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<title>
Entry
- #300623 - FRAGILE X TREMOR/ATAXIA SYNDROME; FXTAS
- OMIM
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<span class="h4">#300623</span>
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<strong>Table of Contents</strong>
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<a href="/clinicalSynopsis/300623"><strong>Clinical Synopsis</strong></a>
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<a href="#diagnosis">Diagnosis</a>
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<a href="#molecularGenetics">Molecular Genetics</a>
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<a href="#pathogenesis">Pathogenesis</a>
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<div><a href="https://clinicaltrials.gov/search?cond=FRAGILE X TREMOR/ATAXIA SYNDROME" class="mim-tip-hint" title="A registry of federally and privately supported clinical trials conducted in the United States and around the world." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Clinical Trials', 'domain': 'clinicaltrials.gov'})">Clinical Trials</a></div>
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<div 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:0050879" 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/300623" 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>
</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> 448045004<br />
<strong>ORPHA:</strong> 93256<br />
<strong>DO:</strong> 0050879<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>
300623
</span>
</span>
</div>
</div>
<div>
<a id="preferredTitle" class="mim-anchor"></a>
<h3>
<span class="mim-font">
FRAGILE X TREMOR/ATAXIA SYNDROME; FXTAS
</span>
</h3>
</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/X/769?start=-3&limit=10&highlight=769">
Xq27.3
</a>
</span>
</td>
<td>
<span class="mim-font">
Fragile X tremor/ataxia syndrome
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/300623"> 300623 </a>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="X-linked dominant">XLD</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">
FMR1
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/309550"> 309550 </a>
</span>
</td>
</tr>
</tbody>
</table>
</div>
</div>
<div>
<div class="btn-group ">
<a href="/clinicalSynopsis/300623" 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">
<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/300623" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Linear'})"> Linear </a></li>
<li><a href="/graph/radial/300623" 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">
- X-linked dominant <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1847879&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1847879</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001423" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001423</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001423" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001423</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> Face </em>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
- Masked facies <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/103606006" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">103606006</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0424448&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0424448</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000298" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000298</a>]</span><br />
</span>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<em> Ears </em>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
- Hearing loss <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/103276001" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">103276001</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/343087000" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">343087000</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/15188001" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">15188001</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/H91.9" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">H91.9</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/389.9" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">389.9</a>, <a href="https://purl.bioontology.org/ontology/ICD9CM/389" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">389</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0011053&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0011053</a>, <a href="https://bioportal.bioontology.org/search?q=C0018772&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0018772</a>, <a href="https://bioportal.bioontology.org/search?q=C1384666&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1384666</a>, <a href="https://bioportal.bioontology.org/search?q=C3887873&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C3887873</a>, <a href="https://bioportal.bioontology.org/search?q=C2029884&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C2029884</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000365" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000365</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000365" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000365</a>]</span><br />
</span>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<em> Eyes </em>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
- Saccadic pursuit <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/77219005" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">77219005</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0036019&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0036019</a>]</span><br /> -
Nystagmus <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/563001" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">563001</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/H55.0" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">H55.0</a>, <a href="https://purl.bioontology.org/ontology/ICD10CM/H55.00" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">H55.00</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/379.50" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">379.50</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0028738&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0028738</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000639" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000639</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000639" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000639</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">
- Incontinence <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/48340000" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">48340000</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0021167&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0021167</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> External Genitalia (Male) </em>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
- Impotence <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/860914002" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">860914002</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/N52.9" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">N52.9</a>, <a href="https://purl.bioontology.org/ontology/ICD10CM/N52" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">N52</a>, <a href="https://purl.bioontology.org/ontology/ICD10CM/F52.21" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">F52.21</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C2187990&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C2187990</a>, <a href="https://bioportal.bioontology.org/search?q=C0242350&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0242350</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0100639" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0100639</a>, <a href="https://hpo.jax.org/app/browse/term/HP:0000802" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000802</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000802" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000802</a>]</span><br />
</span>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<em> Internal Genitalia (Female) </em>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
- Premature ovarian failure <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/373717006" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">373717006</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/65846009" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">65846009</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/237788002" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">237788002</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/E28.31" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">E28.31</a>, <a href="https://purl.bioontology.org/ontology/ICD10CM/E28.3" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">E28.3</a>, <a href="https://purl.bioontology.org/ontology/ICD10CM/E28.319" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">E28.319</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/256.31" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">256.31</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0025322&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0025322</a>, <a href="https://bioportal.bioontology.org/search?q=C0085215&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0085215</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0008209" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0008209</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0008209" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0008209</a>]</span><br />
</span>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<em> Bladder </em>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
- Urinary incontinence <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/165232002" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">165232002</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/R32" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">R32</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/788.30" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">788.30</a>, <a href="https://purl.bioontology.org/ontology/ICD9CM/788.3" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">788.3</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0042024&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0042024</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000020" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000020</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000020" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000020</a>]</span><br />
</span>
</div>
</div>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<strong> MUSCLE, SOFT TISSUES </strong>
</span>
</div>
<div style="margin-left: 2em;">
<div>
<span class="mim-font">
- Muscle pain <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/68962001" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">68962001</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/M79.1" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">M79.1</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0231528&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0231528</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003326" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003326</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003326" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003326</a>]</span><br /> -
Fibromyalgia <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/56557000" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">56557000</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/203102006" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">203102006</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/203082005" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">203082005</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/726531007" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">726531007</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/24693007" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">24693007</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/M79.7" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">M79.7</a>, <a href="https://purl.bioontology.org/ontology/ICD10CM/M79.1" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">M79.1</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0016053&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0016053</a>]</span><br />
</span>
</div>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<strong> NEUROLOGIC </strong>
</span>
</div>
<div style="margin-left: 2em;">
<div>
<div>
<span class="h5 mim-font">
<em> Central Nervous System </em>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
- Action tremor <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/30721006" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">30721006</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/G25.2" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">G25.2</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C4551520&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C4551520</a>, <a href="https://bioportal.bioontology.org/search?q=C0234376&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0234376</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002345" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002345</a>, <a href="https://hpo.jax.org/app/browse/term/HP:0002080" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002080</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002345" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002345</a>]</span><br /> -
Intention tremor <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/30721006" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">30721006</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/G25.2" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">G25.2</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C4551520&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C4551520</a>, <a href="https://bioportal.bioontology.org/search?q=C0234376&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0234376</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002345" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002345</a>, <a href="https://hpo.jax.org/app/browse/term/HP:0002080" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002080</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002080" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002080</a>]</span><br /> -
Resting tremor <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/25082004" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">25082004</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0234379&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0234379</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002322" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002322</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002322" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002322</a>]</span><br /> -
Postural tremor <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/56610005" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">56610005</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0234378&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0234378</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002174" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002174</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002174" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002174</a>]</span><br /> -
Ataxic gait <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/25136009" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">25136009</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/R26.0" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">R26.0</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0751837&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0751837</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002066" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002066</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002066" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002066</a>]</span><br /> -
Impaired tandem gait <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C3275367&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C3275367</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0031629" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0031629</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0031629" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0031629</a>]</span><br /> -
Parkinsonism <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/32798002" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">32798002</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/G20.C" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">G20.C</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0242422&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0242422</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001300" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001300</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001300" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001300</a>]</span><br /> -
Bradykinesia <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/399317006" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">399317006</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0233565&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0233565</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002067" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002067</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002067" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002067</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 /> -
Impaired fine motor skills <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1867864&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1867864</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0007010" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0007010</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0007010" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0007010</a>]</span><br /> -
Illegible handwriting <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C3275369&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C3275369</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 /> -
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 /> -
Loss of executive function <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1843023&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1843023</a>]</span><br /> -
Cognitive decline <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/386806002" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">386806002</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0338656&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0338656</a>, <a href="https://bioportal.bioontology.org/search?q=C0234985&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0234985</a> 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>, <a href="https://hpo.jax.org/app/browse/term/HP:0001268" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001268</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001268" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001268</a>]</span><br /> -
Memory defects <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C3275370&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C3275370</a>]</span><br /> -
Dementia, progressive (more common in males) <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/52448006" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">52448006</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/F03.90" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">F03.90</a>, <a href="https://purl.bioontology.org/ontology/ICD10CM/F03" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">F03</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/294.2" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">294.2</a>, <a href="https://purl.bioontology.org/ontology/ICD9CM/290" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">290</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0497327&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0497327</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000726" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000726</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000726" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000726</a>]</span><br /> -
MRI shows generalized atrophy <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C3275372&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C3275372</a>]</span><br /> -
Cerebellar atrophy <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0740279&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0740279</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001272" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001272</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001272" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001272</a>]</span><br /> -
Increased T2 signal intensities in the middle cerebellar peduncles <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C3275373&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C3275373</a>]</span><br /> -
Neuropathology shows FMR1 mRNA-positive inclusions in neurons and astrocytes <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C3275374&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C3275374</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 /> -
Hyporeflexia <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/835279003" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">835279003</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/405946002" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">405946002</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0700078&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0700078</a>, <a href="https://bioportal.bioontology.org/search?q=C0151888&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0151888</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001265" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001265</a>, <a href="https://hpo.jax.org/app/browse/term/HP:0001315" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001315</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001265" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001265</a>]</span><br /> -
Decreased distal vibratory sensation <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C3275375&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C3275375</a>]</span><br /> -
Lower extremity numbness <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0858585&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0858585</a>]</span><br /> -
Lower extremity paresthesias <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/429783005" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">429783005</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0948992&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0948992</a>]</span><br />
</span>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<em> Behavioral Psychiatric Manifestations </em>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
- Executive dysfunction <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C2748208&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C2748208</a>]</span><br /> -
Disinhibition <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/247977003" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">247977003</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/66347000" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">66347000</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/40662008" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">40662008</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/F63.9" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">F63.9</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/312.30" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">312.30</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0021122&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0021122</a>, <a href="https://bioportal.bioontology.org/search?q=C0234410&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0234410</a>, <a href="https://bioportal.bioontology.org/search?q=C0424296&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0424296</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:5200029" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:5200029</a>, <a href="https://hpo.jax.org/app/browse/term/HP:0000734" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000734</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000734" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000734</a>]</span><br /> -
