794 lines
No EOL
233 KiB
HTML
794 lines
No EOL
233 KiB
HTML
<?xml version="1.0" encoding="utf-8"?>
|
||
<!DOCTYPE html PUBLIC "-//W3C//DTD XHTML 1.0 Transitional//EN" "http://www.w3.org/TR/xhtml1/DTD/xhtml1-transitional.dtd">
|
||
<html xmlns="http://www.w3.org/1999/xhtml" xml:lang="en" lang="en">
|
||
|
||
<head><meta http-equiv="Content-Type" content="text/html; charset=utf-8" />
|
||
<!-- AppResources meta begin -->
|
||
<meta name="paf-app-resources" content="" />
|
||
<script type="text/javascript">var ncbi_startTime = new Date();</script>
|
||
|
||
<!-- AppResources meta end -->
|
||
|
||
<!-- TemplateResources meta begin -->
|
||
<meta name="paf_template" content="" />
|
||
|
||
<!-- TemplateResources meta end -->
|
||
|
||
<!-- Logger begin -->
|
||
<meta name="ncbi_db" content="books" /><meta name="ncbi_pdid" content="book-part" /><meta name="ncbi_acc" content="NBK299312" /><meta name="ncbi_domain" content="gene" /><meta name="ncbi_report" content="record" /><meta name="ncbi_type" content="fulltext" /><meta name="ncbi_objectid" content="" /><meta name="ncbi_pcid" content="/NBK299312/" /><meta name="ncbi_pagename" content="Riboflavin Transporter Deficiency - GeneReviews® - NCBI Bookshelf" /><meta name="ncbi_bookparttype" content="chapter" /><meta name="ncbi_app" content="bookshelf" />
|
||
<!-- Logger end -->
|
||
|
||
<title>Riboflavin Transporter Deficiency - GeneReviews® - NCBI Bookshelf</title>
|
||
|
||
<!-- AppResources external_resources begin -->
|
||
<link rel="stylesheet" href="/core/jig/1.15.2/css/jig.min.css" /><script type="text/javascript" src="/core/jig/1.15.2/js/jig.min.js"></script>
|
||
|
||
<!-- AppResources external_resources end -->
|
||
|
||
<!-- Page meta begin -->
|
||
<meta name="robots" content="INDEX,FOLLOW,NOARCHIVE" /><meta name="citation_inbook_title" content="GeneReviews® [Internet]" /><meta name="citation_title" content="Riboflavin Transporter Deficiency" /><meta name="citation_publisher" content="University of Washington, Seattle" /><meta name="citation_date" content="2021/04/08" /><meta name="citation_author" content="Elisa Cali" /><meta name="citation_author" content="Natalia Dominik" /><meta name="citation_author" content="Andreea Manole" /><meta name="citation_author" content="Henry Houlden" /><meta name="citation_pmid" content="26072523" /><meta name="citation_fulltext_html_url" content="https://www.ncbi.nlm.nih.gov/books/NBK299312/" /><meta name="citation_keywords" content="Solute carrier family 52, riboflavin transporter, member 1" /><meta name="citation_keywords" content="Solute carrier family 52, riboflavin transporter, member 2" /><meta name="citation_keywords" content="Solute carrier family 52, riboflavin transporter, member 3" /><meta name="citation_keywords" content="SLC52A1" /><meta name="citation_keywords" content="SLC52A2" /><meta name="citation_keywords" content="SLC52A3" /><meta name="citation_keywords" content="Riboflavin Transporter Deficiency" /><link rel="schema.DC" href="http://purl.org/DC/elements/1.0/" /><meta name="DC.Title" content="Riboflavin Transporter Deficiency" /><meta name="DC.Type" content="Text" /><meta name="DC.Publisher" content="University of Washington, Seattle" /><meta name="DC.Contributor" content="Elisa Cali" /><meta name="DC.Contributor" content="Natalia Dominik" /><meta name="DC.Contributor" content="Andreea Manole" /><meta name="DC.Contributor" content="Henry Houlden" /><meta name="DC.Date" content="2021/04/08" /><meta name="DC.Identifier" content="https://www.ncbi.nlm.nih.gov/books/NBK299312/" /><meta name="description" content="Riboflavin transporter deficiency (RTD), comprising RTD2 and RTD3 (caused by biallelic pathogenic variants in SLC52A2 and SLC52A3, respectively) is a rare neurologic condition characterized by progressive peripheral and cranial neuronopathy that causes muscle weakness (and consequent respiratory compromise), vision loss, deafness, and sensory ataxia. Onset is usually in infancy or in childhood; however, on occasion individuals with genetically confirmed RTD present as adults and even as late as the fifth decade. When untreated, most infants with riboflavin transporter deficiency rapidly become ventilator dependent and die in the first decade of life." /><meta name="og:title" content="Riboflavin Transporter Deficiency" /><meta name="og:type" content="book" /><meta name="og:description" content="Riboflavin transporter deficiency (RTD), comprising RTD2 and RTD3 (caused by biallelic pathogenic variants in SLC52A2 and SLC52A3, respectively) is a rare neurologic condition characterized by progressive peripheral and cranial neuronopathy that causes muscle weakness (and consequent respiratory compromise), vision loss, deafness, and sensory ataxia. Onset is usually in infancy or in childhood; however, on occasion individuals with genetically confirmed RTD present as adults and even as late as the fifth decade. When untreated, most infants with riboflavin transporter deficiency rapidly become ventilator dependent and die in the first decade of life." /><meta name="og:url" content="https://www.ncbi.nlm.nih.gov/books/NBK299312/" /><meta name="og:site_name" content="NCBI Bookshelf" /><meta