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<title>
Entry
- #614707 - BROWN-VIALETTO-VAN LAERE SYNDROME 2; BVVLS2
- OMIM
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<span class="h4">#614707</span>
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<strong>Table of Contents</strong>
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<a href="#phenotypeMap"><strong>Phenotype-Gene Relationships</strong></a>
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<a href="/clinicalSynopsis/614707"><strong>Clinical Synopsis</strong></a>
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<a href="/phenotypicSeries/PS211530"> <strong>Phenotypic Series</strong> </a>
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<a href="#clinicalManagement">Clinical Management</a>
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<a href="#inheritance">Inheritance</a>
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<a href="#molecularGenetics">Molecular Genetics</a>
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<div><a href="https://clinicaltrials.gov/search?cond=BROWN-VIALETTO-VAN LAERE 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 style="margin-left: 0.5em;"><a href="https://www.orpha.net/consor/cgi-bin/ClinicalLabs_Search_Simple.php?lng=EN&LnkId=28755&Typ=Pat" title="RFVT3-related riboflavin transporter deficiency" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'EuroGentest', 'domain': 'orpha.net'})">RFVT3-related riboflavin t…&nbsp;</a></div><div style="margin-left: 0.5em;"><a href="https://www.orpha.net/consor/cgi-bin/ClinicalLabs_Search_Simple.php?lng=EN&LnkId=12856&Typ=Pat" title="Riboflavin transporter deficiency" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'EuroGentest', 'domain': 'orpha.net'})">Riboflavin transporter def…&nbsp;</a></div>
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<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:0080786" 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/614707" class="mim-tip-hint" title="Phenotypes, alleles, and disease models from Mouse Genome Informatics." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MGI Mouse Phenotype', 'domain': 'informatics.jax.org'})">MGI Mouse Phenotype</a></div>
<div><a href="https://wormbase.org/resources/disease/DOID:0080786" class="mim-tip-hint" title="Database of the biology and genome of Caenorhabditis elegans and related nematodes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Wormbase Disease Ontology', 'domain': 'wormbase.org'})">Wormbase Disease Ontology</a></div>
</div>
</div>
</div>
</div>
</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>ORPHA:</strong> 572550, 97229<br />
<strong>DO:</strong> 0080786<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>
614707
</span>
</span>
</div>
</div>
<div>
<a id="preferredTitle" class="mim-anchor"></a>
<h3>
<span class="mim-font">
BROWN-VIALETTO-VAN LAERE SYNDROME 2; BVVLS2
</span>
</h3>
</div>
<div>
<br />
</div>
<div>
<a id="alternativeTitles" class="mim-anchor"></a>
<div>
<p>
<span class="mim-font">
<em>Alternative titles; symbols</em>
</span>
</p>
</div>
<div>
<h4>
<span class="mim-font">
RIBOFLAVIN TRANSPORTER DEFICIENCY, TYPE 2; RTD2
</span>
</h4>
</div>
</div>
<div>
<br />
</div>
</div>
<div>
<a id="phenotypeMap" class="mim-anchor"></a>
<h4>
<span class="mim-font">
<strong>Phenotype-Gene Relationships</strong>
</span>
</h4>
<div>
<table class="table table-bordered table-condensed table-hover small mim-table-padding">
<thead>
<tr class="active">
<th>
Location
</th>
<th>
Phenotype
</th>
<th>
Phenotype <br /> MIM number
</th>
<th>
Inheritance
</th>
<th>
Phenotype <br /> mapping key
</th>
<th>
Gene/Locus
</th>
<th>
Gene/Locus <br /> MIM number
</th>
</tr>
</thead>
<tbody>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/8/639?start=-3&limit=10&highlight=639">
8q24.3
</a>
</span>
</td>
<td>
<span class="mim-font">
Brown-Vialetto-Van Laere syndrome 2
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/614707"> 614707 </a>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
</span>
</td>
<td>
<span class="mim-font">
SLC52A2
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/607882"> 607882 </a>
</span>
</td>
</tr>
</tbody>
</table>
</div>
</div>
<div>
<div class="btn-group ">
<a href="/clinicalSynopsis/614707" 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>
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</div>
&nbsp;
<div class="btn-group">
<a href="/phenotypicSeries/PS211530" class="btn btn-info" role="button"> Phenotypic Series </a>
<button type="button" id="mimPhenotypicSeriesToggle" class="btn btn-info dropdown-toggle mimSingletonFoldToggle" data-toggle="collapse" href="#mimPhenotypicSeriesFold" onclick="ga('send', 'event', 'Unfurl', 'PhenotypicSeries', 'omim.org')">
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&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/614707" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Linear'})"> Linear </a></li>
<li><a href="/graph/radial/614707" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Radial'})"> Radial </a></li>
</ul>
</div>
<span class="glyphicon glyphicon-question-sign mim-tip-hint" title="OMIM PheneGene graphics depict relationships between phenotypes, groups of related phenotypes (Phenotypic Series), and genes.<br /><a href='/static/omim/pdf/OMIM_Graphics.pdf' target='_blank'>A quick reference overview and guide (PDF)</a>"></span>
<div>
<p />
</div>
<div id="mimClinicalSynopsisFold" class="well well-sm collapse mimSingletonToggleFold">
<div class="small" style="margin: 5px">
<div>
<div>
<span class="h5 mim-font">
<strong> INHERITANCE </strong>
</span>
</div>
<div style="margin-left: 2em;">
<div>
<span class="mim-font">
- Autosomal recessive <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/258211005" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">258211005</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0441748&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0441748</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000007" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000007</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000007" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000007</a>]</span><br />
</span>
</div>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<strong> 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">
- Facial muscle weakness <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/95666008" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">95666008</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/R29.810" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">R29.810</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/438.83" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">438.83</a>, <a href="https://purl.bioontology.org/ontology/ICD9CM/781.94" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">781.94</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0427055&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0427055</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0007209" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0007209</a>, <a href="https://hpo.jax.org/app/browse/term/HP:0030319" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0030319</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0030319" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0030319</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, sensorineural <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/60700002" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">60700002</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/H90.5" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">H90.5</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/389.10" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">389.10</a>, <a href="https://purl.bioontology.org/ontology/ICD9CM/389.1" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">389.1</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0018784&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0018784</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000407" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000407</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000407" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000407</a>]</span><br /> -
Absent brainstem auditory-evoked responses <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C3553543&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C3553543</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">
- Absent pupillary reflex <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/13353005" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">13353005</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0423302&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0423302</a>]</span><br /> -
Optic atrophy <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/76976005" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">76976005</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/H47.2" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">H47.2</a>, <a href="https://purl.bioontology.org/ontology/ICD10CM/H47.20" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">H47.20</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/377.10" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">377.10</a>, <a href="https://purl.bioontology.org/ontology/ICD9CM/377.1" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">377.1</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0029124&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0029124</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000648" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000648</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000648" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000648</a>]</span><br /> -
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 /> -