Depression <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/78667006" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">78667006</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/35489007" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">35489007</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/366979004" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">366979004</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/255339005" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">255339005</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/F34.1" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">F34.1</a>, <a href="https://purl.bioontology.org/ontology/ICD10CM/F32.A" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">F32.A</a>, <a href="https://purl.bioontology.org/ontology/ICD10CM/F33.9" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">F33.9</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0812393&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0812393</a>, <a href="https://bioportal.bioontology.org/search?q=C0011581&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0011581</a>, <a href="https://bioportal.bioontology.org/search?q=C0460137&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0460137</a>, <a href="https://bioportal.bioontology.org/search?q=C1579931&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1579931</a>, <a href="https://bioportal.bioontology.org/search?q=C0344315&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0344315</a>, <a href="https://bioportal.bioontology.org/search?q=C4085311&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C4085311</a>, <a href="https://bioportal.bioontology.org/search?q=C0011570&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0011570</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000716" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000716</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000716" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000716</a>]</span><br /> -
Anxiety <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/48694002" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">48694002</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/197480006" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">197480006</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/F41.9" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">F41.9</a>, <a href="https://purl.bioontology.org/ontology/ICD10CM/F41.1" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">F41.1</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0003469&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0003469</a>, <a href="https://bioportal.bioontology.org/search?q=C0003467&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0003467</a>, <a href="https://bioportal.bioontology.org/search?q=C0860603&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0860603</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000739" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000739</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000739" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000739</a>]</span><br /> -
Obsessive-compulsive disorder <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/191736004" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">191736004</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/12479006" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">12479006</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/F42" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">F42</a>, <a href="https://purl.bioontology.org/ontology/ICD10CM/F42.9" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">F42.9</a>, <a href="https://purl.bioontology.org/ontology/ICD10CM/R46.81" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">R46.81</a>, <a href="https://purl.bioontology.org/ontology/ICD10CM/F42.8" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">F42.8</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/300.3" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">300.3</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0028768&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0028768</a>, <a href="https://bioportal.bioontology.org/search?q=C0600104&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0600104</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000722" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000722</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000722" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000722</a>]</span><br />
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<strong> ENDOCRINE FEATURES </strong>
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- Premature ovarian failure <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/373717006" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">373717006</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/65846009" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">65846009</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/237788002" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">237788002</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/E28.31" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">E28.31</a>, <a href="https://purl.bioontology.org/ontology/ICD10CM/E28.3" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">E28.3</a>, <a href="https://purl.bioontology.org/ontology/ICD10CM/E28.319" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">E28.319</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/256.31" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">256.31</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0025322&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0025322</a>, <a href="https://bioportal.bioontology.org/search?q=C0085215&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0085215</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0008209" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0008209</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0008209" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0008209</a>]</span><br /> -
Hypothyroidism <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/40930008" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">40930008</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/E03.9" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">E03.9</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/244.9" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">244.9</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0020676&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0020676</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000821" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000821</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000821" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000821</a>]</span><br />
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<strong> LABORATORY ABNORMALITIES </strong>
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- Increased intracellular FMRP mRNA <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C3275376&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C3275376</a>]</span><br /> -
Decreased intracellular FMR protein <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C3275377&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C3275377</a>]</span><br />
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<strong> MISCELLANEOUS </strong>
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- Onset in fifties or sixties<br /> -
Caused by 55-200 expanded trinucleotide repeats in the FMR1 gene (<a href="/entry/309550">309550</a>) referred to as a 'premutation'<br /> -
Most patients have a family history of fragile X syndrome<br /> -
Full mutations with expanded trinucleotide repeats greater than 200 result in fragile X mental retardation syndrome (<a href="/entry/300624">300624</a>)<br /> -
Males are more commonly affected than females<br />
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<strong> MOLECULAR BASIS </strong>
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- Caused by trinucleotide repeat expansion (CGG)n in the fragile X messenger ribonucleoprotein gene (FMR1, <a href="/entry/309550#0004">309550.0004</a>)<br />
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<p>A number sign (#) is used with this entry because fragile X tremor/ataxia syndrome (FXTAS) is caused by an expanded trinucleotide repeat in the FMR1 gene (<a href="/entry/309550#0004">309550.0004</a>).</p><p>In FXTAS, the expanded repeats range in size from 55 to 200 repeats and are referred to as 'premutations;' full repeat expansions with greater than 200 repeats results in fragile X syndrome (FXS; <a href="/entry/300624">300624</a>) (<a href="#22" class="mim-tip-reference" title="Jacquemont, S., Hagerman, R. J., Leehey, M., Grigsby, J., Zhang, L., Brunberg, J. A., Greco, C., Des Portes, V., Jardini, T., Levine, R., Berry-Kravis, E., Brown, W. T., Schaeffer, S., Kissel, J., Tassone, F., Hagerman, P. J. &lt;strong&gt;Fragile X premutation tremor/ataxia syndrome: molecular, clinical, and neuroimaging correlates.&lt;/strong&gt; Am. J. Hum. Genet. 72: 869-878, 2003.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/12638084/&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;12638084&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=12638084[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/10.1086/374321&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="12638084">Jacquemont et al., 2003</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12638084" 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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<strong>Description</strong>
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<p><a href="#21" class="mim-tip-reference" title="Jacquemont, S., Hagerman, R. J., Hagerman, P. J., Leehey, M. A. &lt;strong&gt;Fragile-X syndrome and fragile X-associated tremor/ataxia syndrome: two faces of FMR1.&lt;/strong&gt; Lancet Neurol. 6: 45-55, 2007.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/17166801/&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;17166801&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/S1474-4422(06)70676-7&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="17166801">Jacquemont et al. (2007)</a> provided a review of fragile X syndrome, which they characterized as a neurodevelopmental disorder, and FXTAS, which they characterized as a neurodegenerative disorder. <a href="#2" class="mim-tip-reference" title="Amiri, K., Hagerman, R. J., Hagerman, P. J. &lt;strong&gt;Fragile X-associated tremor/ataxia syndrome: an aging face of the fragile X gene.&lt;/strong&gt; Arch. Neurol. 65: 19-25, 2008.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/18195136/&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;18195136&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1001/archneurol.2007.30&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="18195136">Amiri et al. (2008)</a> provided a review of FXTAS and noted that the pathogenesis of the disorder is distinct from that in fragile X syndrome. FXTAS results form a toxic gain of function of FMR1 RNA, whereas fragile X syndrome results from a loss of FMR1 function. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=18195136+17166801" 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 penetrance of FXTAS in male carriers aged 50 years and over, ascertained through families with a fragile X syndrome proband, is at least 33% (<a href="#12" class="mim-tip-reference" title="Hagerman, P. J., Hagerman, R. J. &lt;strong&gt;The fragile-X premutation: a maturing perspective.&lt;/strong&gt; Am. J. Hum. Genet. 74: 805-816, 2004. Note: Erratum: Am. J. Hum. Genet. 75: 352 only, 2004.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/15052536/&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;15052536&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=15052536[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/10.1086/386296&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="15052536">Hagerman and Hagerman, 2004</a>); its penetrance in female carriers is approximately 5-10% (<a href="#11" class="mim-tip-reference" title="Greco, C. M., Tassone, F., Garcia-Arocena, D., Tartaglia, N., Coffey, S. M., Vartanian, T. K., Brunberg, J. A., Hagerman, P. J., Hagerman, R. J. &lt;strong&gt;Clinical and neuropathologic findings in a woman with the FMR1 premutation and multiple sclerosis.&lt;/strong&gt; Arch. Neurol. 65: 1114-1116, 2008.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/18695063/&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;18695063&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=18695063[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/10.1001/archneur.65.8.1114&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="18695063">Greco et al., 2008</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=15052536+18695063" 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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<strong>Clinical Features</strong>
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<p><a href="#15" class="mim-tip-reference" title="Hagerman, R. J., Leehey, M., Heinrichs, W., Tassone, F., Wilson, R., Hills, J., Grigsby, J., Gage, B., Hagerman, P. J. &lt;strong&gt;Intention tremor, parkinsonism, and generalized brain atrophy in male carriers of fragile X.&lt;/strong&gt; Neurology 57: 127-130, 2001.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/11445641/&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;11445641&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1212/wnl.57.1.127&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="11445641">Hagerman et al. (2001)</a> reported 5 men with a fragile X premutation, ranging from 78 to 98 repeats, who presented in the sixth decade with progressive intention tremor, parkinsonism, cognitive decline, generalized atrophy on MRI, and impotence. Two of the patients were college professors and 1 had a PhD in education. Levels of FMR1 mRNA were 2 to 4 times higher than normal, which the authors suggested resulted in a pathogenic gain-of-function effect. <a href="#25" class="mim-tip-reference" title="Leehey, M. A., Munhoz, R. P., Lang, A. E., Brunberg, J. A., Grigsby, J., Greco, C., Jacquemont, S., Tassone, F., Lozano, A. M., Hagerman, P. J., Hagerman, R. J. &lt;strong&gt;The fragile X premutation presenting as essential tremor.&lt;/strong&gt; Arch. Neurol. 60: 117-121, 2003.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/12533098/&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;12533098&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1001/archneur.60.1.117&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="12533098">Leehey et al. (2003)</a> reported 2 unrelated men who presented with essential tremor at ages 58 and 49 years and were later found to carry the fragile X premutation (90 and 160 repeats, respectively). Besides the disabling intention tremor, both patients had tandem gait difficulties, generalized brain atrophy, and elevated FMR1 mRNA. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=12533098+11445641" 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>Comparing 21 fragile X premutation carriers (7 male and 14 female) to 16 noncarriers, <a href="#5" class="mim-tip-reference" title="Berry-Kravis, E., Lewin, F., Wuu, J., Leehey, M., Hagerman, R., Hagerman, P., Goetz, C. G. &lt;strong&gt;Tremor and ataxia in fragile X premutation carriers: blinded videotape study.&lt;/strong&gt; Ann. Neurol. 53: 616-623, 2003.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/12730995/&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;12730995&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ana.10522&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="12730995">Berry-Kravis et al. (2003)</a> found that the male premutation carriers had significantly increased postural and kinetic tremor and limb ataxia, as measured by standard scale scoring. The female carrier and control groups did not differ on any measure. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12730995" 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>Late-onset tremor, gait unsteadiness, and dementia can be associated with brain atrophy in males of normal intelligence who are premutation carriers of the fragile X syndrome. By means of a telephone survey, <a href="#32" class="mim-tip-reference" title="Rogers, C., Partington, M. W., Turner, G. M. &lt;strong&gt;Tremor, ataxia and dementia in older men may indicate a carrier of the fragile X syndrome.&lt;/strong&gt; Clin. Genet. 64: 54-56, 2003.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/12791039/&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;12791039&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1034/j.1399-0004.2003.00089.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="12791039">Rogers et al. (2003)</a> showed that this association is probably causal rather than coincidental. The premutation males were grandfathers ascertained through one of their daughter's sons having had the fragile X syndrome. The control subjects were the corresponding grandfathers on the paternal side of the family. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12791039" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#22" class="mim-tip-reference" title="Jacquemont, S., Hagerman, R. J., Leehey, M., Grigsby, J., Zhang, L., Brunberg, J. A., Greco, C., Des Portes, V., Jardini, T., Levine, R., Berry-Kravis, E., Brown, W. T., Schaeffer, S., Kissel, J., Tassone, F., Hagerman, P. J. &lt;strong&gt;Fragile X premutation tremor/ataxia syndrome: molecular, clinical, and neuroimaging correlates.&lt;/strong&gt; Am. J. Hum. Genet. 72: 869-878, 2003.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/12638084/&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;12638084&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=12638084[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/10.1086/374321&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="12638084">Jacquemont et al. (2003)</a> demonstrated that carriers of the fragile X premutation can be affected by a multisystem, progressive neurologic disorder, which they termed the 'fragile X tremor/ataxia syndrome.' They presented a series of 26 patients, all more than 50 years of age, who were carriers of the fragile X premutation and affected by a neurologic disorder with 2 main clinical features, cerebellar ataxia and/or intention tremor. Other documented symptoms were short-term memory loss, executive function deficits, cognitive decline, parkinsonism, peripheral neuropathy, lower limb proximal muscle weakness, and autonomic dysfunction. Symmetric regions of increased T2 signal intensity in the middle cerebellar peduncles and adjacent cerebellar white matter were considered to be highly sensitive for this neurologic condition, and their presence was the radiologic inclusion criterion for this series of cases. Molecular findings included elevated mRNA and low-normal or mildly decreased levels of FMR1 protein. The clinical presentation of these patients, coupled with a specific lesion visible on MRI and with neuropathologic findings, afforded a more complete delineation of this fragile X premutation-associated tremor/ataxia syndrome and distinguished it from other movement disorders. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12638084" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#29" class="mim-tip-reference" title="Macpherson, J., Waghorn, A., Hammans, S., Jacobs, P. &lt;strong&gt;Observation of an excess of fragile-X premutations in a population of males referred with spinocerebellar ataxia. (Letter)&lt;/strong&gt; Hum. Genet. 112: 619-620, 2003.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/12612802/&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;12612802&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1007/s00439-003-0939-z&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="12612802">Macpherson et al. (2003)</a> presented further evidence that premutations of the FMR1 gene may have clinical effects. They analyzed a cohort of patients with neurodegenerative disorders referred for genetic analysis of spinocerebellar ataxia genes and found that 3 of 59 males carried the premutation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12612802" 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="Hagerman, R. J., Leavitt, B. R., Farzin, F., Jacquemont, S., Greco, C. M., Brunberg, J. A., Tassone, F., Hessl, D., Harris, S. W., Zhang, L., Jardini, T., Gane, L. W., Ferranti, J., Ruiz, L., Leehey, M. A., Grigsby, J., Hagerman, P. J. &lt;strong&gt;Fragile-X-associated tremor/ataxia syndrome (FXTAS) in females with the FMR1 premutation.&lt;/strong&gt; Am. J. Hum. Genet. 74: 1051-1056, 2004.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/15065016/&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;15065016&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=15065016[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/10.1086/420700&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="15065016">Hagerman et al. (2004)</a> described 5 female carriers of the FMR1 premutation who presented with symptoms of tremor and ataxia and received a diagnosis of FXTAS. Unlike their male counterparts with FXTAS, none of the women had dementia. Females had not been reported in previous studies of FXTAS, suggesting that they may be relatively protected from this disorder. Brain tissue was available from 1 of the 5 patients, who died at age 85 years; microscopic examination revealed intranuclear neuronal and astrocytic inclusions, in accord with the previously reported findings in males with FXTAS. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15065016" 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="#12" class="mim-tip-reference" title="Hagerman, P. J., Hagerman, R. J. &lt;strong&gt;The fragile-X premutation: a maturing perspective.&lt;/strong&gt; Am. J. Hum. Genet. 74: 805-816, 2004. Note: Erratum: Am. J. Hum. Genet. 75: 352 only, 2004.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/15052536/&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;15052536&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=15052536[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/10.1086/386296&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="15052536">Hagerman and Hagerman (2004)</a> pointed out that carriers of premutation alleles (55 to 200 CGG repeats) of the FMR1 gene can present with 1 or more of 3 distinct clinical disorders: mild cognitive and/or behavioral deficits on the fragile X spectrum; premature ovarian failure; and fragile X tremor/ataxia syndrome. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15052536" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#6" class="mim-tip-reference" title="Biancalana, V., Toft, M., Le Ber, I., Tison, F., Scherrer, E., Thibodeau, S., Mandel, J. L., Brice, A., Farrer, M. J., Durr, A. &lt;strong&gt;FMR1 premutations associated with fragile X-associated tremor/ataxia syndrome in multiple system atrophy.&lt;/strong&gt; Arch. Neurol. 62: 962-966, 2005.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/15956167/&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;15956167&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1001/archneur.62.6.962&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="15956167">Biancalana et al. (2005)</a> reported a woman with FXTAS who had an FMR1 premutation of 135 CGG repeats. She was originally diagnosed with multiple system atrophy with cerebellar signs. The patient had a long history of bipolar disorder and developed progressive ataxic gait at age 54 years. Examination at age 58 showed gait and limb ataxia, rigidity, hyperreflexia, and bladder incontinence. At age 64, she was bedridden with dysarthria, retrocollis, dysphagia, and horizontal nystagmus, and she died at age 65; she was not demented. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15956167" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#7" class="mim-tip-reference" title="Brussino, A., Gellera, C., Saluto, A., Mariotti, C., Arduino, C., Castellotti, B., Camerlingo, M., de Angelis, V., Orsi, L., Tosca, P., Migone, N., Taroni, F., Brusco, A. &lt;strong&gt;FMR1 gene premutation is a frequent genetic cause of late-onset sporadic cerebellar ataxia.&lt;/strong&gt; Neurology 64: 145-147, 2005.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/15642922/&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;15642922&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1212/01.WNL.0000148723.37489.3F&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="15642922">Brussino et al. (2005)</a> identified FMR1 premutations, ranging from 83 to 109 repeats, in 6 (2.2%) of 275 unrelated Italian men with adult-onset sporadic progressive cerebellar ataxia. The frequency increased to 4.2% when considering only those patients with onset after age 50 years. Two relatives of 1 of the probands were also affected. Age at onset ranged from 53 to 69 years, and all individuals had cerebellar atrophy on neuroradiologic examination. In contrast to previous reports, tremor was infrequent in this group, present in only 3 of 8 individuals. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15642922" 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 retrospective analysis of patient data, <a href="#16" class="mim-tip-reference" title="Hall, D. A., Berry-Kravis, E., Jacquemont, S., Rice, C. D., Cogswell, J., Zhang, L., Hagerman, R. J., Hagerman, P. J., Leehey, M. A. &lt;strong&gt;Initial diagnoses given to persons with the fragile X associated tremor/ataxia syndrome (FXTAS).&lt;/strong&gt; Neurology 65: 299-301, 2005. Note: Erratum: Neurology 65: 784 only, 2005.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/16043804/&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;16043804&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1212/01.wnl.0000168900.86323.9c&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="16043804">Hall et al. (2005)</a> found that 56 patients with FXTAS were initially given 98 prior diagnoses, most commonly parkinsonism, tremor, ataxia, dementia, or stroke. A review of published studies showed that 16 (3%) of 539 patients diagnosed with ataxia were FMR1 premutation carriers. <a href="#16" class="mim-tip-reference" title="Hall, D. A., Berry-Kravis, E., Jacquemont, S., Rice, C. D., Cogswell, J., Zhang, L., Hagerman, R. J., Hagerman, P. J., Leehey, M. A. &lt;strong&gt;Initial diagnoses given to persons with the fragile X associated tremor/ataxia syndrome (FXTAS).&lt;/strong&gt; Neurology 65: 299-301, 2005. Note: Erratum: Neurology 65: 784 only, 2005.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/16043804/&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;16043804&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1212/01.wnl.0000168900.86323.9c&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="16043804">Hall et al. (2005)</a> suggested that FMR1 DNA testing should be performed in men over age 50 years with unexplained cerebellar ataxia, and in men over age 50 with action tremor, parkinsonism, or dementia who also have either a family history of developmental delay, autism, mental retardation, or premature ovarian failure, or who have the middle cerebellar peduncle sign on MRI. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16043804" 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 MRI, <a href="#28" class="mim-tip-reference" title="Loesch, D. Z., Litewka, L., Brotchie, P., Huggins, R. M., Tassone, F., Cook, M. &lt;strong&gt;Magnetic resonance imaging study in older fragile X premutation male carriers.&lt;/strong&gt; Ann. Neurol. 58: 326-330, 2005.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/16049924/&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;16049924&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ana.20542&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="16049924">Loesch et al. (2005)</a> found that 8 older male premutation carriers (average age of 58.9 years) had significantly reduced volumes of cerebrum, cerebellum, and cerebral cortex compared to 21 age-matched controls. Total brain and cerebral volumes were inversely related to the number of CGG repeats in the FMR1 gene. The 8 premutation carriers also had increased hippocampal volumes compared to controls, suggesting neurodevelopmental changes such as lack of normal synaptic pruning. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16049924" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#4" class="mim-tip-reference" title="Bacalman, S., Farzin, F., Bourgeois, J. A., Cogswell, J., Goodlin-Jones, B. L., Gane, L. W., Grigsby, J., Leehey, M. A., Tassone, F., Hagerman, R. J. &lt;strong&gt;Psychiatric phenotype of the fragile X-associated tremor/ataxia syndrome (FXTAS) in males: newly described fronto-subcortical dementia.&lt;/strong&gt; J. Clin. Psychiat. 67: 87-94, 2006.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/16426093/&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;16426093&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.4088/jcp.v67n0112&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="16426093">Bacalman et al. (2006)</a> described and quantified the neuropsychiatric symptoms present in a cohort of males with the FMR1 premutation allele who had developed the FXTAS phenotype. Fourteen male carriers with FXTAS syndrome and 14 age- and education-matched controls were assessed with the Neuropsychiatric Inventory (NPI) profile, formal cognitive testing, and genetic analysis. Males with FXTAS had significantly higher total NPI scores (p less than 0.004) and significantly higher scores on the agitation/aggression, depression, apathy, disinhibition, and irritability scales (each p value less than 0.004), compared with controls. Cognitive performances on the Mini-Mental State Examination did not correlate with severity of symptoms on the NPI. <a href="#4" class="mim-tip-reference" title="Bacalman, S., Farzin, F., Bourgeois, J. A., Cogswell, J., Goodlin-Jones, B. L., Gane, L. W., Grigsby, J., Leehey, M. A., Tassone, F., Hagerman, R. J. &lt;strong&gt;Psychiatric phenotype of the fragile X-associated tremor/ataxia syndrome (FXTAS) in males: newly described fronto-subcortical dementia.&lt;/strong&gt; J. Clin. Psychiat. 67: 87-94, 2006.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/16426093/&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;16426093&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.4088/jcp.v67n0112&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="16426093">Bacalman et al. (2006)</a> found that the neuropsychiatric manifestations of FXTAS appear to cluster as a frontosubcortical dementia. They strongly advised clinicians encountering patients with clinical dementia and motor symptoms suggesting FXTAS to consider genetic testing to determine whether the patient's dementia syndrome is secondary to a fragile X premutation carrier status, which could have further implications for other family members. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16426093" 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 brain MRI studies, <a href="#1" class="mim-tip-reference" title="Adams, J. S., Adams, P. E., Nguyen, D., Brunberg, J. A., Tassone, F., Zhang, W., Koldewyn, K., Rivera, S. M., Grigsby, J., Zhang, L., DeCarli, C., Hagerman, P. J., Hagerman, R. J. &lt;strong&gt;Volumetric brain changes in females with fragile X-associated tremor/ataxia syndrome (FXTAS).&lt;/strong&gt; Neurology 69: 851-859, 2007.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/17724287/&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;17724287&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1212/01.wnl.0000269781.10417.7b&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="17724287">Adams et al. (2007)</a> observed less pronounced reductions in middle cerebellar peduncle volumes in females with FXTAS compared to males with FXTAS (13% and 58% reductions, respectively). Both affected males and females had significantly smaller whole brain volumes and increased white matter abnormalities compared to sex-matched unaffected premutation carriers and controls, respectively. There was no difference between unaffected premutation carriers and controls. Decreased cerebellar volume was associated with increased length of the CGG repeat and more advanced clinical disease in male, but not in female, premutation carriers. Milder radiographic findings in affected females compared to affected males suggested that a buffering effect may be present in females. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17724287" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#9" class="mim-tip-reference" title="Goncalves, M. R. R., Capelli, L. P., Nitrini, R., Barbosa, E. R., Porto, C. S., Lucato, L. T., Vianna-Morgante, A. M. &lt;strong&gt;Atypical clinical course of FXTAS: rapidly progressive dementia as the major symptom.&lt;/strong&gt; Neurology 68: 1864-1866, 2007.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/17515552/&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;17515552&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1212/01.wnl.0000262058.68100.ea&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="17515552">Goncalves et al. (2007)</a> reported a 69-year-old man with an 85-repeat premutation allele who had onset of reclusive, apathetic behavior, imbalance, and gait difficulties. By age 70, he had severe cognitive impairment suggestive of frontal-subcortical network involvement. MRI showed white matter lesions in the middle cerebellar peduncle and the cerebellar hemispheres associated with diffuse brain atrophy. His grandson had full fragile X mental retardation syndrome. <a href="#9" class="mim-tip-reference" title="Goncalves, M. R. R., Capelli, L. P., Nitrini, R., Barbosa, E. R., Porto, C. S., Lucato, L. T., Vianna-Morgante, A. M. &lt;strong&gt;Atypical clinical course of FXTAS: rapidly progressive dementia as the major symptom.&lt;/strong&gt; Neurology 68: 1864-1866, 2007.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/17515552/&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;17515552&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1212/01.wnl.0000262058.68100.ea&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="17515552">Goncalves et al. (2007)</a> emphasized the unusual presentation of FXTAS in the elder patient. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17515552" 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="Hagerman, R. J., Coffey, S. M., Maselli, R., Soontarapornchai, K., Brunberg, J. A., Leehey, M. A., Zhang, L., Gane, L. W., Fenton-Farrell, G., Tassone, F., Hagerman, P. J. &lt;strong&gt;Neuropathy as a presenting feature in fragile X-associated tremor/ataxia syndrome.&lt;/strong&gt; Am. J. Med. Genet. 143A: 2256-2260, 2007.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/17726686/&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;17726686&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ajmg.a.31920&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="17726686">Hagerman et al. (2007)</a> reported 5 unrelated FXTAS patients who presented with peripheral neuropathy. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17726686" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#11" class="mim-tip-reference" title="Greco, C. M., Tassone, F., Garcia-Arocena, D., Tartaglia, N., Coffey, S. M., Vartanian, T. K., Brunberg, J. A., Hagerman, P. J., Hagerman, R. J. &lt;strong&gt;Clinical and neuropathologic findings in a woman with the FMR1 premutation and multiple sclerosis.&lt;/strong&gt; Arch. Neurol. 65: 1114-1116, 2008.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/18695063/&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;18695063&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=18695063[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/10.1001/archneur.65.8.1114&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="18695063">Greco et al. (2008)</a> reported a woman diagnosed with relapsing-remitting multiple sclerosis (MS; see <a href="/entry/126200">126200</a>) at age 38 who was found to have a 75-repeat FMR1 premutation allele. Clinical features included distal sensory loss, intention tremor, gait ataxia, spastic paraparesis, short-term memory deficits, progressive dysarthria, disinhibition, and depression. She died at the age of 52 years after progressive memory impairment and loss of motor control. Postmortem examination showed demyelinating plaques in the cerebral and cerebellar white matter, reactive astrocytosis, and intranuclear inclusions in astrocytes and cortical neurons. <a href="#11" class="mim-tip-reference" title="Greco, C. M., Tassone, F., Garcia-Arocena, D., Tartaglia, N., Coffey, S. M., Vartanian, T. K., Brunberg, J. A., Hagerman, P. J., Hagerman, R. J. &lt;strong&gt;Clinical and neuropathologic findings in a woman with the FMR1 premutation and multiple sclerosis.&lt;/strong&gt; Arch. Neurol. 65: 1114-1116, 2008.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/18695063/&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;18695063&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=18695063[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/10.1001/archneur.65.8.1114&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="18695063">Greco et al. (2008)</a> noted that clinical features of FXTAS and MS overlap and suggested that the pathologic processes may be related or may be additive. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18695063" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#8" class="mim-tip-reference" title="Coffey, S. M., Cook, K., Tartaglia, N., Tassone, F., Nguyen, D. V., Pan, R., Bronsky, H. E., Yuhas, J., Borodyanskaya, M., Grigsby, J., Doerflinger, M., Hagerman, P. J., Hagerman, R. J. &lt;strong&gt;Expanded clinical phenotype of women with the FMR1 premutation.&lt;/strong&gt; Am. J. Med. Genet. 146A: 1009-1016, 2008.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/18348275/&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;18348275&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ajmg.a.32060&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="18348275">Coffey et al. (2008)</a> evaluated 146 female carriers with (18 patients) or without (128 patients) core features of FXTAS (tremor and gait ataxia) and 69 age-matched controls. Compared with controls, carriers with FXTAS had a significantly higher prevalence by history of thyroid disorders (50% vs 15.4%; p = 0.0096), hypertension (61.1% vs 18%; p = 0.002), seizures (22.2% vs 0%; p = 0.0077), peripheral neuropathy (52.9% vs 9.1%; p = 0.004), and fibromyalgia (43.8% vs 9.4%, p = 0.0097). Thyroid disease was more common in the non-FXTAS carrier group (17.3%) compared to the control group (10.1%) but this was not statistically significant. <a href="#8" class="mim-tip-reference" title="Coffey, S. M., Cook, K., Tartaglia, N., Tassone, F., Nguyen, D. V., Pan, R., Bronsky, H. E., Yuhas, J., Borodyanskaya, M., Grigsby, J., Doerflinger, M., Hagerman, P. J., Hagerman, R. J. &lt;strong&gt;Expanded clinical phenotype of women with the FMR1 premutation.&lt;/strong&gt; Am. J. Med. Genet. 146A: 1009-1016, 2008.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/18348275/&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;18348275&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ajmg.a.32060&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="18348275">Coffey et al. (2008)</a> recommended thyroid function studies in all female premutation carriers, especially those with features of FXTAS. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18348275" 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="#19" class="mim-tip-reference" title="Hunter, J. E., Allen, E. G., Abramowitz, A., Rusin, M., Leslie, M., Novak, G., Hamilton, D., Shubeck, L., Charen, K., Sherman, S. L. &lt;strong&gt;No evidence for a difference in neuropsychological profile among carriers and noncarriers of the FMR1 premutation in adults under the age of 50.&lt;/strong&gt; Am. J. Hum. Genet. 83: 692-702, 2008.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/19026394/&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;19026394&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/j.ajhg.2008.10.021&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="19026394">Hunter et al. (2008)</a> found no significant differences in neuropsychologic testing scores between 63 males carriers under the age of 50 who were intermediate (20 to 55 repeats) or premutation (55 to 199 repeats) FMR1 alleles compared to 75 male controls. A comparison of 389 female intermediate or premutation allele carriers showed an association with increasing repeat length and self-reported attention difficulties compared to 117 female controls, but there were no differences in the other neuropsychologic testing scores. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19026394" 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="#37" class="mim-tip-reference" title="Soontarapornchai, K., Maselli, R., Fenton-Farrell, G., Tassone, F., Hagerman, P. J., Hessl, D., Hagerman, R. J. &lt;strong&gt;Abnormal nerve conduction features in fragile X premutation carriers.&lt;/strong&gt; Arch. Neurol. 65: 495-498, 2008.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/18413472/&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;18413472&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1001/archneur.65.4.495&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="18413472">Soontarapornchai et al. (2008)</a> observed mildly decreased peripheral nerve conduction velocities in motor and sensory nerves of 16 males FXTAS premutation carriers compared to unaffected premutation carriers and controls. There was a correlation between longer CGG repeat number and slowing of the conduction velocity, suggesting that the premutation was a causal factor. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18413472" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In a study of 74 men over age 50 years, including 35 carriers of FMR1 premutation alleles and 39 controls, <a href="#33" class="mim-tip-reference" title="Sevin, M., Kutalik, Z., Bergman, S., Vercelletto, M., Renou, P., Lamy, E., Vingerhoets, F. J., Di Virgilio, G., Boisseau, P., Bezieau, S., Pasqiuer, L., Rival, J.-M., Beckmann, J. S., Damier, P., Jacquemont, S. &lt;strong&gt;Penetrance of marked cognitive impairment in older male carriers of the FMR1 gene premutation.&lt;/strong&gt; J. Med. Genet. 46: 818-824, 2009.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/19542082/&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;19542082&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1136/jmg.2008.065953&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="19542082">Sevin et al. (2009)</a> found that those with large FMR1 premutation alleles (70 to 200 repeats) had a 6-fold increased risk of developing cognitive decline compared to controls. The penetrance of cognitive impairment increased with allele size: 33.3% for 70 to 200 repeats compared to only 5.9% for 55 to 69 repeats and 5.1% for controls. Cognitive impairment was observed to precede motor symptoms in some cases. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19542082" 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="#31" class="mim-tip-reference" title="Rodriguez-Revenga, L., Pagonabarraga, J., Gomez-Anson, B., Lopez-Mourelo, O., Madrigal, I., Xuncla, M., Kulisevsky, J., Mila, M. &lt;strong&gt;Motor and mental dysfunction in mother-daughter transmitted FXTAS.&lt;/strong&gt; Neurology 75: 1370-1376, 2010.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/20938029/&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;20938029&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1212/WNL.0b013e3181f73660&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="20938029">Rodriguez-Revenga et al. (2010)</a> reported 2 unrelated Spanish families in which 2 mothers with FXTAS and dementia with an expanded CGG repeat (98 and 88 repeats, respectively) transmitted an expanded CGG repeat (156 and 134, respectively) to each of their daughters. The mothers developed symptoms of gait ataxia and tremor at ages 73 and 56 years, respectively, which progressed to frontal lobe dysfunction. MRI showed cerebral, cerebellar, and brainstem atrophy, with the older woman having marked hyperintensities in the putamen and middle cerebellar peduncles. The daughters, aged 58 and 44, respectively, developed tremor at ages 54 and 29, respectively. The older woman also had gait ataxia. Both daughters showed subtle cognitive deficits, particularly in executive function and working memory. Brain MRI showed mild cerebral and cerebellar atrophy with variable hyperintensities in the basal ganglia. Other features in all 4 women included hearing loss in 3, muscle pain in 4, fibromyalgia in 3, and hypothyroidism in 2. Peripheral blood cells of all patients showed increased levels of FMR1 mRNA compared to controls, and all showed skewed X-chromosome inactivation favoring the mutant allele. The findings expanded the phenotype of FXTAS in females. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20938029" 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="#30" class="mim-tip-reference" title="Ng, A. S. L., Xu, Z., Chen, Z., Tan, Y. J., Lim, W. K., Ting, S. K. S., Yu, W. Y., Cheng, Q. H., Foo, J. N., Tan, E. K., Lim, T. C. C. &lt;strong&gt;NOTCH2NLC-linked neuronal intranuclear inclusion body disease and fragile X-associated tremor/ataxia syndrome.&lt;/strong&gt; Brain 143: e69, 2020. Note: Electronic Article.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/32789443/&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;32789443&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1093/brain/awaa210&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="32789443">Ng et al. (2020)</a> reported a man of East Asian descent who presented with cognitive impairment at age 64. He had no family history of a similar disorder, and there were no motor signs. Brain imaging showed a diffusion-weighted imaging (DWI) signal at the gray-white matter junction, characteristic of NIID (<a href="/entry/603472">603472</a>), as well as the MCP sign, a T2-weighted abnormality in the middle cerebral peduncles. He was predicted to have NIID, but genetic analysis was negative for the pathogenic repeat expansion in the NOTCH2NLC gene (<a href="/entry/618025#0001">618025.0001</a>). As suggested by <a href="#36" class="mim-tip-reference" title="Sone, J., Mori, K. Inagaki, T., Katsumata, R., Takagi, S., Yokoi, S., Araki, K., Kato, T., Nakamura, T., Koike, H., Takashima, H., Hashiguchi, A., 20 others. &lt;strong&gt;Clinicopathological features of adult-onset neuronal intranuclear inclusion disease.&lt;/strong&gt; Brain 139: 3170-3186, 2016.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/27797808/&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;27797808&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=27797808[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/10.1093/brain/aww249&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="27797808">Sone et al. (2016)</a>, the authors tested the FMR1 gene and identified an abnormal repeat expansion (110 CGG repeats), confirming the diagnosis of FXTAS. The authors emphasized the need for genetic studies including both NOTCH2NLC and FMR1 for patients in whom MRI is used as a screening tool for neurodegenerative disorders. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=27797808+32789443" 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 5 men with FXTAS, <a href="#15" class="mim-tip-reference" title="Hagerman, R. J., Leehey, M., Heinrichs, W., Tassone, F., Wilson, R., Hills, J., Grigsby, J., Gage, B., Hagerman, P. J. &lt;strong&gt;Intention tremor, parkinsonism, and generalized brain atrophy in male carriers of fragile X.