name="og:image" content="https://www.ncbi.nlm.nih.gov/corehtml/pmc/pmcgifs/bookshelf/thumbs/th-gene-lrg.png" /><meta name="twitter:card" content="summary" /><meta name="twitter:site" content="@ncbibooks" /><meta name="bk-non-canon-loc" content="/books/n/gene/riboflavin-tn/" /><link rel="canonical" href="https://www.ncbi.nlm.nih.gov/books/NBK299312/" /><link rel="stylesheet" href="/corehtml/pmc/css/figpopup.css" type="text/css" media="screen" /><link rel="stylesheet" href="/corehtml/pmc/css/bookshelf/2.26/css/books.min.css" type="text/css" /><link rel="stylesheet" href="/corehtml/pmc/css/bookshelf/2.26/css/books_print.min.css" type="text/css" media="print" /><style type="text/css">p a.figpopup{display:inline !important} .bk_tt {font-family: monospace} .first-line-outdent .bk_ref {display: inline} .body-content h2, .body-content .h2 {border-bottom: 1px solid #97B0C8} .body-content h2.inline {border-bottom: none} a.page-toc-label , .jig-ncbismoothscroll a {text-decoration:none;border:0 !important} .temp-labeled-list .graphic {display:inline-block !important} .temp-labeled-list img{width:100%}</style><script type="text/javascript" src="/corehtml/pmc/js/jquery.hoverIntent.min.js"> </script><script type="text/javascript" src="/corehtml/pmc/js/common.min.js?_=3.18"> </script><script type="text/javascript" src="/corehtml/pmc/js/large-obj-scrollbars.min.js"> </script><script type="text/javascript">window.name="mainwindow";</script><script type="text/javascript" src="/corehtml/pmc/js/bookshelf/2.26/book-toc.min.js"> </script><script type="text/javascript" src="/corehtml/pmc/js/bookshelf/2.26/books.min.js"> </script><script type="text/javascript">if (typeof (jQuery) != 'undefined') { (function ($) { $(function () { var min = Math.ceil(1); var max = Math.floor(100000); var randomNum = Math.floor(Math.random() * (max - min)) + min; var surveyUrl = "/projects/Gene/portal/surveys/seqdbui-survey.js?rando=" + randomNum.toString(); $.getScript(surveyUrl, function () { try { ncbi.seqDbUISurvey.init(); } catch (err) { console.info(err); } }).fail(function (jqxhr, settings, exception) { console.info('Cannot load survey script', jqxhr); });; }); })(jQuery); };</script><meta name="book-collection" content="NONE" />
|
||
|
||
<!-- Page meta end -->
|
||
<link rel="shortcut icon" href="//www.ncbi.nlm.nih.gov/favicon.ico" /><meta name="ncbi_phid" content="CE8BBBA87D2AD0110000000000310021.m_13" />
|
||
<meta name='referrer' content='origin-when-cross-origin'/><link type="text/css" rel="stylesheet" href="//static.pubmed.gov/portal/portal3rc.fcgi/4216699/css/3852956/3985586/3808861/4121862/3974050/3917732/251717/4216701/14534/45193/4113719/3849091/3984811/3751656/4033350/3840896/3577051/3852958/4008682/4207974/4206132/4062871/12930/3964959/3854974/36029/4128070/9685/3549676/3609192/3609193/3609213/3395586.css" /><link type="text/css" rel="stylesheet" href="//static.pubmed.gov/portal/portal3rc.fcgi/4216699/css/3411343/3882866.css" media="print" /></head>
|
||
<body class="book-part">
|
||
<div class="grid">
|
||
<div class="col twelve_col nomargin shadow">
|
||
<!-- System messages like service outage or JS required; this is handled by the TemplateResources portlet -->
|
||
<div class="sysmessages">
|
||
<noscript>
|
||
<p class="nojs">
|
||
<strong>Warning:</strong>
|
||
The NCBI web site requires JavaScript to function.
|
||
<a href="/guide/browsers/#enablejs" title="Learn how to enable JavaScript" target="_blank">more...</a>
|
||
</p>
|
||
</noscript>
|
||
</div>
|
||
<!--/.sysmessage-->
|
||
<div class="wrap">
|
||
<div class="page">
|
||
<div class="top">
|
||
<div id="universal_header">
|
||
<section class="usa-banner">
|
||
<div class="usa-accordion">
|
||
<header class="usa-banner-header">
|
||
<div class="usa-grid usa-banner-inner">
|
||
<img src="https://www.ncbi.nlm.nih.gov/coreutils/uswds/img/favicons/favicon-57.png" alt="U.S. flag" />
|
||
<p>An official website of the United States government</p>
|
||
<button class="non-usa-accordion-button usa-banner-button" aria-expanded="false" aria-controls="gov-banner-top" type="button">
|
||
<span class="usa-banner-button-text">Here's how you know</span>
|
||
</button>
|
||
</div>
|
||
</header>
|
||
<div class="usa-banner-content usa-grid usa-accordion-content" id="gov-banner-top" aria-hidden="true">
|
||
<div class="usa-banner-guidance-gov usa-width-one-half">
|
||
<img class="usa-banner-icon usa-media_block-img" src="https://www.ncbi.nlm.nih.gov/coreutils/uswds/img/icon-dot-gov.svg" alt="Dot gov" />
|
||
<div class="usa-media_block-body">
|
||
<p>
|
||
<strong>The .gov means it's official.</strong>
|
||
<br />
|
||
Federal government websites often end in .gov or .mil. Before
|
||
sharing sensitive information, make sure you're on a federal
|
||
government site.
|
||
</p>
|
||
</div>
|
||
</div>
|
||
<div class="usa-banner-guidance-ssl usa-width-one-half">
|
||
<img class="usa-banner-icon usa-media_block-img" src="https://www.ncbi.nlm.nih.gov/coreutils/uswds/img/icon-https.svg" alt="Https" />
|
||
<div class="usa-media_block-body">
|
||
<p>
|
||
<strong>The site is secure.</strong>
|
||
<br />
|
||
The <strong>https://</strong> ensures that you are connecting to the
|
||
official website and that any information you provide is encrypted
|
||
and transmitted securely.