Visual loss <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/7973008" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">7973008</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/H54.7" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">H54.7</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/369.9" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">369.9</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C3665346&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C3665346</a>, <a href="https://bioportal.bioontology.org/search?q=C3665386&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C3665386</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000572" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000572</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000572" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000572</a>]</span><br />
</span>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<em> Mouth </em>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
- Tongue fasciculations <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/249878001" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">249878001</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0239548&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0239548</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001308" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001308</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001308" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001308</a>]</span><br />
</span>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<em> Neck </em>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
- Neck muscle weakness <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0240479&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0240479</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000467" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000467</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000467" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000467</a>]</span><br />
</span>
</div>
</div>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<strong> RESPIRATORY </strong>
</span>
</div>
<div style="margin-left: 2em;">
<div>
<span class="mim-font">
- Respiratory insufficiency <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/409622000" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">409622000</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/409623005" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">409623005</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/J96.9" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">J96.9</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1145670&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1145670</a>, <a href="https://bioportal.bioontology.org/search?q=C0035229&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0035229</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002878" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002878</a>, <a href="https://hpo.jax.org/app/browse/term/HP:0002093" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002093</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002093" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002093</a>]</span><br /> -
Sleep hypoventilation (rare) <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/443760008" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">443760008</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C2732337&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C2732337</a>]</span><br />
</span>
</div>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<strong> ABDOMEN </strong>
</span>
</div>
<div style="margin-left: 2em;">
<div>
<div>
<span class="h5 mim-font">
<em> Gastrointestinal </em>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
- Dysphagia (in some patients) <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/288939007" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">288939007</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/40739000" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">40739000</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/R13.1" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">R13.1</a>, <a href="https://purl.bioontology.org/ontology/ICD10CM/R13.10" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">R13.10</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/787.2" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">787.2</a>, <a href="https://purl.bioontology.org/ontology/ICD9CM/787.20" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">787.20</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0011168&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0011168</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002015" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002015</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002015" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002015</a>]</span><br />
</span>
</div>
</div>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<strong> SKELETAL </strong>
</span>
</div>
<div style="margin-left: 2em;">
<div>
<div>
<span class="h5 mim-font">
<em> Spine </em>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
- Scoliosis (in some patients) <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/298382003" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">298382003</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/20944008" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">20944008</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/111266001" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">111266001</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/M41.9" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">M41.9</a>, <a href="https://purl.bioontology.org/ontology/ICD10CM/M41" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">M41</a>, <a href="https://purl.bioontology.org/ontology/ICD10CM/Q67.5" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">Q67.5</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0559260&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0559260</a>, <a href="https://bioportal.bioontology.org/search?q=C0036439&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0036439</a>, <a href="https://bioportal.bioontology.org/search?q=C0700208&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0700208</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002650" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002650</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002650" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002650</a>]</span><br /> -
Kyphoscoliosis (in some patients) <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/405771009" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">405771009</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/405772002" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">405772002</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/405773007" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">405773007</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/M41" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">M41</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0600033&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0600033</a>, <a href="https://bioportal.bioontology.org/search?q=C0575158&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0575158</a>, <a href="https://bioportal.bioontology.org/search?q=C0345392&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0345392</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002751" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002751</a>, <a href="https://hpo.jax.org/app/browse/term/HP:0008453" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0008453</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002751" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002751</a>]</span><br />
</span>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<em> Hands </em>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
- Claw hands <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/299034005" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">299034005</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C5550991&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C5550991</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 weakness, proximal, distal, and axial, severe <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C3553541&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C3553541</a>]</span><br /> -
Upper limb muscle weakness may be more severe than lower limb weakness <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C3808563&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C3808563</a>]</span><br /> -
Hypotonia <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/398151007" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">398151007</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/398152000" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">398152000</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0026827&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0026827</a>, <a href="https://bioportal.bioontology.org/search?q=C1858120&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1858120</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001290" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001290</a>, <a href="https://hpo.jax.org/app/browse/term/HP:0001252" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001252</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001252" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001252</a>]</span><br /> -
Muscle atrophy, diffuse, severe <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C3553542&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C3553542</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003700" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003700</a>]</span><br /> -
Neurogenic changes seen on EMG <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C3808564&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C3808564</a>]</span><br /> -
Fibrillations <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/40593004" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">40593004</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0232197&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0232197</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">
