gt; Am. J. Hum. Genet. 45 (suppl.): A155, 1989."None>Orr and Rich (1989)</a> studied the linkage of SCA1 in 2 '7-generation kindreds' (the Schut-Swier kindred) with the conclusion that the locus is distal to HLA and proximal to F13A. Three-point linkage analysis on the 2 kindreds combined favored the gene order HLAA--ATXN1--F13A--6pter over the second most likely order ATXN1--HLAA--F13A by odds of 9 million to 1. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=6504324+3477955+3468044" 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="#119" class="mim-tip-reference" title="Zoghbi, H. Y., Pollack, M. S., Ferrell, R. E., Daiger, S. P., Lyons, L. A., O&#x27;Brien, W. E., Beaudet, A. L. &lt;strong&gt;Linkage studies in spinocerebellar ataxia (SCA1). (Abstract)&lt;/strong&gt; Cytogenet. Cell Genet. 46: 727, 1987."None>Zoghbi et al. (1987)</a> demonstrated HLA linkage in a large black kindred with variable age of onset. Although the mean age of onset was 34 years, in 6 of 41 affected individuals onset was under 15 years of age and was accompanied by the unique clinical features of mental retardation and rapid progression of disease. Linkage to HLA showed a lod score of 5.83 at a recombination fraction of 0.12. Linkage to HLA-DR and HLA-DQ showed lod scores of 3.39 and 2.51 at recombination fractions of 0.15 and 0.17, respectively. This suggested that the SCA1 locus is distal to the MHC region. However, Zoghbi et al. (<a href="#120" class="mim-tip-reference" title="Zoghbi, H. Y., Pollack, M. S., Lyons, L. A., Ferrell, R. E., Daiger, S. P., Beaudet, A. L. &lt;strong&gt;Spinocerebellar ataxia: variable age of onset and linkage to human leukocyte antigen in a large kindred.&lt;/strong&gt; Ann. Neurol. 23: 580-584, 1988.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/3165612/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;3165612&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ana.410230609&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="3165612">1988</a>, <a href="#122" class="mim-tip-reference" title="Zoghbi, H. Y., Sandkuyl, L. A., Ott, J., Daiger, S. P., Pollack, M., O&#x27;Brien, W. E., Beaudet, A. L. &lt;strong&gt;Assignment of autosomal dominant spinocerebellar ataxia (SCA1) centromeric to the HLA region on the short arm of chromosome 6, using multilocus linkage analysis.&lt;/strong&gt; Am. J. Hum. Genet. 44: 255-263, 1989.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/2563195/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;2563195&lt;/a&gt;]" pmid="2563195">1989</a>), by multilocus linkage analysis, obtained results indicating that the SCA1 gene locus is centromeric to HLA-DP, with odds of 46:1 favoring this most likely location over the second most likely location, i.e., telomeric to the HLA complex but proximal to F13A (<a href="/entry/134570">134570</a>). This appears to indicate localization in the 6p21.3-p21.2 region. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=3165612+2563195" 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="#105" class="mim-tip-reference" title="Wakisaka, A., Sasaki, H., Taakenouchi, T., Katoh, T., Yoshida, M. C., Hamada, T., Shima, K., Matsuura, T., Tashiro, K. &lt;strong&gt;Linkage study of dominantly inherited spinocerebellar degeneration. (Abstract)&lt;/strong&gt; Cytogenet. Cell Genet. 51: 1101, 1989."None>Wakisaka et al. (1989)</a> and <a href="#93" class="mim-tip-reference" title="Shrimpton, A. E., Vijayalaxmi, (NI), Evans, H. J. &lt;strong&gt;Dominantly inherited spinocerebellar ataxia (SCA1) linkage studies. (Abstract)&lt;/strong&gt; Cytogenet. Cell Genet. 51: 1080, 1989."None>Shrimpton et al. (1989)</a> described linkage studies in families with autosomal dominant ataxia. In 2 large Italian pedigrees with HLA-linked spinocerebellar ataxia, <a href="#19" class="mim-tip-reference" title="Frontali, M., Iodice, C., Lulli, P., Spadaro, M., Cappellacci, S., Giunti, P., Malaspina, P., Morellini, M., Morocutti, C., Novelletto, A., Persichetti, F., Trabace, S., Anastasi, R., Terrenato, L. &lt;strong&gt;Spinocerebellar ataxia (SCA1) in two large Italian kindreds: evidence in favour of a locus position distal to GLO1 and the HLA cluster.&lt;/strong&gt; Ann. Hum. Genet. 55: 7-15, 1991.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/1675045/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;1675045&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1111/j.1469-1809.1991.tb00393.x&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="1675045">Frontali et al. (1991)</a> excluded linkage with F13A at less than 5% recombination and with GLO1 at less than 10% recombination. The results favored the view that ATXN1 is distal to HLA. Thus, they favored the order cen--GLO1--HLA--ATXN1--tel. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1675045" 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>Studies of 2 large kindreds led <a href="#75" class="mim-tip-reference" title="Ranum, L. P. W., Duvick, L. A., Rich, S. S., Schut, L. J., Litt, M., Orr, H. T. &lt;strong&gt;Localization of the autosomal dominant HLA-linked spinocerebellar ataxia (SCA1) locus, in two kindreds, within an 8-cM subregion of chromosome 6p.&lt;/strong&gt; Am. J. Hum. Genet. 49: 31-41, 1991.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/1676561/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;1676561&lt;/a&gt;]" pmid="1676561">Ranum et al. (1991)</a> to conclude that ATXN1 is unequivocally located distal to HLA and proximal to F13A. Furthermore, ATXN1 was found to lie centromeric and genetically very close to the highly informative D6S89 marker. In the 2 kindreds, 1 recombinant was observed between D6S89 and ATXN1, resulting in a recombination fraction of 0.014. Linkage analysis in the Schut-Swier kindred led <a href="#114" class="mim-tip-reference" title="Wilkie, P. J., Schut, L. J., Rich, S. S. &lt;strong&gt;Spinocerebellar ataxia: multipoint linkage analysis of genes associated with the disease locus.&lt;/strong&gt; Hum. Genet. 87: 405-408, 1991.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/1879827/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;1879827&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1007/BF00197157&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="1879827">Wilkie et al. (1991)</a> likewise to conclude that ATXN1 is telomeric to HLA-A and lies between HLA-A and F13A. The maximum pairwise lod score for linkage between ATXN1 and HLA-A was 8.52; male theta = 0.10, female theta = 0.22. In a 5-generation American black family, <a href="#38" class="mim-tip-reference" title="Keats, B. J. B., Pollack, M. S., McCall, A., Wilensky, M. A., Ward, L. J., Lu, M., Zoghbi, H. Y. &lt;strong&gt;Tight linkage of the gene for spinocerebellar ataxia to D6S89 on the short arm of chromosome 6 in a kindred for which close linkage to both HLA and F13A1 is excluded.&lt;/strong&gt; Am. J. Hum. Genet. 49: 972-977, 1991.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/1928103/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;1928103&lt;/a&gt;]" pmid="1928103">Keats et al. (1991)</a> excluded close linkage between the SCA1 locus and both HLA and F13A1; lod scores for all locations of the disease locus between these 2 loci were less than -1.4. However, the disease locus was found to be closely linked to a microsatellite polymorphism, D6S89, which is situated between HLA and F13A1; maximum lod = 4.90 at theta = 0.0, both in males and in females. The findings indicated that exclusion of close linkage to HLA and F13A1 in a kindred with spinocerebellar ataxia does not rule out the possibility that the disease locus is in fact on 6p. Accordingly, all families segregating a dominantly inherited ataxia should be evaluated for linkage to D6S89. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=1676561+1928103+1879827" 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="#118" class="mim-tip-reference" title="Zoghbi, H. Y., Jodice, C., Sandkuijl, L. A., Kwiatkowski, T. J., Jr., McCall, A. E., Huntoon, S. A., Lulli, P., Spadaro, M., Litt, M., Cann, H. M., Frontali, M., Terrenato, L. &lt;strong&gt;The gene for autosomal dominant spinocerebellar ataxia (SCA1) maps telomeric to the HLA complex and is closely linked to the D6S89 locus in three large kindreds.&lt;/strong&gt; Am. J. Hum. Genet. 49: 23-30, 1991.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/2063871/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;2063871&lt;/a&gt;]" pmid="2063871">Zoghbi et al. (1991)</a> tested for linkage with 2 highly informative dinucleotide repeat sequences in 3 large kindreds, 1 in Houston, Texas, and 2 in Calabria. Pairwise linkage analysis of ATXN1 and D6S89 revealed a maximum lod score of 5.86 in the Houston kindred and of 8.08 in the Calabrian kindreds, at recombination fractions of 0.050 and 0.022, respectively. A maximum pairwise lod score of 4.54 at recombination frequency of 0.100 was obtained for ATXN1 and TCTE1 (<a href="/entry/186975">186975</a>) in the Houston pedigree but no evidence of linkage was detected between these loci in the case of the Calabrian kindreds. Multilocus linkage analysis supported strongly localization of ATXN1 telomeric to HLA. <a href="#103" class="mim-tip-reference" title="Volz, A., Fonatsch, C., Ziegler, A. &lt;strong&gt;Regional mapping of the gene for autosomal dominant spinocerebellar ataxia (SCA1) by localizing the closely linked D6S89 locus to 6p24.2-p23.05.&lt;/strong&gt; Cytogenet. Cell Genet. 60: 37-39, 1992.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/1582256/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;1582256&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1159/000133291&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="1582256">Volz et al. (1992)</a> studied D6S89 in mutant cell lines with cytogenetically detectable interstitial 6p deletions to map the marker to 6p24.2-p23.05. This would place ATXN1 in the 6p24-p23 segment. In 4 of 10 French families with autosomal dominant cerebellar ataxia type 1, <a href="#39" class="mim-tip-reference" title="Khati, C., Stevanin, G., Durr, A., Chneiweiss, H., Belal, S., Seck, A., Cann, H., Brice, A., Agid, Y. &lt;strong&gt;Genetic heterogeneity of autosomal dominant cerebellar ataxia type 1: clinical and genetic analysis of 10 French families.&lt;/strong&gt; Neurology 43: 1131-1137, 1993.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/8170557/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;8170557&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1212/wnl.43.6.1131&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="8170557">Khati et al. (1993)</a> found very close linkage of the neurologic disorder to the D6S89 marker, with no evidence of recombination. Linkage to D6S89 was excluded in the other 6. After the cloning of the ataxin-1 gene (<a href="/entry/601556">601556</a>), <a href="#102" class="mim-tip-reference" title="Volz, A., Boyle, J. M., Cann, H. M., Cottingham, R. W., Orr, H. T., Ziegler, A. &lt;strong&gt;Report of the second international workshop on human chromosome 6.&lt;/strong&gt; Genomics 21: 464, 1994.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/8088851/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;8088851&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1006/geno.1994.1302&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="8088851">Volz et al. (1994)</a> reported that it was mapped to 6p23 by in situ hybridization. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=8170557+2063871+1582256+8088851" 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="#47" class="mim-tip-reference" title="Kwiatkowski, T. J., Jr., Orr, H. T., Banfi, S., McCall, A. E., Jodice, C., Persichetti, F., Novelletto, A., LeBorgne-DeMarquoy, F., Duvick, L. A., Frontali, M., Subramony, S. H., Beaudet, A. L., Terrenato, L., Zoghbi, H. Y., Ranum, L. P. W. &lt;strong&gt;The gene for autosomal dominant spinocerebellar ataxia (SCA1) maps centromeric to D6S89 and shows no recombination, in nine large kindreds, with a dinucleotide repeat at the AM10 locus.&lt;/strong&gt; Am. J. Hum. Genet. 53: 391-400, 1993.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/8101039/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;8101039&lt;/a&gt;]" pmid="8101039">Kwiatkowski et al. (1993)</a> reported a new marker, AM10GA, that demonstrated no recombination with ATXN1; maximum lod = 42.14 at theta = 0. Linkage analysis and analysis of recombination events confirmed that ATXN1 maps centromeric to D6S89 (which showed a maximum lod score of 67.58 at a maximum recombination fraction of 0.004 with ATXN1). They cited multipoint linkage analysis indicating that ATXN1 is telomeric to HLA. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8101039" 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 7 families from a Siberian founder population with autosomal dominant SCA, <a href="#54" class="mim-tip-reference" title="Lunkes, A., Goldfarb, L. G., Platonov, F. A., Alexeev, V. P., Duenas-Barajas, E., Gajdusek, D. C., Auburger, G. &lt;strong&gt;Autosomal dominant spinocerebellar ataxia (SCA) in a Siberian founder population: assignment to the SCA1 locus.&lt;/strong&gt; Exp. Neurol. 126: 310-312, 1994.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/7925830/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;7925830&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1006/exnr.1994.1070&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="7925830">Lunkes et al. (1994)</a> demonstrated allelic association of the disease with polymorphisms known to flank the SCA1 locus on 6p. The association was absolute in the case of microsatellite D6S274, whereas an allele switch was observed for D6S89 in 2 families, suggesting a historic recombinant. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7925830" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="heterogeneity" class="mim-anchor"></a>
<h4 href="#mimHeterogeneityFold" id="mimHeterogeneityToggle" class="mimTriangleToggle" style="cursor: pointer;" data-toggle="collapse">
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<strong>Heterogeneity</strong>
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<div id="mimHeterogeneityFold" class="collapse in mimTextToggleFold">
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<p><strong><em>Genetic Heterogeneity</em></strong></p><p>
<a href="#43" class="mim-tip-reference" title="Koeppen, A. H., Goedde, H. W., Hirth, L., Benkmann, H.-G., Hiller, C. &lt;strong&gt;Genetic linkage in hereditary ataxia. (Letter)&lt;/strong&gt; Lancet 1: 92-93, 1980.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/6101435/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;6101435&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/s0140-6736(80)90514-0&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="6101435">Koeppen et al. (1980)</a> found no evidence of linkage to chromosome 6 markers in 5 families with 'dominant ataxia' and 3 with 'recessive ataxia' (Friedreich disease). <a href="#46" class="mim-tip-reference" title="Kumar, D., Blank, C. E., Gelsthorpe, K. &lt;strong&gt;Hereditary cerebellar ataxia and genetic linkage with HLA.&lt;/strong&gt; Hum. Genet. 72: 327-332, 1986.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/3457760/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;3457760&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1007/BF00290959&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="3457760">Kumar et al. (1986)</a> found negative lod scores for linkage to HLA in all of 5 families in which at least 3 generations were affected with autosomal dominant SCA. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=6101435+3457760" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>By linkage studies in families with Machado-Joseph disease (MJD; <a href="/entry/109150">109150</a>), <a href="#10" class="mim-tip-reference" title="Carson, W. J., Radvany, J., Farrer, L. A., Vincent, D., Rosenberg, R. N., MacLeod, P. M., Rouleau, G. A. &lt;strong&gt;The Machado-Joseph disease locus is different from the spinocerebellar ataxia locus (SCA1).&lt;/strong&gt; Genomics 13: 852-855, 1992.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/1639414/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;1639414&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/0888-7543(92)90168-r&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="1639414">Carson et al. (1992)</a> demonstrated conclusively that MJD cannot be allelic to SCA1. A clinically indistinguishable form of spinocerebellar ataxia, SCA2, occurs in high frequency in Cuba. <a href="#53" class="mim-tip-reference" title="Lunkes, A., Gispert, S., Enczmann, J., Auburger, G. &lt;strong&gt;Molecular heterogeneity of autosomal dominant cerebellar ataxia: analysis of flanking microsatellites of the spinocerebellar ataxia 1 locus in a northern European family unequivocally demonstrates non-linkage.&lt;/strong&gt; Hum. Genet. 91: 362-366, 1993.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/8099059/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;8099059&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1007/BF00217357&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="8099059">Lunkes et al. (1993)</a> excluded linkage to 6p in a 5-generation Danish family. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=8099059+1639414" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="pathogenesis" class="mim-anchor"></a>
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<strong>Pathogenesis</strong>
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</h4>
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<p><a href="#64" class="mim-tip-reference" title="Orr, H. T., Chung, M., Banfi, S., Kwiatkowski, T. J., Jr., Servadio, A., Beaudet, A. L., McCall, A. E., Duvick, L. A., Ranum, L. P. W., Zoghbi, H. Y. &lt;strong&gt;Expansion of an unstable trinucleotide CAG repeat in spinocerebellar ataxia type 1.&lt;/strong&gt; Nature Genet. 4: 221-226, 1993.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/8358429/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;8358429&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1038/ng0793-221&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="8358429">Orr et al. (1993)</a> demonstrated that the basic genetic defect in spinocerebellar ataxia-1 consists of expansion of a trinucleotide CAG repeat. They showed that the repeat is present not only in genomic DNA but also in a 10-kb mRNA transcript. <a href="#2" class="mim-tip-reference" title="Banfi, S., Servadio, A., Chung, M., Kwiatkowski, T. J., Jr., McCall, A. E., Duvick, L. A., Shen, Y., Roth, E. J., Orr, H. T., Zoghbi, H. Y. &lt;strong&gt;Identification and characterization of the gene causing type 1 spinocerebellar ataxia.&lt;/strong&gt; Nature Genet. 7: 513-520, 1994.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/7951322/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;7951322&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1038/ng0894-513&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="7951322">Banfi et al. (1994)</a> identified the gene, termed ataxin-1. This was the fifth example of a pathologic state resulting from expansion of an unstable trinucleotide repeat. The others, in chronologic order of discovery, were the fragile X syndrome (<a href="/entry/300624">300624</a>), myotonic dystrophy (<a href="/entry/160900">160900</a>), Kennedy spinal and bulbar muscular atrophy (<a href="/entry/313200">313200</a>), and Huntington disease (<a href="/entry/143100">143100</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=7951322+8358429" 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>After the lesion in SCA1 was found to involve an expanded trinucleotide repeat, this lesion was demonstrated in affected members of the Schut-Swier kindred, thus proving that it was, in fact, SCA1 (<a href="#112" class="mim-tip-reference" title="Wexler, N. S. &lt;strong&gt;Personal Communication.&lt;/strong&gt; New York, N. Y. 11/1993."None>Wexler, 1993</a>).</p><p>By immunoblot analysis, <a href="#91" class="mim-tip-reference" title="Servadio, A., Koshy, B., Armstrong, D., Antalffy, B., Orr, H. T., Zoghbi, H. Y. &lt;strong&gt;Expression analysis of the ataxin-1 protein in tissues from normal and spinocerebellar ataxia type 1 individuals.&lt;/strong&gt; Nature Genet. 10: 94-98, 1995.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/7647801/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;7647801&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1038/ng0595-94&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="7647801">Servadio et al. (1995)</a> demonstrated that a mutant protein that varies in its electrophoretic migration properties according to the size of the CAG repeat is detected in cultured cells and tissues from SCA1 individuals along with the wildtype protein. The ataxin-1 protein has a nuclear localization in all normal and SCA1 brain regions examined, but a cytoplasmic localization of ataxin-1 was also observed in cerebellar Purkinje cells, leading to progressive degeneration of Purkinje cells. The data showed that the expanded ATXN1 alleles are also translated into proteins of apparently normal stability and distribution. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7647801" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#66" class="mim-tip-reference" title="Orr, H. T., Zoghbi, H. Y. &lt;strong&gt;Toward understanding polyglutamine-induced neurological disease in spinocerebellar ataxia type 1.&lt;/strong&gt; Cold Spring Harbor Symp. Quant. Biol. 61: 649-657, 1996.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/9246491/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;9246491&lt;/a&gt;]" pmid="9246491">Orr and Zoghbi (1996)</a> reviewed the work elucidating polyglutamine-induced neurologic disease in SCA1. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9246491" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#13" class="mim-tip-reference" title="Cummings, C. J., Mancini, M. A., Antalffy, B., DeFranco, D. B., Orr, H. T., Zoghbi, H. Y. &lt;strong&gt;Chaperone suppression of aggregation and altered subcellular proteasome localization imply protein misfolding in SCA1.&lt;/strong&gt; Nature Genet. 19: 148-154, 1998.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/9620770/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;9620770&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1038/502&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="9620770">Cummings et al. (1998)</a> found colocalization of the 20S proteasome (see <a href="/entry/602175">602175</a>) and chaperone HSJ2 (<a href="/entry/602837">602837</a>), a member of the Hsp40 family, with large nuclear inclusions of ataxin-1 in brain neurons of patients with SCA1 and in mice transgenic for a mutant ATXN1 allele containing 82 glutamines. In these nuclear inclusions, there was also faint staining for Hsc70 (HSPA8; <a href="/entry/600816">600816</a>), a member of the Hsp70 chaperone family. Similar colocalization was seen in HeLa cells transfected with ataxin-1. In the transfected HeLa cells, unlike in the brains, there was apparent induction of Hsc70 chaperone. Overexpression of HSJ2 in these cells reduced aggregation of ataxin-1, suggesting a possible therapeutic strategy. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9620770" 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="#48" class="mim-tip-reference" title="Lam, Y. C., Bowman, A. B., Jafar-Nejad, P., Lim, J., Richman, R., Fryer, J. D., Hyun, E. D., Duvick, L. A., Orr, H. T., Botas, J., Zoghbi, H. Y. &lt;strong&gt;ATAXIN-1 interacts with the repressor Capicua in its native complex to cause SCA1 neuropathology.&lt;/strong&gt; Cell 127: 1335-1347, 2006.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/17190598/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;17190598&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/j.cell.2006.11.038&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="17190598">Lam et al. (2006)</a> examined soluble protein complexes from mouse cerebellum and found that the majority of wildtype and expanded Atxn1 assembles into large stable complexes containing the transcriptional repressor Capicua (CIC; <a href="/entry/612082">612082</a>). Atxn1 directly bound Cic and modulated Cic repressor activity in Drosophila and mammalian cells, and its loss decreased the steady state level of Cic. Interestingly, the S776A mutation, which abrogates the neurotoxicity of expanded Atxn1 (<a href="#18" class="mim-tip-reference" title="Emamian, E. S., Kaytor, M. D., Duvick, L. A., Zu, T., Tousey, S. K., Zoghbi, H. Y., Clark, H. B., Orr, H. T. &lt;strong&gt;Serine 776 of ataxin-1 is critical for polyglutamine-induced disease in SCA1 transgenic mice.&lt;/strong&gt; Neuron 38: 375-387, 2003.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/12741986/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;12741986&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/s0896-6273(03)00258-7&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="12741986">Emamian et al., 2003</a>), substantially reduced the association of mutant Atxn1 with Cic in vivo. <a href="#48" class="mim-tip-reference" title="Lam, Y. C., Bowman, A. B., Jafar-Nejad, P., Lim, J., Richman, R., Fryer, J. D., Hyun, E. D., Duvick, L. A., Orr, H. T., Botas, J., Zoghbi, H. Y. &lt;strong&gt;ATAXIN-1 interacts with the repressor Capicua in its native complex to cause SCA1 neuropathology.&lt;/strong&gt; Cell 127: 1335-1347, 2006.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/17190598/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;17190598&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/j.cell.2006.11.038&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="17190598">Lam et al. (2006)</a> concluded that their data provided insight into the function of Atxn1 and suggested that the neuropathology of SCA1, caused by expansion of the ATXN1 polyglutamine tract, depends on native, not novel, protein interactions. <a href="#48" class="mim-tip-reference" title="Lam, Y. C., Bowman, A. B., Jafar-Nejad, P., Lim, J., Richman, R., Fryer, J. D., Hyun, E. D., Duvick, L. A., Orr, H. T., Botas, J., Zoghbi, H. Y. &lt;strong&gt;ATAXIN-1 interacts with the repressor Capicua in its native complex to cause SCA1 neuropathology.&lt;/strong&gt; Cell 127: 1335-1347, 2006.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/17190598/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;17190598&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/j.cell.2006.11.038&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="17190598">Lam et al. (2006)</a> found that the majority of CIC associates with ATXN1 in vivo and that ATXN1 binds CIC through an 8-amino-acid sequence conserved across species. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=17190598+12741986" 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="#50" class="mim-tip-reference" title="Lim, J., Crespo-Barreto, J., Jafar-Nejad, P., Bowman, A. B., Richman, R., Hill, D. E., Orr, H. T., Zoghbi, H. Y. &lt;strong&gt;Opposing effects of polyglutamine expansion on native protein complexes contribute to SCA1.&lt;/strong&gt; Nature 452: 713-718, 2008.