|
||
</p>
|
||
</div>
|
||
</div>
|
||
</div>
|
||
</div>
|
||
</section>
|
||
<div class="usa-overlay"></div>
|
||
<header class="ncbi-header" role="banner" data-section="Header">
|
||
|
||
<div class="usa-grid">
|
||
<div class="usa-width-one-whole">
|
||
|
||
<div class="ncbi-header__logo">
|
||
<a href="/" class="logo" aria-label="NCBI Logo" data-ga-action="click_image" data-ga-label="NIH NLM Logo">
|
||
<img src="https://www.ncbi.nlm.nih.gov/coreutils/nwds/img/logos/AgencyLogo.svg" alt="NIH NLM Logo" />
|
||
</a>
|
||
</div>
|
||
|
||
<div class="ncbi-header__account">
|
||
<a id="account_login" href="https://account.ncbi.nlm.nih.gov" class="usa-button header-button" style="display:none" data-ga-action="open_menu" data-ga-label="account_menu">Log in</a>
|
||
<button id="account_info" class="header-button" style="display:none" aria-controls="account_popup" type="button">
|
||
<span class="fa fa-user" aria-hidden="true">
|
||
<svg xmlns="http://www.w3.org/2000/svg" viewBox="0 0 24 24" width="20px" height="20px">
|
||
<g style="fill: #fff">
|
||
<ellipse cx="12" cy="8" rx="5" ry="6"></ellipse>
|
||
<path d="M21.8,19.1c-0.9-1.8-2.6-3.3-4.8-4.2c-0.6-0.2-1.3-0.2-1.8,0.1c-1,0.6-2,0.9-3.2,0.9s-2.2-0.3-3.2-0.9 C8.3,14.8,7.6,14.7,7,15c-2.2,0.9-3.9,2.4-4.8,4.2C1.5,20.5,2.6,22,4.1,22h15.8C21.4,22,22.5,20.5,21.8,19.1z"></path>
|
||
</g>
|
||
</svg>
|
||
</span>
|
||
<span class="username desktop-only" aria-hidden="true" id="uname_short"></span>
|
||
<span class="sr-only">Show account info</span>
|
||
</button>
|
||
</div>
|
||
|
||
<div class="ncbi-popup-anchor">
|
||
<div class="ncbi-popup account-popup" id="account_popup" aria-hidden="true">
|
||
<div class="ncbi-popup-head">
|
||
<button class="ncbi-close-button" data-ga-action="close_menu" data-ga-label="account_menu" type="button">
|
||
<span class="fa fa-times">
|
||
<svg xmlns="http://www.w3.org/2000/svg" viewBox="0 0 48 48" width="24px" height="24px">
|
||
<path d="M38 12.83l-2.83-2.83-11.17 11.17-11.17-11.17-2.83 2.83 11.17 11.17-11.17 11.17 2.83 2.83 11.17-11.17 11.17 11.17 2.83-2.83-11.17-11.17z"></path>
|
||
</svg>
|
||
</span>
|
||
<span class="usa-sr-only">Close</span></button>
|
||
<h4>Account</h4>
|
||
</div>
|
||
<div class="account-user-info">
|
||
Logged in as:<br />
|
||
<b><span class="username" id="uname_long">username</span></b>
|
||
</div>
|
||
<div class="account-links">
|
||
<ul class="usa-unstyled-list">
|
||
<li><a id="account_myncbi" href="/myncbi/" class="set-base-url" data-ga-action="click_menu_item" data-ga-label="account_myncbi">Dashboard</a></li>
|
||
<li><a id="account_pubs" href="/myncbi/collections/bibliography/" class="set-base-url" data-ga-action="click_menu_item" data-ga-label="account_pubs">Publications</a></li>
|
||
<li><a id="account_settings" href="/account/settings/" class="set-base-url" data-ga-action="click_menu_item" data-ga-label="account_settings">Account settings</a></li>
|
||
<li><a id="account_logout" href="/account/signout/" class="set-base-url" data-ga-action="click_menu_item" data-ga-label="account_logout">Log out</a></li>
|
||
</ul>
|
||
</div>
|
||
</div>
|
||
</div>
|
||
|
||
</div>
|
||
</div>
|
||
</header>
|
||
<div role="navigation" aria-label="access keys">
|
||
<a id="nws_header_accesskey_0" href="https://www.ncbi.nlm.nih.gov/guide/browsers/#ncbi_accesskeys" class="usa-sr-only" accesskey="0" tabindex="-1">Access keys</a>
|
||
<a id="nws_header_accesskey_1" href="https://www.ncbi.nlm.nih.gov" class="usa-sr-only" accesskey="1" tabindex="-1">NCBI Homepage</a>
|
||
<a id="nws_header_accesskey_2" href="/myncbi/" class="set-base-url usa-sr-only" accesskey="2" tabindex="-1">MyNCBI Homepage</a>
|
||
<a id="nws_header_accesskey_3" href="#maincontent" class="usa-sr-only" accesskey="3" tabindex="-1">Main Content</a>
|
||
<a id="nws_header_accesskey_4" href="#" class="usa-sr-only" accesskey="4" tabindex="-1">Main Navigation</a>
|
||
</div>
|
||
<section data-section="Alerts">
|
||
<div class="ncbi-alerts-placeholder"></div>
|
||
</section>
|
||
</div>
|
||
<div class="header">
|
||
<div class="res_logo"><h1 class="res_name"><a href="/books/" title="Bookshelf home">Bookshelf</a></h1><h2 class="res_tagline"></h2></div>
|
||
<div class="search"><form method="get" action="/books/"><div class="search_form"><label for="database" class="offscreen_noflow">Search database</label><select id="database"><optgroup label="Recent"><option value="books" selected="selected" data-ac_dict="bookshelf-search">Books</option><option value="pubmed">PubMed</option><option value="clinvar">ClinVar</option><option value="medgen" class="last">MedGen</option></optgroup><optgroup label="All"><option value="gquery">All Databases</option><option value="assembly">Assembly</option><option value="biocollections">Biocollections</option><option value="bioproject">BioProject</option><option value="biosample">BioSample</option><option value="books" data-ac_dict="bookshelf-search">Books</option><option value="clinvar">ClinVar</option><option value="cdd">Conserved Domains</option><option value="gap">dbGaP</option><option value="dbvar">dbVar</option><option value="gene">Gene</option><option value="genome">Genome</option><option value="gds">GEO DataSets</option><option value="geoprofiles">GEO Profiles</option><option value="gtr">GTR</option><option value="ipg">Identical