- Cranial nerve palsies <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/73013002" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">73013002</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0151311&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0151311</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0006824" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0006824</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0006824" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0006824</a>]</span><br /> -
Bulbar palsy <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/54304004" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">54304004</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/G12.22" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">G12.22</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/335.22" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">335.22</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C4082299&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C4082299</a>, <a href="https://bioportal.bioontology.org/search?q=C0030442&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0030442</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001283" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001283</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001283" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001283</a>]</span><br /> -
Ataxia <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/20262006" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">20262006</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/39384006" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">39384006</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/85102008" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">85102008</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/R27.0" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">R27.0</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/438.84" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">438.84</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0004134&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0004134</a>, <a href="https://bioportal.bioontology.org/search?q=C1135207&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1135207</a>, <a href="https://bioportal.bioontology.org/search?q=C0007758&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0007758</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001251" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001251</a>, <a href="https://hpo.jax.org/app/browse/term/HP:0010867" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0010867</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001251" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001251</a>]</span><br /> -
Loss of independent ambulation <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C3278950&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C3278950</a>]</span><br /> -
Decreased spontaneous movements <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/43994002" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">43994002</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/255385008" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">255385008</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0086439&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0086439</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002375" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002375</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002375" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002375</a>]</span><br /> -
Inability to hold head up <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C3553539&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C3553539</a>]</span><br /> -
Clumsiness <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/7006003" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">7006003</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0233844&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0233844</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002312" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002312</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002312" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002312</a>]</span><br /> -
Cognition is preserved <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C3808562&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C3808562</a>]</span><br />
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<span class="h5 mim-font">
<em> Peripheral Nervous System </em>
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<div style="margin-left: 2em;">
<span class="mim-font">
- Areflexia <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/37280007" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">37280007</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0234146&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0234146</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001284" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001284</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001284" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001284</a>]</span><br /> -
Axonal sensorimotor neuropathy <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/230657007" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">230657007</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0393907&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0393907</a>]</span><br /> -
Sural nerve biopsy shows loss of large myelinated fibers <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1853771&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1853771</a>]</span><br />
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<span class="h5 mim-font">
<em> Behavioral Psychiatric Manifestations </em>
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<div style="margin-left: 2em;">
<span class="mim-font">
- Aggressive behavior (in some patients) <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/61372001" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">61372001</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0001807&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0001807</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0006919" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0006919</a>, <a href="https://hpo.jax.org/app/browse/term/HP:0000718" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000718</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000718" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000718</a>]</span><br />
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<span class="h5 mim-font">
<strong> LABORATORY ABNORMALITIES </strong>
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<div style="margin-left: 2em;">
<div>
<span class="mim-font">
- Abnormal acylcarnitine profiles <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C3553544&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C3553544</a>]</span><br /> -
Organic aciduria <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0241775&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0241775</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001992" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001992</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001992" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001992</a>]</span><br />
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<div>
<span class="h5 mim-font">
<strong> MISCELLANEOUS </strong>
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<span class="mim-font">
- Onset in first few years of life<br /> -
Progressive disorder <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1864985&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1864985</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003676" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003676</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003676" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003676</a>]</span><br /> -
Variable severity <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1861403&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1861403</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003828" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003828</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003828" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003828</a>]</span><br /> -
Early death from respiratory failure may occur<br /> -
Some patients show significant clinical improvement with riboflavin supplementation<br />
</span>
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<div>
<div>
<span class="h5 mim-font">
<strong> MOLECULAR BASIS </strong>
</span>
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<div style="margin-left: 2em;">
<div>
<span class="mim-font">
- Caused by mutation in the solute carrier family 52 (riboflavin transporter), member 2 gene (SLC52A2, <a href="/entry/607882#0001">607882.0001</a>)<br />
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<h5>
Brown-Vialetto-Van Laere syndrome
- <a href="/phenotypicSeries/PS211530">PS211530</a>
- 2 Entries
</h5>
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<div class="row" style="margin-left: 0.125em; margin-right: 0.125em;">
<table class="table table-bordered table-condensed table-hover mim-table-padding">
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<strong>Location</strong>
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<th class="col-lg-5 col-md-5 col-sm-5 col-xs-6 text-nowrap">
<strong>Phenotype</strong>
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<th class="col-lg-1 col-md-1 col-sm-1 col-xs-1 text-nowrap">
<strong>Inheritance</strong>
</th>
<th class="col-lg-1 col-md-1 col-sm-1 col-xs-1 text-nowrap">
<strong>Phenotype<br />mapping key</strong>
</th>
<th class="col-lg-1 col-md-1 col-sm-1 col-xs-1 text-nowrap">
<strong>Phenotype<br />MIM number</strong>
</th>
<th class="col-lg-1 col-md-1 col-sm-1 col-xs-1 text-nowrap">
<strong>Gene/Locus</strong>
</th>
<th class="col-lg-1 col-md-1 col-sm-1 col-xs-1 text-nowrap">
<strong>Gene/Locus<br />MIM number</strong>
</th>
</tr>
</thead>
<tbody>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/8/639?start=-3&limit=10&highlight=639"> 8q24.3 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/614707"> Brown-Vialetto-Van Laere syndrome 2 </a>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/614707"> 614707 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/607882"> SLC52A2 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/607882"> 607882 </a>