&lt;/strong&gt; Neurology 57: 127-130, 2001.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/11445641/&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;11445641&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1212/wnl.57.1.127&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="11445641">Hagerman et al. (2001)</a> identified a premutation in the FMR1 gene, ranging from 78 to 98 repeats (<a href="/entry/309550#0004">309550.0004</a>). Levels of FMR1 mRNA were 2 to 4 times higher than normal, which the authors suggested resulted in a pathogenic gain-of-function effect. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11445641" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In 2 unrelated men with FXTAS, <a href="#25" class="mim-tip-reference" title="Leehey, M. A., Munhoz, R. P., Lang, A. E., Brunberg, J. A., Grigsby, J., Greco, C., Jacquemont, S., Tassone, F., Lozano, A. M., Hagerman, P. J., Hagerman, R. J. &lt;strong&gt;The fragile X premutation presenting as essential tremor.&lt;/strong&gt; Arch. Neurol. 60: 117-121, 2003.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/12533098/&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;12533098&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1001/archneur.60.1.117&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="12533098">Leehey et al. (2003)</a> identified a fragile X premutation (90 and 160 repeats, respectively). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12533098" 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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<p>In patients with FXTAS, <a href="#5" class="mim-tip-reference" title="Berry-Kravis, E., Lewin, F., Wuu, J., Leehey, M., Hagerman, R., Hagerman, P., Goetz, C. G. &lt;strong&gt;Tremor and ataxia in fragile X premutation carriers: blinded videotape study.&lt;/strong&gt; Ann. Neurol. 53: 616-623, 2003.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/12730995/&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;12730995&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ana.10522&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="12730995">Berry-Kravis et al. (2003)</a> found that the premutation was associated with increased levels of CGG repeat-containing FMR1 mRNA, which may interfere with nuclear function and lead to neurodegenerative symptoms. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12730995" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#3" class="mim-tip-reference" title="Arocena, D. G., Iwahashi, C. K., Won, N., Beilina, A., Ludwig, A. L., Tassone, F., Schwartz, P. H., Hagerman, P. J. &lt;strong&gt;Induction of inclusion formation and disruption of lamin A/C structure by premutation CGG-repeat RNA in human cultured neural cells.&lt;/strong&gt; Hum. Molec. Genet. 14: 3661-3671, 2005.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/16239243/&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;16239243&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1093/hmg/ddi394&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="16239243">Arocena et al. (2005)</a> noted that FXTAS appears to affect only carriers of premutation alleles, who have normal or near-normal FMR1 protein levels in both peripheral blood leukocytes and brain tissue, suggesting that FXTAS may result from a toxic gain-of-function of the FMR1 mRNA itself. In human neural SK cells, expression of an 88-repeat premutation allele resulted in development of inclusions containing the heat shock protein alpha-B-crystallin (CRYAB; <a href="/entry/123590">123590</a>) and lamin A/C (LMNA; <a href="/entry/150330">150330</a>). The expanded FMR1 repeat was cytotoxic. The findings suggested that the neuropathology of FXTAS may be mediated in part by dysregulation of lamin A/C function, which would be consistent with the peripheral neuropathy that is common among FXTAS patients. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16239243" 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 postmortem examination of 11 males with FXTAS, <a href="#10" class="mim-tip-reference" title="Greco, C. M., Berman, R. F., Martin, R. M., Tassone, F., Schwartz, P. H., Chang, A., Trapp, B. D., Iwahashi, C., Brunberg, J., Grigsby, J., Hessl, D., Becker, E. J., Papazian, J., Leehey, M. A., Hagerman, R. J., Hagerman, P. J. &lt;strong&gt;Neuropathology of fragile X-associated tremor/ataxia syndrome (FXTAS).&lt;/strong&gt; Brain 129: 243-255, 2006.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/16332642/&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;16332642&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1093/brain/awh683&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="16332642">Greco et al. (2006)</a> reported significant cerebral and cerebellar white matter disease, astrocytic pathology with enlarged inclusion-bearing astrocytes, and intranuclear inclusions in the brain and spinal cord. Seven of 8 patients examined had spongiosis in the middle cerebellar peduncles. There was a highly significant association between the number of CGG repeats in the FMR1 gene and the number of intranuclear inclusions. Analysis of the intracellular inclusions identified in patients with FXTAS showed that they contain FMR1 mRNA, lamin A/C, neurofilaments, and ubiquitin (UBB; <a href="/entry/191339">191339</a>) (<a href="#20" class="mim-tip-reference" title="Iwahashi, C. K., Yasui, D. H., An, H.-J., Greco, C. M., Tassone, F., Nannen, K., Babineau, B., Lebrilla, C. B., Hagerman, R. J., Hagerman, P. J. &lt;strong&gt;Protein composition of the intranuclear inclusions of FXTAS.&lt;/strong&gt; Brain 129: 256-271, 2006.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/16246864/&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;16246864&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1093/brain/awh650&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="16246864">Iwahashi et al., 2006</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=16246864+16332642" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#17" class="mim-tip-reference" title="Handa, V., Goldwater, D., Stiles, D., Cam, M., Poy, G., Kumari, D., Usdin, K. &lt;strong&gt;Long CGG-repeat tracts are toxic to human cells: implications for carriers of fragile X premutation alleles.&lt;/strong&gt; FEBS Lett. 579: 2702-2708, 2005.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/15862312/&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;15862312&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/j.febslet.2005.04.004&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="15862312">Handa et al. (2005)</a> found that transcribed but untranslated expanded CGG premutation alleles were toxic to human cells, and microarray analysis detected altered expression of a wide variety of genes, including upregulation of CASP8 (<a href="/entry/601763">601763</a>), CYFIP1 (<a href="/entry/606322">606322</a>), NTS (<a href="/entry/162650">162650</a>), and UBE3A (<a href="/entry/601623">601623</a>), which was confirmed by RT-PCR analysis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15862312" 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 gel-shift assays with mouse and fly brain lysates, followed by protein purification and mass spectroscopy, <a href="#23" class="mim-tip-reference" title="Jin, P., Duan, R., Qurashi, A., Qin, Y., Tian, D., Rosser, T. C., Liu, H., Feng, Y., Warren, S. T. &lt;strong&gt;Pur alpha binds to rCGG repeats and modulates repeat-mediated neurodegeneration in a Drosophila model of fragile X tremor/ataxia syndrome.&lt;/strong&gt; Neuron 55: 556-564, 2007.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/17698009/&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;17698009&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=17698009[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/10.1016/j.neuron.2007.07.020&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="17698009">Jin et al. (2007)</a> showed that the RNA-binding protein Pur-alpha (PURA; <a href="/entry/600473">600473</a>) bound (CGG)105. Pur-alpha bound CGG repeats in a sequence-specific manner, and overexpression of Pur-alpha in a Drosophila model of FXTAS suppressed CGG repeat-mediated neurodegeneration in a dose-dependent manner. Furthermore, immunohistochemical analysis showed that Pur-alpha was ubiquitously expressed in wildtype fly eyes, but it was sequestered in inclusions in fly eyes expressing (CGG)105. Human PURA was present in ubiquitin-positive inclusions in postmortem FXTAS brain tissues. <a href="#23" class="mim-tip-reference" title="Jin, P., Duan, R., Qurashi, A., Qin, Y., Tian, D., Rosser, T. C., Liu, H., Feng, Y., Warren, S. T. &lt;strong&gt;Pur alpha binds to rCGG repeats and modulates repeat-mediated neurodegeneration in a Drosophila model of fragile X tremor/ataxia syndrome.&lt;/strong&gt; Neuron 55: 556-564, 2007.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/17698009/&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;17698009&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=17698009[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/10.1016/j.neuron.2007.07.020&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="17698009">Jin et al. (2007)</a> hypothesized that PURA is sequestered from its normal function by binding premutation CGG repeats, leading to pathologic changes in FXTAS. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17698009" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#26" class="mim-tip-reference" title="Loesch, D. Z., Godler, D. E., Evans, A., Bui, Q. M., Gehling, F., Kotschet, K. E., Trost, N., Storey, E., Stimpson, P., Kinsella, G., Francis, D., Thorburn, D. R., Venn, A., Slater, H. R., Horne, M. &lt;strong&gt;Evidence for the toxicity of bidirectional transcripts and mitochondrial dysfunction in blood associated with small CGG expansions in the FMR1 gene in patients with parkinsonism.&lt;/strong&gt; Genet. Med. 13: 392-399, 2011.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/21270637/&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;21270637&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=21270637[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/10.1097/GIM.0b013e3182064362&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="21270637">Loesch et al. (2011)</a> performed detailed clinical assessment and genetic testing in 14 male carriers of premutation and gray zone FMR1 alleles and 24 noncarriers identified in a sample of males with parkinsonism. The premutation and gray zone carriers presented with more severe symptoms than disease controls matched for age, diagnosis, disease duration, and treatment. The Parkinson disease motor score and the measure of cognitive decline were significantly correlated with the size of the CGG repeat and elevated levels of antisense FMR1 and cytochrome C1 (<a href="/entry/123980">123980</a>) mRNAs in blood leukocytes. In addition, the carriers showed a significant depletion of the NADH dehydrogenase subunit-1 mitochondrial gene (ND1, or MTND1; <a href="/entry/516000">516000</a>) in whole blood. <a href="#26" class="mim-tip-reference" title="Loesch, D. Z., Godler, D. E., Evans, A., Bui, Q. M., Gehling, F., Kotschet, K. E., Trost, N., Storey, E., Stimpson, P., Kinsella, G., Francis, D., Thorburn, D. R., Venn, A., Slater, H. R., Horne, M. &lt;strong&gt;Evidence for the toxicity of bidirectional transcripts and mitochondrial dysfunction in blood associated with small CGG expansions in the FMR1 gene in patients with parkinsonism.&lt;/strong&gt; Genet. Med. 13: 392-399, 2011.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/21270637/&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;21270637&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=21270637[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/10.1097/GIM.0b013e3182064362&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="21270637">Loesch et al. (2011)</a> concluded that small CGG expansion FMR1 alleles in the gray zone and lower end premutation play a significant role in the development of the parkinsonian phenotype, possibly through the cytotoxic effect of elevated sense and/or antisense FMR1 transcripts involving mitochondrial dysfunction and leading to progressive neurodegeneration. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21270637" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#34" class="mim-tip-reference" title="Silva, F., Rodriguez-Revenga, L., Madrigal, I., Alvarez-Mora, M. I., Oliva, R., Mila, M. &lt;strong&gt;High apolipoprotein E4 allele frequency in FXTAS patients.&lt;/strong&gt; Genet. Med. 15: 639-642, 2013.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/23492875/&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;23492875&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1038/gim.2013.12&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="23492875">Silva et al. (2013)</a> studied a total of 44 unrelated FMR1 premutation carriers, 22 with FXTAS and 22 without, and genotyped them for the ApoE locus (<a href="/entry/107741">107741</a>). All ApoE4 (<a href="/entry/107741#0016">107741.0016</a>) homozygous genotype carriers detected and 6 of the 7 ApoE4/3 (<a href="/entry/107741#0015">107741.0015</a>) genotype carriers (85.7%) were patients presenting with FXTAS, whereas only 40% of the ApoE3/3 genotype carriers belonged to the FXTAS group. These results showed that the presence of the ApoE4 allele increases the risk of developing FXTAS (OR = 12.041; p = 0.034). <a href="#34" class="mim-tip-reference" title="Silva, F., Rodriguez-Revenga, L., Madrigal, I., Alvarez-Mora, M. I., Oliva, R., Mila, M. &lt;strong&gt;High apolipoprotein E4 allele frequency in FXTAS patients.&lt;/strong&gt; Genet. Med. 15: 639-642, 2013.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/23492875/&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;23492875&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1038/gim.2013.12&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="23492875">Silva et al. (2013)</a> concluded that the presence of at least 1 ApoE4 allele acts as a genetic factor predisposing individuals to develop FXTAS. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23492875" 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="#27" class="mim-tip-reference" title="Loesch, D. Z., Khaniani, M. S., Slater, H. R., Rubio, J. P., Bui, Q. M., Kotschet, K., D&#x27;Souza, W., Venn, A., Kalitsis, P., Choo, A. K. H., Burgess, T., Johnson, L., Evans, A., Horne, M. &lt;strong&gt;Small CGG repeat expansion alleles of FMR1 gene are associated with parkinsonism.&lt;/strong&gt; Clin. Genet. 76: 471-476, 2009.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/19796183/&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;19796183&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1111/j.1399-0004.2009.01275.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="19796183">Loesch et al. (2009)</a> identified 4 carriers of FMR1 premutation alleles (56, 58, 83 and 87 CGGs, respectively) among 228 Australian males with idiopathic parkinsonism; no premutation alleles were found in 576 controls (p = 0.006). The frequency of premutation carriers was 1.75%, an almost 10-fold increase compared with the population frequency range of approximately 0.1 to 0.4%. There were also significantly more carriers of 'gray zone' alleles (ranging from 40 to 54 CGG repeats) among patients compared to controls (odds ratio of 2.36; p = 0.012). <a href="#27" class="mim-tip-reference" title="Loesch, D. Z., Khaniani, M. S., Slater, H. R., Rubio, J. P., Bui, Q. M., Kotschet, K., D&#x27;Souza, W., Venn, A., Kalitsis, P., Choo, A. K. H., Burgess, T., Johnson, L., Evans, A., Horne, M. &lt;strong&gt;Small CGG repeat expansion alleles of FMR1 gene are associated with parkinsonism.&lt;/strong&gt; Clin. Genet. 76: 471-476, 2009.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/19796183/&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;19796183&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1111/j.1399-0004.2009.01275.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="19796183">Loesch et al. (2009)</a> suggested that both premutation and gray zone FMR1 alleles may contribute to increased susceptibility to of parkinsonism, and that toxic effects of expanded FMR1 mRNA may also occur when the expansions are smaller. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19796183" 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="#38" class="mim-tip-reference" title="Willemsen, R., Hoogeveen-Westerveld, M., Reis, S., Holstege, J., Severijnen, L.-A. W. F. M., Nieuwenhuizen, I. M., Schrier, M., van Unen, L., Tassone, F., Hoogeveen, A. T., Hagerman, P. J., Mientjes, E. J., Oostra, B. A. &lt;strong&gt;The FMR1 CGG repeat mouse displays ubiquitin-positive intranuclear neuronal inclusions; implications for the cerebellar tremor/ataxia syndrome.&lt;/strong&gt; Hum. Molec. Genet. 12: 949-959, 2003.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/12700164/&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;12700164&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1093/hmg/ddg114&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="12700164">Willemsen et al. (2003)</a> described neurohistologic, biochemical, and molecular studies of the brains of transgenic mice with an expanded CGG repeat (102 to 110 repeats) in human FMR1, and reported elevated Fmr1 mRNA levels and intranuclear inclusions with ubiquitin, Hsp40 (see <a href="/entry/604572">604572</a>), and the 20S catalytic core complex of the proteasome as constituents. An increase was observed in both the number and the size of the inclusions during the course of life, which correlated with the progressive character of the cerebellar tremor/ataxia syndrome in humans. <a href="#38" class="mim-tip-reference" title="Willemsen, R., Hoogeveen-Westerveld, M., Reis, S., Holstege, J., Severijnen, L.-A. W. F. M., Nieuwenhuizen, I. M., Schrier, M., van Unen, L., Tassone, F., Hoogeveen, A. T., Hagerman, P. J., Mientjes, E. J., Oostra, B. A. &lt;strong&gt;The FMR1 CGG repeat mouse displays ubiquitin-positive intranuclear neuronal inclusions; implications for the cerebellar tremor/ataxia syndrome.&lt;/strong&gt; Hum. Molec. Genet. 12: 949-959, 2003.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/12700164/&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;12700164&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1093/hmg/ddg114&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="12700164">Willemsen et al. (2003)</a> concluded that the observations in expanded-repeat mice supported a direct role of the Fmr1 gene, by either CGG expansion per se or by mRNA level, in the formation of the inclusions and suggested a correlation between the presence of intranuclear inclusions in distinct regions of the brain and the clinical features in symptomatic premutation carriers. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12700164" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#24" class="mim-tip-reference" title="Jin, P., Zarnescu, D. C., Zhang, F., Pearson, C. E., Lucchesi, J. C., Moses, K., Warren, S. T. &lt;strong&gt;RNA-mediated neurodegeneration caused by the fragile X premutation rCGG repeats in Drosophila.&lt;/strong&gt; Neuron 39: 739-747, 2003.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/12948442/&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;12948442&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/s0896-6273(03)00533-6&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="12948442">Jin et al. (2003)</a> expressed a human FMR1 premutation allele of 90 CGG repeats in Drosophila using a heterologous transcript (EGFP). The expanded RNA alone induced neuron-specific degeneration, as observed in retinal cells, characterized by Hsp70 (see <a href="/entry/140550">140550</a>)- and ubiquitin-positive inclusion bodies similar to those seen in patients with FXTAS. The findings suggested a role for a toxic RNA-mediated gain-of-function in FXTAS. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12948442" 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 transgenic fly model of FXTAS in which the 5-prime UTR of human FMR1 containing 90 CGG repeats is expressed specifically in the eye results in disorganized ommatidia, depigmentation, and progressive loss of photoreceptor neurons. <a href="#35" class="mim-tip-reference" title="Sofola, O. A., Jin, P., Qin, Y., Duan, R., Liu, H., de Haro, M., Nelson, D. L., Botas, J. &lt;strong&gt;RNA-binding proteins hnRNP A2/B1 and CUGBP1 suppress fragile X CGG premutation repeat-induced neurodegeneration in a Drosophila model of FXTAS.&lt;/strong&gt; Neuron 55: 565-571, 2007.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/17698010/&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;17698010&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=17698010[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/10.1016/j.neuron.2007.07.021&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="17698010">Sofola et al. (2007)</a> found that overexpression of human CUGBP1 (<a href="/entry/601074">601074</a>) suppressed the neurodegenerative eye phenotype in FXTAS flies. CUGBP1 did not interact directly with the CGG repeats, but did so via HNRNPA2B1 (<a href="/entry/600124">600124</a>). Expression of the A2 isoform of human HNRNPA2B1, or the Drosophila orthologs, also suppressed the eye phenotype of FXTAS flies. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17698010" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#18" class="mim-tip-reference" title="Hashem, V., Galloway, J. N., Mori, M., Willemsen, R., Oostra, B. A., Paylor, R., Nelson, D. L. &lt;strong&gt;Ectopic expression of CGG containing mRNA is neurotoxic in mammals.&lt;/strong&gt; Hum. Molec. Genet. 18: 2443-2451, 2009.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/19377084/&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;19377084&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=19377084[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/10.1093/hmg/ddp182&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="19377084">Hashem et al. (2009)</a> generated mice expressing the human 90 CGG premutation in the context of the mouse Fmr1 5-prime UTR or the EGFP (enhanced green fluorescent protein) 5-prime UTR, specifically in Purkinje neurons, in order to segregate the effects of CGG repeat from alterations in Fmr1 and to provide evidence that CGG repeat is necessary and sufficient to cause pathology similar to human FXTAS. CGG(90)-EGFP was sufficient to produce ubiquitin-positive intranuclear inclusion formation. They also demonstrated CGG(90)-EGFP overexpression resulted in Purkinje neuron axonal swellings and neurotoxicity and in a mouse phenotype showing progressive age-dependent decline in neuromotor learning ability. <a href="#18" class="mim-tip-reference" title="Hashem, V., Galloway, J. N., Mori, M., Willemsen, R., Oostra, B. A., Paylor, R., Nelson, D. L. &lt;strong&gt;Ectopic expression of CGG containing mRNA is neurotoxic in mammals.&lt;/strong&gt; Hum. Molec. Genet. 18: 2443-2451, 2009.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/19377084/&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;19377084&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=19377084[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/10.1093/hmg/ddp182&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="19377084">Hashem et al. (2009)</a> concluded that CGG expressed in Purkinje neurons outside the context of Fmr1 mRNA may result in neuronal pathology in a mammalian system, and that expanded CGG repeats in RNA are the likely cause of the neurodegeneration in FXTAS. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19377084" 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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<strong>REFERENCES</strong>
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<div id="mimReferencesFold" class="collapse in mimTextToggleFold">
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<a id="Adams2007" class="mim-anchor"></a>
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<p class="mim-text-font">
Adams, J. S., Adams, P. E., Nguyen, D., Brunberg, J. A., Tassone, F., Zhang, W., Koldewyn, K., Rivera, S. M., Grigsby, J., Zhang, L., DeCarli, C., Hagerman, P. J., Hagerman, R. J.