Protein Groups</option><option value="medgen">MedGen</option><option value="mesh">MeSH</option><option value="nlmcatalog">NLM Catalog</option><option value="nuccore">Nucleotide</option><option value="omim">OMIM</option><option value="pmc">PMC</option><option value="protein">Protein</option><option value="proteinclusters">Protein Clusters</option><option value="protfam">Protein Family Models</option><option value="pcassay">PubChem BioAssay</option><option value="pccompound">PubChem Compound</option><option value="pcsubstance">PubChem Substance</option><option value="pubmed">PubMed</option><option value="snp">SNP</option><option value="sra">SRA</option><option value="structure">Structure</option><option value="taxonomy">Taxonomy</option><option value="toolkit">ToolKit</option><option value="toolkitall">ToolKitAll</option><option value="toolkitbookgh">ToolKitBookgh</option></optgroup></select><div class="nowrap"><label for="term" class="offscreen_noflow" accesskey="/">Search term</label><div class="nowrap"><input type="text" name="term" id="term" title="Search Books. Use up and down arrows to choose an item from the autocomplete." value="" class="jig-ncbiclearbutton jig-ncbiautocomplete" data-jigconfig="dictionary:'bookshelf-search',disableUrl:'NcbiSearchBarAutoComplCtrl'" autocomplete="off" data-sbconfig="ds:'no',pjs:'no',afs:'no'" /></div><button id="search" type="submit" class="button_search nowrap" cmd="go">Search</button></div></div></form><ul class="searchlinks inline_list"><li>
|
||
<a href="/books/browse/">Browse Titles</a>
|
||
</li><li>
|
||
<a href="/books/advanced/">Advanced</a>
|
||
</li><li class="help">
|
||
<a href="/books/NBK3833/">Help</a>
|
||
</li><li class="disclaimer">
|
||
<a target="_blank" data-ga-category="literature_resources" data-ga-action="link_click" data-ga-label="disclaimer_link" href="https://www.ncbi.nlm.nih.gov/books/about/disclaimer/">Disclaimer</a>
|
||
</li></ul></div>
|
||
</div>
|
||
|
||
|
||
|
||
<!--<component id="Page" label="headcontent"/>-->
|
||
|
||
</div>
|
||
<div class="content">
|
||
<!-- site messages -->
|
||
<!-- Custom content 1 -->
|
||
<div class="col1">
|
||
|
||
</div>
|
||
|
||
<div class="container">
|
||
<div id="maincontent" class="content eight_col col">
|
||
<!-- Custom content in the left column above book nav -->
|
||
<div class="col2">
|
||
|
||
</div>
|
||
|
||
<!-- Book content -->
|
||
|
||
|
||
<!-- Custom content between navigation and content -->
|
||
<div class="col3">
|
||
|
||
</div>
|
||
|
||
<div class="document">
|
||
<div class="pre-content"><div><div class="bk_prnt"><p class="small">NCBI Bookshelf. A service of the National Library of Medicine, National Institutes of Health.</p><p>Adam MP, Feldman J, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2025. </p></div><div class="iconblock clearfix whole_rhythm no_top_margin bk_noprnt"><a class="img_link icnblk_img" title="All GeneReviews" href="/books/n/gene/"><img class="source-thumb" src="/corehtml/pmc/pmcgifs/bookshelf/thumbs/th-gene-lrg.png" alt="Cover of GeneReviews®" height="100px" width="80px" /></a><div class="icnblk_cntnt eight_col"><h2>GeneReviews<sup>®</sup> [Internet].</h2><a data-jig="ncbitoggler" href="#__NBK299312_dtls__">Show details</a><div style="display:none" class="ui-widget" id="__NBK299312_dtls__"><div>Adam MP, Feldman J, Mirzaa GM, et al., editors.</div><div>Seattle (WA): <a href="http://www.washington.edu" ref="pagearea=page-banner&targetsite=external&targetcat=link&targettype=publisher">University of Washington, Seattle</a>; 1993-2025.</div></div><div class="half_rhythm"><ul class="inline_list"><li style="margin-right:1em"><a class="bk_cntns" href="/books/n/gene/">GeneReviews by Title</a></li></ul></div><div class="bk_noprnt"><form method="get" action="/books/n/gene/" id="bk_srch"><div class="bk_search"><label for="bk_term" class="offscreen_noflow">Search term</label><input type="text" title="Search GeneReviews" id="bk_term" name="term" value="" data-jig="ncbiclearbutton" /> <input type="submit" class="jig-ncbibutton" value="Search GeneReviews" submit="false" style="padding: 0.1em 0.4em;" /></div></form><div><ul class="inline_list"><li><a href="/books/n/gene/advanced/">GeneReviews Advanced Search</a></li><li style="margin-left:.5em"><a href="/books/n/gene/helpadvsearch/">Help</a></li></ul></div></div></div><div class="icnblk_cntnt two_col"><div class="pagination bk_noprnt"><a class="active page_link prev" href="/books/n/gene/rcdp/" title="Previous page in this title">< Prev</a><a class="active page_link next" href="/books/n/gene/ritscher-schinzel/" title="Next page in this title">Next ></a></div></div></div></div></div>
|
||