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/18337722/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;18337722&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=18337722[PMID]&amp;report=imagesdocsum&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed Image&#x27;, &#x27;domain&#x27;: &#x27;ncbi.nlm.nih.gov&#x27;})&quot;&gt;images&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1038/nature06731&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="18337722">Lim et al. (2008)</a> demonstrated that the expanded polyglutamine tract of ATXN1 differentially affects the function of the host protein in the context of different endogenous protein complexes. Polyglutamine expansion in ATXN1 favors the formation of a particular protein complex containing RBM17 (<a href="/entry/606935">606935</a>), contributing to SCA1 neuropathology by means of a gain-of-function mechanism. Concomitantly, polyglutamine expansion attenuates the formation and function of another protein complex containing ATXN1 and capicua, contributing to SCA1 through a partial loss-of-function mechanism. <a href="#50" class="mim-tip-reference" title="Lim, J., Crespo-Barreto, J., Jafar-Nejad, P., Bowman, A. B., Richman, R., Hill, D. E., Orr, H. T., Zoghbi, H. Y. &lt;strong&gt;Opposing effects of polyglutamine expansion on native protein complexes contribute to SCA1.&lt;/strong&gt; Nature 452: 713-718, 2008.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/18337722/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;18337722&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=18337722[PMID]&amp;report=imagesdocsum&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed Image&#x27;, &#x27;domain&#x27;: &#x27;ncbi.nlm.nih.gov&#x27;})&quot;&gt;images&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1038/nature06731&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="18337722">Lim et al. (2008)</a> concluded that their model provides mechanistic insight into the molecular pathogenesis of SCA1 as well as other polyglutamine diseases. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18337722" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#35" class="mim-tip-reference" title="Jain, A., Vale, R. D. &lt;strong&gt;RNA phase transitions in repeat expansion disorders.&lt;/strong&gt; Nature 546: 243-247, 2017.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/28562589/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;28562589&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=28562589[PMID]&amp;report=imagesdocsum&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed Image&#x27;, &#x27;domain&#x27;: &#x27;ncbi.nlm.nih.gov&#x27;})&quot;&gt;images&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1038/nature22386&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="28562589">Jain and Vale (2017)</a> showed that repeat expansions create templates for multivalent basepairing, which causes purified RNA to undergo a sol-gel transition in vitro at a similar critical repeat number as observed in Huntington disease, spinocerebellar ataxia, myotonic dystrophy, and FTDALS1 (<a href="/entry/105550">105550</a>). In human cells, RNA foci form by phase separation of the repeat-containing RNA and can be dissolved by agents that disrupt RNA gelation in vitro. <a href="#35" class="mim-tip-reference" title="Jain, A., Vale, R. D. &lt;strong&gt;RNA phase transitions in repeat expansion disorders.&lt;/strong&gt; Nature 546: 243-247, 2017.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/28562589/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;28562589&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=28562589[PMID]&amp;report=imagesdocsum&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed Image&#x27;, &#x27;domain&#x27;: &#x27;ncbi.nlm.nih.gov&#x27;})&quot;&gt;images&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1038/nature22386&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="28562589">Jain and Vale (2017)</a> concluded that, analogous to protein aggregation disorders, their results suggested that the sequence-specific gelation of RNAs could be a contributing factor to neurologic disease. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=28562589" 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="#2" class="mim-tip-reference" title="Banfi, S., Servadio, A., Chung, M., Kwiatkowski, T. J., Jr., McCall, A. E., Duvick, L. A., Shen, Y., Roth, E. J., Orr, H. T., Zoghbi, H. Y. &lt;strong&gt;Identification and characterization of the gene causing type 1 spinocerebellar ataxia.&lt;/strong&gt; Nature Genet. 7: 513-520, 1994.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/7951322/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;7951322&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1038/ng0894-513&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="7951322">Banfi et al. (1994)</a> determined that the CAG trinucleotide repeat identified by <a href="#64" class="mim-tip-reference" title="Orr, H. T., Chung, M., Banfi, S., Kwiatkowski, T. J., Jr., Servadio, A., Beaudet, A. L., McCall, A. E., Duvick, L. A., Ranum, L. P. W., Zoghbi, H. Y. &lt;strong&gt;Expansion of an unstable trinucleotide CAG repeat in spinocerebellar ataxia type 1.&lt;/strong&gt; Nature Genet. 4: 221-226, 1993.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/8358429/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;8358429&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1038/ng0793-221&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="8358429">Orr et al. (1993)</a> in SCA1 occurs in the ataxin-1 gene (<a href="/entry/601556#0001">601556.0001</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=7951322+8358429" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Genetic Anticipation</em></strong></p><p>
<a href="#11" class="mim-tip-reference" title="Chung, M., Ranum, L. P. W., Duvick, L. A., Servadio, A., Zoghbi, H. Y., Orr, H. T. &lt;strong&gt;Evidence for a mechanism predisposing to intergenerational CAG repeat instability in spinocerebellar ataxia type 1.&lt;/strong&gt; Nature Genet. 5: 254-258, 1993.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/8275090/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;8275090&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1038/ng1193-254&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="8275090">Chung et al. (1993)</a> found that 63% of paternal transmissions show an increase in repeat number, whereas 69% of maternal transmissions show no change or a decrease in repeat number. Sequence analysis showed that 98% of unexpanded alleles had an interrupted repeat configuration, whereas a contiguous repeat (CAG)n was found in expanded alleles. This indicated that the repeat instability in ATXN1 is more complex than a simple variation in repeat number and that the loss of an interruption predisposes the ATXN1 (CAG)n to expansion. <a href="#56" class="mim-tip-reference" title="Matilla, T., Volpini, V., Genis, D., Rosell, J., Corral, J., Davalos, A., Molins, A., Estivill, X. &lt;strong&gt;Presymptomatic analysis of spinocerebellar ataxia type 1 (SCA1) via the expansion of the SCA1 CAG-repeat in a large pedigree displaying anticipation and parental male bias.&lt;/strong&gt; Hum. Molec. Genet. 2: 2123-2128, 1993.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/8111382/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;8111382&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1093/hmg/2.12.2123&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="8111382">Matilla et al. (1993)</a> studied the expansion of the ATXN1 gene CAG repeat in a large family in which spinocerebellar ataxia showed the phenomenon of anticipation. There were 41 affected members with no juvenile cases of SCA1, the mean age of onset being 36 years. The family also showed the phenomenon of parental male bias; i.e., the age of onset was younger and the duration of illness before death was shorter in the members of the family who inherited the disorder from the father. In this large Spanish kindred, <a href="#56" class="mim-tip-reference" title="Matilla, T., Volpini, V., Genis, D., Rosell, J., Corral, J., Davalos, A., Molins, A., Estivill, X. &lt;strong&gt;Presymptomatic analysis of spinocerebellar ataxia type 1 (SCA1) via the expansion of the SCA1 CAG-repeat in a large pedigree displaying anticipation and parental male bias.&lt;/strong&gt; Hum. Molec. Genet. 2: 2123-2128, 1993.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/8111382/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;8111382&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1093/hmg/2.12.2123&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="8111382">Matilla et al. (1993)</a> found 9 clinically unaffected persons between ages 18 and 40 years who had expansions of the CAG repeat within the pathogenetic range. In 22 other genetically 'at risk' individuals, they found that the number of CAG repeats in the ATXN1 gene was within the normal range. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=8275090+8111382" 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="#74" class="mim-tip-reference" title="Ranum, L. P. W., Chung, M., Banfi, S., Bryer, A., Schut, L. J., Ramesar, R., Duvick, L. A., McCall, A., Subramony, S. H., Goldfarb, L., Gomez, C., Sandkuijl, L. A., Orr, H. T., Zoghbi, H. Y. &lt;strong&gt;Molecular and clinical correlations in spinocerebellar ataxia type I: evidence for familial effects on the age at onset.&lt;/strong&gt; Am. J. Hum. Genet. 55: 244-252, 1994.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/8037204/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;8037204&lt;/a&gt;]" pmid="8037204">Ranum et al. (1994)</a> examined the frequency and variability of the ATXN1 repeat expansion in 87 kindreds with diverse ethnic backgrounds and dominantly inherited ataxia. All 9 families for which linkage to the ATXN1 region of 6p had previously been established showed repeat expansion, while 3 of the remaining 78 showed a similar abnormality. For 113 patients from the families with repeat expansion, inverse correlations between CAG repeat size and both age at onset and disease duration were observed. Repeat size accounted for 66% of the variation in age at onset in these patients. After correction for repeat size, interfamilial differences in age at onset remained significant, suggesting that additional genetic factors affect the expression of the ATXN1 gene product. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8037204" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#36" class="mim-tip-reference" title="Jodice, C., Malaspina, P., Persichetti, F., Novelletto, A., Spadaro, M., Giunti, P., Morocutti, C., Terrenato, L., Harding, A. E., Frontali, M. &lt;strong&gt;Effect of trinucleotide repeat length and parental sex on phenotypic variation in spinocerebellar ataxia 1.&lt;/strong&gt; Am. J. Hum. Genet. 54: 959-965, 1994.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/8198139/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;8198139&lt;/a&gt;]" pmid="8198139">Jodice et al. (1994)</a> found trinucleotide repeat expansion in 64 subjects from 19 families: 57 patients with SCA1 and 7 subjects predicted, by haplotype analysis, to carry the mutation. Comparison with a large set of normal chromosomes showed 2 distinct distributions with a much wider variation among expanded chromosomes. The sex of the transmitting parent played a major role in the size distribution of expanded alleles, those with more than 54 repeats being transmitted by affected fathers exclusively. Alleles with 46 to 54 repeats were transmitted by affected fathers and mothers in equal proportions. On the other hand, the sex ratio of offspring receiving either more than 54 or less than 54 repeats approached the expected 50:50. If a steady-state distribution of repeat numbers is assumed to persist through the generations, this raises the question as to why affected females transmitting alleles with more than 54 repeats are lacking, while females receiving more than 54 repeats exist. This may be explained, at least in part, by reduced biologic fitness. Detailed clinical follow-up of a subset of patients by <a href="#36" class="mim-tip-reference" title="Jodice, C., Malaspina, P., Persichetti, F., Novelletto, A., Spadaro, M., Giunti, P., Morocutti, C., Terrenato, L., Harding, A. E., Frontali, M. &lt;strong&gt;Effect of trinucleotide repeat length and parental sex on phenotypic variation in spinocerebellar ataxia 1.&lt;/strong&gt; Am. J. Hum. Genet. 54: 959-965, 1994.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/8198139/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;8198139&lt;/a&gt;]" pmid="8198139">Jodice et al. (1994)</a> demonstrated significant relationships between increasing repeat number on expanded chromosomes and earlier age at onset, faster progression of the disease, and earlier age at death. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8198139" 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="#42" class="mim-tip-reference" title="Koefoed, P., Hasholt, L., Fenger, K., Nielsen, J. E., Eiberg, H., Buschard, K., Sorensen, S. A. &lt;strong&gt;Mitotic and meiotic instability of the CAG trinucleotide repeat in spinocerebellar ataxia type 1.&lt;/strong&gt; Hum. Genet. 103: 564-569, 1998.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/9860298/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;9860298&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1007/s004390050870&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="9860298">Koefoed et al. (1998)</a> performed single sperm analysis of (CAG)n stretches in SCA1 patients and asymptomatic carriers. A pronounced variation in the size of the expanded allele was found in sperm cells and in peripheral blood leukocytes, with a higher degree of instability in sperm cells, where an allele with 50 repeat units was contracted in 11.8%, further expanded in 63.5%, and unchanged in 24.6% of the single sperm analyzed. They also found a low instability of the normal alleles; the normal alleles from the individuals carrying a CAG repeat expansion was significantly more unstable than the normal alleles from control individuals (P less than 0.001), indicating an interallelic interaction between the expanded and the normal alleles. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9860298" 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="#57" class="mim-tip-reference" title="Matsuyama, Z., Izumi, Y., Kameyama, M., Kawakami, H., Nakamura, S. &lt;strong&gt;The effect of CAT trinucleotide interruptions on the age at onset of spinocerebellar ataxia type 1 (SCA1).&lt;/strong&gt; J. Med. Genet. 36: 546-548, 1999.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/10424816/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;10424816&lt;/a&gt;]" pmid="10424816">Matsuyama et al. (1999)</a> studied 17 patients with SCA1. In one of these patients the expanded ATXN1 allele was interrupted by a CAT trinucleotide. The total number of CAG repeats was 58, predicting an age at onset of 22.0 years, in contrast to the actual age at onset of 50 years. In addition, brainstem atrophy was mild compared to that of a patient with 52 CAG repeats. Sequence analysis showed the repeat portion of the ATXN1 allele contained 45 uninterrupted CAG repeats with 2 interspersed CAT repeats in the subsequent 12 trinucleotides. <a href="#57" class="mim-tip-reference" title="Matsuyama, Z., Izumi, Y., Kameyama, M., Kawakami, H., Nakamura, S. &lt;strong&gt;The effect of CAT trinucleotide interruptions on the age at onset of spinocerebellar ataxia type 1 (SCA1).&lt;/strong&gt; J. Med. Genet. 36: 546-548, 1999.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/10424816/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;10424816&lt;/a&gt;]" pmid="10424816">Matsuyama et al. (1999)</a> concluded that the age at onset of SCA1 is not determined by the total number of CAG repeats, but rather by the total number of uninterrupted CAG repeats. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10424816" 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="#123" class="mim-tip-reference" title="Zuhlke, C., Dalski, A., Hellenbroich, Y., Bubel, S., Schwinger, E., Burk, K. &lt;strong&gt;Spinocerebellar ataxia type 1 (SCA1): Phenotype-genotype correlation studies in intermediate alleles.&lt;/strong&gt; Europ. J. Hum. Genet. 10: 204-209, 2002.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/11973625/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;11973625&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1038/sj.ejhg.5200788&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="11973625">Zuhlke et al. (2002)</a> performed genotype-phenotype correlation in intermediate alleles from 36 to 43 CAG repeats in the ATXN1 gene with respect to the presence of interrupting CAT trinucleotides. Alleles with 36 to 38 triplets were present in individuals with ataxia but without additional characteristic features of SCA1. SCA1 phenotypes were found for patients with 41 and 43 triplets. The 39 triplet allele missing CAT interruptions was associated with symptoms characteristic for SCA1 in 4 patients, whereas the interrupted allele with 39 triplets did not cause characteristic SCA1 features in 1 individual. These findings suggested a change from normal to pathologic alleles at 39 triplets depending on the presence of CAT interruptions in the CAG repeat. Stable inheritance of the uninterrupted 39 triplet allele was observed in 1 familial case of SCA1. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11973625" 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="#100" class="mim-tip-reference" title="van de Warrenburg, B. P. C., Hendriks, H., Durr, A., van Zuijlen, M. C. A., Stevanin, G., Camuzat, A., Sinke, R. J., Brice, A., Kremer, B. P. H. &lt;strong&gt;Age at onset variance analysis in spinocerebellar ataxias: a study in a Dutch-French cohort.&lt;/strong&gt; Ann. Neurol. 57: 505-512, 2005.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/15747371/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;15747371&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ana.20424&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="15747371">Van de Warrenburg et al. (2005)</a> applied statistical analysis to examine the relationship between age at onset and number of expanded triplet repeats from a Dutch-French cohort of 802 patients with SCA1 (138 patients), SCA2 (166 patients), SCA3 (342 patients), SCA6 (53 patients), and SCA7 (103 patients). The size of the expanded repeat explained 66 to 75% of the variance in age at onset for SCA1, SCA2, and SCA7, but less than 50% for SCA3 and SCA6. The relation between age at onset and CAG repeat was similar for all groups except for SCA2, suggesting that the polyglutamine repeat in the ataxin-2 protein exerts its pathologic effect in a different way. A contribution of the nonexpanded allele to age at onset was observed for only SCA1 and SCA6. <a href="#100" class="mim-tip-reference" title="van de Warrenburg, B. P. C., Hendriks, H., Durr, A., van Zuijlen, M. C. A., Stevanin, G., Camuzat, A., Sinke, R. J., Brice, A., Kremer, B. P. H. &lt;strong&gt;Age at onset variance analysis in spinocerebellar ataxias: a study in a Dutch-French cohort.&lt;/strong&gt; Ann. Neurol. 57: 505-512, 2005.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/15747371/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;15747371&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ana.20424&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="15747371">Van de Warrenburg et al. (2005)</a> acknowledged that their results were purely mathematical, but suggested that they reflected biologic variations among the diseases. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15747371" 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>
For discussion of a possible association between autosomal dominant SCA and variation in the ZFYVE27 gene, see <a href="/entry/610243#0002">610243.0002</a>.</p><p>For discussion of a possible association between autosomal dominant SCA and variation in the KIF26B gene, see <a href="/entry/614026#0001">614026.0001</a>.</p><p>For discussion of a possible association between autosomal dominant SCA and variation in the EP300 gene, see <a href="/entry/602700">602700</a>.</p>
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<p><a href="#86" class="mim-tip-reference" title="Schols, L., Amoiridis, G., Buttner, T., Przuntek, H., Epplen, J. T., Riess, O. &lt;strong&gt;Autosomal dominant cerebellar ataxia: phenotypic differences in genetically defined subtypes?&lt;/strong&gt; Ann. Neurol. 42: 924-932, 1997.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/9403486/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;9403486&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ana.410420615&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="9403486">Schols et al. (1997)</a> compared clinical, electrophysiologic, and magnetic resonance imaging (MRI) findings to identify phenotypic characteristics of genetically defined SCA subtypes. Slow saccades, hyporeflexia, myoclonus, and action tremor suggested SCA2. SCA3 patients frequently developed diplopia, severe spasticity or pronounced peripheral neuropathy, and impaired temperature discrimination, apart from ataxia. SCA6 presented with a predominantly cerebellar syndrome, and patients often had onset after 55 years of age. SCA1 was characterized by markedly prolonged peripheral and central motor conduction times in motor evoked potentials. MRI scans showed pontine and cerebellar atrophy in SCA1 and SCA2. In SCA3, enlargement of the fourth ventricle was the main sequel of atrophy. SCA6 presented with pure cerebellar atrophy on MRI. Overlap between the 4 SCA subtypes was broad, however. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9403486" 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 65 patients with SCA1, SCA2, or SCA3, <a href="#6" class="mim-tip-reference" title="Burk, K., Abele, M., Fetter, M., Dichgans, J., Skalej, M., Laccone, F., Didierjean, O., Brice, A., Klockgether, T. &lt;strong&gt;Autosomal dominant cerebellar ataxia type I: clinical features and MRI in families with SCA1, SCA2 and SCA3.&lt;/strong&gt; Brain 119: 1497-1505, 1996.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/8931575/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;8931575&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1093/brain/119.5.1497&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="8931575">Burk et al. (1996)</a> found reduced saccade velocity in 56%, 100%, and 30% of patients, respectively. MRI showed severe olivopontocerebellar atrophy in SCA2, similar but milder changes in SCA1, and very mild atrophy with sparing of the olives in SCA3. Careful examination of 3 major criteria of eye movements, saccade amplitude, saccade velocity, and presence of gaze-evoked nystagmus, permitted <a href="#81" class="mim-tip-reference" title="Rivaud-Pechoux, S., Durr, A., Gaymard, B., Cancel, G., Ploner, C. J., Agid, Y., Brice, A., Pierrot-Deseilligny, C. &lt;strong&gt;Eye movement abnormalities correlate with genotype in autosomal dominant cerebellar ataxia type I.&lt;/strong&gt; Ann. Neurol. 43: 297-302, 1998.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/9506545/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;9506545&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ana.410430306&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="9506545">Rivaud-Pechoux et al. (1998)</a> to assign over 90% of patients with SCA1, SCA2, or SCA3 to their genetically confirmed patient group. In SCA1, saccade amplitude was significantly increased, resulting in hypermetria. In SCA2, saccade velocity was markedly decreased. In SCA3, the most characteristic finding was the presence of gaze-evoked nystagmus. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=9506545+8931575" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In an investigation of oculomotor function, <a href="#9" class="mim-tip-reference" title="Buttner, N., Geschwind, D., Jen, J. C., Perlman, S., Pulst, S. M., Baloh, R. W. &lt;strong&gt;Oculomotor phenotypes in autosomal dominant ataxias.&lt;/strong&gt; Arch. Neurol. 55: 1353-1357, 1998.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/9779665/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;9779665&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1001/archneur.55.10.1353&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="9779665">Buttner et al. (1998)</a> found that all 3 patients with SCA1, all 7 patients with SCA3, and all 5 patients with SCA6 had gaze-evoked nystagmus. Three of 5 patients with SCA2 did not have gaze-evoked nystagmus, perhaps because they could not generate corrective fast components. Rebound nystagmus occurred in all SCA3 patients, 33% of SCA1 patients, 40% of SCA6 patients, and none of SCA2. Spontaneous downbeat nystagmus only occurred in SCA6. Peak saccade velocity was decreased in 100% of patients with SCA2, 1 patient with SCA1, and no patients with SCA3 or SCA6. Saccade hypermetria was found in all types, but was most common in SCA3. <a href="#7" class="mim-tip-reference" title="Burk, K., Fetter, M., Abele, M., Laccone, F., Brice, A., Dichgans, J., Klockgether, T. &lt;strong&gt;Autosomal dominant cerebellar ataxia type I: oculomotor abnormalities in families with SCA1, SCA2, and SCA3.&lt;/strong&gt; J. Neurol. 246: 789-797, 1999.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/10525976/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;10525976&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1007/s004150050456&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="10525976">Burk et al. (1999)</a> found that gaze-evoked nystagmus was not associated with SCA2. However, severe saccade slowing was highly characteristic of SCA2. Saccade velocity in SCA3 was normal to mildly reduced. The gain in vestibuloocular reflex was significantly impaired in SCA3 and SCA1. Eye movement disorders of SCA1 overlapped with both SCA2 and SCA3. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=10525976+9779665" 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 reticulotegmental nucleus of the pons (RTTG), also known as the nucleus of Bechterew, is a precerebellar nucleus important in the premotor oculomotor circuits crucial for the accuracy of horizontal saccades and the generation of horizontal smooth pursuit. By postmortem examination, <a href="#83" class="mim-tip-reference" title="Rub, U., Burk, K., Schols, L., Brunt, E. R., de Vos, R. A. I., Orozco Diaz, G., Gierga, K., Ghebremedhin, E., Schultz, C., Del Turco, D., Mittelbronn, M., Auburger, G., Deller, T., Braak, H. &lt;strong&gt;Damage to the reticulotegmental nucleus of the pons in spinocerebellar ataxia type 1, 2, and 3.&lt;/strong&gt; Neurology 63: 1258-1263, 2004.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/15477548/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;15477548&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1212/01.wnl.0000140498.24112.8c&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="15477548">Rub et al. (2004)</a> identified neuronal loss and astrogliosis in the RTTG in 1 of 2 SCA1 patients, 2 of 4 SCA2 patients, and 4 of 4 SCA3 patients that correlated with clinical findings of hypometric saccades and slowed and saccadic smooth pursuits. The 3 patients without these specific oculomotor findings had intact RTTG regions. The authors concluded that the neurodegeneration associated with SCA1, SCA2, and SCA3 affects premotor networks in addition to motor nuclei in a subset of patients. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15477548" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Using an analysis of covariance and multivariate models to examine symptom severity in 526 patients with SCA1, SCA2, SCA3, or SCA6, <a href="#85" class="mim-tip-reference" title="Schmitz-Hubsch, T., Coudert, M., Bauer, P., Giunti, P., Globas, C., Baliko, L., Filla, A., Mariotti, C., Rakowicz, M., Charles, P., Ribai, P., Szymanski, S., and 19 others. &lt;strong&gt;Spinocerebellar ataxia types 1, 2, 3, and 6: disease severity and nonataxia symptoms.&lt;/strong&gt; Neurology 71: 982-989, 2008.