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[<a href="https://doi.org/10.1212/01.wnl.0000269781.10417.7b" target="_blank">Full Text</a>]
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<a id="Amiri2008" class="mim-anchor"></a>
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Amiri, K., Hagerman, R. J., Hagerman, P. J.
<strong>Fragile X-associated tremor/ataxia syndrome: an aging face of the fragile X gene.</strong>
Arch. Neurol. 65: 19-25, 2008.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18195136/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18195136</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18195136" 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/archneurol.2007.30" target="_blank">Full Text</a>]
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<a id="Arocena2005" class="mim-anchor"></a>
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Arocena, D. G., Iwahashi, C. K., Won, N., Beilina, A., Ludwig, A. L., Tassone, F., Schwartz, P. H., Hagerman, P. J.
<strong>Induction of inclusion formation and disruption of lamin A/C structure by premutation CGG-repeat RNA in human cultured neural cells.</strong>
Hum. Molec. Genet. 14: 3661-3671, 2005.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16239243/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16239243</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16239243" 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/ddi394" target="_blank">Full Text</a>]
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<a id="Bacalman2006" class="mim-anchor"></a>
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Bacalman, S., Farzin, F., Bourgeois, J. A., Cogswell, J., Goodlin-Jones, B. L., Gane, L. W., Grigsby, J., Leehey, M. A., Tassone, F., Hagerman, R. J.
<strong>Psychiatric phenotype of the fragile X-associated tremor/ataxia syndrome (FXTAS) in males: newly described fronto-subcortical dementia.</strong>
J. Clin. Psychiat. 67: 87-94, 2006.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16426093/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16426093</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16426093" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.4088/jcp.v67n0112" target="_blank">Full Text</a>]
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<a id="Berry-Kravis2003" class="mim-anchor"></a>
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Berry-Kravis, E., Lewin, F., Wuu, J., Leehey, M., Hagerman, R., Hagerman, P., Goetz, C. G.
<strong>Tremor and ataxia in fragile X premutation carriers: blinded videotape study.</strong>
Ann. Neurol. 53: 616-623, 2003.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12730995/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12730995</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12730995" 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.10522" target="_blank">Full Text</a>]
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<a id="Biancalana2005" class="mim-anchor"></a>
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Biancalana, V., Toft, M., Le Ber, I., Tison, F., Scherrer, E., Thibodeau, S., Mandel, J. L., Brice, A., Farrer, M. J., Durr, A.
<strong>FMR1 premutations associated with fragile X-associated tremor/ataxia syndrome in multiple system atrophy.</strong>
Arch. Neurol. 62: 962-966, 2005.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15956167/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15956167</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15956167" 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.62.6.962" target="_blank">Full Text</a>]
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<a id="Brussino2005" class="mim-anchor"></a>
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Brussino, A., Gellera, C., Saluto, A., Mariotti, C., Arduino, C., Castellotti, B., Camerlingo, M., de Angelis, V., Orsi, L., Tosca, P., Migone, N., Taroni, F., Brusco, A.
<strong>FMR1 gene premutation is a frequent genetic cause of late-onset sporadic cerebellar ataxia.</strong>
Neurology 64: 145-147, 2005.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15642922/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15642922</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15642922" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1212/01.WNL.0000148723.37489.3F" target="_blank">Full Text</a>]
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<a id="Coffey2008" class="mim-anchor"></a>
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Coffey, S. M., Cook, K., Tartaglia, N., Tassone, F., Nguyen, D. V., Pan, R., Bronsky, H. E., Yuhas, J., Borodyanskaya, M., Grigsby, J., Doerflinger, M., Hagerman, P. J., Hagerman, R. J.
<strong>Expanded clinical phenotype of women with the FMR1 premutation.</strong>
Am. J. Med. Genet. 146A: 1009-1016, 2008.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18348275/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18348275</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18348275" 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/ajmg.a.32060" target="_blank">Full Text</a>]
</p>
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<a id="9" class="mim-anchor"></a>
<a id="Goncalves2007" class="mim-anchor"></a>
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<p class="mim-text-font">
Goncalves, M. R. R., Capelli, L. P., Nitrini, R., Barbosa, E. R., Porto, C. S., Lucato, L. T., Vianna-Morgante, A. M.
<strong>Atypical clinical course of FXTAS: rapidly progressive dementia as the major symptom.</strong>
Neurology 68: 1864-1866, 2007.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17515552/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17515552</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17515552" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1212/01.wnl.0000262058.68100.ea" target="_blank">Full Text</a>]
</p>
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<a id="10" class="mim-anchor"></a>
<a id="Greco2006" class="mim-anchor"></a>
<div class="">
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Greco, C. M., Berman, R. F., Martin, R. M., Tassone, F., Schwartz, P. H., Chang, A., Trapp, B. D., Iwahashi, C., Brunberg, J., Grigsby, J., Hessl, D., Becker, E. J., Papazian, J., Leehey, M. A., Hagerman, R. J., Hagerman, P. J.
<strong>Neuropathology of fragile X-associated tremor/ataxia syndrome (FXTAS).</strong>
Brain 129: 243-255, 2006.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16332642/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16332642</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16332642" 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/awh683" target="_blank">Full Text</a>]
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<a id="11" class="mim-anchor"></a>
<a id="Greco2008" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Greco, C. M., Tassone, F., Garcia-Arocena, D., Tartaglia, N., Coffey, S. M., Vartanian, T. K., Brunberg, J. A., Hagerman, P. J., Hagerman, R. J.
<strong>Clinical and neuropathologic findings in a woman with the FMR1 premutation and multiple sclerosis.</strong>
Arch. Neurol. 65: 1114-1116, 2008.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18695063/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18695063</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18695063[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18695063" 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.65.8.1114" target="_blank">Full Text</a>]
</p>
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<a id="12" class="mim-anchor"></a>
<a id="Hagerman2004" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Hagerman, P. J., Hagerman, R. J.
<strong>The fragile-X premutation: a maturing perspective.</strong>
Am. J. Hum. Genet. 74: 805-816, 2004. Note: Erratum: Am. J. Hum. Genet. 75: 352 only, 2004.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15052536/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15052536</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15052536[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15052536" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1086/386296" target="_blank">Full Text</a>]
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<a id="13" class="mim-anchor"></a>
<a id="Hagerman2007" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Hagerman, R. J., Coffey, S. M., Maselli, R., Soontarapornchai, K., Brunberg, J. A., Leehey, M. A., Zhang, L., Gane, L. W., Fenton-Farrell, G., Tassone, F., Hagerman, P. J.
<strong>Neuropathy as a presenting feature in fragile X-associated tremor/ataxia syndrome.</strong>
Am. J. Med. Genet. 143A: 2256-2260, 2007.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17726686/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17726686</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17726686" 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/ajmg.a.31920" target="_blank">Full Text</a>]
</p>
</div>
</li>
<li>
<a id="14" class="mim-anchor"></a>
<a id="Hagerman2004" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Hagerman, R. J., Leavitt, B. R., Farzin, F., Jacquemont, S., Greco, C. M., Brunberg, J. A., Tassone, F., Hessl, D., Harris, S. W., Zhang, L., Jardini, T., Gane, L. W., Ferranti, J., Ruiz, L., Leehey, M. A., Grigsby, J., Hagerman, P. J.
<strong>Fragile-X-associated tremor/ataxia syndrome (FXTAS) in females with the FMR1 premutation.</strong>
Am. J. Hum. Genet. 74: 1051-1056, 2004.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15065016/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15065016</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15065016[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15065016" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1086/420700" target="_blank">Full Text</a>]
</p>
</div>
</li>
<li>
<a id="15" class="mim-anchor"></a>
<a id="Hagerman2001" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Hagerman, R. J., Leehey, M., Heinrichs, W., Tassone, F., Wilson, R., Hills, J., Grigsby, J., Gage, B., Hagerman, P. J.
<strong>Intention tremor, parkinsonism, and generalized brain atrophy in male carriers of fragile X.</strong>
Neurology 57: 127-130, 2001.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11445641/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11445641</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11445641" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1212/wnl.57.1.127" target="_blank">Full Text</a>]
</p>
</div>
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<li>
<a id="16" class="mim-anchor"></a>
<a id="Hall2005" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Hall, D. A., Berry-Kravis, E., Jacquemont, S., Rice, C. D., Cogswell, J., Zhang, L., Hagerman, R. J., Hagerman, P. J., Leehey, M. A.
<strong>Initial diagnoses given to persons with the fragile X associated tremor/ataxia syndrome (FXTAS).</strong>
Neurology 65: 299-301, 2005. Note: Erratum: Neurology 65: 784 only, 2005.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16043804/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16043804</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16043804" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1212/01.wnl.0000168900.86323.9c" target="_blank">Full Text</a>]
</p>
</div>
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<li>
<a id="17" class="mim-anchor"></a>
<a id="Handa2005" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Handa, V., Goldwater, D., Stiles, D., Cam, M., Poy, G., Kumari, D., Usdin, K.
<strong>Long CGG-repeat tracts are toxic to human cells: implications for carriers of fragile X premutation alleles.</strong>
FEBS Lett. 579: 2702-2708, 2005.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15862312/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15862312</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15862312" 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/j.febslet.2005.04.004" target="_blank">Full Text</a>]
</p>
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<li>
<a id="18" class="mim-anchor"></a>
<a id="Hashem2009" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Hashem, V., Galloway, J. N., Mori, M., Willemsen, R., Oostra, B. A., Paylor, R., Nelson, D. L.
<strong>Ectopic expression of CGG containing mRNA is neurotoxic in mammals.</strong>
Hum. Molec. Genet. 18: 2443-2451, 2009.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19377084/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19377084</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19377084[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19377084" 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/ddp182" target="_blank">Full Text</a>]
</p>
</div>
</li>
<li>
<a id="19" class="mim-anchor"></a>
<a id="Hunter2008" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Hunter, J. E., Allen, E. G., Abramowitz, A., Rusin, M., Leslie, M., Novak, G., Hamilton, D., Shubeck, L., Charen, K., Sherman, S. L.
<strong>No evidence for a difference in neuropsychological profile among carriers and noncarriers of the FMR1 premutation in adults under the age of 50.</strong>
Am. J. Hum. Genet. 83: 692-702, 2008.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19026394/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19026394</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19026394" 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/j.ajhg.2008.10.021" target="_blank">Full Text</a>]
</p>
</div>
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<li>
<a id="20" class="mim-anchor"></a>
<a id="Iwahashi2006" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Iwahashi, C. K., Yasui, D. H., An, H.-J., Greco, C. M., Tassone, F., Nannen, K., Babineau, B., Lebrilla, C. B., Hagerman, R. J., Hagerman, P. J.
<strong>Protein composition of the intranuclear inclusions of FXTAS.</strong>
Brain 129: 256-271, 2006.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16246864/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16246864</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16246864" 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/awh650" target="_blank">Full Text</a>]
</p>
</div>
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<li>
<a id="21" class="mim-anchor"></a>
<a id="Jacquemont2007" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Jacquemont, S., Hagerman, R. J., Hagerman, P. J., Leehey, M. A.
<strong>Fragile-X syndrome and fragile X-associated tremor/ataxia syndrome: two faces of FMR1.</strong>
Lancet Neurol. 6: 45-55, 2007.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17166801/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17166801</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17166801" 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/S1474-4422(06)70676-7" target="_blank">Full Text</a>]
</p>
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<a id="22" class="mim-anchor"></a>
<a id="Jacquemont2003" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Jacquemont, S., Hagerman, R. J., Leehey, M., Grigsby, J., Zhang, L., Brunberg, J. A., Greco, C., Des Portes, V., Jardini, T., Levine, R., Berry-Kravis, E., Brown, W. T., Schaeffer, S., Kissel, J., Tassone, F., Hagerman, P. J.