<div class="main-content lit-style" itemscope="itemscope" itemtype="http://schema.org/CreativeWork"><div class="meta-content fm-sec"><h1 id="_NBK299312_"><span class="title" itemprop="name">Riboflavin Transporter Deficiency</span></h1><p class="contrib-group"><span itemprop="author">Elisa Cali</span>, MD, <span itemprop="author">Natalia Dominik</span>, BSc, MSc, <span itemprop="author">Andreea Manole</span>, BSc, PhD, and <span itemprop="author">Henry Houlden</span>, MD, PhD.</p><a data-jig="ncbitoggler" href="#__NBK299312_ai__" style="border:0;text-decoration:none">Author Information and Affiliations</a><div style="display:none" class="ui-widget" id="__NBK299312_ai__"><div class="contrib half_rhythm"><span itemprop="author">Elisa Cali</span>, MD<div class="affiliation small">MRC Centre for Neuromuscular Diseases<br />UCL Queen Square Institute of Neurology<br />London, United Kingdom<div><span class="email-label">Email: </span><a href="mailto:dev@null" data-email="ku.ca.lcu@ilac.e" class="oemail">ku.ca.lcu@ilac.e</a></div></div></div><div class="contrib half_rhythm"><span itemprop="author">Natalia Dominik</span>, BSc, MSc<div class="affiliation small">MRC Centre for Neuromuscular Diseases<br />UCL Queen Square Institute of Neurology<br />London, United Kingdom<div><span class="email-label">Email: </span><a href="mailto:dev@null" data-email="ku.ca.lcu@kinimod.n" class="oemail">ku.ca.lcu@kinimod.n</a></div></div></div><div class="contrib half_rhythm"><span itemprop="author">Andreea Manole</span>, BSc, PhD<div class="affiliation small">MRC Centre for Neuromuscular Diseases<br />UCL Queen Square Institute of Neurology and National Hospital for Neurology and Neurosurgery<br />London, United Kingdom<div><span class="email-label">Email: </span><a href="mailto:dev@null" data-email="ku.ca.lcu@31.elonam.aeerdna" class="oemail">ku.ca.lcu@31.elonam.aeerdna</a></div></div></div><div class="contrib half_rhythm"><span itemprop="author">Henry Houlden</span>, MD, PhD<div class="affiliation small">Department of Molecular Neurosciences and MRC Centre for Neuromuscular Diseases<br />UCL Queen Square Institute of Neurology and National Hospital for Neurology and Neurosurgery<br />London, United Kingdom<div><span class="email-label">Email: </span><a href="mailto:dev@null" data-email="ku.ca.lcu@nedluoh.h" class="oemail">ku.ca.lcu@nedluoh.h</a></div></div></div></div><p class="small">Initial Posting: <span itemprop="datePublished">June 11, 2015</span>; Last Update: <span itemprop="dateModified">April 8, 2021</span>.</p><p><em>Estimated reading time: 34 minutes</em></p></div><div class="jig-ncbiinpagenav body-content whole_rhythm" data-jigconfig="allHeadingLevels: ['h2'],smoothScroll: false" itemprop="text"><div id="riboflavin-tn.Summary" itemprop="description"><h2 id="_riboflavin-tn_Summary_">Summary</h2><div><h4 class="inline">Clinical description.</h4><p>Riboflavin transporter deficiency (RTD), comprising RTD2 and RTD3 (caused by <a class="def" href="/books/n/gene/glossary/def-item/biallelic/">biallelic</a> pathogenic variants in <i>SLC52A2</i> and <i>SLC52A3</i>, respectively<i>)</i> is a rare neurologic condition characterized by progressive peripheral and cranial neuronopathy that causes muscle weakness (and consequent respiratory compromise), vision loss, deafness, and sensory ataxia. Onset is usually in infancy or in childhood; however, on occasion individuals with genetically confirmed RTD present as adults and even as late as the fifth decade. When untreated, most infants with riboflavin transporter deficiency rapidly become ventilator dependent and die in the first decade of life.</p><p>In the majority of affected individuals, the initial finding is sensorineural hearing loss, which is usually progressive and severe. The time between the onset of hearing loss and the development of other manifestations varies but is usually one to two years. In some individuals an intercurrent event, usually an injury or infection, appears to precipitate the initial manifestations or worsen existing findings.</p><p>One case report (which requires additional confirmation) suggests that <a class="def" href="/books/n/gene/glossary/def-item/biallelic/">biallelic</a> expression of pathogenic variants in <i>SLC52A1</i> (i.e., RTD1) is associated with infantile-onset of riboflavin-responsive seizures associated with hyperammonemia.</p></div><div><h4 class="inline">Diagnosis/testing.</h4><p>The diagnosis of RTD2 and RTD3 is established in an individual with suggestive findings and <a class="def" href="/books/n/gene/glossary/def-item/biallelic/">biallelic</a> pathogenic variants in either <i>SLC52A2</i> or <i>SLC52A3,</i> respectively, identified on <a class="def" href="/books/n/gene/glossary/def-item/molecular-genetic-testing/">molecular genetic testing</a>.</p></div><div><h4 class="inline">Management.</h4><p><i>Treatment of manifestations:</i> High-dose oral supplementation of riboflavin (vitamin B<sub>2</sub>) between 10 mg and 50 mg/kg/day improves symptoms and signs on clinical examination, improves objective testing (vital capacity, brain stem evoked potentials, nerve conduction studies), and normalizes acylcarnitine levels. Liquid riboflavin is available but is often difficult to obtain; therefore, riboflavin capsules are often opened and mixed with food such as yogurt. The amount of riboflavin supplementation varies depending on the severity of the disease and response of the individual to the treatment. When riboflavin supplementation is given earlier in the disease course, the response can be very good; if given later in the disease course, the response is less, likely reflecting the effect of existing neuronal damage.</p><p>Because oral riboflavin supplementation is effective (and possibly lifesaving), it should begin as soon as a riboflavin transporter deficiency is suspected and continued lifelong unless <a class="def" href="/books/n/gene/glossary/def-item/molecular-genetic-testing/">molecular genetic testing</a> fails to identify <a class="def" href="/books/n/gene/glossary/def-item/biallelic/">biallelic</a> pathogenic variants in either <i>SLC52A2</i> or <i>SLC52A3</i>.