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/18685131/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;18685131&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1212/01.wnl.0000325057.33666.72&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="18685131">Schmitz-Hubsch et al. (2008)</a> found that repeat length of the expanded allele, age at onset, and disease duration explained 60.4% of the ataxia score in SCA1, 45.4% in SCA2, 46.8% in SCA3. However, only age at onset and disease duration appeared to explain 33.7% of the score in SCA6. Similar findings were obtained for nonataxic symptoms. The study suggested that SCA1, SCA2, and SCA3 share a number of common biologic properties, whereas SCA6 is distinct in that its phenotype is more determined by age than by disease-related factors. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18685131" 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="#25" class="mim-tip-reference" title="Giunti, P., Sweeney, M. G., Spadaro, M., Jodice, C., Novelletto, A., Malaspina, P., Frontali, M., Harding, A. E. &lt;strong&gt;The trinucleotide repeat expansion on chromosome 6p (SCA1) in autosomal dominant cerebellar ataxias.&lt;/strong&gt; Brain 117: 645-649, 1994.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/7922453/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;7922453&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1093/brain/117.4.645&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="7922453">Giunti et al. (1994)</a> examined members of 73 families who were affected with a variety of autosomal dominant late-onset cerebellar ataxias for the trinucleotide repeat expansion associated with the SCA1 locus. The mutation was found in 19 of 38 kindreds with the SCA1 phenotype. However, it was not found in any of 8 families with olivopontocerebellar atrophy with maculopathy (<a href="/entry/164500">164500</a>), or in 24 kindreds with pure adult-onset cerebellar ataxia (SCA31; <a href="/entry/117210">117210</a>), or in 12 patients with sporadic degenerative ataxia. The patients with the expansion were Italian, British, Malaysian, Bangladeshi, and Jamaican. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7922453" 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="#76" class="mim-tip-reference" title="Ranum, L. P. W., Lundgren, J. K., Schut, L. J., Ahrens, M. J., Perlman, S., Aita, J., Bird, T. D., Gomez, C., Orr, H. T. &lt;strong&gt;Spinocerebellar ataxia type 1 and Machado-Joseph disease: incidence of CAG expansions among adult-onset ataxia patients from 311 families with dominant, recessive, or sporadic ataxia.&lt;/strong&gt; Am. J. Hum. Genet. 57: 603-608, 1995.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/7668288/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;7668288&lt;/a&gt;]" pmid="7668288">Ranum et al. (1995)</a> made use of the fact that the genes involved in 2 forms of autosomal dominant ataxia, that for Machado-Joseph disease (<a href="/entry/109150">109150</a>) and that for SCA1, have been isolated to assess the frequency of trinucleotide repeat expansions among individuals diagnosed with ataxia. They collected and analyzed DNA from individuals with both disorders. In both cases, the genes responsible for the disorder were found to have an expansion of an unstable CAG trinucleotide repeat. These individuals represented 311 families with adult-onset ataxia of unknown etiology, of which 149 families had dominantly inherited ataxia. <a href="#76" class="mim-tip-reference" title="Ranum, L. P. W., Lundgren, J. K., Schut, L. J., Ahrens, M. J., Perlman, S., Aita, J., Bird, T. D., Gomez, C., Orr, H. T. &lt;strong&gt;Spinocerebellar ataxia type 1 and Machado-Joseph disease: incidence of CAG expansions among adult-onset ataxia patients from 311 families with dominant, recessive, or sporadic ataxia.&lt;/strong&gt; Am. J. Hum. Genet. 57: 603-608, 1995.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/7668288/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;7668288&lt;/a&gt;]" pmid="7668288">Ranum et al. (1995)</a> found that of these, 3% had SCA1 trinucleotide repeat expansions, whereas 21% were positive for the MJD trinucleotide expansion. For the 57 patients with MJD trinucleotide repeat expansions, strong inverse correlation between CAG repeat size and age at onset was observed (r = -0.838). Among the MJD patients, the normal and affected ranges of CAG repeat size were 14 to 40 and 68 to 82 repeats, respectively. For SCA1, the normal and affected ranges were much closer, namely 19 to 38 and 40 to 81 CAG repeats, respectively. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7668288" 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 nationwide survey of Japanese patients, <a href="#33" class="mim-tip-reference" title="Hirayama, K., Takayanagi, T., Nakamura, R., Yanagisawa, N., Hattori, T., Kita, K., Yanagimoto, S., Fujita, M., Nagaoka, M., Satomura, Y., Sobue, I., Iizuka, R., Toyokura, Y., Satoyoshi, E. &lt;strong&gt;Spinocerebellar degenerations in Japan: a nationwide epidemiological and clinical study.&lt;/strong&gt; Acta Neurol. Scand. 89 (suppl. 153): 1-22, 1994.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/8059595/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;8059595&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1111/j.1600-0404.1994.tb05401.x&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="8059595">Hirayama et al. (1994)</a> found an estimated prevalence of the various forms of spinocerebellar degeneration to be 4.53 per 100,000. Of these, 12.6% were thought to have the Menzel type of spinocerebellar atrophy (SCA1). However, it was not clear how they distinguished this disorder from the other forms of OPCA. In Japan, <a href="#97" class="mim-tip-reference" title="Suzuki, Y., Sasaki, H., Wakisaka, A., Takada, A., Yoshiki, T., Iwabuchi, K., Tashiro, K., Fukazawa, T., Hamada, T. &lt;strong&gt;Spinocerebellar ataxia 1 (SCA1) in the Japanese: analysis of CAG trinucleitide (sic) repeat expansion and instability of the repeat for paternal transmission.&lt;/strong&gt; Jpn. J. Hum. Genet. 40: 131-143, 1995.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/7780164/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;7780164&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1007/BF01874077&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="7780164">Suzuki et al. (1995)</a> found that all affected and presymptomatic individuals in 12 pedigrees with SCA1 (determined by haplotype per segregation analyses) carried an abnormally expanded allele with a range of 39 to 63 repeat units. This repeat size inversely correlated with the age of onset. However, contrary to previous reports, the size of the repeat did not correlate with gender of the transmitting parent. CAG triplet repeat instability on paternal transmission was not observed. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=7780164+8059595" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#106" class="mim-tip-reference" title="Wakisaka, A., Sasaki, H., Takada, A., Fukazawa, T., Suzuki, Y., Hamada, T., Iwabuchi, K., Tashiro, K., Yoshiki, T. &lt;strong&gt;Spinocerebellar ataxia 1 (SCA1) in the Japanese in Hokkaido may derive from a single common ancestry.&lt;/strong&gt; J. Med. Genet. 32: 590-592, 1995.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/7473647/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;7473647&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1136/jmg.32.8.590&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="7473647">Wakisaka et al. (1995)</a> determined the haplotype cosegregating with SCA1 in 12 Japanese pedigrees. Although the alleles of the ATXN1 haplotype varied from pedigree to pedigree depending on the distance from the SCA1 locus, the affected and presymptomatic subjects carried the same alleles at 2 loci, D6S288 and D6S274. All the families with SCA1 had migrated from either the Miyagi or Yamagata Prefectures, neighboring areas in the Tokohu District, the northern part of Honshu, which is the main island of Japan. The findings suggested to the authors that SCA1 in the Japanese, at least those residing in Hokkaido, derived from a single common ancestry. <a href="#26" class="mim-tip-reference" title="Goldfarb, L. G., Vasconcelos, O., Platonov, F. A., Lunkes, A., Kipnis, V., Kononova, S., Chabrashvili, T., Vladimirtsev, V. A., Alexeev, V. P., Gajdusek, D. C. &lt;strong&gt;Unstable triplet repeat and phenotypic variability of spinocerebellar ataxia type 1.&lt;/strong&gt; Ann. Neurol. 39: 500-506, 1996.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/8619528/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;8619528&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ana.410390412&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="8619528">Goldfarb et al. (1996)</a> studied 78 SCA1 patients from a large Siberian kindred which included 1,484 individuals, 225 of whom are known to be affected and 656 of whom were at risk. Normal alleles had 25 to 37 trinucleotide repeats, whereas expanded alleles contained 40 to 55 repeats. The disease was not fully penetrant inasmuch as there was one 66-year-old woman with 44 CAG repeats who was asymptomatic. Of her 7 children, 4 were affected, including a homozygous daughter and another child with 44 repeats. Two symptomatic individuals who had expansions on both chromosomes demonstrated clinical manifestations that corresponded to the size of the larger allele. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=8619528+7473647" 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 Catalonia, <a href="#23" class="mim-tip-reference" title="Genis, D., Matilla, T., Volpini, V., Rosell, J., Davalos, A., Ferrer, I., Molins, A., Estivill, X. &lt;strong&gt;Clinical, neuropathologic, and genetic studies of a large spinocerebellar ataxia type 1 (SCA1) kindred: (CAG)n expansion and early premonitory signs and symptoms.&lt;/strong&gt; Neurology 45: 24-30, 1995.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/7824128/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;7824128&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1212/wnl.45.1.24&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="7824128">Genis et al. (1995)</a> found a large kindred traced to a common ancestor born in 1735 that segregated spinocerebellar ataxia-1. Affected individuals all had 1 allele with between 41 in 59 repeats, whereas asymptomatic individuals for the most part fell in the range of 6 to 39 repeats. Two asymptomatic individuals, an 18-year-old female and a 25-year-old male, had 41 repeats. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7824128" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#41" class="mim-tip-reference" title="Klockgether, T., Burk, K., Schulz, J. B., Dichgans, J., Wessel, K., Auburger, G. &lt;strong&gt;Absence of SCA1 mutation in idiopathic cerebellar ataxia. (Letter)&lt;/strong&gt; J. Neurol. Neurosurg. Psychiat. 57: 1439-1440, 1994.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/7964835/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;7964835&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1136/jnnp.57.11.1439-a&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="7964835">Klockgether et al. (1994)</a> analyzed DNA from 19 German families with autosomal dominant cerebellar ataxia and 61 unrelated individuals with idiopathic cerebellar ataxia with a mean age of onset of 53.6 years. Heterozygosity for the ATXN1 triplet repeat expansion was diagnosed in 5 out of 19 of the autosomal dominant kindreds. In contrast, none of the 61 cases of idiopathic adult-onset cerebellar ataxia showed this expansion. This suggested that SCA1 is not a significant cause of idiopathic cerebellar ataxia in Germany. Studying 77 German families with autosomal dominant cerebellar ataxia of SCA types 1, 2, 3, and 6, <a href="#86" class="mim-tip-reference" title="Schols, L., Amoiridis, G., Buttner, T., Przuntek, H., Epplen, J. T., Riess, O. &lt;strong&gt;Autosomal dominant cerebellar ataxia: phenotypic differences in genetically defined subtypes?&lt;/strong&gt; Ann. Neurol. 42: 924-932, 1997.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/9403486/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;9403486&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ana.410420615&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="9403486">Schols et al. (1997)</a> found that the SCA1 mutation accounted for 9%, SCA2 for 10%, SCA3 for 42%, and SCA6 for 22%. There was no family history of ataxia in 7 of 27 SCA6 patients. Age at onset correlated inversely with repeat length in all subtypes. Yet the average effect of 1 CAG unit on age of onset was different for each SCA subtype. <a href="#80" class="mim-tip-reference" title="Riess, O., Epplen, J. T., Amoiridis, G., Przuntek, H., Schols, L. &lt;strong&gt;Transmission distortion of the mutant alleles in spinocerebellar ataxia.&lt;/strong&gt; Hum. Genet. 99: 282-284, 1997.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/9048937/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;9048937&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1007/s004390050355&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="9048937">Riess et al. (1997)</a> found that in both SCA1 and SCA3 patients in German families there was distortion of the mendelian 1:1 segregation of the disease. They noted that mutations in the ataxin-1 gene are responsible for autosomal dominant spinocerebellar ataxia in about 10% of all families, whereas SCA3 is the most common cause in Germany, accounting for up to 50% of cases. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=7964835+9048937+9403486" 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="#73" class="mim-tip-reference" title="Ramesar, R. S., Bardien, S., Beighton, P., Bryer, A. &lt;strong&gt;Expanded CAG repeats in spinocerebellar ataxia (SCA1) segregate with distinct haplotypes in South African families.&lt;/strong&gt; Hum. Genet. 100: 131-137, 1997.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/9225982/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;9225982&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1007/s004390050478&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="9225982">Ramesar et al. (1997)</a> investigated 14 South African kindreds and 22 sporadic individuals with SCA for expanded ATXN1 (<a href="/entry/601556#0001">601556.0001</a>) and ATXN3 (<a href="/entry/607047#0001">607047.0001</a>) repeats. The authors stated that, in the present study, ATXN1 mutations accounted for 43% of known ataxia families in the Western Cape region. They found that expanded ATXN1 and CAG repeats cosegregated with the disorder in 6 of the families, 5 of mixed ancestry and 1 Caucasian, and were also observed in a sporadic case from the indigenous Black African population. The use of the microsatellite markers D6S260, D6S89, and D6S274 provided evidence that the expanded ATXN1 repeats segregated with 3 distinct haplotypes in the 6 families. None of the families nor the sporadic individuals showed expansion of the MJD repeat. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9225982" 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 202 Japanese and 177 Caucasian families with autosomal dominant SCA, <a href="#98" class="mim-tip-reference" title="Takano, H., Cancel, G., Ikeuchi, T., Lorenzetti, D., Mawad, R., Stevanin, G., Didierjean, O., Durr, A., Oyake, M., Shimohata, T., Sasaki, R., Koide, R., Igarashi, S., Hayashi, S., Takiyama, Y., Nishizawa, M., Tanaka, H., Zoghbi, H., Brice, A., Tsuji, S. &lt;strong&gt;Close associations between prevalences of dominantly inherited spinocerebellar ataxias with CAG-repeat expansions and frequencies of large normal CAG alleles in Japanese and Caucasian populations.&lt;/strong&gt; Am. J. Hum. Genet. 63: 1060-1066, 1998.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/9758625/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;9758625&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1086/302067&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="9758625">Takano et al. (1998)</a> found that the prevalence of SCA1 was significantly higher in the Caucasian population (15%) compared to the Japanese population (3%). This corresponded to higher frequencies of large normal ATXN1 CAG repeat alleles (greater than 30 repeats) in Caucasian controls compared to Japanese controls. The findings suggested that large normal alleles contribute to the generation of expanded alleles that lead to dominant SCA. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9758625" 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 Spain, <a href="#72" class="mim-tip-reference" title="Pujana, M. A., Corral, J., Gratacos, M., Combarros, O., Berciano, J., Genis, D., Banchs, I., Estivill, X., Volpini, V., Ataxia Study Group. &lt;strong&gt;Spinocerebellar ataxias in Spanish patients: genetic analysis of familial and sporadic cases.&lt;/strong&gt; Hum. Genet. 104: 516-522, 1999. Note: Erratum: Hum. Genet. 105: 376 only, 1999.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/10453742/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;10453742&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1007/s004390050997&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="10453742">Pujana et al. (1999)</a> performed molecular analysis on 87 unrelated familial and 60 sporadic cases of spinocerebellar ataxia of autosomal dominant type. For the familial cases of ADCA, 6% were SCA1, 15% were SCA2, 15% were SCA3, 1% represented SCA6, 3% were SCA7, and, in 1%, the diagnosis was DRPLA (<a href="/entry/125370">125370</a>), an extremely rare mutation in Caucasoid populations. About 58% of ADCA cases remained genetically unclassified. All the SCA1 cases belonged to the same geographic area and shared a common haplotype for the SCA1 mutation. The expanded alleles ranged from 41 to 59 repeats for SCA1, 35 to 46 for SCA2, 67 to 77 for SCA3, and 38 to 113 for SCA7. The 1 SCA6 case had 25 repeats and the 1 DRPLA case had 63 repeats. The highest CAG repeat variation in meiotic transmission of expanded alleles was detected in SCA7, this being an expansion of 67 units in one paternal transmission, giving rise to a 113 CAG repeat allele in a patient who died at 3 years of age. Meiotic transmissions showed a tendency to more frequent paternal transmission of expanded alleles in SCA1 and maternal in SCA7. All SCA1 and SCA2 expanded alleles analyzed consisted of pure CAG repeats, whereas normal alleles were interrupted by 1 to 2 CAT trinucleotides in SCA1, except for 3 alleles of 6, 14, and 21 CAG repeats, and by 1 to 3 CAA trinucleotides in SCA2. The failure to find SCA or DRPLA mutations in the 60 sporadic cases of spinocerebellar ataxia is consistent with the lack of evidence of de novo mutations noted by <a href="#1" class="mim-tip-reference" title="Andrew, S. E., Goldberg, Y. P., Hayden, M. R. &lt;strong&gt;Rethinking genotype and phenotype correlations in polyglutamine expansion disorders.&lt;/strong&gt; Hum. Molec. Genet. 6: 2005-2010, 1997.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/9328463/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;9328463&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1093/hmg/6.12.2005&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="9328463">Andrew et al. (1997)</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=9328463+10453742" 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="#67" class="mim-tip-reference" title="Pareyson, D., Gellera, C., Castellotti, B., Antonelli, A., Riggio, M. C., Mazzucchelli, F., Girotti, F., Pietrini, V., Mariotti, C., Di Donato, S. &lt;strong&gt;Clinical and molecular studies of 73 Italian families with autosomal dominant cerebellar ataxia type I: SCA1 and SCA2 are the most common genotypes.&lt;/strong&gt; J. Neurol. 246: 389-393, 1999.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/10399872/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;10399872&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1007/s004150050369&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="10399872">Pareyson et al. (1999)</a> evaluated 73 Italian families with type I ADCA. SCA1 was the most common genotype, accounting for 41% of cases (30 families); SCA2 was slightly less frequent (29%, 21 families), and the remaining families were negative for the SCA1, SCA2, and SCA3 mutations. Among the positively genotyped families, SCA1 was found most frequently in families from northern Italy (50%), while SCA2 was the most common mutation in families from the southern part of the country (56%). Slow saccades and decreased deep tendon reflexes were observed significantly more frequently in SCA2 patients, while increased deep tendon reflexes and nystagmus were more common in SCA1. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10399872" 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="#96" class="mim-tip-reference" title="Storey, E., du Sart, D., Shaw, J. H., Lorentzos, P., Kelly, L., Gardner, R. J. M., Forrest, S. M., Biros, I., Nicholson, G. A. &lt;strong&gt;Frequency of spinocerebellar ataxia types 1, 2, 3, 6, and 7 in Australian patients with spinocerebellar ataxia.&lt;/strong&gt; Am. J. Med. Genet. 95: 351-357, 2000.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/11186889/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;11186889&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/1096-8628(20001211)95:4&lt;351::aid-ajmg10&gt;3.0.co;2-r&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="11186889">Storey et al. (2000)</a> examined the frequency of mutations for SCA types 1, 2, 3, 6, and 7 in southeastern Australia. Of 63 pedigrees or individuals with positive tests, 30% had SCA1, 15% had SCA2, 22% had SCA3, 30% had SCA6, and 3% had SCA7. Ethnic origin was of importance in determining SCA type: 4 of 9 SCA2 index cases were of Italian origin, and 4 of 14 SCA3 index cases were of Chinese origin. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11186889" 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="#117" class="mim-tip-reference" title="Zhou, Y.-X., Qiao, W.-H., Gu, W.-H., Xie, H., Tang, B.-S., Zhou, L.-S., Yang, B.-X., Takiyama, Y., Tsuji, S., He, H.-Y., Deng, C.-X., Goldfarb, L. G., Wang, G.-X. &lt;strong&gt;Spinocerebellar ataxia type 1 in China: molecular analysis and genotype-phenotype correlation in 5 families.&lt;/strong&gt; Arch. Neurol. 58: 789-794, 2001.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/11346374/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;11346374&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1001/archneur.58.5.789&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="11346374">Zhou et al. (2001)</a> performed molecular analysis of 109 patients in 75 Chinese families with autosomal dominant SCA and 16 patients with sporadic SCA or spastic paraplegia. SCA type 1 was found in 5 families (7%), and all patients with the SCA1 phenotype were heterozygous for alleles with CAG repeat numbers ranging from 51 to 64 (control groups, 26-35). There was a significant negative correlation between age of disease onset and number of CAG repeat units. SCA3/MJD was found in 26 families, SCA2 in 9 families, SCA6 in 2 families, and SCA7 in 2 families. The combined frequency of SCA1, SCA2, and SCA3/MJD was 53%. None of the 16 sporadic cases was positive for the mutations tested, and no patients were positive for SCA8 (<a href="/entry/608768">608768</a>), SCA12, or DRPLA. Clinically, the authors noted that SCA3/MJD tended to manifest more frequently with ophthalmoparesis, eyelid retraction, facial myokymia, ataxia, spasticity, and amyotrophy. The frequency of single CAT interruptions in the ATXN1 gene was higher in the Siberian Sakha control group, which also had a higher prevalence of SCA1 than the Chinese population, suggesting that a substitution of CAT for CAG may be the initial event contributing to the generation of expanded alleles. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11346374" 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>Of 253 unrelated Korean patients with progressive cerebellar ataxia, <a href="#49" class="mim-tip-reference" title="Lee, W. Y., Jin, D. K., Oh, M. R., Lee, J. E., Song, S. M., Lee, E. A., Kim, G., Chung, J. S., Lee, K. H. &lt;strong&gt;Frequency analysis and clinical characterization of spinocerebellar ataxia types 1, 2, 3, 6, and 7 in Korean patients.&lt;/strong&gt; Arch. Neurol. 60: 858-863, 2003. Note: Erratum: Arch. Neurol. 60: 1256 only, 2003.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/12810491/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;12810491&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1001/archneur.60.6.858&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="12810491">Lee et al. (2003)</a> identified 52 (20.6%) with expanded CAG repeats. The most frequent SCA type was SCA2 (33%), followed by SCA3 (29%), SCA6 (19%), SCA1 (12%), and SCA7 (8%). There were characteristic clinical features, such as hypotonia and optic atrophy for SCA1, hyporeflexia for SCA2, nystagmus, bulging eye, and dystonia for SCA3, and macular degeneration for SCA7. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12810491" 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="#59" class="mim-tip-reference" title="Mittal, U., Sharma, S., Chopra, R., Dheeraj, K., Pal, P. K., Srivastava, A. K., Mukerji, M. &lt;strong&gt;Insights into the mutational history and prevalence of SCA1 in the Indian population through anchored polymorphisms.&lt;/strong&gt; Hum. Genet. 118: 107-114, 2005.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/16133185/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;16133185&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1007/s00439-005-0018-8&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="16133185">Mittal et al. (2005)</a> found SCA1 in 37 (22%) of 167 Indian families with ADCA. The frequency of SCA1 in the south Indian population was twice (33%) that of the north Indian population (16%). The nonaffected repeat length ranged from 21 to 39 triplets. Haplotype analysis identified an ancestral C-4-C haplotype (<a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1476464;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs1476464</a>, D6S288, and <a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs2075974;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs2075974</a>) that was mostly present in the affected individuals, suggesting that this background might have been predisposed for repeat expansion. This haplotype, when present in the nonaffected chromosomes, had multiple interruptions in the repeat tract, which the authors hypothesized would provide genetic stability. However, in disease chromosomes, this haplotype showed large normal (greater than 30 repeats) expansions and was associated with the expanded chromosomes in about 44% of SCA1 families. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16133185" 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 113 Japanese families from the island of Hokkaido with autosomal dominant SCA, <a href="#4" class="mim-tip-reference" title="Basri, R., Yabe, I., Soma, H., Sasaki, H. &lt;strong&gt;Spectrum and prevalence of autosomal dominant spinocerebellar ataxia in Hokkaido, the northern island of Japan: a study of 113 Japanese families.&lt;/strong&gt; J. Hum. Genet. 52: 848-855, 2007.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/17805477/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;17805477&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1007/s10038-007-0182-x&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="17805477">Basri et al. (2007)</a> found that SCA6 was the most common form of the disorder, identified in 35 (31%) families. Thirty (27%) families had SCA3, 11 (10%) had SCA1, 5 (4%) had SCA2, 5 (4%) had DRPLA, 10 (9%) had 16q22-linked SCA, and 1 (1%) had SCA14 (<a href="/entry/605361">605361</a>). The specific disorder could not be identified in 16 (14%) families. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17805477" 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="#110" class="mim-tip-reference" title="Weiner, L. P., Konigsmark, B. W. &lt;strong&gt;Hereditary disease of the cerebellar parenchyma.&lt;/strong&gt; Birth Defects Orig. Art. Ser. VII(1): 192-196, 1971."None>Weiner and Konigsmark (1971)</a> provided a review of hereditary diseases of the cerebellum. Affected families have been described by <a href="#29" class="mim-tip-reference" title="Hall, B., Noad, K. B., Latham, O. &lt;strong&gt;Familial cortical cerebellar atrophy.&lt;/strong&gt; Brain 64: 178-194, 1941."None>Hall et al. (1941)</a>, <a href="#79" class="mim-tip-reference" title="Richter, R. B. &lt;strong&gt;Late cortical cerebellar atrophy: a form of hereditary cerebellar ataxia.&lt;/strong&gt; Am. J. Hum. Genet. 2: 1-29, 1950.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/15425502/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;15425502&lt;/a&gt;]" pmid="15425502">Richter (1950)</a>, <a href="#109" class="mim-tip-reference" title="Weber, F. P., Greenfield, J. G. &lt;strong&gt;Cerebello-olivary degeneration: an example of heredo-familial incidence.&lt;/strong&gt; Brain 65: 220-231, 1942."None>Weber and Greenfield (1942)</a>, and others. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15425502" 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="#92" class="mim-tip-reference" title="Servadio, A., McCall, A., Zoghbi, H., Eicher, E. M. &lt;strong&gt;Mapping of the Sca1 and pcd genes on mouse chromosome 13 provides evidence that they are different genes.&lt;/strong&gt; Genomics 29: 812-813, 1995.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/8575786/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;8575786&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1006/geno.1995.9925&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="8575786">Servadio et al. (1995)</a> mapped the mouse homolog of the ATXN1 gene to mouse chromosome 13. Although human SCA1 is characterized by progressive Purkinje cell degeneration, <a href="#92" class="mim-tip-reference" title="Servadio, A., McCall, A., Zoghbi, H., Eicher, E. M. &lt;strong&gt;Mapping of the Sca1 and pcd genes on mouse chromosome 13 provides evidence that they are different genes.&lt;/strong&gt; Genomics 29: 812-813, 1995.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/8575786/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;8575786&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1006/geno.1995.9925&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="8575786">Servadio et al. (1995)</a> showed that pcd (Purkinje cell degeneration) mutation in the mouse, which also maps to mouse chromosome 13, is not caused by mutation in the murine Sca1 gene since linkage studies indicated that the 2 loci are separated by 7 or more cM. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8575786" 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>To gain insight into the pathogenesis of SCA1 and the intergenerational stability of trinucleotide repeats in mice, <a href="#8" class="mim-tip-reference" title="Burright, E. N., Clark, H. B., Servadio, A., Matilla, T., Feddersen, R. M., Yunis, W. S., Duvick, L. A., Zoghbi, H. Y., Orr, H. T. &lt;strong&gt;SCA1 transgenic mice: a model for neurodegeneration caused by an expanded CAG trinucleotide repeat.&lt;/strong&gt; Cell 82: 937-948, 1995.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/7553854/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;7553854&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/0092-8674(95)90273-2&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="7553854">Burright et al. (1995)</a> generated transgenic mice expressing the human ATXN1 gene with either a normal or an expanded CAG tract. Both transgenes were stable in parent-to-offspring transmissions. While all 6 transgenic lines expressing the unexpanded human ATXN1 allele had normal Purkinje cells, transgenic animals from 5 of 6 lines with the expanded ATXN1 allele developed ataxia and Purkinje cell degeneration. These data indicated to the authors that expanded CAG repeats expressed in Purkinje cells are sufficient to produce degeneration and ataxia and demonstrated that a mouse model can be established from neurodegeneration caused by CAG repeat expansions. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7553854" 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>To examine genetic aspects of trinucleotide repeat instability, <a href="#37" class="mim-tip-reference" title="Kaytor, M. D., Burright, E. N., Duvick, L. A., Zoghbi, H. Y., Orr, H. T. &lt;strong&gt;Increased trinucleotide repeat instability with advanced maternal age.&lt;/strong&gt; Hum. Molec. Genet. 6: 2135-2139, 1997.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/9328478/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;9328478&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1093/hmg/6.12.2135&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="9328478">Kaytor et al. (1997)</a> introduced an ATXN1 cDNA containing a CAG trinucleotide repeat tract into transgenic mice and analyzed both maternal and paternal transmission of the repeat. Intergenerational CAG repeat instability was detected only when the transgene was maternally transmitted. The intergenerational instability increased in frequency and magnitude as the transgenic mother aged. Furthermore, triplet repeat variations were detected in unfertilized oocytes and were comparable with those in the offspring. These data showed that maternal repeat instability in the transgenic mice occurs after meiotic DNA replication and before oocyte fertilization. The findings demonstrated that advanced maternal age is an important factor for instability of nucleotide repeats in mammalian DNA. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9328478" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#40" class="mim-tip-reference" title="Klement, I. A., Skinner, P. J., Kaytor, M. D., Yi, H., Hersch, S. M., Clark, H. B., Zoghbi, H. Y., Orr, H. T. &lt;strong&gt;Ataxin-1 nuclear localization and aggregation: role in polyglutamine-induced disease in SCA1 transgenic mice.&lt;/strong&gt; Cell 95: 41-53, 1998.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/9778246/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;9778246&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/s0092-8674(00)81781-x&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="9778246">Klement et al. (1998)</a> stated that transgenic mice carrying the Sca1 gene develop ataxia with ataxin-1 localized to aggregates within cerebellar Purkinje cell nuclei. To examine the importance of nuclear localization and aggregation in pathogenesis, mice expressing ataxin-1(82) with a mutated NLS (nuclear localization signal K772T) were established. These mice did not develop disease, demonstrating that nuclear localization is critical for pathogenesis. In another transgenic mouse colony, ataxin-1(77) containing a deletion within the self-association region (amino acid residues 472-594) was expressed within Purkinje cell nuclei. These mice developed ataxia and Purkinje cell pathology similar to the original SCA1 mice. However, no evidence of nuclear ataxin-1 aggregates was found. Thus <a href="#40" class="mim-tip-reference" title="Klement, I. A., Skinner, P. J., Kaytor, M. D., Yi, H., Hersch, S. M., Clark, H. B., Zoghbi, H. Y., Orr, H. T. &lt;strong&gt;Ataxin-1 nuclear localization and aggregation: role in polyglutamine-induced disease in SCA1 transgenic mice.&lt;/strong&gt; Cell 95: 41-53, 1998.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/9778246/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;9778246&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/s0092-8674(00)81781-x&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="9778246">Klement et al. (1998)</a> concluded that although nuclear localization of ataxin-1 is necessary, nuclear aggregation of ataxin-1 is not required to initiate pathogenesis in transgenic mice. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9778246" 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="#51" class="mim-tip-reference" title="Lorenzetti, D., Watase, K., Xu, B., Matzuk, M. M., Orr, H. T., Zoghbi, H. Y. &lt;strong&gt;Repeat instability and motor incoordination in mice with a targeted expanded CAG repeat in the Sca1 locus.&lt;/strong&gt; Hum. Molec. Genet. 9: 779-785, 2000.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/10749985/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;10749985&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1093/hmg/9.5.779&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="10749985">Lorenzetti et al. (2000)</a> generated knockin mice by inserting an expanded tract of 78 CAG repeats into the mouse Sca1 locus. Mice heterozygous for the CAG expansion showed intergenerational repeat instability (+2 to -6) at a much higher frequency in maternal transmission than in paternal transmission. Mice homozygous for mutant ataxin-1 on a C57BL/6J-129/SvEv mixed background performed significantly less well on the rotating rod than did wildtype littermates at 9 months of age, although they were not ataxic by cage behavior. Histologic examination of brain tissue from mutant mice up to 18 months of age revealed none of the neuropathologic changes observed in other transgenic models overexpressing expanded polyglutamine tracts. The authors hypothesized that, even with 78 glutamines, prolonged exposure to mutant ataxin-1 at endogenous levels is necessary to produce a neurologic phenotype reminiscent of human SCA1, and that pathogenesis may be a function of polyglutamine length, protein levels, and duration of neuronal exposure to the mutant protein. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10749985" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#14" class="mim-tip-reference" title="Cummings, C. J., Sun, Y., Opal, P., Antalffy, B., Mestril, R., Orr, H. T., Dillmann, W. H., Zoghbi, H. Y. &lt;strong&gt;Over-expression of inducible HSP70 chaperone suppresses neuropathology and improves motor function in SCA1 mice.&lt;/strong&gt; Hum. Molec. Genet. 10: 1511-1518, 2001.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/11448943/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;11448943&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1093/hmg/10.14.1511&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="11448943">Cummings et al. (2001)</a> crossbred SCA1 mice with mice overexpressing the molecular chaperone inducible HSP70 (HSPA1A; <a href="/entry/140550">140550</a>). Although the amount of nuclear inclusions in Purkinje cells persisted, physiologic and histopathologic analysis revealed that high levels of HSP70 appeared to afford protection against neurodegeneration and preserved dendritic arborization in the cerebellum. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11448943" 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="#63" class="mim-tip-reference" title="Okuda, T., Hattori, H., Takeuchi, S., Shimizu, J., Ueda, H., Palvimo, J. J., Kanazawa, I., Kawano, H., Nakagawa, M., Okazawa, H. &lt;strong&gt;PQBP-1 transgenic mice show a late-onset motor neuron disease-like phenotype.&lt;/strong&gt; Hum. Molec. Genet. 12: 711-725, 2003.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/12651867/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;12651867&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1093/hmg/ddg084&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="12651867">Okuda et al. (2003)</a> generated transgenic mice overexpressing human PQBP1 (<a href="/entry/300463">300463</a>), a polyglutamine-binding nuclear protein that interacts with ataxin-1. The mice showed a late-onset and gradually progressive motor neuron disease-like phenotype suggestive of the neurogenic muscular atrophy observed in SCA1 patients. Ataxia could not be discriminated from predominant progressive weakness. Pathologic examinations of the transgenic mice revealed loss of Purkinje and granular cells in the cerebellum as well as loss of motor neurons in the spinal anterior horn, corresponding to the pathology of human SCA1. <a href="#63" class="mim-tip-reference" title="Okuda, T., Hattori, H., Takeuchi, S., Shimizu, J., Ueda, H., Palvimo, J. J., Kanazawa, I., Kawano, H., Nakagawa, M., Okazawa, H. &lt;strong&gt;PQBP-1 transgenic mice show a late-onset motor neuron disease-like phenotype.&lt;/strong&gt; Hum. Molec. Genet. 12: 711-725, 2003.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/12651867/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;12651867&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1093/hmg/ddg084&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="12651867">Okuda et al. (2003)</a> concluded that excessive action of PQBP1 causes neuronal dysfunction and that PQBP1 may be involved in the pathology of SCA1. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12651867" 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="#108" class="mim-tip-reference" title="Watase, K., Venken, K. J. T., Sun, Y., Orr, H. T., Zoghbi, H. Y. &lt;strong&gt;Regional differences of somatic CAG repeat instability do not account for selective neuronal vulnerability in a knock-in mouse model of SCA1.&lt;/strong&gt; Hum. Molec. Genet. 12: 2789-2795, 2003.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/12952864/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;12952864&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1093/hmg/ddg300&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="12952864">Watase et al. (2003)</a> investigated the pattern of CAG repeat instability in a knockin mouse model of SCA1. Small pool (SP)-PCR analysis on DNA from various neuronal and nonneuronal tissues revealed that somatic repeat instability was highest in the striatum. In 2 SCA1-vulnerable tissues, cerebellum and spinal cord, there were substantial differences in the profile of mosaicism. <a href="#108" class="mim-tip-reference" title="Watase, K., Venken, K. J. T., Sun, Y., Orr, H. T., Zoghbi, H. Y. &lt;strong&gt;Regional differences of somatic CAG repeat instability do not account for selective neuronal vulnerability in a knock-in mouse model of SCA1.&lt;/strong&gt; Hum. Molec. Genet. 12: 2789-2795, 2003.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/12952864/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;12952864&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1093/hmg/ddg300&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="12952864">Watase et al. (2003)</a> suggested that in SCA1 there is no clear causal relationship between the degree of somatic instability and selective neuronal vulnerability. The finding that somatic instability is most pronounced in the striatum of various knockin models of polyglutamine diseases may suggest a role of trans-acting tissue- or cell-specific factors in mediating the instability. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12952864" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In a mouse model of SCA1, <a href="#115" class="mim-tip-reference" title="Xia, H., Mao, Q., Eliason, S. L., Harper, S. Q., Martins, I. H., Orr, H. T., Paulson, H. L., Yang, L., Kotin, R. M., Davidson, B. L. &lt;strong&gt;RNAi suppresses polyglutamine-induced neurodegeneration in a model of spinocerebellar ataxia.&lt;/strong&gt; Nature Med. 10: 816-820, 2004.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/15235598/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;15235598&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1038/nm1076&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="15235598">Xia et al. (2004)</a> performed intracerebellar delivery of viral vectors expressing short hairpin RNAs targeting ataxin-1 as a therapeutic use of RNA interference (RNAi). The treated mice showed reduced ataxin-1 expression in Purkinje cells, resolution of intracellular ataxin-1 inclusions in the cerebellum, and improved motor performance. <a href="#115" class="mim-tip-reference" title="Xia, H., Mao, Q., Eliason, S. L., Harper, S. Q., Martins, I. H., Orr, H. T., Paulson, H. L., Yang, L., Kotin, R. M., Davidson, B. L. &lt;strong&gt;RNAi suppresses polyglutamine-induced neurodegeneration in a model of spinocerebellar ataxia.&lt;/strong&gt; Nature Med. 10: 816-820, 2004.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/15235598/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;15235598&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1038/nm1076&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="15235598">Xia et al. (2004)</a> noted the importance of screening multiple hairpins before identifying an appropriate one for targeted gene silencing. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15235598" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>By comparing previously reported genetic modifiers in 3 Drosophila models of human neurodegenerative disease, <a href="#24" class="mim-tip-reference" title="Ghosh, S., Feany, M. B. &lt;strong&gt;Comparison of pathways controlling toxicity in the eye and brain in Drosophila models of human neurodegenerative diseases.&lt;/strong&gt; Hum. Molec. Genet. 13: 2011-2018, 2004.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/15254017/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;15254017&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1093/hmg/ddh214&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="15254017">Ghosh and Feany (2004)</a> confirmed that protein folding, histone acetylation, and apoptosis are common features of neurotoxicity. Two novel genetic modifiers, the Drosophila homolog of ATXN2 (<a href="/entry/601517">601517</a>) and CGI7231, were identified. Cell-type specificity was demonstrated as many, but not all, retinal modifiers also modified toxicity in postmitotic neurons. <a href="#24" class="mim-tip-reference" title="Ghosh, S., Feany, M. B. &lt;strong&gt;Comparison of pathways controlling toxicity in the eye and brain in Drosophila models of human neurodegenerative diseases.&lt;/strong&gt; Hum. Molec. Genet. 13: 2011-2018, 2004.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/15254017/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;15254017&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1093/hmg/ddh214&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="15254017">Ghosh and Feany (2004)</a> identified nicotinamide, which has histone deacetylase-inhibiting activity, as a potent suppressor of polyglutamine toxicity. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15254017" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Using a conditional transgenic mouse model of SCA1, <a href="#90" class="mim-tip-reference" title="Serra, H. G., Duvick, L., Zu, T., Carlson, K., Stevens, S., Jorgensen, N., Lysholm, A., Burright, E., Zoghbi, H. Y., Clark, H. B., Andresen, J. M., Orr, H. T. &lt;strong&gt;ROR-alpha-mediated Purkinje cell development determines disease severity in adult SCA1 mice.&lt;/strong&gt; Cell 127: 697-708, 2006.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/17110330/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;17110330&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/j.cell.2006.09.036&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="17110330">Serra et al. (2006)</a> showed that delaying postnatal expression of mutant human ATXN1 until completion of cerebellar maturation led to a substantial reduction in disease severity in adults compared with early postnatal expression of mutant ATXN1. Microarray analysis revealed that genes regulated by Rora (<a href="/entry/600825">600825</a>), a transcription factor critical for cerebellar development, were downregulated at an early stage of disease in Purkinje cells of SCA1 transgenic mice. Rora mRNA and protein levels were reduced in Purkinje cells of SCA1 transgenic mice, and the effect of mutant ATXN1 on Rora protein levels appeared to be independent of its effect on Rora mRNA levels. Partial loss of Rora enhanced the pathogenicity of mutant ATXN1 in transgenic mice. Coimmunoprecipitation and pull-down analyses suggested the existence of a complex containing Atxn1, Rora, and the Rora coactivator Tip60 (HTATIP; <a href="/entry/601409">601409</a>), with Atxn1 and Tip60 interacting directly. <a href="#90" class="mim-tip-reference" title="Serra, H. G., Duvick, L., Zu, T., Carlson, K., Stevens, S., Jorgensen, N., Lysholm, A., Burright, E., Zoghbi, H. Y., Clark, H. B., Andresen, J. M., Orr, H. T. &lt;strong&gt;ROR-alpha-mediated Purkinje cell development determines disease severity in adult SCA1 mice.&lt;/strong&gt; Cell 127: 697-708, 2006.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/17110330/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;17110330&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/j.cell.2006.09.036&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="17110330">Serra et al. (2006)</a> concluded that RORA and TIP60 have a role in SCA1 and proposed that their findings provide a mechanism by which compromised cerebellar development contributes to the severity of neurodegeneration in an adult. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17110330" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Using microarray analysis of the cerebellum in mouse models of SCA1 and SCA7, <a href="#21" class="mim-tip-reference" title="Gatchel, J. R., Watase, K., Thaller, C., Carson, J. P., Jafar-Nejad, P., Shaw, C., Zu, T., Orr, H. T., Zoghbi, H. Y. &lt;strong&gt;The insulin-like growth factor pathway is altered in spinocerebellar ataxia type 1 and type 7.&lt;/strong&gt; Proc. Nat. Acad. Sci. 105: 1291-1296, 2008.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/18216249/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;18216249&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=18216249[PMID]&amp;report=imagesdocsum&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed Image&#x27;, &#x27;domain&#x27;: &#x27;ncbi.nlm.nih.gov&#x27;})&quot;&gt;images&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1073/pnas.0711257105&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="18216249">Gatchel et al. (2008)</a> found that both disorders were associated with significant downregulation of Igfbp5 (<a href="/entry/146734">146734</a>) in the granular cell layer. Further analysis showed additional misregulation in both models, including activation of the IGF pathway and the Igf1 receptor (IGF1R; <a href="/entry/147370">147370</a>) in Purkinje cells. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18216249" 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>To determine the long-term effects of exercise, <a href="#20" class="mim-tip-reference" title="Fryer, J. D., Yu, P., Kang, H., Mandel-Brehm, C., Carter, A. N., Crespo-Barreto, J., Gao, V., Flora, A., Shaw, C., Orr, H. T., Zoghbi, H. Y. &lt;strong&gt;Exercise and genetic rescue of SCA1 via the transcriptional repressor Capicua.&lt;/strong&gt; Science 334: 690-693, 2011.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/22053053/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;22053053&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=22053053[PMID]&amp;report=imagesdocsum&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed Image&#x27;, &#x27;domain&#x27;: &#x27;ncbi.nlm.nih.gov&#x27;})&quot;&gt;images&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1126/science.1212673&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="22053053">Fryer et al. (2011)</a> implemented a mild exercise regimen in a mouse model of SCA1 and found a considerable improvement in survival accompanied by upregulation of epidermal growth factor and consequential downregulation of Capicua (<a href="/entry/612082">612082</a>), which is an ATXN1 (<a href="/entry/601556">601556</a>) interactor. Offspring of Capicua mutant mice bred to Sca1 mice showed significant improvement of all disease phenotypes. Although polyglutamine-expanded Atxn1 caused some loss of Capicua function, further reduction of Capicua levels--either genetically or by exercise--mitigated the disease phenotypes by dampening the toxic gain of function. <a href="#20" class="mim-tip-reference" title="Fryer, J. D., Yu, P., Kang, H., Mandel-Brehm, C., Carter, A. N., Crespo-Barreto, J., Gao, V., Flora, A., Shaw, C., Orr, H. T., Zoghbi, H. Y. &lt;strong&gt;Exercise and genetic rescue of SCA1 via the transcriptional repressor Capicua.&lt;/strong&gt; Science 334: 690-693, 2011.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/22053053/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;22053053&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=22053053[PMID]&amp;report=imagesdocsum&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed Image&#x27;, &#x27;domain&#x27;: &#x27;ncbi.nlm.nih.gov&#x27;})&quot;&gt;images&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1126/science.1212673&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="22053053">Fryer et al. (2011)</a> concluded that exercise might have long-term beneficial effects in other ataxias and neurodegenerative diseases. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22053053" 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 Sca1 mice, <a href="#16" class="mim-tip-reference" title="Cvetanovic, M., Patel, J. M., Marti, H. H., Kini, A. R., Opal, P. &lt;strong&gt;Vascular endothelial growth factor ameliorates the ataxic phenotype in a mouse model of spinocerebellar ataxia type 1.&lt;/strong&gt; Nature Med. 17: 1445-1447, 2011.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/22001907/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;22001907&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=22001907[PMID]&amp;report=imagesdocsum&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed Image&#x27;, &#x27;domain&#x27;: &#x27;ncbi.nlm.nih.gov&#x27;})&quot;&gt;images&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1038/nm.2494&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="22001907">Cvetanovic et al. (2011)</a> found that mutant Atxn1 repressed transcription of Vegfa (<a href="/entry/192240">192240</a>), resulting in decreased Vegfa mRNA and protein levels in cerebellar Purkinje cells. Sca1 mice showed a decrease in cerebellar microvessel density and length, as well as evidence of cellular hypoxia. Inhibition of Vegfa in neuronal cell culture resulted in decreased neurite length and increased cell death. Genetic overexpression or pharmacologic infusion of Vegfa ameliorated the phenotype of Sca1 mice and improved cerebellar pathology. The findings suggested a role for VEGFA in SCA1 pathogenesis and suggested that restoration of VEGFA may be a therapeutic strategy. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22001907" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a href="#Banfi1996" class="mim-tip-reference" title="Banfi, S., Servadio, A., Chung, M.-y., Capozzoli, F., Duvick, L. A., Elde, R., Zoghbi, H. Y., Orr, H. T. &lt;strong&gt;Cloning and developmental expression analysis of the murine homolog of the spinocerebellar ataxia type 1 gene (Sca1).&lt;/strong&gt; Hum. Molec. Genet. 5: 33-40, 1996.">Banfi et al. (1996)</a>; <a href="#Critchley1948" class="mim-tip-reference" title="Critchley, M., Greenfield, J. G. &lt;strong&gt;Olivoponto-cerebellar atrophy.&lt;/strong&gt; Brain 71: 344-364, 1948.">Critchley and Greenfield (1948)</a>; <a href="#Geary1956" class="mim-tip-reference" title="Geary, J. R., Jr., Earle, K. M., Rose, A. S. &lt;strong&gt;Case report: olivoponto-cerebellar atrophy.&lt;/strong&gt; Neurology 6: 218-224, 1956.">Geary et al.