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/20/16?start=-3&limit=10&highlight=16"> 20p13 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/211530"> Brown-Vialetto-Van Laere syndrome 1 </a>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/211530"> 211530 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/613350"> SLC52A3 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/613350"> 613350 </a>
</span>
</td>
</tr>
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<strong>TEXT</strong>
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<p>A number sign (#) is used with this entry because Brown-Vialetto-Van Laere syndrome-2 (BVVLS2) is caused by homozygous or compound heterozygous mutation in the SLC52A2 gene (<a href="/entry/607882">607882</a>) on chromosome 8q24.</p>
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<strong>Description</strong>
</span>
</h4>
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<p>Brown-Vialetto-Van Laere syndrome-2 (BVVLS2) is an autosomal recessive progressive neurologic disorder characterized by early childhood onset of sensorineural deafness, bulbar dysfunction, and severe diffuse muscle weakness and wasting of the upper and lower limbs and axial muscles, resulting in respiratory insufficiency. Some patients may lose independent ambulation. Because it results from a defect in riboflavin metabolism, some patients may benefit from high-dose riboflavin supplementation (summary by <a href="#5" class="mim-tip-reference" title="Johnson, J. O., Gibbs, J. R., Megarbane, A., Urtizberea, J. A., Hernandez, D. G., Foley, A. R., Arepalli, S., Pandraud, A., Simon-Sanchez, J., Clayton, P., Reilly, M. M., Muntoni, F., Abramzon, Y., Houlden, H., Singleton, A. B. &lt;strong&gt;Exome sequencing reveals riboflavin transporter mutations as a cause of motor neuron disease.&lt;/strong&gt; Brain 135: 2875-2882, 2012.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/22740598/&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;22740598&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=22740598[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/aws161&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="22740598">Johnson et al., 2012</a>; <a href="#2" class="mim-tip-reference" title="Foley, A. R., Menezes, M. P., Pandraud, A., Gonzalez, M. A., Al-Odaib, A., Abrams, A. J., Sugano, K., Yonezawa, A., Manzur, A. Y., Burns, J., Hughes, I., McCullagh, B. G., and 42 others. &lt;strong&gt;Treatable childhood neuronopathy caused by mutations in riboflavin transporter RFVT2.&lt;/strong&gt; Brain 137: 44-56, 2014.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/24253200/&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;24253200&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=24253200[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/awt315&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="24253200">Foley et al., 2014</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=22740598+24253200" 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>For discussion of genetic heterogeneity of Brown-Vialetto-Van Laere syndrome, see BVVLS1 (<a href="/entry/211530">211530</a>).</p>
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<strong>Clinical Features</strong>
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<p><a href="#6" class="mim-tip-reference" title="Megarbane, A., Desguerres, I., Rizkallah, E., Delague, V., Nabbout, R., Barois, A., Urtizberea, A. &lt;strong&gt;Brown-Vialetto-Van Laere syndrome in a large inbred Lebanese family: confirmation of autosomal recessive inheritance?&lt;/strong&gt; Am. J. Med. Genet. 92: 117-121, 2000.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/10797435/&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;10797435&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/(sici)1096-8628(20000515)92:2&lt;117::aid-ajmg7&gt;3.0.co;2-c&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="10797435">Megarbane et al. (2000)</a> reported a large inbred Lebanese family with 4 patients, including 3 males and 1 female, with severe features of Brown-Vialetto-Van Laere syndrome. The proband showed normal early childhood development until about age 2.5 years, when he developed progressively abnormal hearing and walking. Physical examination at age 8 years showed profound deafness with absent brainstem auditory-evoked potentials, tongue fasciculations, bulbar dysfunction, scoliosis, and axial and limb hypotonia with little spontaneous movements. He had severe neck weakness with an inability to hold up his head, proximal and distal limb weakness and atrophy, and claw hands. Deep tendon reflexes and plantar responses were absent. Intelligence appeared to be normal. He died of respiratory failure at age 11 years. His younger brother was similarly affected, and also had facial paresis, inability to close the eyes tightly, absent pupillary reflexes, and poor gag reflex, which indicated multiple cranial nerve abnormalities. EMG was neurogenic with fibrillation activity. He died suddenly at age 7 years. The boys' sister was reportedly affected, but died at age 4 years. A male first cousin had slightly less severe muscle weakness and slightly later onset at age 3.5 years, but also showed deafness and diffuse muscle weakness and atrophy. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10797435" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#5" class="mim-tip-reference" title="Johnson, J. O., Gibbs, J. R., Megarbane, A., Urtizberea, J. A., Hernandez, D. G., Foley, A. R., Arepalli, S., Pandraud, A., Simon-Sanchez, J., Clayton, P., Reilly, M. M., Muntoni, F., Abramzon, Y., Houlden, H., Singleton, A. B. &lt;strong&gt;Exome sequencing reveals riboflavin transporter mutations as a cause of motor neuron disease.&lt;/strong&gt; Brain 135: 2875-2882, 2012.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/22740598/&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;22740598&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=22740598[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/aws161&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="22740598">Johnson et al. (2012)</a> reported an 11-year-old Scottish girl with BVVLS2. She presented with ataxic gait at age 18 months. At age 6 years, she showed weakness of the fingers, which rapidly progressed to severe upper limb weakness over the course of a few weeks. She also developed bilateral sensorineural hearing loss. By 7 years of age, she was wheelchair-bound due to axial hypotonia and weakness, but could walk with support as her lower limbs retained strength. Other features included optic atrophy, sleep hypoventilation, and severe axonal sensorimotor neuropathy. Metabolic testing showed evidence of carnitine deficiency and a urinary organic acid profile suggestive of MADD (<a href="/entry/231680">231680</a>). Treatment with high-dose riboflavin resulted in the normalization of her acylcarnitine and urinary organic acid profiles. She also showed quantitative improvements in her pulmonary function, brainstem auditory evoked potentials, and visual evoked potentials, and some improvement in upper limb strength. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22740598" 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="Haack, T. B., Makowski, C., Yao, Y., Graf, E., Hempel, M., Wieland, T., Tauer, U., Ahting, U., Mayr, J. A., Freisinger, P., Yoshimatsu, H., Inui, K., Strom, T. M., Meitinger, T., Yonezawa, A., Prokisch, H. &lt;strong&gt;Impaired riboflavin transport due to missense mutations in SLC52A2 causes Brown-Vialetto-Van Laere syndrome.&lt;/strong&gt; J. Inherit. Metab. Dis. 35: 943-948, 2012.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/22864630/&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;22864630&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=22864630[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/10.1007/s10545-012-9513-y&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="22864630">Haack et al. (2012)</a> reported a girl with BVVLS2. After normal psychomotor development, she presented at age 3 years with impaired hearing, clumsiness, impaired walking due to ataxia, and vertical nystagmus. She also developed progressive optic atrophy with visual impairment and aggressive behavior. Neurologic studies showed absent reflexes in the lower extremities and an axonal sensory neuropathy. She was confined to a wheelchair from the age of 5 years. At age 5.5 years, she showed right-sided facial nerve palsy and tongue wasting with fasciculations. Laboratory analysis showed increased levels of several acylcarnitine and hydroxy-acylcarnitine species; however, plasma riboflavin was normal. Treatment with oral riboflavin supplementation resulted in improvement in fine motor skills and assisted gait, as well as normalization of laboratory findings. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22864630" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#1" class="mim-tip-reference" title="Ciccolella, M., Corti, S., Catteruccia, M., Petrini, S., Tozzi, F., Rizza, T., Carrozzo, R., Nizzardo, M., Bordoni, A., Ronchi, D., D&#x27;Amico, A., Rizzo, C., Comi, G. P., Bertini, E. &lt;strong&gt;Riboflavin transporter 3 involvement in infantile Brown-Vialetto-Van Laere disease: two novel mutations.&lt;/strong&gt; J. Med. Genet. 50: 104-107, 2013.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/23243084/&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;23243084&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1136/jmedgenet-2012-101204&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="23243084">Ciccolella et al. (2013)</a> reported a boy with severe, early-onset BVVLS2. He had normal early psychomotor development and began to walk at age 12 months. At age 2 years, he presented with progressive dysphonia and exercise intolerance with dyspnea and cyanosis. He later developed sensorineural hearing loss, decreased visual acuity, shoulder and axial muscle weakness, kyphosis, wasting and weakness of the hand muscles, and walking difficulties with foot drop. The disorder was rapidly progressive; at age 3 years, he was hospitalized for acute respiratory failure and died. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23243084" 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="#2" class="mim-tip-reference" title="Foley, A. R., Menezes, M. P., Pandraud, A., Gonzalez, M. A., Al-Odaib, A., Abrams, A. J., Sugano, K., Yonezawa, A., Manzur, A. Y., Burns, J., Hughes, I., McCullagh, B. G., and 42 others. &lt;strong&gt;Treatable childhood neuronopathy caused by mutations in riboflavin transporter RFVT2.&lt;/strong&gt; Brain 137: 44-56, 2014.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/24253200/&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;24253200&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=24253200[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/awt315&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="24253200">Foley et al. (2014)</a> reported 18 patients from 13 families with BVVLS2 confirmed by genetic analysis. One of the patients had previously been reported by <a href="#5" class="mim-tip-reference" title="Johnson, J. O., Gibbs, J. R., Megarbane, A., Urtizberea, J. A., Hernandez, D. G., Foley, A. R., Arepalli, S., Pandraud, A., Simon-Sanchez, J., Clayton, P., Reilly, M. M., Muntoni, F., Abramzon, Y., Houlden, H., Singleton, A. B. &lt;strong&gt;Exome sequencing reveals riboflavin transporter mutations as a cause of motor neuron disease.&lt;/strong&gt; Brain 135: 2875-2882, 2012.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/22740598/&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;22740598&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=22740598[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/aws161&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="22740598">Johnson et al. (2012)</a>. The most common presenting symptom was an ataxic gait, reported in 9 (50%) of 18 patients, secondary to a progressive sensory neuropathy. Symptom onset occurred in childhood, but varied between ages 7 months (nystagmus) and 8 years (ataxic gait). Most (93%) patients had optic atrophy, and all had sensorineural hearing loss. Other features included tongue fasciculations, respiratory distress, rapidly progressive upper limb weakness, weakness of the neck muscles, and areflexia. All had normal cognition despite significant visual and hearing impairment. Ten (59%) of 17 patients tested had abnormal acylcarnitine profiles. Neurophysiologic studies were consistent with an axonal sensorimotor neuropathy, and sural nerve biopsy showed loss of large diameter myelinated axons without regenerative features. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=22740598+24253200" 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="Gorcenco, S., Vaz, F. M., Tracewska-Siemiatkowska, A., Tranebjaerg, L., Cremers, F. P. M., Ygland, E., Kisci, J., Rendtorff, N. D., Moller, C., Kjellstrom, U., Andreasson, S., Puschmann, A. &lt;strong&gt;Oral therapy for riboflavin transporter deficiency--what is the regimen of choice?&lt;/strong&gt; Parkinsonism Relat. Disord. 61: 245-247, 2019.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/30343981/&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;30343981&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/j.parkreldis.2018.10.017&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="30343981">Gorcenco et al. (2019)</a> reported a 35-year-old Swedish man with BVVLS2 who had sensory ataxia, severe hearing and vision loss, polyneuropathy with proprioception difficulties, dysarthria, and decreased deep tendon reflexes. He had normal development until age 3 years when he developed hearing loss. Progressive vision loss with bilateral optic atrophy began at age 4 years. His balance and gate abnormalities presented in childhood and progressed. Neurography studies showed reduced amplitude in sensory fibers. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30343981" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#2" class="mim-tip-reference" title="Foley, A. R., Menezes, M. P., Pandraud, A., Gonzalez, M. A., Al-Odaib, A., Abrams, A. J., Sugano, K., Yonezawa, A., Manzur, A. Y., Burns, J., Hughes, I., McCullagh, B. G., and 42 others. &lt;strong&gt;Treatable childhood neuronopathy caused by mutations in riboflavin transporter RFVT2.&lt;/strong&gt; Brain 137: 44-56, 2014.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/24253200/&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;24253200&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=24253200[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/awt315&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="24253200">Foley et al. (2014)</a> found that high-dose riboflavin resulted in significant and sustained clinical and biochemical improvement in patients with BVVLS2 confirmed by genetic analysis. Two patients were reported in detail: a child who presented at age 22 months and was started on riboflavin immediately with favorable response within a month, and a patient (<a href="#5" class="mim-tip-reference" title="Johnson, J. O., Gibbs, J. R., Megarbane, A., Urtizberea, J. A., Hernandez, D. G., Foley, A. R., Arepalli, S., Pandraud, A., Simon-Sanchez, J., Clayton, P., Reilly, M. M., Muntoni, F., Abramzon, Y., Houlden, H., Singleton, A. B. &lt;strong&gt;Exome sequencing reveals riboflavin transporter mutations as a cause of motor neuron disease.&lt;/strong&gt; Brain 135: 2875-2882, 2012.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/22740598/&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;22740598&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=22740598[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/aws161&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="22740598">Johnson et al., 2012</a>) who was started on riboflavin therapy at age 10 years with a favorable response within 3 months. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=22740598+24253200" 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="Gorcenco, S., Vaz, F. M., Tracewska-Siemiatkowska, A., Tranebjaerg, L., Cremers, F. P. M., Ygland, E., Kisci, J., Rendtorff, N. D., Moller, C., Kjellstrom, U., Andreasson, S., Puschmann, A. &lt;strong&gt;Oral therapy for riboflavin transporter deficiency--what is the regimen of choice?&lt;/strong&gt; Parkinsonism Relat. Disord. 61: 245-247, 2019.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/30343981/&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;30343981&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/j.parkreldis.2018.10.017&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="30343981">Gorcenco et al. (2019)</a> reported plasma riboflavin levels in response to interval oral dosing in a 35-year-old man with BVVLS2. Initially, oral riboflavin was administered at a dose of 500 mg 3 times daily. On this dosing regimen, plasma riboflavin levels were low first thing in the morning, rose up to 4 hours after intake, and then gradually decreased. Riboflavin administration was then changed to 250 mg 6 times per day, which resulted in a more constant plasma level and led to a calculated 27% higher plasma riboflavin level over a 24-hour period. One year after the 6 times per day dosing was initiated, the patient had a slight improvement in gait, sitting stability, and alternating hand movements. The patient also experienced a slight improvement in visual acuity, had almost normal color vision, and had improved peripheral vision with central scotomas. <a href="#3" class="mim-tip-reference" title="Gorcenco, S., Vaz, F. M., Tracewska-Siemiatkowska, A., Tranebjaerg, L., Cremers, F. P. M., Ygland, E., Kisci, J., Rendtorff, N. D., Moller, C., Kjellstrom, U., Andreasson, S., Puschmann, A. &lt;strong&gt;Oral therapy for riboflavin transporter deficiency--what is the regimen of choice?&lt;/strong&gt; Parkinsonism Relat. Disord. 61: 245-247, 2019.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/30343981/&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;30343981&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/j.parkreldis.2018.10.017&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="30343981">Gorcenco et al. (2019)</a> concluded that their approach does not demonstrate an improved clinical effect of 6 times per day dosing of riboflavin compared to other riboflavin dosing regimens in BVVLS2, but does support the use of more frequent dosing based on plasma concentrations. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30343981" 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>Inheritance</strong>
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<p>The transmission pattern of BVVLS2 in the family reported by <a href="#6" class="mim-tip-reference" title="Megarbane, A., Desguerres, I., Rizkallah, E., Delague, V., Nabbout, R., Barois, A., Urtizberea, A. &lt;strong&gt;Brown-Vialetto-Van Laere syndrome in a large inbred Lebanese family: confirmation of autosomal recessive inheritance?&lt;/strong&gt; Am. J. Med. Genet. 92: 117-121, 2000.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/10797435/&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;10797435&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/(sici)1096-8628(20000515)92:2&lt;117::aid-ajmg7&gt;3.0.co;2-c&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="10797435">Megarbane et al. (2000)</a> was consistent with autosomal recessive inheritance. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10797435" 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="molecularGenetics" class="mim-anchor"></a>
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<strong>Molecular Genetics</strong>