</p><p>Supportive care includes respiratory support; physiotherapy to avoid contractures; occupational therapy to support activities of daily living; orthotics for limb and trunk bracing; speech and language therapy to avoid choking and respiratory problems; wheelchair as needed; low vision aids as needed; routine management of scoliosis to avoid long-term respiratory problems; and routine management of depression.</p><p><i>Surveillance:</i> At three months and six months after initiation of riboflavin supplementation, routine follow-up physical and neurologic examinations, measurement of blood riboflavin/FAD/FMN, and analysis of blood acylcarnitine profile. Thereafter, follow up is usually biannually in older individuals and more frequently in younger children.</p><p><i>Agents/circumstances to avoid:</i> Dietary restriction of riboflavin and strenuous physical activity.</p><p><i>Evaluation of relatives at risk:</i> When the <i>SLC52A2</i> or <i>SLC52A3</i> pathogenic variants in the family are known, it is appropriate to perform <a class="def" href="/books/n/gene/glossary/def-item/molecular-genetic-testing/">molecular genetic testing</a> on the older and younger sibs of an affected individual to identify as early as possible those who are affected and would benefit from early treatment with riboflavin supplementation and monitoring for potential complications of the disorder.</p><p><i>Pregnancy management:</i> A diet rich in ribolflavin is recommended for women who have RTD or are <a class="def" href="/books/n/gene/glossary/def-item/heterozygous/">heterozygous</a> for a <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a> in either <i>SLC52A2</i> or <i>SLC52A3.</i> If necessary, riboflavin supplements should be taken before and during pregnancy and when breast feeding to avoid inducing riboflavin deficiency in the baby.</p></div><div><h4 class="inline">Genetic counseling.</h4><p>RTD caused by <a class="def" href="/books/n/gene/glossary/def-item/biallelic/">biallelic</a> pathogenic variants in either <i>SLC52A2</i> (RTD2) or <i>SLC52A3</i> (RTD3) is inherited in an <a class="def" href="/books/n/gene/glossary/def-item/autosomal-recessive/">autosomal recessive</a> manner. If both parents are known to be <a class="def" href="/books/n/gene/glossary/def-item/heterozygous/">heterozygous</a> for an RTD-causing <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a>, each sib of an affected individual has at conception a 25% chance of inheriting biallelic pathogenic variants and being affected, a 50% chance of inheriting one pathogenic variant and being heterozygous, and a 25% chance of inheriting neither of the <a class="def" href="/books/n/gene/glossary/def-item/familial/">familial</a> RTD-causing pathogenic variants. Carrier testing for at-risk relatives and <a class="def" href="/books/n/gene/glossary/def-item/prenatal-testing/">prenatal testing</a> for a pregnancy at increased risk are possible if both RTD-causing pathogenic variants have been identified in an affected family member.</p></div></div><div id="riboflavin-tn.GeneReview_Scope"><h2 id="_riboflavin-tn_GeneReview_Scope_"><i>GeneReview</i> Scope</h2><p>Riboflavin transporter deficiency (RTD), comprising RTD2 and RTD3 (caused by <a class="def" href="/books/n/gene/glossary/def-item/biallelic/">biallelic</a> pathogenic variants in <i>SLC52A2</i> and <i>SLC52A3,</i> respectively<i>)</i> is a well-defined phenotypic continuum of motor, sensory, and cranial nerve neuronopathy that encompasses the previously recognized phenotypes Brown-Vialetto-Van Laere (BVVL) syndrome and Fazio-Londe syndrome [<a class="bk_pop" href="#riboflavin-tn.REF.green.2010.485">Green et al 2010</a>, <a class="bk_pop" href="#riboflavin-tn.REF.johnson.2010.567">Johnson et al 2010</a>, <a class="bk_pop" href="#riboflavin-tn.REF.johnson.2012.2875">Johnson et al 2012</a>, <a class="bk_pop" href="#riboflavin-tn.REF.foley.2014.44">Foley et al 2014</a>].</p><p>One case report (which requires additional confirmation) suggests that <a class="def" href="/books/n/gene/glossary/def-item/biallelic/">biallelic</a> expression of pathogenic variants in <i>SLC52A1</i> (i.e., RTD1) is associated with infantile onset of riboflavin-responsive seizures associated with hyperammonemia [<a class="bk_pop" href="#riboflavin-tn.REF.kang.2020.160">Kang et al 2020</a>].</p></div><div id="riboflavin-tn.Diagnosis"><h2 id="_riboflavin-tn_Diagnosis_">Diagnosis</h2><div id="riboflavin-tn.Suggestive_Findings"><h3>Suggestive Findings</h3><p><b>Riboflavin transporter deficiency 2 (RTD2)</b> and <b>riboflavin transporter deficiency 3 (RTD3)</b>
|
||
<b>should be suspected</b> in individuals with the following clinical, neurophysiologic, brain MRI, and laboratory findings.</p><p><b>Clinical features.</b> Progressive, usually childhood onset (range: a few months to early teen years; very rarely adulthood) of the following:</p><ul><li class="half_rhythm"><div><b>Cranial</b>
|
||