(1956)</a>; <a href="#Harding1983" class="mim-tip-reference" title="Harding, A. E. &lt;strong&gt;Classification of the hereditary ataxias and paraplegias.&lt;/strong&gt; Lancet 321: 1151-1155, 1983. Note: Originally Volume I.">Harding (1983)</a>; <a href="#Koeppen1977" class="mim-tip-reference" title="Koeppen, A. H., Hans, M. B., Sheperd, D. I., Best, P. V. &lt;strong&gt;Adult-onset hereditary ataxia in Scotland.&lt;/strong&gt; Arch. Neurol. 34: 611-618, 1977.">Koeppen et al. (1977)</a>; <a href="#Spadaro1992" class="mim-tip-reference" title="Spadaro, M., Giunti, P., Lulli, P., Frontali, M., Jodice, C., Cappellacci, S., Morellini, M., Persichetti, F., Trabace, S., Anastasi, R., Morocutti, C. &lt;strong&gt;HLA-linked spinocerebellar ataxia: a clinical and genetic study of large Italian kindreds.&lt;/strong&gt; Acta Neurol. Scand. 85: 257-265, 1992.">Spadaro et al. (1992)</a>; <a href="#Wang1996" class="mim-tip-reference" title="Wang, S., Detera-Wadleigh, S. D., Coon, H., Sun, C., Goldin, L. R., Duffy, D. L., Byerley, W. F., Gershon, E. S., Diehl, S. R. &lt;strong&gt;Evidence of linkage disequilibrium between schizophrenia and the SCA1 CAG repeat on chromosome 6p23. (Letter)&lt;/strong&gt; Am. J. Hum. Genet. 59: 731-736, 1996.">Wang et al. (1996)</a>; <a href="#Werdelin1984" class="mim-tip-reference" title="Werdelin, L., Platz, P., Lamm, L. U. &lt;strong&gt;Linkage between late onset, dominant spinocerebellar ataxia and HLA.&lt;/strong&gt; Hum. Genet. 66: 85-89, 1984.">Werdelin et al. (1984)</a>; <a href="#Whittington1980" class="mim-tip-reference" title="Whittington, J. E., Keats, B. J. B., Jackson, J. F., Currier, R. D., Terasaki, P. I. &lt;strong&gt;Linkage studies on glyoxalase I (GLO), pepsinogen (PG), spinocerebellar ataxia (SCA1), and HLA.&lt;/strong&gt; Cytogenet. Cell Genet. 28: 145-150, 1980.">Whittington et al.
(1980)</a>; <a href="#Yakura1974" class="mim-tip-reference" title="Yakura, H., Wakisaka, A., Fujimoto, S., Itakura, K. &lt;strong&gt;Hereditary ataxia and HL-A genotypes. (Letter)&lt;/strong&gt; New Eng. J. Med. 291: 154-155, 1974.">Yakura et al. (1974)</a>; <a href="#Zoghbi1988" class="mim-tip-reference" title="Zoghbi, H. Y., Sandkuyl, L. A., Ott, J., Daiger, S. P., O&#x27;Brien, W. E., Beaudet, A. L. &lt;strong&gt;Multilocus linkage analysis localizes the gene for autosomal dominant spinocerebellar ataxia (SCA1) centromeric to the HLA region on the short arm of chromosome 6. (Abstract)&lt;/strong&gt; Am. J. Hum. Genet. 43: A164, 1988.">Zoghbi et al. (1988)</a>
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<strong>REFERENCES</strong>
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Banfi, S., Servadio, A., Chung, M., Kwiatkowski, T. J., Jr., McCall, A. E., Duvick, L. A., Shen, Y., Roth, E. J., Orr, H. T., Zoghbi, H. Y.
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<a id="Banfi1996" class="mim-anchor"></a>
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Banfi, S., Servadio, A., Chung, M.-y., Capozzoli, F., Duvick, L. A., Elde, R., Zoghbi, H. Y., Orr, H. T.
<strong>Cloning and developmental expression analysis of the murine homolog of the spinocerebellar ataxia type 1 gene (Sca1).</strong>
Hum. Molec. Genet. 5: 33-40, 1996.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8789437/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8789437</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8789437" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1093/hmg/5.1.33" target="_blank">Full Text</a>]
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Basri, R., Yabe, I., Soma, H., Sasaki, H.
<strong>Spectrum and prevalence of autosomal dominant spinocerebellar ataxia in Hokkaido, the northern island of Japan: a study of 113 Japanese families.</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17805477/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17805477</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17805477" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1007/s10038-007-0182-x" target="_blank">Full Text</a>]
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Berciano, J.
<strong>Olivopontocerebellar atrophy: a review of 117 cases.</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7057212/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7057212</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7057212" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1016/0022-510x(82)90011-9" target="_blank">Full Text</a>]
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<a id="Burk1996" class="mim-anchor"></a>
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Burk, K., Abele, M., Fetter, M., Dichgans, J., Skalej, M., Laccone, F., Didierjean, O., Brice, A., Klockgether, T.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8931575/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8931575</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8931575" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1093/brain/119.5.1497" target="_blank">Full Text</a>]
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<a id="Burk1999" class="mim-anchor"></a>
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Burk, K., Fetter, M., Abele, M., Laccone, F., Brice, A., Dichgans, J., Klockgether, T.
<strong>Autosomal dominant cerebellar ataxia type I: oculomotor abnormalities in families with SCA1, SCA2, and SCA3.</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10525976/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10525976</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10525976" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1007/s004150050456" target="_blank">Full Text</a>]
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Burright, E. N., Clark, H. B., Servadio, A., Matilla, T., Feddersen, R. M., Yunis, W. S., Duvick, L. A., Zoghbi, H. Y., Orr, H. T.
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[<a href="https://doi.org/10.1016/0092-8674(95)90273-2" target="_blank">Full Text</a>]
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Buttner, N., Geschwind, D., Jen, J. C., Perlman, S., Pulst, S. M., Baloh, R. W.
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[<a href="https://doi.org/10.1001/archneur.55.10.1353" target="_blank">Full Text</a>]
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Carson, W. J., Radvany, J., Farrer, L. A., Vincent, D., Rosenberg, R. N., MacLeod, P. M., Rouleau, G. A.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1639414/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1639414</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1639414" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1016/0888-7543(92)90168-r" target="_blank">Full Text</a>]
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<a id="Chung1993" class="mim-anchor"></a>
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Chung, M., Ranum, L. P. W., Duvick, L. A., Servadio, A., Zoghbi, H. Y., Orr, H. T.
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[<a href="https://doi.org/10.1038/ng1193-254" target="_blank">Full Text</a>]
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<a id="Critchley1948" class="mim-anchor"></a>
<div class="">
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Critchley, M., Greenfield, J. G.
<strong>Olivoponto-cerebellar atrophy.</strong>
Brain 71: 344-364, 1948.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18114336/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18114336</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18114336" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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<a id="Cummings1998" class="mim-anchor"></a>
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Cummings, C. J., Mancini, M. A., Antalffy, B., DeFranco, D. B., Orr, H. T., Zoghbi, H. Y.
<strong>Chaperone suppression of aggregation and altered subcellular proteasome localization imply protein misfolding in SCA1.</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9620770/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9620770</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9620770" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1038/502" target="_blank">Full Text</a>]
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<a id="Cummings2001" class="mim-anchor"></a>
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Cummings, C. J., Sun, Y., Opal, P., Antalffy, B., Mestril, R., Orr, H. T., Dillmann, W. H., Zoghbi, H. Y.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11448943/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11448943</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11448943" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1093/hmg/10.14.1511" target="_blank">Full Text</a>]
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<a id="Currier1972" class="mim-anchor"></a>
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Currier, R. D., Glover, G., Jackson, J. F., Tipton, A. C.
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[<a href="https://doi.org/10.1016/s0092-8674(00)81781-x" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1136/jnnp.57.11.1439-a" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1007/s004390050870" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1016/s0140-6736(80)90514-0" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1001/archneur.1977.00500220045007" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1097/00005792-197005000-00003" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1007/BF00290959" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1001/archneur.60.6.858" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1586/14737159.3.6.715" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1002/ajmg.1320060309" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1212/wnl.30.1.12" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1007/BF00291585" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1111/j.1399-0004.1980.tb00168.x" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1212/wnl.27.3.257" target="_blank">Full Text</a>]
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<strong>Linkage between late onset, dominant spinocerebellar ataxia and HLA.</strong>
Hum. Genet. 66: 85-89, 1984.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/6698559/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">6698559</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=6698559" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1007/BF00275192" target="_blank">Full Text</a>]
</p>
</div>
</li>
<li>
<a id="112" class="mim-anchor"></a>
<a id="Wexler1993" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Wexler, N. S.
<strong>Personal Communication.</strong>
New York, N. Y. 11/1993.
</p>
</div>
</li>
<li>
<a id="113" class="mim-anchor"></a>
<a id="Whittington1980" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Whittington, J. E., Keats, B. J. B., Jackson, J. F., Currier, R. D., Terasaki, P. I.
<strong>Linkage studies on glyoxalase I (GLO), pepsinogen (PG), spinocerebellar ataxia (SCA1), and HLA.</strong>
Cytogenet. Cell Genet. 28: 145-150, 1980.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7438789/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7438789</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7438789" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1159/000131524" target="_blank">Full Text</a>]
</p>
</div>
</li>
<li>
<a id="114" class="mim-anchor"></a>
<a id="Wilkie1991" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Wilkie, P. J., Schut, L. J., Rich, S. S.
<strong>Spinocerebellar ataxia: multipoint linkage analysis of genes associated with the disease locus.</strong>
Hum. Genet. 87: 405-408, 1991.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1879827/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1879827</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1879827" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1007/BF00197157" target="_blank">Full Text</a>]
</p>
</div>
</li>
<li>
<a id="115" class="mim-anchor"></a>
<a id="Xia2004" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Xia, H., Mao, Q., Eliason, S. L., Harper, S. Q., Martins, I. H., Orr, H. T., Paulson, H. L., Yang, L., Kotin, R. M., Davidson, B. L.
<strong>RNAi suppresses polyglutamine-induced neurodegeneration in a model of spinocerebellar ataxia.</strong>
Nature Med. 10: 816-820, 2004.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15235598/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15235598</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15235598" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1038/nm1076" target="_blank">Full Text</a>]
</p>
</div>
</li>
<li>
<a id="116" class="mim-anchor"></a>
<a id="Yakura1974" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Yakura, H., Wakisaka, A., Fujimoto, S., Itakura, K.
<strong>Hereditary ataxia and HL-A genotypes. (Letter)</strong>
New Eng. J. Med. 291: 154-155, 1974.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/4833925/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">4833925</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=4833925" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1056/NEJM197407182910314" target="_blank">Full Text</a>]
</p>
</div>
</li>
<li>
<a id="117" class="mim-anchor"></a>
<a id="Zhou2001" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Zhou, Y.-X., Qiao, W.-H., Gu, W.-H., Xie, H., Tang, B.-S., Zhou, L.-S., Yang, B.-X., Takiyama, Y., Tsuji, S., He, H.-Y., Deng, C.-X., Goldfarb, L. G., Wang, G.-X.
<strong>Spinocerebellar ataxia type 1 in China: molecular analysis and genotype-phenotype correlation in 5 families.</strong>
Arch. Neurol. 58: 789-794, 2001.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11346374/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11346374</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11346374" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1001/archneur.58.5.789" target="_blank">Full Text</a>]
</p>
</div>
</li>
<li>
<a id="118" class="mim-anchor"></a>
<a id="Zoghbi1991" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Zoghbi, H. Y., Jodice, C., Sandkuijl, L. A., Kwiatkowski, T. J., Jr., McCall, A. E., Huntoon, S. A., Lulli, P., Spadaro, M., Litt, M., Cann, H. M., Frontali, M., Terrenato, L.
<strong>The gene for autosomal dominant spinocerebellar ataxia (SCA1) maps telomeric to the HLA complex and is closely linked to the D6S89 locus in three large kindreds.</strong>
Am. J. Hum. Genet. 49: 23-30, 1991.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2063871/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2063871</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2063871" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
</p>
</div>
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<a id="119" class="mim-anchor"></a>
<a id="Zoghbi1987" class="mim-anchor"></a>
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<p class="mim-text-font">
Zoghbi, H. Y., Pollack, M. S., Ferrell, R. E., Daiger, S. P., Lyons, L. A., O'Brien, W. E., Beaudet, A. L.
<strong>Linkage studies in spinocerebellar ataxia (SCA1). (Abstract)</strong>
Cytogenet. Cell Genet. 46: 727, 1987.
</p>
</div>
</li>
<li>
<a id="120" class="mim-anchor"></a>
<a id="Zoghbi1988" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Zoghbi, H. Y., Pollack, M. S., Lyons, L. A., Ferrell, R. E., Daiger, S. P., Beaudet, A. L.
<strong>Spinocerebellar ataxia: variable age of onset and linkage to human leukocyte antigen in a large kindred.</strong>
Ann. Neurol. 23: 580-584, 1988.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3165612/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3165612</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=3165612" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1002/ana.410230609" target="_blank">Full Text</a>]
</p>
</div>
</li>
<li>
<a id="121" class="mim-anchor"></a>
<a id="Zoghbi1988" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Zoghbi, H. Y., Sandkuyl, L. A., Ott, J., Daiger, S. P., O'Brien, W. E., Beaudet, A. L.
<strong>Multilocus linkage analysis localizes the gene for autosomal dominant spinocerebellar ataxia (SCA1) centromeric to the HLA region on the short arm of chromosome 6. (Abstract)</strong>
Am. J. Hum. Genet. 43: A164, 1988.
</p>
</div>
</li>
<li>
<a id="122" class="mim-anchor"></a>
<a id="Zoghbi1989" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Zoghbi, H. Y., Sandkuyl, L. A., Ott, J., Daiger, S. P., Pollack, M., O'Brien, W. E., Beaudet, A. L.
<strong>Assignment of autosomal dominant spinocerebellar ataxia (SCA1) centromeric to the HLA region on the short arm of chromosome 6, using multilocus linkage analysis.</strong>
Am. J. Hum. Genet. 44: 255-263, 1989.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2563195/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2563195</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2563195" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
</p>
</div>
</li>
<li>
<a id="123" class="mim-anchor"></a>
<a id="Zuhlke2002" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Zuhlke, C., Dalski, A., Hellenbroich, Y., Bubel, S., Schwinger, E., Burk, K.