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<p>In affected members of a large consanguineous Lebanese family with severe Brown-Vialetto-Van Laere syndrome-2, <a href="#5" class="mim-tip-reference" title="Johnson, J. O., Gibbs, J. R., Megarbane, A., Urtizberea, J. A., Hernandez, D. G., Foley, A. R., Arepalli, S., Pandraud, A., Simon-Sanchez, J., Clayton, P., Reilly, M. M., Muntoni, F., Abramzon, Y., Houlden, H., Singleton, A. B. &lt;strong&gt;Exome sequencing reveals riboflavin transporter mutations as a cause of motor neuron disease.&lt;/strong&gt; Brain 135: 2875-2882, 2012.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/22740598/&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;22740598&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=22740598[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/aws161&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="22740598">Johnson et al. (2012)</a> identified a homozygous mutation in the SLC52A2 gene (G306R; <a href="/entry/607882#0001">607882.0001</a>). A Scottish girl with the disorder was also found to be homozygous for the G306R mutation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22740598" 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 girl with BVVLS2, <a href="#4" class="mim-tip-reference" title="Haack, T. B., Makowski, C., Yao, Y., Graf, E., Hempel, M., Wieland, T., Tauer, U., Ahting, U., Mayr, J. A., Freisinger, P., Yoshimatsu, H., Inui, K., Strom, T. M., Meitinger, T., Yonezawa, A., Prokisch, H. &lt;strong&gt;Impaired riboflavin transport due to missense mutations in SLC52A2 causes Brown-Vialetto-Van Laere syndrome.&lt;/strong&gt; J. Inherit. Metab. Dis. 35: 943-948, 2012.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/22864630/&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;22864630&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=22864630[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/10.1007/s10545-012-9513-y&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="22864630">Haack et al. (2012)</a> identified compound heterozygous mutations in the SLC52A2 gene (<a href="/entry/607882#0002">607882.0002</a> and <a href="/entry/607882#0003">607882.0003</a>). Transfection of the mutations in HEK293 cells showed that both caused a significant decrease in SLC52A2 transporter activity compared to wildtype. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22864630" 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 boy with severe early-onset BVVLS2 resulting in death at age 3, <a href="#1" class="mim-tip-reference" title="Ciccolella, M., Corti, S., Catteruccia, M., Petrini, S., Tozzi, F., Rizza, T., Carrozzo, R., Nizzardo, M., Bordoni, A., Ronchi, D., D&#x27;Amico, A., Rizzo, C., Comi, G. P., Bertini, E. &lt;strong&gt;Riboflavin transporter 3 involvement in infantile Brown-Vialetto-Van Laere disease: two novel mutations.&lt;/strong&gt; J. Med. Genet. 50: 104-107, 2013.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/23243084/&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;23243084&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1136/jmedgenet-2012-101204&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="23243084">Ciccolella et al. (2013)</a> identified compound heterozygous mutations in the SLC52A2 gene (<a href="/entry/607882#0004">607882.0004</a>-<a href="/entry/607882#0005">607882.0005</a>). Each of the unaffected parents was heterozygous for 1 of the mutations. Patient cells showed significantly decreased riboflavin transport (about 29%) compared to controls. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23243084" 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 Sanger sequencing of the SLC52A2 gene in 78 patients of various origins with a phenotype of cranial neuropathies and sensorimotor neuropathy with or without respiratory insufficiency from 21 medical centers, <a href="#2" class="mim-tip-reference" title="Foley, A. R., Menezes, M. P., Pandraud, A., Gonzalez, M. A., Al-Odaib, A., Abrams, A. J., Sugano, K., Yonezawa, A., Manzur, A. Y., Burns, J., Hughes, I., McCullagh, B. G., and 42 others. &lt;strong&gt;Treatable childhood neuronopathy caused by mutations in riboflavin transporter RFVT2.&lt;/strong&gt; Brain 137: 44-56, 2014.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/24253200/&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;24253200&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=24253200[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/awt315&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="24253200">Foley et al. (2014)</a> identified 8 different biallelic mutations (see, e.g., <a href="/entry/607882#0001">607882.0001</a>; <a href="/entry/607882#0003">607882.0003</a>; <a href="/entry/607882#0006">607882.0006</a>-<a href="/entry/607882#0007">607882.0007</a>) in 13 probands (including the Scottish patient previously reported by <a href="#5" class="mim-tip-reference" title="Johnson, J. O., Gibbs, J. R., Megarbane, A., Urtizberea, J. A., Hernandez, D. G., Foley, A. R., Arepalli, S., Pandraud, A., Simon-Sanchez, J., Clayton, P., Reilly, M. M., Muntoni, F., Abramzon, Y., Houlden, H., Singleton, A. B. &lt;strong&gt;Exome sequencing reveals riboflavin transporter mutations as a cause of motor neuron disease.&lt;/strong&gt; Brain 135: 2875-2882, 2012.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/22740598/&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;22740598&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=22740598[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/aws161&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="22740598">Johnson et al., 2012</a>) and 5 affected family members. The most common mutation was G306R, which was found in homozygous state in 3 Lebanese families and in compound heterozygous state in 2 families and 3 singleton patients. In vitro functional expression studies showed that the mutations caused reduced or absent riboflavin uptake and reduced riboflavin transporter protein expression. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=22740598+24253200" 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="references"class="mim-anchor"></a>
<h4 href="#mimReferencesFold" id="mimReferencesToggle" class="mimTriangleToggle" style="cursor: pointer;" data-toggle="collapse">
<span class="mim-font">
<span id="mimReferencesToggleTriangle" class="small mimTextToggleTriangle">&#9660;</span>
<strong>REFERENCES</strong>
</span>
</h4>
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<p />
</div>
<div id="mimReferencesFold" class="collapse in mimTextToggleFold">
<ol>
<li>
<a id="1" class="mim-anchor"></a>
<a id="Ciccolella2013" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Ciccolella, M., Corti, S., Catteruccia, M., Petrini, S., Tozzi, F., Rizza, T., Carrozzo, R., Nizzardo, M., Bordoni, A., Ronchi, D., D'Amico, A., Rizzo, C., Comi, G. P., Bertini, E.
<strong>Riboflavin transporter 3 involvement in infantile Brown-Vialetto-Van Laere disease: two novel mutations.</strong>
J. Med. Genet. 50: 104-107, 2013.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23243084/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23243084</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23243084" 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/jmedgenet-2012-101204" target="_blank">Full Text</a>]
</p>
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</li>
<li>
<a id="2" class="mim-anchor"></a>
<a id="Foley2014" class="mim-anchor"></a>
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<p class="mim-text-font">
Foley, A. R., Menezes, M. P., Pandraud, A., Gonzalez, M. A., Al-Odaib, A., Abrams, A. J., Sugano, K., Yonezawa, A., Manzur, A. Y., Burns, J., Hughes, I., McCullagh, B. G., and 42 others.
<strong>Treatable childhood neuronopathy caused by mutations in riboflavin transporter RFVT2.</strong>
Brain 137: 44-56, 2014.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24253200/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24253200</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=24253200[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=24253200" 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/awt315" target="_blank">Full Text</a>]
</p>
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<a id="3" class="mim-anchor"></a>
<a id="Gorcenco2019" class="mim-anchor"></a>
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<p class="mim-text-font">
Gorcenco, S., Vaz, F. M., Tracewska-Siemiatkowska, A., Tranebjaerg, L., Cremers, F. P. M., Ygland, E., Kisci, J., Rendtorff, N. D., Moller, C., Kjellstrom, U., Andreasson, S., Puschmann, A.
<strong>Oral therapy for riboflavin transporter deficiency--what is the regimen of choice?</strong>
Parkinsonism Relat. Disord. 61: 245-247, 2019.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30343981/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30343981</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30343981" 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.parkreldis.2018.10.017" target="_blank">Full Text</a>]
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<a id="Haack2012" class="mim-anchor"></a>
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Haack, T. B., Makowski, C., Yao, Y., Graf, E., Hempel, M., Wieland, T., Tauer, U., Ahting, U., Mayr, J. A., Freisinger, P., Yoshimatsu, H., Inui, K., Strom, T. M., Meitinger, T., Yonezawa, A., Prokisch, H.
<strong>Impaired riboflavin transport due to missense mutations in SLC52A2 causes Brown-Vialetto-Van Laere syndrome.</strong>
J. Inherit. Metab. Dis. 35: 943-948, 2012.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22864630/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22864630</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22864630[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=22864630" 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/s10545-012-9513-y" target="_blank">Full Text</a>]
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<a id="5" class="mim-anchor"></a>
<a id="Johnson2012" class="mim-anchor"></a>
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Johnson, J. O., Gibbs, J. R., Megarbane, A., Urtizberea, J. A., Hernandez, D. G., Foley, A. R., Arepalli, S., Pandraud, A., Simon-Sanchez, J., Clayton, P., Reilly, M. M., Muntoni, F., Abramzon, Y., Houlden, H., Singleton, A. B.
<strong>Exome sequencing reveals riboflavin transporter mutations as a cause of motor neuron disease.</strong>
Brain 135: 2875-2882, 2012.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22740598/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22740598</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22740598[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=22740598" 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/aws161" target="_blank">Full Text</a>]
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<a id="Megarbane2000" class="mim-anchor"></a>
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Megarbane, A., Desguerres, I., Rizkallah, E., Delague, V., Nabbout, R., Barois, A., Urtizberea, A.