<b>neuronopathy</b></div><ul><li class="half_rhythm"><div>Very frequently affecting cranial nerves II (optic atrophy with bilateral symmetric optic nerve pallor, variably associated nystagmus) and VIII (sensorineural hearing loss is one of the initial findings)</div></li><li class="half_rhythm"><div>Frequently affecting cranial nerves IX and X (bulbar palsy), and XII (tongue fasciculations, weakness, and atrophy)</div></li><li class="half_rhythm"><div>Occasionally affecting cranial nerves III (ptosis) and VII (facial weakness)</div></li></ul></li><li class="half_rhythm"><div><b>Motor</b>
|
||
<b>neuropathy</b></div><ul><li class="half_rhythm"><div>Affecting upper limbs more than lower limbs, resulting in weakness involving proximal and distal limb musculature, often with severe distal wasting. Deep tendon reflexes are consistently absent</div></li><li class="half_rhythm"><div>Resulting in axial weakness, manifest as severe trunk and neck weakness requiring trunk bracing and difficulty with holding the head up</div></li><li class="half_rhythm"><div>Resulting in paralysis of the diaphragm, which can result in respiratory insufficiency</div></li></ul></li><li class="half_rhythm"><div><b>Sensory neuropathy</b> manifesting as gait ataxia</div></li></ul><p>Cognition is usually preserved.</p><p>
|
||
<b>Neurophysiologic studies</b>
|
||
</p><ul><li class="half_rhythm"><div>Electromyogram shows chronic partial denervation.</div></li><li class="half_rhythm"><div>Nerve conduction studies show a sensory > motor axonal neuronopathy. Motor nerve conduction velocities are usually normal.</div></li><li class="half_rhythm"><div>Sensory nerve action potentials are often absent.</div></li><li class="half_rhythm"><div>Visual evoked potentials are frequently abnormal.</div></li><li class="half_rhythm"><div>Brain stem audiometry evoked response has universally shown sensorineural deafness.</div></li><li class="half_rhythm"><div>EEG (electroencephalogram) may show an excess of theta activity or slow waves [<a class="bk_pop" href="#riboflavin-tn.REF.rosemberg.1982.84">Rosemberg et al 1982</a>].</div></li></ul><p><b>Brain MRI.</b> Usually normal; however, in a small number of affected individuals cerebellar atrophy and abnormal T<sub>2</sub>-weighted hyperintensity in the cerebellar, cortical, subcortical, and brain stem regions are observed.</p><p>
|
||
<b>Laboratory findings</b>
|
||
</p><ul><li class="half_rhythm"><div>Acylcarnitine profile in blood is abnormal with accumulation of short- and medium-chain (and sometimes long-chain) acylcarnitine in some but not all individuals with molecularly confirmed RTD [<a class="bk_pop" href="#riboflavin-tn.REF.bosch.2012.83">Bosch et al 2012</a>, <a class="bk_pop" href="#riboflavin-tn.REF.foley.2014.44">Foley et al 2014</a>].</div></li><li class="half_rhythm"><div>Note: Even in children with RTD diagnosed in the first months of life with abnormal acylcarnitine profiles, newborn screening bloodspots demonstrated normal acylcarnitine profiles, probably due to sufficient maternal riboflavin supply to the unborn infant [<a class="bk_pop" href="#riboflavin-tn.REF.bosch.2011.159">Bosch et al 2011</a>].</div></li></ul><p><b>Riboflavin transporter deficiency 1 should be considered</b> (based on preliminary observations) in an infant with recurrent seizures with unexplained hyperammonemia [<a class="bk_pop" href="#riboflavin-tn.REF.kang.2020.160">Kang et al 2020</a>].</p><p><b>As soon as riboflavin transporter deficiency is suspected, begin oral riboflavin supplementation,</b> an effective (and possibly lifesaving) treatment, and continue it lifelong unless <a class="def" href="/books/n/gene/glossary/def-item/molecular-genetic-testing/">molecular genetic testing</a> fails to identify <a class="def" href="/books/n/gene/glossary/def-item/biallelic/">biallelic</a> pathogenic variants in either <i>SLC52A2</i> or <i>SLC52A3</i>.</p></div><div id="riboflavin-tn.Establishing_the_Diagnosis"><h3>Establishing the Diagnosis</h3><p>The diagnosis of riboflavin transporter deficiency (RTD) <b>is established</b> in a <a class="def" href="/books/n/gene/glossary/def-item/proband/">proband</a> with suggestive clinical, neurophysiologic, neuroimaging, and laboratory findings and <a class="def" href="/books/n/gene/glossary/def-item/biallelic/">biallelic</a> pathogenic (or <a class="def" href="/books/n/gene/glossary/def-item/likely-pathogenic/">likely pathogenic</a>) variants in either <i>SLC52A2</i> (RTD2) or <i>SLC52A3</i> (RTD3) on <a class="def" href="/books/n/gene/glossary/def-item/molecular-genetic-testing/">molecular genetic testing</a> (<a href="/books/NBK299312/table/riboflavin-tn.T.molecular_genetic_testin/?report=objectonly" target="object" rid-ob="figobriboflavintnTmoleculargenetictestin">Table 1</a>).</p><p>Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variants" and "<a class="def" href="/books/n/gene/glossary/def-item/likely-pathogenic/">likely pathogenic</a> variants" are synonymous in a clinical setting, meaning that both are considered diagnostic and both can be used for clinical decision making [<a class="bk_pop" href="#riboflavin-tn.REF.richards.2015.405">Richards et al 2015</a>]. Reference to "pathogenic variants" in this section is understood to include any likely pathogenic variants. (2) Identification of either <a class="def" href="/books/n/gene/glossary/def-item/biallelic/">biallelic</a> <i>SLC52A2</i> or <i>SLC52A3</i> variants of <a class="def" href="/books/n/gene/glossary/def-item/uncertain-significance/">uncertain significance</a> (or of one known <i>SLC52A2</i> or <i>SLC52A3</i> <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a> and one <i>SLC52A2</i> or <i>SLC52A3</i> variant of uncertain significance) does not establish or rule out a diagnosis of the disorder. (3) In the only child reported to date with presumed RTD1, the complex <a class="def" href="/books/n/gene/glossary/def-item/genotype/">genotype</a> requires further investigation (see <a href="#riboflavin-tn.Molecular_Genetics">Molecular Genetics</a>).