<strong>Spinocerebellar ataxia type 1 (SCA1): Phenotype-genotype correlation studies in intermediate alleles.</strong>
Europ. J. Hum. Genet. 10: 204-209, 2002.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11973625/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11973625</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11973625" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1038/sj.ejhg.5200788" target="_blank">Full Text</a>]
</p>
</div>
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<a id="contributors" class="mim-anchor"></a>
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<a href="#mimCollapseContributors" role="button" data-toggle="collapse"> Contributors: </a>
</span>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
<span class="mim-text-font">
Cassandra L. Kniffin - updated : 11/15/2017
</span>
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</div>
<div class="row collapse" id="mimCollapseContributors">
<div class="col-lg-offset-2 col-md-offset-4 col-sm-offset-4 col-xs-offset-2 col-lg-6 col-md-6 col-sm-6 col-xs-6">
<span class="mim-text-font">
Ada Hamosh - updated : 07/06/2017<br>Cassandra L. Kniffin - updated : 3/19/2012<br>Cassandra L. Kniffin - updated : 12/1/2011<br>Ada Hamosh - updated : 11/29/2011<br>Cassandra L. Kniffin - updated : 3/30/2010<br>Matthew B. Gross - updated : 5/7/2009<br>Cassandra L. Kniffin - updated : 4/13/2009<br>Ada Hamosh - updated : 5/21/2008<br>Cassandra L. Kniffin - updated : 3/6/2008<br>Cassandra L. Kniffin - updated : 2/26/2008<br>George E. Tiller - updated : 3/21/2007<br>Cassandra L. Kniffin - updated : 7/6/2006<br>George E. Tiller - updated : 1/31/2006<br>Cassandra L. Kniffin - updated : 9/22/2005<br>Cassandra L. Kniffin - updated : 5/18/2005<br>Cassandra L. Kniffin - updated : 4/19/2005<br>George E. Tiller - updated : 2/17/2005<br>Cassandra L. Kniffin - updated : 7/26/2004<br>Cassandra L. Kniffin - updated : 5/25/2004<br>Cassandra L. Kniffin - updated : 8/7/2003<br>Michael B. Petersen - updated : 11/1/2002<br>Cassandra L. Kniffin - reorganized : 8/14/2002<br>Cassandra L. Kniffin - updated : 6/17/2002<br>George E. Tiller - updated : 12/12/2001<br>Victor A. McKusick - updated : 10/12/2001<br>Sonja A. Rasmussen - updated : 1/9/2001<br>George E. Tiller - updated : 4/25/2000<br>Victor A. McKusick - updated : 9/15/1999<br>Victor A. McKusick - updated : 8/31/1999<br>Michael J. Wright - updated : 8/16/1999<br>Orest Hurko - updated : 7/1/1999<br>Victor A. McKusick - updated : 12/10/1998<br>Orest Hurko - updated : 4/7/1998<br>Victor A. McKusick - updated : 3/27/1998<br>Victor A. McKusick - updated : 11/20/1997<br>Victor A. McKusick - updated : 9/10/1997<br>Ethylin Wang Jabs - updated : 7/21/1997<br>Victor A. McKusick - updated : 2/17/1997<br>Orest Hurko - updated : 4/2/1996<br>Orest Hurko - updated : 4/1/1996<br>Moyra Smith - updated : 3/26/1996<br>Orest Hurko - updated : 9/27/1995
</span>
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</div>
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<div>
<a id="creationDate" class="mim-anchor"></a>
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Creation Date:
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
<span class="mim-text-font">
Victor A. McKusick : 6/2/1986
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alopez : 11/29/2023
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alopez : 11/29/2023<br>carol : 05/06/2021<br>alopez : 11/17/2017<br>ckniffin : 11/15/2017<br>alopez : 07/06/2017<br>carol : 08/22/2016<br>alopez : 07/12/2016<br>ckniffin : 6/29/2016<br>carol : 12/16/2015<br>joanna : 12/15/2015<br>alopez : 7/18/2014<br>carol : 3/14/2013<br>carol : 3/20/2012<br>ckniffin : 3/19/2012<br>alopez : 12/16/2011<br>ckniffin : 12/1/2011<br>alopez : 11/30/2011<br>terry : 11/29/2011<br>wwang : 4/6/2010<br>ckniffin : 3/30/2010<br>wwang : 2/5/2010<br>terry : 12/16/2009<br>wwang : 5/11/2009<br>mgross : 5/7/2009<br>wwang : 4/29/2009<br>terry : 4/14/2009<br>ckniffin : 4/13/2009<br>terry : 2/12/2009<br>alopez : 5/27/2008<br>terry : 5/21/2008<br>terry : 5/21/2008<br>wwang : 3/19/2008<br>ckniffin : 3/6/2008<br>wwang : 3/5/2008<br>ckniffin : 2/26/2008<br>carol : 12/26/2007<br>wwang : 3/22/2007<br>terry : 3/21/2007<br>carol : 11/27/2006<br>ckniffin : 7/6/2006<br>joanna : 6/27/2006<br>carol : 6/21/2006<br>wwang : 2/7/2006<br>terry : 1/31/2006<br>ckniffin : 12/2/2005<br>ckniffin : 9/26/2005<br>wwang : 9/23/2005<br>ckniffin : 9/22/2005<br>wwang : 6/1/2005<br>wwang : 5/26/2005<br>ckniffin : 5/18/2005<br>tkritzer : 5/9/2005<br>ckniffin : 4/19/2005<br>wwang : 2/22/2005<br>terry : 2/17/2005<br>tkritzer : 11/9/2004<br>alopez : 8/30/2004<br>tkritzer : 7/26/2004<br>ckniffin : 7/26/2004<br>carol : 7/2/2004<br>tkritzer : 5/27/2004<br>ckniffin : 5/25/2004<br>tkritzer : 1/28/2004<br>ckniffin : 1/21/2004<br>ckniffin : 12/23/2003<br>ckniffin : 8/7/2003<br>ckniffin : 4/3/2003<br>cwells : 11/1/2002<br>carol : 8/14/2002<br>ckniffin : 8/13/2002<br>ckniffin : 6/21/2002<br>carol : 6/17/2002<br>ckniffin : 6/17/2002<br>cwells : 12/18/2001<br>cwells : 12/12/2001<br>carol : 11/24/2001<br>mcapotos : 10/12/2001<br>mcapotos : 1/9/2001<br>alopez : 4/25/2000<br>alopez : 11/23/1999<br>mgross : 9/22/1999<br>terry : 9/15/1999<br>jlewis : 8/31/1999<br>alopez : 8/18/1999<br>terry : 8/16/1999<br>mgross : 7/1/1999<br>kayiaros : 7/1/1999<br>carol : 12/15/1998<br>dkim : 12/15/1998<br>terry : 12/10/1998<br>carol : 7/9/1998<br>carol : 5/19/1998<br>terry : 4/7/1998<br>alopez : 3/27/1998<br>terry : 3/25/1998<br>terry : 11/21/1997<br>terry : 11/20/1997<br>terry : 9/10/1997<br>mark : 9/3/1997<br>mark : 9/3/1997<br>terry : 9/2/1997<br>mark : 8/1/1997<br>mark : 8/1/1997<br>jenny : 8/1/1997<br>mark : 7/31/1997<br>mark : 2/17/1997<br>terry : 2/11/1997<br>terry : 12/5/1996<br>mark : 12/5/1996<br>terry : 12/4/1996<br>terry : 11/13/1996<br>terry : 10/8/1996<br>terry : 5/17/1996<br>terry : 5/14/1996<br>terry : 4/15/1996<br>mark : 4/2/1996<br>terry : 4/1/1996<br>mark : 3/26/1996<br>terry : 3/19/1996<br>mark : 2/14/1996<br>terry : 2/8/1996<br>terry : 11/13/1995<br>mark : 11/7/1995<br>mimadm : 12/2/1994<br>pfoster : 4/22/1994<br>warfield : 4/21/1994
</span>
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<h3>
<span class="mim-font">
<strong>#</strong> 164400
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<h3>
<span class="mim-font">
SPINOCEREBELLAR ATAXIA 1; SCA1
</span>
</h3>
</div>
<div>
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<div >
<p>
<span class="mim-font">
<em>Alternative titles; symbols</em>
</span>
</p>
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<h4>
<span class="mim-font">
SPINOCEREBELLAR ATROPHY I<br />
OLIVOPONTOCEREBELLAR ATROPHY I; OPCA1<br />
OPCA I<br />
OLIVOPONTOCEREBELLAR ATROPHY IV; OPCA4<br />
OPCA IV<br />
CEREBELLOPARENCHYMAL DISORDER I; CPD1<br />
MENZEL TYPE OPCA<br />
SCHUT-HAYMAKER TYPE OPCA
</span>
</h4>
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<br />
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<p>
<span class="mim-text-font">
<strong>SNOMEDCT:</strong> 715748006; &nbsp;
<strong>ORPHA:</strong> 98755; &nbsp;
<strong>DO:</strong> 0050954; &nbsp;
</span>
</p>
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<div>
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<h4>
<span class="mim-font">
<strong>Phenotype-Gene Relationships</strong>
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</h4>
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<table class="table table-bordered table-condensed small mim-table-padding">
<thead>
<tr class="active">
<th>
Location
</th>
<th>
Phenotype
</th>
<th>
Phenotype <br /> MIM number
</th>
<th>
Inheritance
</th>
<th>
Phenotype <br /> mapping key
</th>
<th>
Gene/Locus
</th>
<th>
Gene/Locus <br /> MIM number
</th>
</tr>
</thead>
<tbody>
<tr>
<td>
<span class="mim-font">
6p22.3
</span>
</td>
<td>
<span class="mim-font">
Spinocerebellar ataxia 1
</span>
</td>
<td>
<span class="mim-font">
164400
</span>
</td>
<td>
<span class="mim-font">
Autosomal dominant
</span>
</td>
<td>
<span class="mim-font">
3
</span>
</td>
<td>
<span class="mim-font">
ATXN1
</span>
</td>
<td>
<span class="mim-font">
601556
</span>
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</tr>
</tbody>
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<h4>
<span class="mim-font">
<strong>TEXT</strong>
</span>
</h4>
<span class="mim-text-font">
<p>A number sign (#) is used with this entry because spinocerebellar ataxia-1 (SCA1) is caused by an expanded (CAG)n trinucleotide repeat in the ataxin-1 gene (ATXN1; 601556) on chromosome 6p22.</p>
</span>
<div>
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<h4>
<span class="mim-font">
<strong>Description</strong>
</span>
</h4>
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<span class="mim-text-font">
<p>The autosomal dominant cerebellar degenerative disorders are generally referred to as 'spinocerebellar ataxias,' (SCAs) even though 'spinocerebellar' is a hybrid term, referring to both clinical signs and neuroanatomical regions (Margolis, 2003). Neuropathologists have defined SCAs as cerebellar ataxias with variable involvement of the brainstem and spinal cord, and the clinical features of the disorders are caused by degeneration of the cerebellum and its afferent and efferent connections, which involve the brainstem and spinal cord (Schols et al., 2004; Taroni and DiDonato, 2004). </p><p>Historically, Harding (1982) proposed a clinical classification for autosomal dominant cerebellar ataxias (ADCAs). ADCA I was characterized by cerebellar ataxia in combination with various associated neurologic features, such as ophthalmoplegia, pyramidal and extrapyramidal signs, peripheral neuropathy, and dementia, among others. ADCA II was characterized by the cerebellar ataxia, associated neurologic features, and the additional findings of macular and retinal degeneration. ADCA III was a pure form of late-onset cerebellar ataxia without additional features. SCA1, SCA2 (183090), and SCA3, or Machado-Joseph disease (109150), are considered to be forms of ADCA I. These 3 disorders are characterized at the molecular level by CAG repeat expansions on 6p24-p23, 12q24.1, and 14q32.1, respectively. SCA7 (607640), caused by a CAG repeat expansion in the ATXN7 gene (607640) on chromosome 3p13-p12, is a form of ADCA II. SCA5 (600224), SCA31 (117210), SCA6 (183086), and SCA11 (600432) are associated with phenotypes most suggestive of ADCA III. However, Schelhaas et al. (2000) noted that there is significant phenotypic overlap between different forms of SCA as well as significant phenotypic variability within each subtype. </p><p>Classic reviews of olivopontocerebellar atrophies and of inherited ataxias in general include those of Konigsmark and Weiner (1970), who identified 5 types of olivopontocerebellar atrophy, Berciano (1982), Harding (1993), Schelhaas et al. (2000), and Margolis (2003). </p>
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<h4>
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<strong>Clinical Features</strong>
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<p>Symptoms of SCA1 usually begin in the third or fourth decade of life, most often around age 30. In addition to cerebellar signs, there are upper motor neuron signs and extensor plantar responses. Involuntary choreiform movements may occur. Characteristic families with autosomal dominant spinocerebellar ataxia were reported by Menzel (1891), Waggoner et al. (1938), and Destunis (1944).</p><p>Both the clinical and the pathologic pictures in the disorder described in a large kindred, known as Vandenberg, by Schut (1950) and by Schut and Haymaker (1951) were variable. Symptoms varied from those of spinocerebellar ataxia to spastic paraplegia. Identification as a form of OPCA was based on the presence of the major pathology in the inferior olivary nucleus and cerebellum with variable pontine involvement. The spinal cord showed variable loss of anterior motor horn cells and changes in the spinocerebellar tracts and posterior funiculus. Involvement of cranial nerves IX, X and XII was another distinguishing feature. </p><p>Nino et al. (1980) reported a family in which the mean age of onset was 38.8 years. In addition to ataxia, affected persons showed lower bulbar palsies, hyperreflexia, scanning and explosive speech, incoordination, and, in some, slow motor-nerve conduction. Neuropathologic findings included atrophy of the cerebellum, pons and olives, degeneration of lower cranial nerve nuclei, and atrophy of the dorsal columns and spinocerebellar tracts. Deep tendon reflexes were increased and the Babinski sign was present. Pedersen (1980) reported an extensively affected Danish kindred. Clinical expression was highly variable so that different types of cerebellar ataxia had been diagnosed in individual members of the family. In at least 10, multiple sclerosis had been diagnosed. </p><p>Robitaille et al. (1995) compared the neuropathologic features of SCA1 with those reported for SCA2 and SCA3. Unlike the findings in SCA2 and SCA3, brains in SCA1 show almost no neuronal loss from the pars compacta of the substantia nigra or from the locus ceruleus, whereas there is severe atrophy of the dentatorubral pathways. Both SCA1 and SCA2 show severe loss of Purkinje cell and degeneration of the olivocerebellar pathways, which is not seen in SCA3. All 3 disorders share severe atrophy of the nucleus pontis, sparing of the retina and optic nerve, and marked atrophy of Clarke columns and the spinocerebellar tracts. Argyrophilic glial inclusions have not been reported in any of these disorders. </p><p>In 19 (70%) of 27 patients with confirmed SCA type 1, 2, 3, 6, or 7, van de Warrenburg et al. (2004) found electrophysiologic evidence of peripheral nerve involvement. Eight patients (30%) had findings compatible with a dying-back axonopathy, whereas 11 patients (40%) had findings consistent with a primary neuronopathy involving dorsal root ganglion and/or anterior horn cells; the 2 types were clinically almost indistinguishable. Four of 5 patients with SCA1 had a neuronopathy and 1 had a sensorimotor axonopathy. </p>
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<h4>
<span class="mim-font">
<strong>Biochemical Features</strong>
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<p>In autopsied brain from 2 patients with autosomal dominant OPCA, Perry et al. (1977) found markedly reduced aspartic acid and markedly elevated taurine content. The patients were from the family reported by Currier et al. (1972), in which linkage to HLA was discovered by Jackson et al. (1977). </p><p>Plaitakis et al. (1980) found deficiency of glutamate dehydrogenase (GLUD1; 138130) in 3 patients with a 'spinocerebellar syndrome.' One was a 19-year-old male with juvenile onset of spinocerebellar and extrapyramidal manifestations. The others were 2 sibs, aged 64 and 71, with adult onset of spinocerebellar symptoms. The authors were led to this work by the fact that the nicotinamide antagonist 3-acetylpyridine produces ataxia in rats and CNS changes like those of OPCA IV. Four nicotinamide-adenine dinucleotide phosphate-requiring enzymes were measured. GDH may have an important role in metabolism of glutamate, a putative neurotransmitter in cerebellum, brainstem and spinal cord. </p><p>Sorbi et al. (1986) found a 50 to 60% reduction in platelet GLUD activity in 3 patients out of 4 with a so-called nondominant, i.e., sporadic or recessive, form of adult-onset OPCA and in father and son with a dominant form of OPCA. In another family, affected members (but not unaffected members), despite normal GDH activity, showed lack of activation of GDH by ADP in either the presence or the absence of Triton. </p>
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<h4>
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<strong>Diagnosis</strong>
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<p>Lucotte et al. (2001) demonstrated the feasibility of presymptomatic diagnosis in spinocerebellar ataxia-1. They studied a family in which the mean age of onset of the disorder was 38 years. Hitherto, presymptomatic testing for late-onset autosomal dominant disorders had largely been confined to Huntington disease, which is a genetically homogeneous entity. The same protocol could be applied to dominantly inherited ataxias, with the additional requirement that the SCA type of the disorder must be determined in the family at risk. </p>
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<h4>
<span class="mim-font">
<strong>Mapping</strong>
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<p>Jackson et al. (1977) concluded that a form of spinocerebellar atrophy is linked with HLA on chromosome 6; the lod score was 3.15 for a recombination fraction of about 12. Moller et al. (1978) found further evidence in support of this linkage. In an extensively affected Prussian family, Nino et al. (1980) also found linkage to HLA. The maximum lod score was 1.97 at a male recombination fraction of 0.18 and a female recombination fraction of 0.36. When combined with data from other families, these results yielded a lod score of 4.681 at a recombination frequency of 0.22. Morton et al. (1980) reviewed linkage data on 13 kindreds. For linkage with HLA, they found a lod score of 5.53 at recombination rates of 0.223 in males and 0.327 in females. Nine of the 13 pedigrees, which appeared to have typical OPCA I, showed recombination rates of 0.150 in males and 0.300 in females. The remaining 4 pedigrees were clinically atypical or included discrepant data and gave no evidence of linkage. They suggested that linkage evidence may be decisive in delineation of the confused category of ataxias. In addition to the typical OPCA I of Menzel, other allelic forms of ataxia may exist, e.g., that in the Danish pedigree with pyramidal lesions and dementia (Pedersen et al., 1980). </p><p>In connection with other studies of a large family, the Schut-Swier kindred (Schut, 1950), Haines et al. (1984) concluded that there was linkage with HLA (maximum lod score = 3.71 at theta = 0.18). Haines and Trofatter (1986) placed ATXN1 telomeric to HLA-A. Using a DNA marker (D6S7) to study the Schut-Swier kindred, Rich et al. (1987) demonstrated linkage between the SCA locus and HLA-A. The observed linkage indicated that the position of the gene was about 15 cM telomeric of HLA-A on 6p. Rich and Orr (1989) and Orr and Rich (1989) studied the linkage of SCA1 in 2 '7-generation kindreds' (the Schut-Swier kindred) with the conclusion that the locus is distal to HLA and proximal to F13A. Three-point linkage analysis on the 2 kindreds combined favored the gene order HLAA--ATXN1--F13A--6pter over the second most likely order ATXN1--HLAA--F13A by odds of 9 million to 1. </p><p>Zoghbi et al. (1987) demonstrated HLA linkage in a large black kindred with variable age of onset. Although the mean age of onset was 34 years, in 6 of 41 affected individuals onset was under 15 years of age and was accompanied by the unique clinical features of mental retardation and rapid progression of disease. Linkage to HLA showed a lod score of 5.83 at a recombination fraction of 0.12. Linkage to HLA-DR and HLA-DQ showed lod scores of 3.39 and 2.51 at recombination fractions of 0.15 and 0.17, respectively. This suggested that the SCA1 locus is distal to the MHC region. However, Zoghbi et al. (1988, 1989), by multilocus linkage analysis, obtained results indicating that the SCA1 gene locus is centromeric to HLA-DP, with odds of 46:1 favoring this most likely location over the second most likely location, i.e., telomeric to the HLA complex but proximal to F13A (134570). This appears to indicate localization in the 6p21.3-p21.2 region. </p><p>Wakisaka et al. (1989) and Shrimpton et al. (1989) described linkage studies in families with autosomal dominant ataxia. In 2 large Italian pedigrees with HLA-linked spinocerebellar ataxia, Frontali et al. (1991) excluded linkage with F13A at less than 5% recombination and with GLO1 at less than 10% recombination. The results favored the view that ATXN1 is distal to HLA. Thus, they favored the order cen--GLO1--HLA--ATXN1--tel. </p><p>Studies of 2 large kindreds led Ranum et al. (1991) to conclude that ATXN1 is unequivocally located distal to HLA and proximal to F13A. Furthermore, ATXN1 was found to lie centromeric and genetically very close to the highly informative D6S89 marker. In the 2 kindreds, 1 recombinant was observed between D6S89 and ATXN1, resulting in a recombination fraction of 0.014. Linkage analysis in the Schut-Swier kindred led Wilkie et al. (1991) likewise to conclude that ATXN1 is telomeric to HLA-A and lies between HLA-A and F13A. The maximum pairwise lod score for linkage between ATXN1 and HLA-A was 8.52; male theta = 0.10, female theta = 0.22. In a 5-generation American black family, Keats et al. (1991) excluded close linkage between the SCA1 locus and both HLA and F13A1; lod scores for all locations of the disease locus between these 2 loci were less than -1.4. However, the disease locus was found to be closely linked to a microsatellite polymorphism, D6S89, which is situated between HLA and F13A1; maximum lod = 4.90 at theta = 0.0, both in males and in females. The findings indicated that exclusion of close linkage to HLA and F13A1 in a kindred with spinocerebellar ataxia does not rule out the possibility that the disease locus is in fact on 6p. Accordingly, all families segregating a dominantly inherited ataxia should be evaluated for linkage to D6S89. </p><p>Zoghbi et al. (1991) tested for linkage with 2 highly informative dinucleotide repeat sequences in 3 large kindreds, 1 in Houston, Texas, and 2 in Calabria. Pairwise linkage analysis of ATXN1 and D6S89 revealed a maximum lod score of 5.86 in the Houston kindred and of 8.08 in the Calabrian kindreds, at recombination fractions of 0.050 and 0.022, respectively. A maximum pairwise lod score of 4.54 at recombination frequency of 0.100 was obtained for ATXN1 and TCTE1 (186975) in the Houston pedigree but no evidence of linkage was detected between these loci in the case of the Calabrian kindreds. Multilocus linkage analysis supported strongly localization of ATXN1 telomeric to HLA. Volz et al. (1992) studied D6S89 in mutant cell lines with cytogenetically detectable interstitial 6p deletions to map the marker to 6p24.2-p23.05. This would place ATXN1 in the 6p24-p23 segment. In 4 of 10 French families with autosomal dominant cerebellar ataxia type 1, Khati et al. (1993) found very close linkage of the neurologic disorder to the D6S89 marker, with no evidence of recombination. Linkage to D6S89 was excluded in the other 6. After the cloning of the ataxin-1 gene (601556), Volz et al. (1994) reported that it was mapped to 6p23 by in situ hybridization. </p><p>Kwiatkowski et al. (1993) reported a new marker, AM10GA, that demonstrated no recombination with ATXN1; maximum lod = 42.14 at theta = 0. Linkage analysis and analysis of recombination events confirmed that ATXN1 maps centromeric to D6S89 (which showed a maximum lod score of 67.58 at a maximum recombination fraction of 0.004 with ATXN1). They cited multipoint linkage analysis indicating that ATXN1 is telomeric to HLA. </p><p>In 7 families from a Siberian founder population with autosomal dominant SCA, Lunkes et al. (1994) demonstrated allelic association of the disease with polymorphisms known to flank the SCA1 locus on 6p. The association was absolute in the case of microsatellite D6S274, whereas an allele switch was observed for D6S89 in 2 families, suggesting a historic recombinant. </p>
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<h4>