<strong>Fragile X premutation tremor/ataxia syndrome: molecular, clinical, and neuroimaging correlates.</strong>
Am. J. Hum. Genet. 72: 869-878, 2003.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12638084/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12638084</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=12638084[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12638084" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1086/374321" target="_blank">Full Text</a>]
</p>
</div>
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<li>
<a id="23" class="mim-anchor"></a>
<a id="Jin2007" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Jin, P., Duan, R., Qurashi, A., Qin, Y., Tian, D., Rosser, T. C., Liu, H., Feng, Y., Warren, S. T.
<strong>Pur alpha binds to rCGG repeats and modulates repeat-mediated neurodegeneration in a Drosophila model of fragile X tremor/ataxia syndrome.</strong>
Neuron 55: 556-564, 2007.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17698009/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17698009</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17698009[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17698009" 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/j.neuron.2007.07.020" target="_blank">Full Text</a>]
</p>
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<li>
<a id="24" class="mim-anchor"></a>
<a id="Jin2003" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Jin, P., Zarnescu, D. C., Zhang, F., Pearson, C. E., Lucchesi, J. C., Moses, K., Warren, S. T.
<strong>RNA-mediated neurodegeneration caused by the fragile X premutation rCGG repeats in Drosophila.</strong>
Neuron 39: 739-747, 2003.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12948442/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12948442</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12948442" 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/s0896-6273(03)00533-6" target="_blank">Full Text</a>]
</p>
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<li>
<a id="25" class="mim-anchor"></a>
<a id="Leehey2003" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Leehey, M. A., Munhoz, R. P., Lang, A. E., Brunberg, J. A., Grigsby, J., Greco, C., Jacquemont, S., Tassone, F., Lozano, A. M., Hagerman, P. J., Hagerman, R. J.
<strong>The fragile X premutation presenting as essential tremor.</strong>
Arch. Neurol. 60: 117-121, 2003.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12533098/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12533098</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12533098" 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.60.1.117" target="_blank">Full Text</a>]
</p>
</div>
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<a id="26" class="mim-anchor"></a>
<a id="Loesch2011" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Loesch, D. Z., Godler, D. E., Evans, A., Bui, Q. M., Gehling, F., Kotschet, K. E., Trost, N., Storey, E., Stimpson, P., Kinsella, G., Francis, D., Thorburn, D. R., Venn, A., Slater, H. R., Horne, M.
<strong>Evidence for the toxicity of bidirectional transcripts and mitochondrial dysfunction in blood associated with small CGG expansions in the FMR1 gene in patients with parkinsonism.</strong>
Genet. Med. 13: 392-399, 2011.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21270637/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21270637</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21270637[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21270637" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1097/GIM.0b013e3182064362" target="_blank">Full Text</a>]
</p>
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<li>
<a id="27" class="mim-anchor"></a>
<a id="Loesch2009" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Loesch, D. Z., Khaniani, M. S., Slater, H. R., Rubio, J. P., Bui, Q. M., Kotschet, K., D'Souza, W., Venn, A., Kalitsis, P., Choo, A. K. H., Burgess, T., Johnson, L., Evans, A., Horne, M.
<strong>Small CGG repeat expansion alleles of FMR1 gene are associated with parkinsonism.</strong>
Clin. Genet. 76: 471-476, 2009.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19796183/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19796183</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19796183" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1111/j.1399-0004.2009.01275.x" target="_blank">Full Text</a>]
</p>
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<li>
<a id="28" class="mim-anchor"></a>
<a id="Loesch2005" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Loesch, D. Z., Litewka, L., Brotchie, P., Huggins, R. M., Tassone, F., Cook, M.
<strong>Magnetic resonance imaging study in older fragile X premutation male carriers.</strong>
Ann. Neurol. 58: 326-330, 2005.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16049924/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16049924</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16049924" 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.20542" target="_blank">Full Text</a>]
</p>
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<a id="Macpherson2003" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Macpherson, J., Waghorn, A., Hammans, S., Jacobs, P.
<strong>Observation of an excess of fragile-X premutations in a population of males referred with spinocerebellar ataxia. (Letter)</strong>
Hum. Genet. 112: 619-620, 2003.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12612802/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12612802</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12612802" 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/s00439-003-0939-z" target="_blank">Full Text</a>]
</p>
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<a id="30" class="mim-anchor"></a>
<a id="Ng2020" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Ng, A. S. L., Xu, Z., Chen, Z., Tan, Y. J., Lim, W. K., Ting, S. K. S., Yu, W. Y., Cheng, Q. H., Foo, J. N., Tan, E. K., Lim, T. C. C.
<strong>NOTCH2NLC-linked neuronal intranuclear inclusion body disease and fragile X-associated tremor/ataxia syndrome.</strong>
Brain 143: e69, 2020. Note: Electronic Article.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/32789443/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">32789443</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=32789443" 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/awaa210" target="_blank">Full Text</a>]
</p>
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<a id="Rodriguez-Revenga2010" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Rodriguez-Revenga, L., Pagonabarraga, J., Gomez-Anson, B., Lopez-Mourelo, O., Madrigal, I., Xuncla, M., Kulisevsky, J., Mila, M.
<strong>Motor and mental dysfunction in mother-daughter transmitted FXTAS.</strong>
Neurology 75: 1370-1376, 2010.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20938029/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20938029</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20938029" 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="Rogers2003" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Rogers, C., Partington, M. W., Turner, G. M.
<strong>Tremor, ataxia and dementia in older men may indicate a carrier of the fragile X syndrome.</strong>
Clin. Genet. 64: 54-56, 2003.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12791039/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12791039</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12791039" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1034/j.1399-0004.2003.00089.x" target="_blank">Full Text</a>]
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<a id="Sevin2009" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Sevin, M., Kutalik, Z., Bergman, S., Vercelletto, M., Renou, P., Lamy, E., Vingerhoets, F. J., Di Virgilio, G., Boisseau, P., Bezieau, S., Pasqiuer, L., Rival, J.-M., Beckmann, J. S., Damier, P., Jacquemont, S.
<strong>Penetrance of marked cognitive impairment in older male carriers of the FMR1 gene premutation.</strong>
J. Med. Genet. 46: 818-824, 2009.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19542082/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19542082</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19542082" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1136/jmg.2008.065953" target="_blank">Full Text</a>]
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<a id="Silva2013" class="mim-anchor"></a>
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Silva, F., Rodriguez-Revenga, L., Madrigal, I., Alvarez-Mora, M. I., Oliva, R., Mila, M.
<strong>High apolipoprotein E4 allele frequency in FXTAS patients.</strong>
Genet. Med. 15: 639-642, 2013.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23492875/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23492875</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23492875" 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/gim.2013.12" target="_blank">Full Text</a>]
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<a id="Sofola2007" class="mim-anchor"></a>
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Sofola, O. A., Jin, P., Qin, Y., Duan, R., Liu, H., de Haro, M., Nelson, D. L., Botas, J.
<strong>RNA-binding proteins hnRNP A2/B1 and CUGBP1 suppress fragile X CGG premutation repeat-induced neurodegeneration in a Drosophila model of FXTAS.</strong>
Neuron 55: 565-571, 2007.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17698010/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17698010</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17698010[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17698010" 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/j.neuron.2007.07.021" target="_blank">Full Text</a>]
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<a id="Sone2016" class="mim-anchor"></a>
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Sone, J., Mori, K. Inagaki, T., Katsumata, R., Takagi, S., Yokoi, S., Araki, K., Kato, T., Nakamura, T., Koike, H., Takashima, H., Hashiguchi, A., 20 others.
<strong>Clinicopathological features of adult-onset neuronal intranuclear inclusion disease.</strong>
Brain 139: 3170-3186, 2016.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27797808/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27797808</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=27797808[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27797808" 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/aww249" target="_blank">Full Text</a>]
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<a id="Soontarapornchai2008" class="mim-anchor"></a>
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Soontarapornchai, K., Maselli, R., Fenton-Farrell, G., Tassone, F., Hagerman, P. J., Hessl, D., Hagerman, R. J.
<strong>Abnormal nerve conduction features in fragile X premutation carriers.</strong>
Arch. Neurol. 65: 495-498, 2008.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18413472/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18413472</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18413472" 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.65.4.495" target="_blank">Full Text</a>]
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<a id="Willemsen2003" class="mim-anchor"></a>
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Willemsen, R., Hoogeveen-Westerveld, M., Reis, S., Holstege, J., Severijnen, L.-A. W. F. M., Nieuwenhuizen, I. M., Schrier, M., van Unen, L., Tassone, F., Hoogeveen, A. T., Hagerman, P. J., Mientjes, E. J., Oostra, B. A.
<strong>The FMR1 CGG repeat mouse displays ubiquitin-positive intranuclear neuronal inclusions; implications for the cerebellar tremor/ataxia syndrome.</strong>
Hum. Molec. Genet. 12: 949-959, 2003.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12700164/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12700164</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12700164" 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/ddg114" target="_blank">Full Text</a>]
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Cassandra L. Kniffin - updated : 01/04/2021
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Ada Hamosh - updated : 11/13/2013<br>Ada Hamosh - updated : 10/1/2012<br>Cassandra L. Kniffin - updated : 10/17/2011<br>Cassandra L. Kniffin - updated : 6/4/2010<br>George E. Tiller - updated : 4/2/2010<br>Cassandra L. Kniffin - updated : 12/21/2009<br>Patricia A. Hartz - updated : 9/10/2009<br>Patricia A. Hartz - updated : 4/14/2009<br>Cassandra L. Kniffin - updated : 4/6/2009<br>Cassandra L. Kniffin - updated : 2/5/2009<br>Cassandra L. Kniffin - updated : 1/16/2009<br>Kelly A. Przylepa - updated : 11/20/2008<br>Cassandra L. Kniffin - updated : 10/17/2008<br>Cassandra L. Kniffin - updated : 5/19/2008<br>Cassandra L. Kniffin - updated : 2/29/2008<br>Cassandra L. Kniffin - updated : 1/29/2008<br>Cassandra L. Kniffin - updated : 12/26/2007
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Cassandra L. Kniffin : 11/9/2006
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<strong>#</strong> 300623
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<span class="mim-font">
FRAGILE X TREMOR/ATAXIA SYNDROME; FXTAS
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<strong>SNOMEDCT:</strong> 448045004; &nbsp;
<strong>ORPHA:</strong> 93256; &nbsp;
<strong>DO:</strong> 0050879; &nbsp;
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<strong>Phenotype-Gene Relationships</strong>
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Location
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Phenotype
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Phenotype <br /> MIM number
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Inheritance
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Phenotype <br /> mapping key
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Gene/Locus
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Gene/Locus <br /> MIM number
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Xq27.3
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Fragile X tremor/ataxia syndrome
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300623
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X-linked dominant
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3
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FMR1
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309550
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<strong>TEXT</strong>
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<p>A number sign (#) is used with this entry because fragile X tremor/ataxia syndrome (FXTAS) is caused by an expanded trinucleotide repeat in the FMR1 gene (309550.0004).</p><p>In FXTAS, the expanded repeats range in size from 55 to 200 repeats and are referred to as 'premutations;' full repeat expansions with greater than 200 repeats results in fragile X syndrome (FXS; 300624) (Jacquemont et al., 2003). </p>
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<strong>Description</strong>
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<p>Jacquemont et al. (2007) provided a review of fragile X syndrome, which they characterized as a neurodevelopmental disorder, and FXTAS, which they characterized as a neurodegenerative disorder. Amiri et al. (2008) provided a review of FXTAS and noted that the pathogenesis of the disorder is distinct from that in fragile X syndrome. FXTAS results form a toxic gain of function of FMR1 RNA, whereas fragile X syndrome results from a loss of FMR1 function. </p><p>The penetrance of FXTAS in male carriers aged 50 years and over, ascertained through families with a fragile X syndrome proband, is at least 33% (Hagerman and Hagerman, 2004); its penetrance in female carriers is approximately 5-10% (Greco et al., 2008). </p>
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<strong>Clinical Features</strong>
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<p>Hagerman et al. (2001) reported 5 men with a fragile X premutation, ranging from 78 to 98 repeats, who presented in the sixth decade with progressive intention tremor, parkinsonism, cognitive decline, generalized atrophy on MRI, and impotence. Two of the patients were college professors and 1 had a PhD in education. Levels of FMR1 mRNA were 2 to 4 times higher than normal, which the authors suggested resulted in a pathogenic gain-of-function effect. Leehey et al. (2003) reported 2 unrelated men who presented with essential tremor at ages 58 and 49 years and were later found to carry the fragile X premutation (90 and 160 repeats, respectively). Besides the disabling intention tremor, both patients had tandem gait difficulties, generalized brain atrophy, and elevated FMR1 mRNA. </p><p>Comparing 21 fragile X premutation carriers (7 male and 14 female) to 16 noncarriers, Berry-Kravis et al. (2003) found that the male premutation carriers had significantly increased postural and kinetic tremor and limb ataxia, as measured by standard scale scoring. The female carrier and control groups did not differ on any measure. </p><p>Late-onset tremor, gait unsteadiness, and dementia can be associated with brain atrophy in males of normal intelligence who are premutation carriers of the fragile X syndrome. By means of a telephone survey, Rogers et al. (2003) showed that this association is probably causal rather than coincidental. The premutation males were grandfathers ascertained through one of their daughter's sons having had the fragile X syndrome. The control subjects were the corresponding grandfathers on the paternal side of the family. </p><p>Jacquemont et al. (2003) demonstrated that carriers of the fragile X premutation can be affected by a multisystem, progressive neurologic disorder, which they termed the 'fragile X tremor/ataxia syndrome.' They presented a series of 26 patients, all more than 50 years of age, who were carriers of the fragile X premutation and affected by a neurologic disorder with 2 main clinical features, cerebellar ataxia and/or intention tremor. Other documented symptoms were short-term memory loss, executive function deficits, cognitive decline, parkinsonism, peripheral neuropathy, lower limb proximal muscle weakness, and autonomic dysfunction. Symmetric regions of increased T2 signal intensity in the middle cerebellar peduncles and adjacent cerebellar white matter were considered to be highly sensitive for this neurologic condition, and their presence was the radiologic inclusion criterion for this series of cases. Molecular findings included elevated mRNA and low-normal or mildly decreased levels of FMR1 protein. The clinical presentation of these patients, coupled with a specific lesion visible on MRI and with neuropathologic findings, afforded a more complete delineation of this fragile X premutation-associated tremor/ataxia syndrome and distinguished it from other movement disorders. </p><p>Macpherson et al. (2003) presented further evidence that premutations of the FMR1 gene may have clinical effects. They analyzed a cohort of patients with neurodegenerative disorders referred for genetic analysis of spinocerebellar ataxia genes and found that 3 of 59 males carried the premutation. </p><p>Hagerman et al. (2004) described 5 female carriers of the FMR1 premutation who presented with symptoms of tremor and ataxia and received a diagnosis of FXTAS. Unlike their male counterparts with FXTAS, none of the women had dementia. Females had not been reported in previous studies of FXTAS, suggesting that they may be relatively protected from this disorder. Brain tissue was available from 1 of the 5 patients, who died at age 85 years; microscopic examination revealed intranuclear neuronal and astrocytic inclusions, in accord with the previously reported findings in males with FXTAS. </p><p>Hagerman and Hagerman (2004) pointed out that carriers of premutation alleles (55 to 200 CGG repeats) of the FMR1 gene can present with 1 or more of 3 distinct clinical disorders: mild cognitive and/or behavioral