<strong>Brown-Vialetto-Van Laere syndrome in a large inbred Lebanese family: confirmation of autosomal recessive inheritance?</strong>
Am. J. Med. Genet. 92: 117-121, 2000.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10797435/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10797435</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10797435" 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/(sici)1096-8628(20000515)92:2&lt;117::aid-ajmg7&gt;3.0.co;2-c" target="_blank">Full Text</a>]
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Hilary J. Vernon - updated : 10/20/2020
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Cassandra L. Kniffin - updated : 1/15/2014<br>Cassandra L. Kniffin - updated : 2/25/2013<br>Cassandra L. Kniffin - updated : 1/22/2013<br>Cassandra L. Kniffin - updated : 7/10/2012
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Cassandra L. Kniffin : 7/10/2012
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carol : 03/06/2023
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carol : 10/20/2020<br>carol : 02/26/2018<br>carol : 06/07/2017<br>carol : 04/04/2014<br>carol : 1/16/2014<br>ckniffin : 1/15/2014<br>carol : 4/16/2013<br>carol : 3/11/2013<br>ckniffin : 2/25/2013<br>alopez : 2/5/2013<br>ckniffin : 1/22/2013<br>terry : 9/19/2012<br>carol : 7/10/2012<br>ckniffin : 7/10/2012
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<strong>#</strong> 614707
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BROWN-VIALETTO-VAN LAERE SYNDROME 2; BVVLS2
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<em>Alternative titles; symbols</em>
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RIBOFLAVIN TRANSPORTER DEFICIENCY, TYPE 2; RTD2
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<strong>ORPHA:</strong> 572550, 97229; &nbsp;
<strong>DO:</strong> 0080786; &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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8q24.3
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Brown-Vialetto-Van Laere syndrome 2
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614707
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Autosomal recessive
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3
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SLC52A2
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607882
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<strong>TEXT</strong>
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<p>A number sign (#) is used with this entry because Brown-Vialetto-Van Laere syndrome-2 (BVVLS2) is caused by homozygous or compound heterozygous mutation in the SLC52A2 gene (607882) on chromosome 8q24.</p>
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<strong>Description</strong>
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<p>Brown-Vialetto-Van Laere syndrome-2 (BVVLS2) is an autosomal recessive progressive neurologic disorder characterized by early childhood onset of sensorineural deafness, bulbar dysfunction, and severe diffuse muscle weakness and wasting of the upper and lower limbs and axial muscles, resulting in respiratory insufficiency. Some patients may lose independent ambulation. Because it results from a defect in riboflavin metabolism, some patients may benefit from high-dose riboflavin supplementation (summary by Johnson et al., 2012; Foley et al., 2014). </p><p>For discussion of genetic heterogeneity of Brown-Vialetto-Van Laere syndrome, see BVVLS1 (211530).</p>
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<strong>Clinical Features</strong>
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<p>Megarbane et al. (2000) reported a large inbred Lebanese family with 4 patients, including 3 males and 1 female, with severe features of Brown-Vialetto-Van Laere syndrome. The proband showed normal early childhood development until about age 2.5 years, when he developed progressively abnormal hearing and walking. Physical examination at age 8 years showed profound deafness with absent brainstem auditory-evoked potentials, tongue fasciculations, bulbar dysfunction, scoliosis, and axial and limb hypotonia with little spontaneous movements. He had severe neck weakness with an inability to hold up his head, proximal and distal limb weakness and atrophy, and claw hands. Deep tendon reflexes and plantar responses were absent. Intelligence appeared to be normal. He died of respiratory failure at age 11 years. His younger brother was similarly affected, and also had facial paresis, inability to close the eyes tightly, absent pupillary reflexes, and poor gag reflex, which indicated multiple cranial nerve abnormalities. EMG was neurogenic with fibrillation activity. He died suddenly at age 7 years. The boys' sister was reportedly affected, but died at age 4 years. A male first cousin had slightly less severe muscle weakness and slightly later onset at age 3.5 years, but also showed deafness and diffuse muscle weakness and atrophy. </p><p>Johnson et al. (2012) reported an 11-year-old Scottish girl with BVVLS2. She presented with ataxic gait at age 18 months. At age 6 years, she showed weakness of the fingers, which rapidly progressed to severe upper limb weakness over the course of a few weeks. She also developed bilateral sensorineural hearing loss. By 7 years of age, she was wheelchair-bound due to axial hypotonia and weakness, but could walk with support as her lower limbs retained strength. Other features included optic atrophy, sleep hypoventilation, and severe axonal sensorimotor neuropathy. Metabolic testing showed evidence of carnitine deficiency and a urinary organic acid profile suggestive of MADD (231680). Treatment with high-dose riboflavin resulted in the normalization of her acylcarnitine and urinary organic acid profiles. She also showed quantitative improvements in her pulmonary function, brainstem auditory evoked potentials, and visual evoked potentials, and some improvement in upper limb strength. </p><p>Haack et al. (2012) reported a girl with BVVLS2. After normal psychomotor development, she presented at age 3 years with impaired hearing, clumsiness, impaired walking due to ataxia, and vertical nystagmus. She also developed progressive optic atrophy with visual impairment and aggressive behavior. Neurologic studies showed absent reflexes in the lower extremities and an axonal sensory neuropathy. She was confined to a wheelchair from the age of 5 years. At age 5.5 years, she showed right-sided facial nerve palsy and tongue wasting with fasciculations. Laboratory analysis showed increased levels of several acylcarnitine and hydroxy-acylcarnitine species; however, plasma riboflavin was normal. Treatment with oral riboflavin supplementation resulted in improvement in fine motor skills and assisted gait, as well as normalization of laboratory findings. </p><p>Ciccolella et al. (2013) reported a boy with severe, early-onset BVVLS2. He had normal early psychomotor development and began to walk at age 12 months. At age 2 years, he presented with progressive dysphonia and exercise intolerance with dyspnea and cyanosis. He later developed sensorineural hearing loss, decreased visual acuity, shoulder and axial muscle weakness, kyphosis, wasting and weakness of the hand muscles, and walking difficulties with foot drop. The disorder was rapidly progressive; at age 3 years, he was hospitalized for acute respiratory failure and died. </p><p>Foley et al. (2014) reported 18 patients from 13 families with BVVLS2 confirmed by genetic analysis. One of the patients had previously been reported by Johnson et al. (2012). The most common presenting symptom was an ataxic gait, reported in 9 (50%) of 18 patients, secondary to a progressive sensory neuropathy. Symptom onset occurred in childhood, but varied between ages 7 months (nystagmus) and 8 years (ataxic gait). Most (93%) patients had optic atrophy, and all had sensorineural hearing loss. Other features included tongue fasciculations, respiratory distress, rapidly progressive upper limb weakness, weakness of the neck muscles, and areflexia. All had normal cognition despite significant visual and hearing impairment. Ten (59%) of 17 patients tested had abnormal acylcarnitine profiles. Neurophysiologic studies were consistent with an axonal sensorimotor neuropathy, and sural nerve biopsy showed loss of large diameter myelinated axons without regenerative features. </p><p>Gorcenco et al. (2019) reported a 35-year-old Swedish man with BVVLS2 who had sensory ataxia, severe hearing and vision loss, polyneuropathy with proprioception difficulties, dysarthria, and decreased deep tendon reflexes. He had normal development until age 3 years when he developed hearing loss. Progressive vision loss with bilateral optic atrophy began at age 4 years. His balance and gate abnormalities presented in childhood and progressed. Neurography studies showed reduced amplitude in sensory fibers. </p>