<span class="mim-font">
<strong>Heterogeneity</strong>
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</h4>
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<p><strong><em>Genetic Heterogeneity</em></strong></p><p>
Koeppen et al. (1980) found no evidence of linkage to chromosome 6 markers in 5 families with 'dominant ataxia' and 3 with 'recessive ataxia' (Friedreich disease). Kumar et al. (1986) found negative lod scores for linkage to HLA in all of 5 families in which at least 3 generations were affected with autosomal dominant SCA. </p><p>By linkage studies in families with Machado-Joseph disease (MJD; 109150), Carson et al. (1992) demonstrated conclusively that MJD cannot be allelic to SCA1. A clinically indistinguishable form of spinocerebellar ataxia, SCA2, occurs in high frequency in Cuba. Lunkes et al. (1993) excluded linkage to 6p in a 5-generation Danish family. </p>
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<h4>
<span class="mim-font">
<strong>Pathogenesis</strong>
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</h4>
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<p>Orr et al. (1993) demonstrated that the basic genetic defect in spinocerebellar ataxia-1 consists of expansion of a trinucleotide CAG repeat. They showed that the repeat is present not only in genomic DNA but also in a 10-kb mRNA transcript. Banfi et al. (1994) identified the gene, termed ataxin-1. This was the fifth example of a pathologic state resulting from expansion of an unstable trinucleotide repeat. The others, in chronologic order of discovery, were the fragile X syndrome (300624), myotonic dystrophy (160900), Kennedy spinal and bulbar muscular atrophy (313200), and Huntington disease (143100). </p><p>After the lesion in SCA1 was found to involve an expanded trinucleotide repeat, this lesion was demonstrated in affected members of the Schut-Swier kindred, thus proving that it was, in fact, SCA1 (Wexler, 1993).</p><p>By immunoblot analysis, Servadio et al. (1995) demonstrated that a mutant protein that varies in its electrophoretic migration properties according to the size of the CAG repeat is detected in cultured cells and tissues from SCA1 individuals along with the wildtype protein. The ataxin-1 protein has a nuclear localization in all normal and SCA1 brain regions examined, but a cytoplasmic localization of ataxin-1 was also observed in cerebellar Purkinje cells, leading to progressive degeneration of Purkinje cells. The data showed that the expanded ATXN1 alleles are also translated into proteins of apparently normal stability and distribution. </p><p>Orr and Zoghbi (1996) reviewed the work elucidating polyglutamine-induced neurologic disease in SCA1. </p><p>Cummings et al. (1998) found colocalization of the 20S proteasome (see 602175) and chaperone HSJ2 (602837), a member of the Hsp40 family, with large nuclear inclusions of ataxin-1 in brain neurons of patients with SCA1 and in mice transgenic for a mutant ATXN1 allele containing 82 glutamines. In these nuclear inclusions, there was also faint staining for Hsc70 (HSPA8; 600816), a member of the Hsp70 chaperone family. Similar colocalization was seen in HeLa cells transfected with ataxin-1. In the transfected HeLa cells, unlike in the brains, there was apparent induction of Hsc70 chaperone. Overexpression of HSJ2 in these cells reduced aggregation of ataxin-1, suggesting a possible therapeutic strategy. </p><p>Lam et al. (2006) examined soluble protein complexes from mouse cerebellum and found that the majority of wildtype and expanded Atxn1 assembles into large stable complexes containing the transcriptional repressor Capicua (CIC; 612082). Atxn1 directly bound Cic and modulated Cic repressor activity in Drosophila and mammalian cells, and its loss decreased the steady state level of Cic. Interestingly, the S776A mutation, which abrogates the neurotoxicity of expanded Atxn1 (Emamian et al., 2003), substantially reduced the association of mutant Atxn1 with Cic in vivo. Lam et al. (2006) concluded that their data provided insight into the function of Atxn1 and suggested that the neuropathology of SCA1, caused by expansion of the ATXN1 polyglutamine tract, depends on native, not novel, protein interactions. Lam et al. (2006) found that the majority of CIC associates with ATXN1 in vivo and that ATXN1 binds CIC through an 8-amino-acid sequence conserved across species. </p><p>Lim et al. (2008) demonstrated that the expanded polyglutamine tract of ATXN1 differentially affects the function of the host protein in the context of different endogenous protein complexes. Polyglutamine expansion in ATXN1 favors the formation of a particular protein complex containing RBM17 (606935), contributing to SCA1 neuropathology by means of a gain-of-function mechanism. Concomitantly, polyglutamine expansion attenuates the formation and function of another protein complex containing ATXN1 and capicua, contributing to SCA1 through a partial loss-of-function mechanism. Lim et al. (2008) concluded that their model provides mechanistic insight into the molecular pathogenesis of SCA1 as well as other polyglutamine diseases. </p><p>Jain and Vale (2017) showed that repeat expansions create templates for multivalent basepairing, which causes purified RNA to undergo a sol-gel transition in vitro at a similar critical repeat number as observed in Huntington disease, spinocerebellar ataxia, myotonic dystrophy, and FTDALS1 (105550). In human cells, RNA foci form by phase separation of the repeat-containing RNA and can be dissolved by agents that disrupt RNA gelation in vitro. Jain and Vale (2017) concluded that, analogous to protein aggregation disorders, their results suggested that the sequence-specific gelation of RNAs could be a contributing factor to neurologic disease. </p>
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<div>
<h4>
<span class="mim-font">
<strong>Molecular Genetics</strong>
</span>
</h4>
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<span class="mim-text-font">
<p>Banfi et al. (1994) determined that the CAG trinucleotide repeat identified by Orr et al. (1993) in SCA1 occurs in the ataxin-1 gene (601556.0001). </p><p><strong><em>Genetic Anticipation</em></strong></p><p>
Chung et al. (1993) found that 63% of paternal transmissions show an increase in repeat number, whereas 69% of maternal transmissions show no change or a decrease in repeat number. Sequence analysis showed that 98% of unexpanded alleles had an interrupted repeat configuration, whereas a contiguous repeat (CAG)n was found in expanded alleles. This indicated that the repeat instability in ATXN1 is more complex than a simple variation in repeat number and that the loss of an interruption predisposes the ATXN1 (CAG)n to expansion. Matilla et al. (1993) studied the expansion of the ATXN1 gene CAG repeat in a large family in which spinocerebellar ataxia showed the phenomenon of anticipation. There were 41 affected members with no juvenile cases of SCA1, the mean age of onset being 36 years. The family also showed the phenomenon of parental male bias; i.e., the age of onset was younger and the duration of illness before death was shorter in the members of the family who inherited the disorder from the father. In this large Spanish kindred, Matilla et al. (1993) found 9 clinically unaffected persons between ages 18 and 40 years who had expansions of the CAG repeat within the pathogenetic range. In 22 other genetically 'at risk' individuals, they found that the number of CAG repeats in the ATXN1 gene was within the normal range. </p><p>Ranum et al. (1994) examined the frequency and variability of the ATXN1 repeat expansion in 87 kindreds with diverse ethnic backgrounds and dominantly inherited ataxia. All 9 families for which linkage to the ATXN1 region of 6p had previously been established showed repeat expansion, while 3 of the remaining 78 showed a similar abnormality. For 113 patients from the families with repeat expansion, inverse correlations between CAG repeat size and both age at onset and disease duration were observed. Repeat size accounted for 66% of the variation in age at onset in these patients. After correction for repeat size, interfamilial differences in age at onset remained significant, suggesting that additional genetic factors affect the expression of the ATXN1 gene product. </p><p>Jodice et al. (1994) found trinucleotide repeat expansion in 64 subjects from 19 families: 57 patients with SCA1 and 7 subjects predicted, by haplotype analysis, to carry the mutation. Comparison with a large set of normal chromosomes showed 2 distinct distributions with a much wider variation among expanded chromosomes. The sex of the transmitting parent played a major role in the size distribution of expanded alleles, those with more than 54 repeats being transmitted by affected fathers exclusively. Alleles with 46 to 54 repeats were transmitted by affected fathers and mothers in equal proportions. On the other hand, the sex ratio of offspring receiving either more than 54 or less than 54 repeats approached the expected 50:50. If a steady-state distribution of repeat numbers is assumed to persist through the generations, this raises the question as to why affected females transmitting alleles with more than 54 repeats are lacking, while females receiving more than 54 repeats exist. This may be explained, at least in part, by reduced biologic fitness. Detailed clinical follow-up of a subset of patients by Jodice et al. (1994) demonstrated significant relationships between increasing repeat number on expanded chromosomes and earlier age at onset, faster progression of the disease, and earlier age at death. </p><p>Koefoed et al. (1998) performed single sperm analysis of (CAG)n stretches in SCA1 patients and asymptomatic carriers. A pronounced variation in the size of the expanded allele was found in sperm cells and in peripheral blood leukocytes, with a higher degree of instability in sperm cells, where an allele with 50 repeat units was contracted in 11.8%, further expanded in 63.5%, and unchanged in 24.6% of the single sperm analyzed. They also found a low instability of the normal alleles; the normal alleles from the individuals carrying a CAG repeat expansion was significantly more unstable than the normal alleles from control individuals (P less than 0.001), indicating an interallelic interaction between the expanded and the normal alleles. </p><p>Matsuyama et al. (1999) studied 17 patients with SCA1. In one of these patients the expanded ATXN1 allele was interrupted by a CAT trinucleotide. The total number of CAG repeats was 58, predicting an age at onset of 22.0 years, in contrast to the actual age at onset of 50 years. In addition, brainstem atrophy was mild compared to that of a patient with 52 CAG repeats. Sequence analysis showed the repeat portion of the ATXN1 allele contained 45 uninterrupted CAG repeats with 2 interspersed CAT repeats in the subsequent 12 trinucleotides. Matsuyama et al. (1999) concluded that the age at onset of SCA1 is not determined by the total number of CAG repeats, but rather by the total number of uninterrupted CAG repeats. </p><p>Zuhlke et al. (2002) performed genotype-phenotype correlation in intermediate alleles from 36 to 43 CAG repeats in the ATXN1 gene with respect to the presence of interrupting CAT trinucleotides. Alleles with 36 to 38 triplets were present in individuals with ataxia but without additional characteristic features of SCA1. SCA1 phenotypes were found for patients with 41 and 43 triplets. The 39 triplet allele missing CAT interruptions was associated with symptoms characteristic for SCA1 in 4 patients, whereas the interrupted allele with 39 triplets did not cause characteristic SCA1 features in 1 individual. These findings suggested a change from normal to pathologic alleles at 39 triplets depending on the presence of CAT interruptions in the CAG repeat. Stable inheritance of the uninterrupted 39 triplet allele was observed in 1 familial case of SCA1. </p><p>Van de Warrenburg et al. (2005) applied statistical analysis to examine the relationship between age at onset and number of expanded triplet repeats from a Dutch-French cohort of 802 patients with SCA1 (138 patients), SCA2 (166 patients), SCA3 (342 patients), SCA6 (53 patients), and SCA7 (103 patients). The size of the expanded repeat explained 66 to 75% of the variance in age at onset for SCA1, SCA2, and SCA7, but less than 50% for SCA3 and SCA6. The relation between age at onset and CAG repeat was similar for all groups except for SCA2, suggesting that the polyglutamine repeat in the ataxin-2 protein exerts its pathologic effect in a different way. A contribution of the nonexpanded allele to age at onset was observed for only SCA1 and SCA6. Van de Warrenburg et al. (2005) acknowledged that their results were purely mathematical, but suggested that they reflected biologic variations among the diseases. </p><p><strong><em>Associations Pending Confirmation</em></strong></p><p>
For discussion of a possible association between autosomal dominant SCA and variation in the ZFYVE27 gene, see 610243.0002.</p><p>For discussion of a possible association between autosomal dominant SCA and variation in the KIF26B gene, see 614026.0001.</p><p>For discussion of a possible association between autosomal dominant SCA and variation in the EP300 gene, see 602700.</p>
</span>
<div>
<br />
</div>
<div>
<h4>
<span class="mim-font">
<strong>Genotype/Phenotype Correlations</strong>
</span>
</h4>
</div>
<span class="mim-text-font">
<p>Schols et al. (1997) compared clinical, electrophysiologic, and magnetic resonance imaging (MRI) findings to identify phenotypic characteristics of genetically defined SCA subtypes. Slow saccades, hyporeflexia, myoclonus, and action tremor suggested SCA2. SCA3 patients frequently developed diplopia, severe spasticity or pronounced peripheral neuropathy, and impaired temperature discrimination, apart from ataxia. SCA6 presented with a predominantly cerebellar syndrome, and patients often had onset after 55 years of age. SCA1 was characterized by markedly prolonged peripheral and central motor conduction times in motor evoked potentials. MRI scans showed pontine and cerebellar atrophy in SCA1 and SCA2. In SCA3, enlargement of the fourth ventricle was the main sequel of atrophy. SCA6 presented with pure cerebellar atrophy on MRI. Overlap between the 4 SCA subtypes was broad, however. </p><p>Among 65 patients with SCA1, SCA2, or SCA3, Burk et al. (1996) found reduced saccade velocity in 56%, 100%, and 30% of patients, respectively. MRI showed severe olivopontocerebellar atrophy in SCA2, similar but milder changes in SCA1, and very mild atrophy with sparing of the olives in SCA3. Careful examination of 3 major criteria of eye movements, saccade amplitude, saccade velocity, and presence of gaze-evoked nystagmus, permitted Rivaud-Pechoux et al. (1998) to assign over 90% of patients with SCA1, SCA2, or SCA3 to their genetically confirmed patient group. In SCA1, saccade amplitude was significantly increased, resulting in hypermetria. In SCA2, saccade velocity was markedly decreased. In SCA3, the most characteristic finding was the presence of gaze-evoked nystagmus. </p><p>In an investigation of oculomotor function, Buttner et al. (1998) found that all 3 patients with SCA1, all 7 patients with SCA3, and all 5 patients with SCA6 had gaze-evoked nystagmus. Three of 5 patients with SCA2 did not have gaze-evoked nystagmus, perhaps because they could not generate corrective fast components. Rebound nystagmus occurred in all SCA3 patients, 33% of SCA1 patients, 40% of SCA6 patients, and none of SCA2. Spontaneous downbeat nystagmus only occurred in SCA6. Peak saccade velocity was decreased in 100% of patients with SCA2, 1 patient with SCA1, and no patients with SCA3 or SCA6. Saccade hypermetria was found in all types, but was most common in SCA3. Burk et al. (1999) found that gaze-evoked nystagmus was not associated with SCA2. However, severe saccade slowing was highly characteristic of SCA2. Saccade velocity in SCA3 was normal to mildly reduced. The gain in vestibuloocular reflex was significantly impaired in SCA3 and SCA1. Eye movement disorders of SCA1 overlapped with both SCA2 and SCA3. </p><p>The reticulotegmental nucleus of the pons (RTTG), also known as the nucleus of Bechterew, is a precerebellar nucleus important in the premotor oculomotor circuits crucial for the accuracy of horizontal saccades and the generation of horizontal smooth pursuit. By postmortem examination, Rub et al. (2004) identified neuronal loss and astrogliosis in the RTTG in 1 of 2 SCA1 patients, 2 of 4 SCA2 patients, and 4 of 4 SCA3 patients that correlated with clinical findings of hypometric saccades and slowed and saccadic smooth pursuits. The 3 patients without these specific oculomotor findings had intact RTTG regions. The authors concluded that the neurodegeneration associated with SCA1, SCA2, and SCA3 affects premotor networks in addition to motor nuclei in a subset of patients. </p><p>Using an analysis of covariance and multivariate models to examine symptom severity in 526 patients with SCA1, SCA2, SCA3, or SCA6, Schmitz-Hubsch et al. (2008) found that repeat length of the expanded allele, age at onset, and disease duration explained 60.4% of the ataxia score in SCA1, 45.4% in SCA2, 46.8% in SCA3. However, only age at onset and disease duration appeared to explain 33.7% of the score in SCA6. Similar findings were obtained for nonataxic symptoms. The study suggested that SCA1, SCA2, and SCA3 share a number of common biologic properties, whereas SCA6 is distinct in that its phenotype is more determined by age than by disease-related factors. </p>
</span>
<div>
<br />
</div>
<div>
<h4>
<span class="mim-font">
<strong>Population Genetics</strong>
</span>
</h4>
</div>
<span class="mim-text-font">
<p>Giunti et al. (1994) examined members of 73 families who were affected with a variety of autosomal dominant late-onset cerebellar ataxias for the trinucleotide repeat expansion associated with the SCA1 locus. The mutation was found in 19 of 38 kindreds with the SCA1 phenotype. However, it was not found in any of 8 families with olivopontocerebellar atrophy with maculopathy (164500), or in 24 kindreds with pure adult-onset cerebellar ataxia (SCA31; 117210), or in 12 patients with sporadic degenerative ataxia. The patients with the expansion were Italian, British, Malaysian, Bangladeshi, and Jamaican. </p><p>Ranum et al. (1995) made use of the fact that the genes involved in 2 forms of autosomal dominant ataxia, that for Machado-Joseph disease (109150) and that for SCA1, have been isolated to assess the frequency of trinucleotide repeat expansions among individuals diagnosed with ataxia. They collected and analyzed DNA from individuals with both disorders. In both cases, the genes responsible for the disorder were found to have an expansion of an unstable CAG trinucleotide repeat. These individuals represented 311 families with adult-onset ataxia of unknown etiology, of which 149 families had dominantly inherited ataxia. Ranum et al. (1995) found that of these, 3% had SCA1 trinucleotide repeat expansions, whereas 21% were positive for the MJD trinucleotide expansion. For the 57 patients with MJD trinucleotide repeat expansions, strong inverse correlation between CAG repeat size and age at onset was observed (r = -0.838). Among the MJD patients, the normal and affected ranges of CAG repeat size were 14 to 40 and 68 to 82 repeats, respectively. For SCA1, the normal and affected ranges were much closer, namely 19 to 38 and 40 to 81 CAG repeats, respectively. </p><p>In a nationwide survey of Japanese patients, Hirayama et al. (1994) found an estimated prevalence of the various forms of spinocerebellar degeneration to be 4.53 per 100,000. Of these, 12.6% were thought to have the Menzel type of spinocerebellar atrophy (SCA1). However, it was not clear how they distinguished this disorder from the other forms of OPCA. In Japan, Suzuki et al. (1995) found that all affected and presymptomatic individuals in 12 pedigrees with SCA1 (determined by haplotype per segregation analyses) carried an abnormally expanded allele with a range of 39 to 63 repeat units. This repeat size inversely correlated with the age of onset. However, contrary to previous reports, the size of the repeat did not correlate with gender of the transmitting parent. CAG triplet repeat instability on paternal transmission was not observed. </p><p>Wakisaka et al. (1995) determined the haplotype cosegregating with SCA1 in 12 Japanese pedigrees. Although the alleles of the ATXN1 haplotype varied from pedigree to pedigree depending on the distance from the SCA1 locus, the affected and presymptomatic subjects carried the same alleles at 2 loci, D6S288 and D6S274. All the families with SCA1 had migrated from either the Miyagi or Yamagata Prefectures, neighboring areas in the Tokohu District, the northern part of Honshu, which is the main island of Japan. The findings suggested to the authors that SCA1 in the Japanese, at least those residing in Hokkaido, derived from a single common ancestry. Goldfarb et al. (1996) studied 78 SCA1 patients from a large Siberian kindred which included 1,484 individuals, 225 of whom are known to be affected and 656 of whom were at risk. Normal alleles had 25 to 37 trinucleotide repeats, whereas expanded alleles contained 40 to 55 repeats. The disease was not fully penetrant inasmuch as there was one 66-year-old woman with 44 CAG repeats who was asymptomatic. Of her 7 children, 4 were affected, including a homozygous daughter and another child with 44 repeats. Two symptomatic individuals who had expansions on both chromosomes demonstrated clinical manifestations that corresponded to the size of the larger allele. </p><p>In Catalonia, Genis et al. (1995) found a large kindred traced to a common ancestor born in 1735 that segregated spinocerebellar ataxia-1. Affected individuals all had 1 allele with between 41 in 59 repeats, whereas asymptomatic individuals for the most part fell in the range of 6 to 39 repeats. Two asymptomatic individuals, an 18-year-old female and a 25-year-old male, had 41 repeats. </p><p>Klockgether et al. (1994) analyzed DNA from 19 German families with autosomal dominant cerebellar ataxia and 61 unrelated individuals with idiopathic cerebellar ataxia with a mean age of onset of 53.6 years. Heterozygosity for the ATXN1 triplet repeat expansion was diagnosed in 5 out of 19 of the autosomal dominant kindreds. In contrast, none of the 61 cases of idiopathic adult-onset cerebellar ataxia showed this expansion. This suggested that SCA1 is not a significant cause of idiopathic cerebellar ataxia in Germany. Studying 77 German families with autosomal dominant cerebellar ataxia of SCA types 1, 2, 3, and 6, Schols et al. (1997) found that the SCA1 mutation accounted for 9%, SCA2 for 10%, SCA3 for 42%, and SCA6 for 22%. There was no family history of ataxia in 7 of 27 SCA6 patients. Age at onset correlated inversely with repeat length in all subtypes. Yet the average effect of 1 CAG unit on age of onset was different for each SCA subtype. Riess et al. (1997) found that in both SCA1 and SCA3 patients in German families there was distortion of the mendelian 1:1 segregation of the disease. They noted that mutations in the ataxin-1 gene are responsible for autosomal dominant spinocerebellar ataxia in about 10% of all families, whereas SCA3 is the most common cause in Germany, accounting for up to 50% of cases. </p><p>Ramesar et al. (1997) investigated 14 South African