deficits on the fragile X spectrum; premature ovarian failure; and fragile X tremor/ataxia syndrome. </p><p>Biancalana et al. (2005) reported a woman with FXTAS who had an FMR1 premutation of 135 CGG repeats. She was originally diagnosed with multiple system atrophy with cerebellar signs. The patient had a long history of bipolar disorder and developed progressive ataxic gait at age 54 years. Examination at age 58 showed gait and limb ataxia, rigidity, hyperreflexia, and bladder incontinence. At age 64, she was bedridden with dysarthria, retrocollis, dysphagia, and horizontal nystagmus, and she died at age 65; she was not demented. </p><p>Brussino et al. (2005) identified FMR1 premutations, ranging from 83 to 109 repeats, in 6 (2.2%) of 275 unrelated Italian men with adult-onset sporadic progressive cerebellar ataxia. The frequency increased to 4.2% when considering only those patients with onset after age 50 years. Two relatives of 1 of the probands were also affected. Age at onset ranged from 53 to 69 years, and all individuals had cerebellar atrophy on neuroradiologic examination. In contrast to previous reports, tremor was infrequent in this group, present in only 3 of 8 individuals. </p><p>By retrospective analysis of patient data, Hall et al. (2005) found that 56 patients with FXTAS were initially given 98 prior diagnoses, most commonly parkinsonism, tremor, ataxia, dementia, or stroke. A review of published studies showed that 16 (3%) of 539 patients diagnosed with ataxia were FMR1 premutation carriers. Hall et al. (2005) suggested that FMR1 DNA testing should be performed in men over age 50 years with unexplained cerebellar ataxia, and in men over age 50 with action tremor, parkinsonism, or dementia who also have either a family history of developmental delay, autism, mental retardation, or premature ovarian failure, or who have the middle cerebellar peduncle sign on MRI. </p><p>Using MRI, Loesch et al. (2005) found that 8 older male premutation carriers (average age of 58.9 years) had significantly reduced volumes of cerebrum, cerebellum, and cerebral cortex compared to 21 age-matched controls. Total brain and cerebral volumes were inversely related to the number of CGG repeats in the FMR1 gene. The 8 premutation carriers also had increased hippocampal volumes compared to controls, suggesting neurodevelopmental changes such as lack of normal synaptic pruning. </p><p>Bacalman et al. (2006) described and quantified the neuropsychiatric symptoms present in a cohort of males with the FMR1 premutation allele who had developed the FXTAS phenotype. Fourteen male carriers with FXTAS syndrome and 14 age- and education-matched controls were assessed with the Neuropsychiatric Inventory (NPI) profile, formal cognitive testing, and genetic analysis. Males with FXTAS had significantly higher total NPI scores (p less than 0.004) and significantly higher scores on the agitation/aggression, depression, apathy, disinhibition, and irritability scales (each p value less than 0.004), compared with controls. Cognitive performances on the Mini-Mental State Examination did not correlate with severity of symptoms on the NPI. Bacalman et al. (2006) found that the neuropsychiatric manifestations of FXTAS appear to cluster as a frontosubcortical dementia. They strongly advised clinicians encountering patients with clinical dementia and motor symptoms suggesting FXTAS to consider genetic testing to determine whether the patient's dementia syndrome is secondary to a fragile X premutation carrier status, which could have further implications for other family members. </p><p>In brain MRI studies, Adams et al. (2007) observed less pronounced reductions in middle cerebellar peduncle volumes in females with FXTAS compared to males with FXTAS (13% and 58% reductions, respectively). Both affected males and females had significantly smaller whole brain volumes and increased white matter abnormalities compared to sex-matched unaffected premutation carriers and controls, respectively. There was no difference between unaffected premutation carriers and controls. Decreased cerebellar volume was associated with increased length of the CGG repeat and more advanced clinical disease in male, but not in female, premutation carriers. Milder radiographic findings in affected females compared to affected males suggested that a buffering effect may be present in females. </p><p>Goncalves et al. (2007) reported a 69-year-old man with an 85-repeat premutation allele who had onset of reclusive, apathetic behavior, imbalance, and gait difficulties. By age 70, he had severe cognitive impairment suggestive of frontal-subcortical network involvement. MRI showed white matter lesions in the middle cerebellar peduncle and the cerebellar hemispheres associated with diffuse brain atrophy. His grandson had full fragile X mental retardation syndrome. Goncalves et al. (2007) emphasized the unusual presentation of FXTAS in the elder patient. </p><p>Hagerman et al. (2007) reported 5 unrelated FXTAS patients who presented with peripheral neuropathy. </p><p>Greco et al. (2008) reported a woman diagnosed with relapsing-remitting multiple sclerosis (MS; see 126200) at age 38 who was found to have a 75-repeat FMR1 premutation allele. Clinical features included distal sensory loss, intention tremor, gait ataxia, spastic paraparesis, short-term memory deficits, progressive dysarthria, disinhibition, and depression. She died at the age of 52 years after progressive memory impairment and loss of motor control. Postmortem examination showed demyelinating plaques in the cerebral and cerebellar white matter, reactive astrocytosis, and intranuclear inclusions in astrocytes and cortical neurons. Greco et al. (2008) noted that clinical features of FXTAS and MS overlap and suggested that the pathologic processes may be related or may be additive. </p><p>Coffey et al. (2008) evaluated 146 female carriers with (18 patients) or without (128 patients) core features of FXTAS (tremor and gait ataxia) and 69 age-matched controls. Compared with controls, carriers with FXTAS had a significantly higher prevalence by history of thyroid disorders (50% vs 15.4%; p = 0.0096), hypertension (61.1% vs 18%; p = 0.002), seizures (22.2% vs 0%; p = 0.0077), peripheral neuropathy (52.9% vs 9.1%; p = 0.004), and fibromyalgia (43.8% vs 9.4%, p = 0.0097). Thyroid disease was more common in the non-FXTAS carrier group (17.3%) compared to the control group (10.1%) but this was not statistically significant. Coffey et al. (2008) recommended thyroid function studies in all female premutation carriers, especially those with features of FXTAS. </p><p>Hunter et al. (2008) found no significant differences in neuropsychologic testing scores between 63 males carriers under the age of 50 who were intermediate (20 to 55 repeats) or premutation (55 to 199 repeats) FMR1 alleles compared to 75 male controls. A comparison of 389 female intermediate or premutation allele carriers showed an association with increasing repeat length and self-reported attention difficulties compared to 117 female controls, but there were no differences in the other neuropsychologic testing scores. </p><p>Soontarapornchai et al. (2008) observed mildly decreased peripheral nerve conduction velocities in motor and sensory nerves of 16 males FXTAS premutation carriers compared to unaffected premutation carriers and controls. There was a correlation between longer CGG repeat number and slowing of the conduction velocity, suggesting that the premutation was a causal factor. </p><p>In a study of 74 men over age 50 years, including 35 carriers of FMR1 premutation alleles and 39 controls, Sevin et al. (2009) found that those with large FMR1 premutation alleles (70 to 200 repeats) had a 6-fold increased risk of developing cognitive decline compared to controls. The penetrance of cognitive impairment increased with allele size: 33.3% for 70 to 200 repeats compared to only 5.9% for 55 to 69 repeats and 5.1% for controls. Cognitive impairment was observed to precede motor symptoms in some cases. </p><p>Rodriguez-Revenga et al. (2010) reported 2 unrelated Spanish families in which 2 mothers with FXTAS and dementia with an expanded CGG repeat (98 and 88 repeats, respectively) transmitted an expanded CGG repeat (156 and 134, respectively) to each of their daughters. The mothers developed symptoms of gait ataxia and tremor at ages 73 and 56 years, respectively, which progressed to frontal lobe dysfunction. MRI showed cerebral, cerebellar, and brainstem atrophy, with the older woman having marked hyperintensities in the putamen and middle cerebellar peduncles. The daughters, aged 58 and 44, respectively, developed tremor at ages 54 and 29, respectively. The older woman also had gait ataxia. Both daughters showed subtle cognitive deficits, particularly in executive function and working memory. Brain MRI showed mild cerebral and cerebellar atrophy with variable hyperintensities in the basal ganglia. Other features in all 4 women included hearing loss in 3, muscle pain in 4, fibromyalgia in 3, and hypothyroidism in 2. Peripheral blood cells of all patients showed increased levels of FMR1 mRNA compared to controls, and all showed skewed X-chromosome inactivation favoring the mutant allele. The findings expanded the phenotype of FXTAS in females. </p>
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<strong>Diagnosis</strong>
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<span class="mim-text-font">
<p><strong><em>Differential Diagnosis</em></strong></p><p>
Ng et al. (2020) reported a man of East Asian descent who presented with cognitive impairment at age 64. He had no family history of a similar disorder, and there were no motor signs. Brain imaging showed a diffusion-weighted imaging (DWI) signal at the gray-white matter junction, characteristic of NIID (603472), as well as the MCP sign, a T2-weighted abnormality in the middle cerebral peduncles. He was predicted to have NIID, but genetic analysis was negative for the pathogenic repeat expansion in the NOTCH2NLC gene (618025.0001). As suggested by Sone et al. (2016), the authors tested the FMR1 gene and identified an abnormal repeat expansion (110 CGG repeats), confirming the diagnosis of FXTAS. The authors emphasized the need for genetic studies including both NOTCH2NLC and FMR1 for patients in whom MRI is used as a screening tool for neurodegenerative disorders. </p>
</span>
<div>
<br />
</div>
<div>
<h4>
<span class="mim-font">
<strong>Molecular Genetics</strong>
</span>
</h4>
</div>
<span class="mim-text-font">
<p>In 5 men with FXTAS, Hagerman et al. (2001) identified a premutation in the FMR1 gene, ranging from 78 to 98 repeats (309550.0004). Levels of FMR1 mRNA were 2 to 4 times higher than normal, which the authors suggested resulted in a pathogenic gain-of-function effect. </p><p>In 2 unrelated men with FXTAS, Leehey et al. (2003) identified a fragile X premutation (90 and 160 repeats, respectively). </p>
</span>
<div>
<br />
</div>
<div>
<h4>
<span class="mim-font">
<strong>Pathogenesis</strong>
</span>
</h4>
</div>
<span class="mim-text-font">
<p>In patients with FXTAS, Berry-Kravis et al. (2003) found that the premutation was associated with increased levels of CGG repeat-containing FMR1 mRNA, which may interfere with nuclear function and lead to neurodegenerative symptoms. </p><p>Arocena et al. (2005) noted that FXTAS appears to affect only carriers of premutation alleles, who have normal or near-normal FMR1 protein levels in both peripheral blood leukocytes and brain tissue, suggesting that FXTAS may result from a toxic gain-of-function of the FMR1 mRNA itself. In human neural SK cells, expression of an 88-repeat premutation allele resulted in development of inclusions containing the heat shock protein alpha-B-crystallin (CRYAB; 123590) and lamin A/C (LMNA; 150330). The expanded FMR1 repeat was cytotoxic. The findings suggested that the neuropathology of FXTAS may be mediated in part by dysregulation of lamin A/C function, which would be consistent with the peripheral neuropathy that is common among FXTAS patients. </p><p>By postmortem examination of 11 males with FXTAS, Greco et al. (2006) reported significant cerebral and cerebellar white matter disease, astrocytic pathology with enlarged inclusion-bearing astrocytes, and intranuclear inclusions in the brain and spinal cord. Seven of 8 patients examined had spongiosis in the middle cerebellar peduncles. There was a highly significant association between the number of CGG repeats in the FMR1 gene and the number of intranuclear inclusions. Analysis of the intracellular inclusions identified in patients with FXTAS showed that they contain FMR1 mRNA, lamin A/C, neurofilaments, and ubiquitin (UBB; 191339) (Iwahashi et al., 2006). </p><p>Handa et al. (2005) found that transcribed but untranslated expanded CGG premutation alleles were toxic to human cells, and microarray analysis detected altered expression of a wide variety of genes, including upregulation of CASP8 (601763), CYFIP1 (606322), NTS (162650), and UBE3A (601623), which was confirmed by RT-PCR analysis. </p><p>Using gel-shift assays with mouse and fly brain lysates, followed by protein purification and mass spectroscopy, Jin et al. (2007) showed that the RNA-binding protein Pur-alpha (PURA; 600473) bound (CGG)105. Pur-alpha bound CGG repeats in a sequence-specific manner, and overexpression of Pur-alpha in a Drosophila model of FXTAS suppressed CGG repeat-mediated neurodegeneration in a dose-dependent manner. Furthermore, immunohistochemical analysis showed that Pur-alpha was ubiquitously expressed in wildtype fly eyes, but it was sequestered in inclusions in fly eyes expressing (CGG)105. Human PURA was present in ubiquitin-positive inclusions in postmortem FXTAS brain tissues. Jin et al. (2007) hypothesized that PURA is sequestered from its normal function by binding premutation CGG repeats, leading to pathologic changes in FXTAS. </p><p>Loesch et al. (2011) performed detailed clinical assessment and genetic testing in 14 male carriers of premutation and gray zone FMR1 alleles and 24 noncarriers identified in a sample of males with parkinsonism. The premutation and gray zone carriers presented with more severe symptoms than disease controls matched for age, diagnosis, disease duration, and treatment. The Parkinson disease motor score and the measure of cognitive decline were significantly correlated with the size of the CGG repeat and elevated levels of antisense FMR1 and cytochrome C1 (123980) mRNAs in blood leukocytes. In addition, the carriers showed a significant depletion of the NADH dehydrogenase subunit-1 mitochondrial gene (ND1, or MTND1; 516000) in whole blood. Loesch et al. (2011) concluded that small CGG expansion FMR1 alleles in the gray zone and lower end premutation play a significant role in the development of the parkinsonian phenotype, possibly through the cytotoxic effect of elevated sense and/or antisense FMR1 transcripts involving mitochondrial dysfunction and leading to progressive neurodegeneration. </p><p>Silva et al. (2013) studied a total of 44 unrelated FMR1 premutation carriers, 22 with FXTAS and 22 without, and genotyped them for the ApoE locus (107741). All ApoE4 (107741.0016) homozygous genotype carriers detected and 6 of the 7 ApoE4/3 (107741.0015) genotype carriers (85.7%) were patients presenting with FXTAS, whereas only 40% of the ApoE3/3 genotype carriers belonged to the FXTAS group. These results showed that the presence of the ApoE4 allele increases the risk of developing FXTAS (OR = 12.041; p = 0.034). Silva et al. (2013) concluded that the presence of at least 1 ApoE4 allele acts as a genetic factor predisposing individuals to develop FXTAS. </p>
</span>
<div>
<br />
</div>
<div>
<h4>
<span class="mim-font">
<strong>Population Genetics</strong>
</span>
</h4>
</div>
<span class="mim-text-font">
<p>Loesch et al. (2009) identified 4 carriers of FMR1 premutation alleles (56, 58, 83 and 87 CGGs, respectively) among 228 Australian males with idiopathic parkinsonism; no premutation alleles were found in 576 controls (p = 0.006). The frequency of premutation carriers was 1.75%, an almost 10-fold increase compared with the population frequency range of approximately 0.1 to 0.4%. There were also significantly more carriers of 'gray zone' alleles (ranging from 40 to 54 CGG repeats) among patients compared to controls (odds ratio of 2.36; p = 0.012). Loesch et al. (2009) suggested that both premutation and gray zone FMR1 alleles may contribute to increased susceptibility to of parkinsonism, and that toxic effects of expanded FMR1 mRNA may also occur when the expansions are smaller. </p>
</span>
<div>
<br />
</div>
<div>
<h4>
<span class="mim-font">
<strong>Animal Model</strong>
</span>
</h4>
</div>
<span class="mim-text-font">
<p>Willemsen et al. (2003) described neurohistologic, biochemical, and molecular studies of the brains of transgenic mice with an expanded CGG repeat (102 to 110 repeats) in human FMR1, and reported elevated Fmr1 mRNA levels and intranuclear inclusions with ubiquitin, Hsp40 (see 604572), and the 20S catalytic core complex of the proteasome as constituents. An increase was observed in both the number and the size of the inclusions during the course of life, which correlated with the progressive character of the cerebellar tremor/ataxia syndrome in humans. Willemsen et al. (2003) concluded that the observations in expanded-repeat mice supported a direct role of the Fmr1 gene, by either CGG expansion per se or by mRNA level, in the formation of the inclusions and suggested a correlation between the presence of intranuclear inclusions in distinct regions of the brain and the clinical features in symptomatic premutation carriers. </p><p>Jin et al. (2003) expressed a human FMR1 premutation allele of 90 CGG repeats in Drosophila using a heterologous transcript (EGFP). The expanded RNA alone induced neuron-specific degeneration, as observed in retinal cells, characterized by Hsp70 (see 140550)- and ubiquitin-positive inclusion bodies similar to those seen in patients with FXTAS. The findings suggested a role for a toxic RNA-mediated gain-of-function in FXTAS. </p><p>The transgenic fly model of FXTAS in which the 5-prime UTR of human FMR1 containing 90 CGG repeats is expressed specifically in the eye results in disorganized ommatidia, depigmentation, and progressive loss of photoreceptor neurons. Sofola et al. (2007) found that overexpression of human CUGBP1 (601074) suppressed the neurodegenerative eye phenotype in FXTAS flies. CUGBP1 did not interact directly with the CGG repeats, but did so via HNRNPA2B1 (600124). Expression of the A2 isoform of human HNRNPA2B1, or the Drosophila orthologs, also suppressed the eye phenotype of FXTAS flies. </p><p>Hashem et al. (2009) generated mice expressing the human 90 CGG premutation in the context of the mouse Fmr1 5-prime UTR or the EGFP (enhanced green fluorescent protein) 5-prime UTR, specifically in Purkinje neurons, in order to segregate the effects of CGG repeat from alterations in Fmr1 and to provide evidence that CGG repeat is necessary and sufficient to cause pathology similar to human FXTAS. CGG(90)-EGFP was sufficient to produce ubiquitin-positive intranuclear inclusion formation. They also demonstrated CGG(90)-EGFP overexpression resulted in Purkinje neuron axonal swellings and neurotoxicity and in a mouse phenotype showing progressive age-dependent decline in neuromotor learning ability. Hashem et al. (2009) concluded that CGG expressed in Purkinje neurons outside the context of Fmr1 mRNA may result in neuronal pathology in a mammalian system, and that expanded CGG repeats in RNA are the likely cause of the neurodegeneration in FXTAS. </p>
</span>
<div>
<br />
</div>
</div>
<div>
<h4>
<span class="mim-font">
<strong>REFERENCES</strong>
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Greco, C. M., Berman, R. F., Martin, R. M., Tassone, F., Schwartz, P. H., Chang, A., Trapp, B. D., Iwahashi, C., Brunberg, J., Grigsby, J., Hessl, D., Becker, E. J., Papazian, J., Leehey, M. A., Hagerman, R. J., Hagerman, P. J.