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<strong>Clinical Management</strong>
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<p>Foley et al. (2014) found that high-dose riboflavin resulted in significant and sustained clinical and biochemical improvement in patients with BVVLS2 confirmed by genetic analysis. Two patients were reported in detail: a child who presented at age 22 months and was started on riboflavin immediately with favorable response within a month, and a patient (Johnson et al., 2012) who was started on riboflavin therapy at age 10 years with a favorable response within 3 months. </p><p>Gorcenco et al. (2019) reported plasma riboflavin levels in response to interval oral dosing in a 35-year-old man with BVVLS2. Initially, oral riboflavin was administered at a dose of 500 mg 3 times daily. On this dosing regimen, plasma riboflavin levels were low first thing in the morning, rose up to 4 hours after intake, and then gradually decreased. Riboflavin administration was then changed to 250 mg 6 times per day, which resulted in a more constant plasma level and led to a calculated 27% higher plasma riboflavin level over a 24-hour period. One year after the 6 times per day dosing was initiated, the patient had a slight improvement in gait, sitting stability, and alternating hand movements. The patient also experienced a slight improvement in visual acuity, had almost normal color vision, and had improved peripheral vision with central scotomas. Gorcenco et al. (2019) concluded that their approach does not demonstrate an improved clinical effect of 6 times per day dosing of riboflavin compared to other riboflavin dosing regimens in BVVLS2, but does support the use of more frequent dosing based on plasma concentrations. </p>
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<strong>Inheritance</strong>
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<p>The transmission pattern of BVVLS2 in the family reported by Megarbane et al. (2000) was consistent with autosomal recessive inheritance. </p>
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<strong>Molecular Genetics</strong>
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<p>In affected members of a large consanguineous Lebanese family with severe Brown-Vialetto-Van Laere syndrome-2, Johnson et al. (2012) identified a homozygous mutation in the SLC52A2 gene (G306R; 607882.0001). A Scottish girl with the disorder was also found to be homozygous for the G306R mutation. </p><p>In a girl with BVVLS2, Haack et al. (2012) identified compound heterozygous mutations in the SLC52A2 gene (607882.0002 and 607882.0003). Transfection of the mutations in HEK293 cells showed that both caused a significant decrease in SLC52A2 transporter activity compared to wildtype. </p><p>In a boy with severe early-onset BVVLS2 resulting in death at age 3, Ciccolella et al. (2013) identified compound heterozygous mutations in the SLC52A2 gene (607882.0004-607882.0005). Each of the unaffected parents was heterozygous for 1 of the mutations. Patient cells showed significantly decreased riboflavin transport (about 29%) compared to controls. </p><p>By Sanger sequencing of the SLC52A2 gene in 78 patients of various origins with a phenotype of cranial neuropathies and sensorimotor neuropathy with or without respiratory insufficiency from 21 medical centers, Foley et al. (2014) identified 8 different biallelic mutations (see, e.g., 607882.0001; 607882.0003; 607882.0006-607882.0007) in 13 probands (including the Scottish patient previously reported by Johnson et al., 2012) and 5 affected family members. The most common mutation was G306R, which was found in homozygous state in 3 Lebanese families and in compound heterozygous state in 2 families and 3 singleton patients. In vitro functional expression studies showed that the mutations caused reduced or absent riboflavin uptake and reduced riboflavin transporter protein expression. </p>
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<strong>REFERENCES</strong>
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Ciccolella, M., Corti, S., Catteruccia, M., Petrini, S., Tozzi, F., Rizza, T., Carrozzo, R., Nizzardo, M., Bordoni, A., Ronchi, D., D'Amico, A., Rizzo, C., Comi, G. P., Bertini, E.
<strong>Riboflavin transporter 3 involvement in infantile Brown-Vialetto-Van Laere disease: two novel mutations.</strong>
J. Med. Genet. 50: 104-107, 2013.
[PubMed: 23243084]
[Full Text: https://doi.org/10.1136/jmedgenet-2012-101204]
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Foley, A. R., Menezes, M. P., Pandraud, A., Gonzalez, M. A., Al-Odaib, A., Abrams, A. J., Sugano, K., Yonezawa, A., Manzur, A. Y., Burns, J., Hughes, I., McCullagh, B. G., and 42 others.
<strong>Treatable childhood neuronopathy caused by mutations in riboflavin transporter RFVT2.</strong>
Brain 137: 44-56, 2014.
[PubMed: 24253200]
[Full Text: https://doi.org/10.1093/brain/awt315]
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Gorcenco, S., Vaz, F. M., Tracewska-Siemiatkowska, A., Tranebjaerg, L., Cremers, F. P. M., Ygland, E., Kisci, J., Rendtorff, N. D., Moller, C., Kjellstrom, U., Andreasson, S., Puschmann, A.
<strong>Oral therapy for riboflavin transporter deficiency--what is the regimen of choice?</strong>
Parkinsonism Relat. Disord. 61: 245-247, 2019.
[PubMed: 30343981]
[Full Text: https://doi.org/10.1016/j.parkreldis.2018.10.017]
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<li>
<p class="mim-text-font">
Haack, T. B., Makowski, C., Yao, Y., Graf, E., Hempel, M., Wieland, T., Tauer, U., Ahting, U., Mayr, J. A., Freisinger, P., Yoshimatsu, H., Inui, K., Strom, T. M., Meitinger, T., Yonezawa, A., Prokisch, H.
<strong>Impaired riboflavin transport due to missense mutations in SLC52A2 causes Brown-Vialetto-Van Laere syndrome.</strong>
J. Inherit. Metab. Dis. 35: 943-948, 2012.
[PubMed: 22864630]
[Full Text: https://doi.org/10.1007/s10545-012-9513-y]
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<p class="mim-text-font">
Johnson, J. O., Gibbs, J. R., Megarbane, A., Urtizberea, J. A., Hernandez, D. G., Foley, A. R., Arepalli, S., Pandraud, A., Simon-Sanchez, J., Clayton, P., Reilly, M. M., Muntoni, F., Abramzon, Y., Houlden, H., Singleton, A. B.
<strong>Exome sequencing reveals riboflavin transporter mutations as a cause of motor neuron disease.</strong>
Brain 135: 2875-2882, 2012.
[PubMed: 22740598]
[Full Text: https://doi.org/10.1093/brain/aws161]
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Megarbane, A., Desguerres, I., Rizkallah, E., Delague, V., Nabbout, R., Barois, A., Urtizberea, A.
<strong>Brown-Vialetto-Van Laere syndrome in a large inbred Lebanese family: confirmation of autosomal recessive inheritance?</strong>
Am. J. Med. Genet. 92: 117-121, 2000.
[PubMed: 10797435]
[Full Text: https://doi.org/10.1002/(sici)1096-8628(20000515)92:2&lt;117::aid-ajmg7&gt;3.0.co;2-c]
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Hilary J. Vernon - updated : 10/20/2020<br>Cassandra L. Kniffin - updated : 1/15/2014<br>Cassandra L. Kniffin - updated : 2/25/2013<br>Cassandra L. Kniffin - updated : 1/22/2013<br>Cassandra L. Kniffin - updated : 7/10/2012
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Cassandra L. Kniffin : 7/10/2012
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carol : 03/06/2023<br>carol : 10/20/2020<br>carol : 02/26/2018<br>carol : 06/07/2017<br>carol : 04/04/2014<br>carol : 1/16/2014<br>ckniffin : 1/15/2014<br>carol : 4/16/2013<br>carol : 3/11/2013<br>ckniffin : 2/25/2013<br>alopez : 2/5/2013<br>ckniffin : 1/22/2013<br>terry : 9/19/2012<br>carol : 7/10/2012<br>ckniffin : 7/10/2012
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