kindreds and 22 sporadic individuals with SCA for expanded ATXN1 (601556.0001) and ATXN3 (607047.0001) repeats. The authors stated that, in the present study, ATXN1 mutations accounted for 43% of known ataxia families in the Western Cape region. They found that expanded ATXN1 and CAG repeats cosegregated with the disorder in 6 of the families, 5 of mixed ancestry and 1 Caucasian, and were also observed in a sporadic case from the indigenous Black African population. The use of the microsatellite markers D6S260, D6S89, and D6S274 provided evidence that the expanded ATXN1 repeats segregated with 3 distinct haplotypes in the 6 families. None of the families nor the sporadic individuals showed expansion of the MJD repeat. </p><p>Among 202 Japanese and 177 Caucasian families with autosomal dominant SCA, Takano et al. (1998) found that the prevalence of SCA1 was significantly higher in the Caucasian population (15%) compared to the Japanese population (3%). This corresponded to higher frequencies of large normal ATXN1 CAG repeat alleles (greater than 30 repeats) in Caucasian controls compared to Japanese controls. The findings suggested that large normal alleles contribute to the generation of expanded alleles that lead to dominant SCA. </p><p>In Spain, Pujana et al. (1999) performed molecular analysis on 87 unrelated familial and 60 sporadic cases of spinocerebellar ataxia of autosomal dominant type. For the familial cases of ADCA, 6% were SCA1, 15% were SCA2, 15% were SCA3, 1% represented SCA6, 3% were SCA7, and, in 1%, the diagnosis was DRPLA (125370), an extremely rare mutation in Caucasoid populations. About 58% of ADCA cases remained genetically unclassified. All the SCA1 cases belonged to the same geographic area and shared a common haplotype for the SCA1 mutation. The expanded alleles ranged from 41 to 59 repeats for SCA1, 35 to 46 for SCA2, 67 to 77 for SCA3, and 38 to 113 for SCA7. The 1 SCA6 case had 25 repeats and the 1 DRPLA case had 63 repeats. The highest CAG repeat variation in meiotic transmission of expanded alleles was detected in SCA7, this being an expansion of 67 units in one paternal transmission, giving rise to a 113 CAG repeat allele in a patient who died at 3 years of age. Meiotic transmissions showed a tendency to more frequent paternal transmission of expanded alleles in SCA1 and maternal in SCA7. All SCA1 and SCA2 expanded alleles analyzed consisted of pure CAG repeats, whereas normal alleles were interrupted by 1 to 2 CAT trinucleotides in SCA1, except for 3 alleles of 6, 14, and 21 CAG repeats, and by 1 to 3 CAA trinucleotides in SCA2. The failure to find SCA or DRPLA mutations in the 60 sporadic cases of spinocerebellar ataxia is consistent with the lack of evidence of de novo mutations noted by Andrew et al. (1997). </p><p>Pareyson et al. (1999) evaluated 73 Italian families with type I ADCA. SCA1 was the most common genotype, accounting for 41% of cases (30 families); SCA2 was slightly less frequent (29%, 21 families), and the remaining families were negative for the SCA1, SCA2, and SCA3 mutations. Among the positively genotyped families, SCA1 was found most frequently in families from northern Italy (50%), while SCA2 was the most common mutation in families from the southern part of the country (56%). Slow saccades and decreased deep tendon reflexes were observed significantly more frequently in SCA2 patients, while increased deep tendon reflexes and nystagmus were more common in SCA1. </p><p>Storey et al. (2000) examined the frequency of mutations for SCA types 1, 2, 3, 6, and 7 in southeastern Australia. Of 63 pedigrees or individuals with positive tests, 30% had SCA1, 15% had SCA2, 22% had SCA3, 30% had SCA6, and 3% had SCA7. Ethnic origin was of importance in determining SCA type: 4 of 9 SCA2 index cases were of Italian origin, and 4 of 14 SCA3 index cases were of Chinese origin. </p><p>Zhou et al. (2001) performed molecular analysis of 109 patients in 75 Chinese families with autosomal dominant SCA and 16 patients with sporadic SCA or spastic paraplegia. SCA type 1 was found in 5 families (7%), and all patients with the SCA1 phenotype were heterozygous for alleles with CAG repeat numbers ranging from 51 to 64 (control groups, 26-35). There was a significant negative correlation between age of disease onset and number of CAG repeat units. SCA3/MJD was found in 26 families, SCA2 in 9 families, SCA6 in 2 families, and SCA7 in 2 families. The combined frequency of SCA1, SCA2, and SCA3/MJD was 53%. None of the 16 sporadic cases was positive for the mutations tested, and no patients were positive for SCA8 (608768), SCA12, or DRPLA. Clinically, the authors noted that SCA3/MJD tended to manifest more frequently with ophthalmoparesis, eyelid retraction, facial myokymia, ataxia, spasticity, and amyotrophy. The frequency of single CAT interruptions in the ATXN1 gene was higher in the Siberian Sakha control group, which also had a higher prevalence of SCA1 than the Chinese population, suggesting that a substitution of CAT for CAG may be the initial event contributing to the generation of expanded alleles. </p><p>Of 253 unrelated Korean patients with progressive cerebellar ataxia, Lee et al. (2003) identified 52 (20.6%) with expanded CAG repeats. The most frequent SCA type was SCA2 (33%), followed by SCA3 (29%), SCA6 (19%), SCA1 (12%), and SCA7 (8%). There were characteristic clinical features, such as hypotonia and optic atrophy for SCA1, hyporeflexia for SCA2, nystagmus, bulging eye, and dystonia for SCA3, and macular degeneration for SCA7. </p><p>Mittal et al. (2005) found SCA1 in 37 (22%) of 167 Indian families with ADCA. The frequency of SCA1 in the south Indian population was twice (33%) that of the north Indian population (16%). The nonaffected repeat length ranged from 21 to 39 triplets. Haplotype analysis identified an ancestral C-4-C haplotype (rs1476464, D6S288, and rs2075974) that was mostly present in the affected individuals, suggesting that this background might have been predisposed for repeat expansion. This haplotype, when present in the nonaffected chromosomes, had multiple interruptions in the repeat tract, which the authors hypothesized would provide genetic stability. However, in disease chromosomes, this haplotype showed large normal (greater than 30 repeats) expansions and was associated with the expanded chromosomes in about 44% of SCA1 families. </p><p>Among 113 Japanese families from the island of Hokkaido with autosomal dominant SCA, Basri et al. (2007) found that SCA6 was the most common form of the disorder, identified in 35 (31%) families. Thirty (27%) families had SCA3, 11 (10%) had SCA1, 5 (4%) had SCA2, 5 (4%) had DRPLA, 10 (9%) had 16q22-linked SCA, and 1 (1%) had SCA14 (605361). The specific disorder could not be identified in 16 (14%) families. </p>
</span>
<div>
<br />
</div>
<div>
<h4>
<span class="mim-font">
<strong>History</strong>
</span>
</h4>
</div>
<span class="mim-text-font">
<p>Weiner and Konigsmark (1971) provided a review of hereditary diseases of the cerebellum. Affected families have been described by Hall et al. (1941), Richter (1950), Weber and Greenfield (1942), and others. </p>
</span>
<div>
<br />
</div>
<div>
<h4>
<span class="mim-font">
<strong>Animal Model</strong>
</span>
</h4>
</div>
<span class="mim-text-font">
<p>Servadio et al. (1995) mapped the mouse homolog of the ATXN1 gene to mouse chromosome 13. Although human SCA1 is characterized by progressive Purkinje cell degeneration, Servadio et al. (1995) showed that pcd (Purkinje cell degeneration) mutation in the mouse, which also maps to mouse chromosome 13, is not caused by mutation in the murine Sca1 gene since linkage studies indicated that the 2 loci are separated by 7 or more cM. </p><p>To gain insight into the pathogenesis of SCA1 and the intergenerational stability of trinucleotide repeats in mice, Burright et al. (1995) generated transgenic mice expressing the human ATXN1 gene with either a normal or an expanded CAG tract. Both transgenes were stable in parent-to-offspring transmissions. While all 6 transgenic lines expressing the unexpanded human ATXN1 allele had normal Purkinje cells, transgenic animals from 5 of 6 lines with the expanded ATXN1 allele developed ataxia and Purkinje cell degeneration. These data indicated to the authors that expanded CAG repeats expressed in Purkinje cells are sufficient to produce degeneration and ataxia and demonstrated that a mouse model can be established from neurodegeneration caused by CAG repeat expansions. </p><p>To examine genetic aspects of trinucleotide repeat instability, Kaytor et al. (1997) introduced an ATXN1 cDNA containing a CAG trinucleotide repeat tract into transgenic mice and analyzed both maternal and paternal transmission of the repeat. Intergenerational CAG repeat instability was detected only when the transgene was maternally transmitted. The intergenerational instability increased in frequency and magnitude as the transgenic mother aged. Furthermore, triplet repeat variations were detected in unfertilized oocytes and were comparable with those in the offspring. These data showed that maternal repeat instability in the transgenic mice occurs after meiotic DNA replication and before oocyte fertilization. The findings demonstrated that advanced maternal age is an important factor for instability of nucleotide repeats in mammalian DNA. </p><p>Klement et al. (1998) stated that transgenic mice carrying the Sca1 gene develop ataxia with ataxin-1 localized to aggregates within cerebellar Purkinje cell nuclei. To examine the importance of nuclear localization and aggregation in pathogenesis, mice expressing ataxin-1(82) with a mutated NLS (nuclear localization signal K772T) were established. These mice did not develop disease, demonstrating that nuclear localization is critical for pathogenesis. In another transgenic mouse colony, ataxin-1(77) containing a deletion within the self-association region (amino acid residues 472-594) was expressed within Purkinje cell nuclei. These mice developed ataxia and Purkinje cell pathology similar to the original SCA1 mice. However, no evidence of nuclear ataxin-1 aggregates was found. Thus Klement et al. (1998) concluded that although nuclear localization of ataxin-1 is necessary, nuclear aggregation of ataxin-1 is not required to initiate pathogenesis in transgenic mice. </p><p>Lorenzetti et al. (2000) generated knockin mice by inserting an expanded tract of 78 CAG repeats into the mouse Sca1 locus. Mice heterozygous for the CAG expansion showed intergenerational repeat instability (+2 to -6) at a much higher frequency in maternal transmission than in paternal transmission. Mice homozygous for mutant ataxin-1 on a C57BL/6J-129/SvEv mixed background performed significantly less well on the rotating rod than did wildtype littermates at 9 months of age, although they were not ataxic by cage behavior. Histologic examination of brain tissue from mutant mice up to 18 months of age revealed none of the neuropathologic changes observed in other transgenic models overexpressing expanded polyglutamine tracts. The authors hypothesized that, even with 78 glutamines, prolonged exposure to mutant ataxin-1 at endogenous levels is necessary to produce a neurologic phenotype reminiscent of human SCA1, and that pathogenesis may be a function of polyglutamine length, protein levels, and duration of neuronal exposure to the mutant protein. </p><p>Cummings et al. (2001) crossbred SCA1 mice with mice overexpressing the molecular chaperone inducible HSP70 (HSPA1A; 140550). Although the amount of nuclear inclusions in Purkinje cells persisted, physiologic and histopathologic analysis revealed that high levels of HSP70 appeared to afford protection against neurodegeneration and preserved dendritic arborization in the cerebellum. </p><p>Okuda et al. (2003) generated transgenic mice overexpressing human PQBP1 (300463), a polyglutamine-binding nuclear protein that interacts with ataxin-1. The mice showed a late-onset and gradually progressive motor neuron disease-like phenotype suggestive of the neurogenic muscular atrophy observed in SCA1 patients. Ataxia could not be discriminated from predominant progressive weakness. Pathologic examinations of the transgenic mice revealed loss of Purkinje and granular cells in the cerebellum as well as loss of motor neurons in the spinal anterior horn, corresponding to the pathology of human SCA1. Okuda et al. (2003) concluded that excessive action of PQBP1 causes neuronal dysfunction and that PQBP1 may be involved in the pathology of SCA1. </p><p>Watase et al. (2003) investigated the pattern of CAG repeat instability in a knockin mouse model of SCA1. Small pool (SP)-PCR analysis on DNA from various neuronal and nonneuronal tissues revealed that somatic repeat instability was highest in the striatum. In 2 SCA1-vulnerable tissues, cerebellum and spinal cord, there were substantial differences in the profile of mosaicism. Watase et al. (2003) suggested that in SCA1 there is no clear causal relationship between the degree of somatic instability and selective neuronal vulnerability. The finding that somatic instability is most pronounced in the striatum of various knockin models of polyglutamine diseases may suggest a role of trans-acting tissue- or cell-specific factors in mediating the instability. </p><p>In a mouse model of SCA1, Xia et al. (2004) performed intracerebellar delivery of viral vectors expressing short hairpin RNAs targeting ataxin-1 as a therapeutic use of RNA interference (RNAi). The treated mice showed reduced ataxin-1 expression in Purkinje cells, resolution of intracellular ataxin-1 inclusions in the cerebellum, and improved motor performance. Xia et al. (2004) noted the importance of screening multiple hairpins before identifying an appropriate one for targeted gene silencing. </p><p>By comparing previously reported genetic modifiers in 3 Drosophila models of human neurodegenerative disease, Ghosh and Feany (2004) confirmed that protein folding, histone acetylation, and apoptosis are common features of neurotoxicity. Two novel genetic modifiers, the Drosophila homolog of ATXN2 (601517) and CGI7231, were identified. Cell-type specificity was demonstrated as many, but not all, retinal modifiers also modified toxicity in postmitotic neurons. Ghosh and Feany (2004) identified nicotinamide, which has histone deacetylase-inhibiting activity, as a potent suppressor of polyglutamine toxicity. </p><p>Using a conditional transgenic mouse model of SCA1, Serra et al. (2006) showed that delaying postnatal expression of mutant human ATXN1 until completion of cerebellar maturation led to a substantial reduction in disease severity in adults compared with early postnatal expression of mutant ATXN1. Microarray analysis revealed that genes regulated by Rora (600825), a transcription factor critical for cerebellar development, were downregulated at an early stage of disease in Purkinje cells of SCA1 transgenic mice. Rora mRNA and protein levels were reduced in Purkinje cells of SCA1 transgenic mice, and the effect of mutant ATXN1 on Rora protein levels appeared to be independent of its effect on Rora mRNA levels. Partial loss of Rora enhanced the pathogenicity of mutant ATXN1 in transgenic mice. Coimmunoprecipitation and pull-down analyses suggested the existence of a complex containing Atxn1, Rora, and the Rora coactivator Tip60 (HTATIP; 601409), with Atxn1 and Tip60 interacting directly. Serra et al. (2006) concluded that RORA and TIP60 have a role in SCA1 and proposed that their findings provide a mechanism by which compromised cerebellar development contributes to the severity of neurodegeneration in an adult. </p><p>Using microarray analysis of the cerebellum in mouse models of SCA1 and SCA7, Gatchel et al. (2008) found that both disorders were associated with significant downregulation of Igfbp5 (146734) in the granular cell layer. Further analysis showed additional misregulation in both models, including activation of the IGF pathway and the Igf1 receptor (IGF1R; 147370) in Purkinje cells. </p><p>To determine the long-term effects of exercise, Fryer et al. (2011) implemented a mild exercise regimen in a mouse model of SCA1 and found a considerable improvement in survival accompanied by upregulation of epidermal growth factor and consequential downregulation of Capicua (612082), which is an ATXN1 (601556) interactor. Offspring of Capicua mutant mice bred to Sca1 mice showed significant improvement of all disease phenotypes. Although polyglutamine-expanded Atxn1 caused some loss of Capicua function, further reduction of Capicua levels--either genetically or by exercise--mitigated the disease phenotypes by dampening the toxic gain of function. Fryer et al. (2011) concluded that exercise might have long-term beneficial effects in other ataxias and neurodegenerative diseases. </p><p>In Sca1 mice, Cvetanovic et al. (2011) found that mutant Atxn1 repressed transcription of Vegfa (192240), resulting in decreased Vegfa mRNA and protein levels in cerebellar Purkinje cells. Sca1 mice showed a decrease in cerebellar microvessel density and length, as well as evidence of cellular hypoxia. Inhibition of Vegfa in neuronal cell culture resulted in decreased neurite length and increased cell death. Genetic overexpression or pharmacologic infusion of Vegfa ameliorated the phenotype of Sca1 mice and improved cerebellar pathology. The findings suggested a role for VEGFA in SCA1 pathogenesis and suggested that restoration of VEGFA may be a therapeutic strategy. </p>
</span>
<div>
<br />
</div>
</div>
<div>
<h4>
<span class="mim-font">
<strong>See Also:</strong>
</span>
</h4>
<span class="mim-text-font">
Banfi et al. (1996); Critchley and Greenfield (1948); Geary et al.
(1956); Harding (1983); Koeppen et al. (1977); Spadaro et al. (1992);
Wang et al. (1996); Werdelin et al. (1984); Whittington et al.
(1980); Yakura et al. (1974); Zoghbi et al. (1988)
</span>
<div>
<br />
</div>
</div>
<div>
<h4>
<span class="mim-font">
<strong>REFERENCES</strong>
</span>
</h4>
<div>
<p />
</div>
<div>
<ol>
<li>
<p class="mim-text-font">
Andrew, S. E., Goldberg, Y. P., Hayden, M. R.
<strong>Rethinking genotype and phenotype correlations in polyglutamine expansion disorders.</strong>
Hum. Molec. Genet. 6: 2005-2010, 1997.
[PubMed: 9328463]
[Full Text: https://doi.org/10.1093/hmg/6.12.2005]
</p>
</li>
<li>
<p class="mim-text-font">
Banfi, S., Servadio, A., Chung, M., Kwiatkowski, T. J., Jr., McCall, A. E., Duvick, L. A., Shen, Y., Roth, E. J., Orr, H. T., Zoghbi, H. Y.
<strong>Identification and characterization of the gene causing type 1 spinocerebellar ataxia.</strong>
Nature Genet. 7: 513-520, 1994.
[PubMed: 7951322]
[Full Text: https://doi.org/10.1038/ng0894-513]
</p>
</li>
<li>
<p class="mim-text-font">
Banfi, S., Servadio, A., Chung, M.-y., Capozzoli, F., Duvick, L. A., Elde, R., Zoghbi, H. Y., Orr, H. T.
<strong>Cloning and developmental expression analysis of the murine homolog of the spinocerebellar ataxia type 1 gene (Sca1).</strong>
Hum. Molec. Genet. 5: 33-40, 1996.
[PubMed: 8789437]
[Full Text: https://doi.org/10.1093/hmg/5.1.33]
</p>
</li>
<li>
<p class="mim-text-font">
Basri, R., Yabe, I., Soma, H., Sasaki, H.
<strong>Spectrum and prevalence of autosomal dominant spinocerebellar ataxia in Hokkaido, the northern island of Japan: a study of 113 Japanese families.</strong>
J. Hum. Genet. 52: 848-855, 2007.
[PubMed: 17805477]
[Full Text: https://doi.org/10.1007/s10038-007-0182-x]
</p>
</li>
<li>
<p class="mim-text-font">
Berciano, J.
<strong>Olivopontocerebellar atrophy: a review of 117 cases.</strong>
J. Neurol. Sci. 53: 253-272, 1982.
[PubMed: 7057212]
[Full Text: https://doi.org/10.1016/0022-510x(82)90011-9]
</p>
</li>
<li>
<p class="mim-text-font">
Burk, K., Abele, M., Fetter, M., Dichgans, J., Skalej, M., Laccone, F., Didierjean, O., Brice, A., Klockgether, T.
<strong>Autosomal dominant cerebellar ataxia type I: clinical features and MRI in families with SCA1, SCA2 and SCA3.</strong>
Brain 119: 1497-1505, 1996.
[PubMed: 8931575]
[Full Text: https://doi.org/10.1093/brain/119.5.1497]
</p>
</li>
<li>
<p class="mim-text-font">
Burk, K., Fetter, M., Abele, M., Laccone, F., Brice, A., Dichgans, J., Klockgether, T.
<strong>Autosomal dominant cerebellar ataxia type I: oculomotor abnormalities in families with SCA1, SCA2, and SCA3.</strong>
J. Neurol. 246: 789-797, 1999.
[PubMed: 10525976]
[Full Text: https://doi.org/10.1007/s004150050456]
</p>
</li>
<li>
<p class="mim-text-font">
Burright, E. N., Clark, H. B., Servadio, A., Matilla, T., Feddersen, R. M., Yunis, W. S., Duvick, L. A., Zoghbi, H. Y., Orr, H. T.
<strong>SCA1 transgenic mice: a model for neurodegeneration caused by an expanded CAG trinucleotide repeat.</strong>
Cell 82: 937-948, 1995.
[PubMed: 7553854]
[Full Text: https://doi.org/10.1016/0092-8674(95)90273-2]
</p>
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Zoghbi, H. Y., Sandkuyl, L. A., Ott, J., Daiger, S. P., Pollack, M., O'Brien, W. E., Beaudet, A. L.
<strong>Assignment of autosomal dominant spinocerebellar ataxia (SCA1) centromeric to the HLA region on the short arm of chromosome 6, using multilocus linkage analysis.</strong>
Am. J. Hum. Genet. 44: 255-263, 1989.
[PubMed: 2563195]
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Zuhlke, C., Dalski, A., Hellenbroich, Y., Bubel, S., Schwinger, E., Burk, K.
<strong>Spinocerebellar ataxia type 1 (SCA1): Phenotype-genotype correlation studies in intermediate alleles.</strong>
Europ. J. Hum. Genet. 10: 204-209, 2002.
[PubMed: 11973625]
[Full Text: https://doi.org/10.1038/sj.ejhg.5200788]
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Cassandra L. Kniffin - updated : 11/15/2017<br>Ada Hamosh - updated : 07/06/2017<br>Cassandra L. Kniffin - updated : 3/19/2012<br>Cassandra L. Kniffin - updated : 12/1/2011<br>Ada Hamosh - updated : 11/29/2011<br>Cassandra L. Kniffin - updated : 3/30/2010<br>Matthew B. Gross - updated : 5/7/2009<br>Cassandra L. Kniffin - updated : 4/13/2009<br>Ada Hamosh - updated : 5/21/2008<br>Cassandra L. Kniffin - updated : 3/6/2008<br>Cassandra L. Kniffin - updated : 2/26/2008<br>George E. Tiller - updated : 3/21/2007<br>Cassandra L. Kniffin - updated : 7/6/2006<br>George E. Tiller - updated : 1/31/2006<br>Cassandra L. Kniffin - updated : 9/22/2005<br>Cassandra L. Kniffin - updated : 5/18/2005<br>Cassandra L. Kniffin - updated : 4/19/2005<br>George E. Tiller - updated : 2/17/2005<br>Cassandra L. Kniffin - updated : 7/26/2004<br>Cassandra L. Kniffin - updated : 5/25/2004<br>Cassandra L. Kniffin - updated : 8/7/2003<br>Michael B. Petersen - updated : 11/1/2002<br>Cassandra L. Kniffin - reorganized : 8/14/2002<br>Cassandra L. Kniffin - updated : 6/17/2002<br>George E. Tiller - updated : 12/12/2001<br>Victor A. McKusick - updated : 10/12/2001<br>Sonja A. Rasmussen - updated : 1/9/2001<br>George E. Tiller - updated : 4/25/2000<br>Victor A. McKusick - updated : 9/15/1999<br>Victor A. McKusick - updated : 8/31/1999<br>Michael J. Wright - updated : 8/16/1999<br>Orest Hurko - updated : 7/1/1999<br>Victor A. McKusick - updated : 12/10/1998<br>Orest Hurko - updated : 4/7/1998<br>Victor A. McKusick - updated : 3/27/1998<br>Victor A. McKusick - updated : 11/20/1997<br>Victor A. McKusick - updated : 9/10/1997<br>Ethylin Wang Jabs - updated : 7/21/1997<br>Victor A. McKusick - updated : 2/17/1997<br>Orest Hurko - updated : 4/2/1996<br>Orest Hurko - updated : 4/1/1996<br>Moyra Smith - updated : 3/26/1996<br>Orest Hurko - updated : 9/27/1995
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Victor A. McKusick : 6/2/1986
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