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Greco, C. M., Tassone, F., Garcia-Arocena, D., Tartaglia, N., Coffey, S. M., Vartanian, T. K., Brunberg, J. A., Hagerman, P. J., Hagerman, R. J.
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Hagerman, P. J., Hagerman, R. J.
<strong>The fragile-X premutation: a maturing perspective.</strong>
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Hagerman, R. J., Coffey, S. M., Maselli, R., Soontarapornchai, K., Brunberg, J. A., Leehey, M. A., Zhang, L., Gane, L. W., Fenton-Farrell, G., Tassone, F., Hagerman, P. J.
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Hagerman, R. J., Leavitt, B. R., Farzin, F., Jacquemont, S., Greco, C. M., Brunberg, J. A., Tassone, F., Hessl, D., Harris, S. W., Zhang, L., Jardini, T., Gane, L. W., Ferranti, J., Ruiz, L., Leehey, M. A., Grigsby, J., Hagerman, P. J.
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Hall, D. A., Berry-Kravis, E., Jacquemont, S., Rice, C. D., Cogswell, J., Zhang, L., Hagerman, R. J., Hagerman, P. J., Leehey, M. A.
<strong>Initial diagnoses given to persons with the fragile X associated tremor/ataxia syndrome (FXTAS).</strong>
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<p class="mim-text-font">
Handa, V., Goldwater, D., Stiles, D., Cam, M., Poy, G., Kumari, D., Usdin, K.
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<p class="mim-text-font">
Hashem, V., Galloway, J. N., Mori, M., Willemsen, R., Oostra, B. A., Paylor, R., Nelson, D. L.
<strong>Ectopic expression of CGG containing mRNA is neurotoxic in mammals.</strong>
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Hunter, J. E., Allen, E. G., Abramowitz, A., Rusin, M., Leslie, M., Novak, G., Hamilton, D., Shubeck, L., Charen, K., Sherman, S. L.
<strong>No evidence for a difference in neuropsychological profile among carriers and noncarriers of the FMR1 premutation in adults under the age of 50.</strong>
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[Full Text: https://doi.org/10.1016/j.ajhg.2008.10.021]
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Iwahashi, C. K., Yasui, D. H., An, H.-J., Greco, C. M., Tassone, F., Nannen, K., Babineau, B., Lebrilla, C. B., Hagerman, R. J., Hagerman, P. J.
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[PubMed: 16246864]
[Full Text: https://doi.org/10.1093/brain/awh650]
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<li>
<p class="mim-text-font">
Jacquemont, S., Hagerman, R. J., Hagerman, P. J., Leehey, M. A.
<strong>Fragile-X syndrome and fragile X-associated tremor/ataxia syndrome: two faces of FMR1.</strong>
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[Full Text: https://doi.org/10.1016/S1474-4422(06)70676-7]
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<p class="mim-text-font">
Jacquemont, S., Hagerman, R. J., Leehey, M., Grigsby, J., Zhang, L., Brunberg, J. A., Greco, C., Des Portes, V., Jardini, T., Levine, R., Berry-Kravis, E., Brown, W. T., Schaeffer, S., Kissel, J., Tassone, F., Hagerman, P. J.
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Am. J. Hum. Genet. 72: 869-878, 2003.
[PubMed: 12638084]
[Full Text: https://doi.org/10.1086/374321]
</p>
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<li>
<p class="mim-text-font">
Jin, P., Duan, R., Qurashi, A., Qin, Y., Tian, D., Rosser, T. C., Liu, H., Feng, Y., Warren, S. T.
<strong>Pur alpha binds to rCGG repeats and modulates repeat-mediated neurodegeneration in a Drosophila model of fragile X tremor/ataxia syndrome.</strong>
Neuron 55: 556-564, 2007.
[PubMed: 17698009]
[Full Text: https://doi.org/10.1016/j.neuron.2007.07.020]
</p>
</li>
<li>
<p class="mim-text-font">
Jin, P., Zarnescu, D. C., Zhang, F., Pearson, C. E., Lucchesi, J. C., Moses, K., Warren, S. T.
<strong>RNA-mediated neurodegeneration caused by the fragile X premutation rCGG repeats in Drosophila.</strong>
Neuron 39: 739-747, 2003.
[PubMed: 12948442]
[Full Text: https://doi.org/10.1016/s0896-6273(03)00533-6]
</p>
</li>
<li>
<p class="mim-text-font">
Leehey, M. A., Munhoz, R. P., Lang, A. E., Brunberg, J. A., Grigsby, J., Greco, C., Jacquemont, S., Tassone, F., Lozano, A. M., Hagerman, P. J., Hagerman, R. J.
<strong>The fragile X premutation presenting as essential tremor.</strong>
Arch. Neurol. 60: 117-121, 2003.
[PubMed: 12533098]
[Full Text: https://doi.org/10.1001/archneur.60.1.117]
</p>
</li>
<li>
<p class="mim-text-font">
Loesch, D. Z., Godler, D. E., Evans, A., Bui, Q. M., Gehling, F., Kotschet, K. E., Trost, N., Storey, E., Stimpson, P., Kinsella, G., Francis, D., Thorburn, D. R., Venn, A., Slater, H. R., Horne, M.
<strong>Evidence for the toxicity of bidirectional transcripts and mitochondrial dysfunction in blood associated with small CGG expansions in the FMR1 gene in patients with parkinsonism.</strong>
Genet. Med. 13: 392-399, 2011.
[PubMed: 21270637]
[Full Text: https://doi.org/10.1097/GIM.0b013e3182064362]
</p>
</li>
<li>
<p class="mim-text-font">
Loesch, D. Z., Khaniani, M. S., Slater, H. R., Rubio, J. P., Bui, Q. M., Kotschet, K., D'Souza, W., Venn, A., Kalitsis, P., Choo, A. K. H., Burgess, T., Johnson, L., Evans, A., Horne, M.
<strong>Small CGG repeat expansion alleles of FMR1 gene are associated with parkinsonism.</strong>
Clin. Genet. 76: 471-476, 2009.
[PubMed: 19796183]
[Full Text: https://doi.org/10.1111/j.1399-0004.2009.01275.x]
</p>
</li>
<li>
<p class="mim-text-font">
Loesch, D. Z., Litewka, L., Brotchie, P., Huggins, R. M., Tassone, F., Cook, M.
<strong>Magnetic resonance imaging study in older fragile X premutation male carriers.</strong>
Ann. Neurol. 58: 326-330, 2005.
[PubMed: 16049924]
[Full Text: https://doi.org/10.1002/ana.20542]
</p>
</li>
<li>
<p class="mim-text-font">
Macpherson, J., Waghorn, A., Hammans, S., Jacobs, P.
<strong>Observation of an excess of fragile-X premutations in a population of males referred with spinocerebellar ataxia. (Letter)</strong>
Hum. Genet. 112: 619-620, 2003.
[PubMed: 12612802]
[Full Text: https://doi.org/10.1007/s00439-003-0939-z]
</p>
</li>
<li>
<p class="mim-text-font">
Ng, A. S. L., Xu, Z., Chen, Z., Tan, Y. J., Lim, W. K., Ting, S. K. S., Yu, W. Y., Cheng, Q. H., Foo, J. N., Tan, E. K., Lim, T. C. C.
<strong>NOTCH2NLC-linked neuronal intranuclear inclusion body disease and fragile X-associated tremor/ataxia syndrome.</strong>
Brain 143: e69, 2020. Note: Electronic Article.
[PubMed: 32789443]
[Full Text: https://doi.org/10.1093/brain/awaa210]
</p>
</li>
<li>
<p class="mim-text-font">
Rodriguez-Revenga, L., Pagonabarraga, J., Gomez-Anson, B., Lopez-Mourelo, O., Madrigal, I., Xuncla, M., Kulisevsky, J., Mila, M.
<strong>Motor and mental dysfunction in mother-daughter transmitted FXTAS.</strong>
Neurology 75: 1370-1376, 2010.
[PubMed: 20938029]
[Full Text: https://doi.org/10.1212/WNL.0b013e3181f73660]
</p>
</li>
<li>
<p class="mim-text-font">
Rogers, C., Partington, M. W., Turner, G. M.
<strong>Tremor, ataxia and dementia in older men may indicate a carrier of the fragile X syndrome.</strong>
Clin. Genet. 64: 54-56, 2003.
[PubMed: 12791039]
[Full Text: https://doi.org/10.1034/j.1399-0004.2003.00089.x]
</p>
</li>
<li>
<p class="mim-text-font">
Sevin, M., Kutalik, Z., Bergman, S., Vercelletto, M., Renou, P., Lamy, E., Vingerhoets, F. J., Di Virgilio, G., Boisseau, P., Bezieau, S., Pasqiuer, L., Rival, J.-M., Beckmann, J. S., Damier, P., Jacquemont, S.
<strong>Penetrance of marked cognitive impairment in older male carriers of the FMR1 gene premutation.</strong>
J. Med. Genet. 46: 818-824, 2009.
[PubMed: 19542082]
[Full Text: https://doi.org/10.1136/jmg.2008.065953]
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</li>
<li>
<p class="mim-text-font">
Silva, F., Rodriguez-Revenga, L., Madrigal, I., Alvarez-Mora, M. I., Oliva, R., Mila, M.
<strong>High apolipoprotein E4 allele frequency in FXTAS patients.</strong>
Genet. Med. 15: 639-642, 2013.
[PubMed: 23492875]
[Full Text: https://doi.org/10.1038/gim.2013.12]
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Sofola, O. A., Jin, P., Qin, Y., Duan, R., Liu, H., de Haro, M., Nelson, D. L., Botas, J.
<strong>RNA-binding proteins hnRNP A2/B1 and CUGBP1 suppress fragile X CGG premutation repeat-induced neurodegeneration in a Drosophila model of FXTAS.</strong>
Neuron 55: 565-571, 2007.
[PubMed: 17698010]
[Full Text: https://doi.org/10.1016/j.neuron.2007.07.021]
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<li>
<p class="mim-text-font">
Sone, J., Mori, K. Inagaki, T., Katsumata, R., Takagi, S., Yokoi, S., Araki, K., Kato, T., Nakamura, T., Koike, H., Takashima, H., Hashiguchi, A., 20 others.
<strong>Clinicopathological features of adult-onset neuronal intranuclear inclusion disease.</strong>
Brain 139: 3170-3186, 2016.
[PubMed: 27797808]
[Full Text: https://doi.org/10.1093/brain/aww249]
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<li>
<p class="mim-text-font">
Soontarapornchai, K., Maselli, R., Fenton-Farrell, G., Tassone, F., Hagerman, P. J., Hessl, D., Hagerman, R. J.
<strong>Abnormal nerve conduction features in fragile X premutation carriers.</strong>
Arch. Neurol. 65: 495-498, 2008.
[PubMed: 18413472]
[Full Text: https://doi.org/10.1001/archneur.65.4.495]
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<li>
<p class="mim-text-font">
Willemsen, R., Hoogeveen-Westerveld, M., Reis, S., Holstege, J., Severijnen, L.-A. W. F. M., Nieuwenhuizen, I. M., Schrier, M., van Unen, L., Tassone, F., Hoogeveen, A. T., Hagerman, P. J., Mientjes, E. J., Oostra, B. A.
<strong>The FMR1 CGG repeat mouse displays ubiquitin-positive intranuclear neuronal inclusions; implications for the cerebellar tremor/ataxia syndrome.</strong>
Hum. Molec. Genet. 12: 949-959, 2003.
[PubMed: 12700164]
[Full Text: https://doi.org/10.1093/hmg/ddg114]
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Cassandra L. Kniffin - updated : 01/04/2021<br>Ada Hamosh - updated : 11/13/2013<br>Ada Hamosh - updated : 10/1/2012<br>Cassandra L. Kniffin - updated : 10/17/2011<br>Cassandra L. Kniffin - updated : 6/4/2010<br>George E. Tiller - updated : 4/2/2010<br>Cassandra L. Kniffin - updated : 12/21/2009<br>Patricia A. Hartz - updated : 9/10/2009<br>Patricia A. Hartz - updated : 4/14/2009<br>Cassandra L. Kniffin - updated : 4/6/2009<br>Cassandra L. Kniffin - updated : 2/5/2009<br>Cassandra L. Kniffin - updated : 1/16/2009<br>Kelly A. Przylepa - updated : 11/20/2008<br>Cassandra L. Kniffin - updated : 10/17/2008<br>Cassandra L. Kniffin - updated : 5/19/2008<br>Cassandra L. Kniffin - updated : 2/29/2008<br>Cassandra L. Kniffin - updated : 1/29/2008<br>Cassandra L. Kniffin - updated : 12/26/2007
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