</p><p>Molecular genetic testing approaches can include a combination of <b><a class="def" href="/books/n/gene/glossary/def-item/gene/">gene</a>-targeted testing</b> (<a class="def" href="/books/n/gene/glossary/def-item/multigene-panel/">multigene panel</a>) and <b>comprehensive</b>
|
||
<b><a class="def" href="/books/n/gene/glossary/def-item/genomic/">genomic</a> testing</b> (<a class="def" href="/books/n/gene/glossary/def-item/exome-sequencing/">exome sequencing</a>, <a class="def" href="/books/n/gene/glossary/def-item/genome-sequencing/">genome sequencing</a>) depending on the <a class="def" href="/books/n/gene/glossary/def-item/phenotype/">phenotype</a>.</p><p>Gene-targeted testing requires that the clinician determine which <a class="def" href="/books/n/gene/glossary/def-item/gene/">gene</a>(s) are likely involved, whereas <a class="def" href="/books/n/gene/glossary/def-item/genomic/">genomic</a> testing does not. Individuals with the distinctive findings described in <a href="#riboflavin-tn.Suggestive_Findings">Suggestive Findings</a> are likely to be diagnosed using <a class="def" href="/books/n/gene/glossary/def-item/multigene-panel/">multigene panel</a> testing (see <a href="#riboflavin-tn.Option_1">Option 1</a>), whereas those in whom the diagnosis of RTD has not been considered are more likely to be diagnosed using genomic testing (see <a href="#riboflavin-tn.Option_2">Option 2</a>).</p><div id="riboflavin-tn.Option_1"><h4>Option 1</h4><p><b>Hearing loss panels, myopathy panels, motor neuron disease panels, inborn error of metabolism panels, neuropathy panels</b> and other multigene panels now include <i>SLC52A2</i> and <i>SLC52A3</i> along with other genes of interest (see <a href="#riboflavin-tn.Differential_Diagnosis">Differential Diagnosis</a>). Multigene panels are most likely to identify the genetic cause of the condition while limiting identification of variants of <a class="def" href="/books/n/gene/glossary/def-item/uncertain-significance/">uncertain significance</a> and pathogenic variants in genes that do not explain the underlying <a class="def" href="/books/n/gene/glossary/def-item/phenotype/">phenotype</a>. Note: (1) The genes included in the panel and the diagnostic <a class="def" href="/books/n/gene/glossary/def-item/sensitivity/">sensitivity</a> of the testing used for each <a class="def" href="/books/n/gene/glossary/def-item/gene/">gene</a> vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this <i>GeneReview</i>. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused <a class="def" href="/books/n/gene/glossary/def-item/exome/">exome</a> analysis that includes genes specified by the clinician. (4) Methods used in a panel may include <a class="def" href="/books/n/gene/glossary/def-item/sequence-analysis/">sequence analysis</a>, <a class="def" href="/books/n/gene/glossary/def-item/deletion-duplication-analysis/">deletion/duplication analysis</a>, and/or other non-sequencing-based tests.</p><p>For an introduction to multigene panels click <a href="/books/n/gene/app5/#app5.Multigene_Panels">here</a>. More detailed information for clinicians ordering genetic tests can be found <a href="/books/n/gene/app5/#app5.Multigene_Panels_FAQs">here</a>.</p></div><div id="riboflavin-tn.Option_2"><h4>Option 2</h4><p><b>Comprehensive</b>
|
||
<b><a class="def" href="/books/n/gene/glossary/def-item/genomic/">genomic</a> testing</b> does not require the clinician to determine which <a class="def" href="/books/n/gene/glossary/def-item/gene/">gene</a> is likely involved. <b>Exome sequencing</b> is most commonly used; <b><a class="def" href="/books/n/gene/glossary/def-item/genome-sequencing/">genome sequencing</a></b> is also possible.</p><p>For an introduction to comprehensive <a class="def" href="/books/n/gene/glossary/def-item/genomic/">genomic</a> testing click <a href="/books/n/gene/app5/#app5.Comprehensive_Genomic_Testing">here</a>. More detailed information for clinicians ordering genomic testing can be found <a href="/books/n/gene/app5/#app5.Comprehensive_Genomic_Testing_1">here</a>.</p><div id="riboflavin-tn.T.molecular_genetic_testin" class="table"><h3><span class="label">Table 1. </span></h3><div class="caption"><p>Molecular Genetic Testing Used in Riboflavin Transporter Deficiency (RTD)</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK299312/table/riboflavin-tn.T.molecular_genetic_testin/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__riboflavin-tn.T.molecular_genetic_testin_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_riboflavin-tn.T.molecular_genetic_testin_1_1_1_1" rowspan="2" scope="col" colspan="1" headers="hd_h_riboflavin-tn.T.molecular_genetic_testin_1_1_1_1" style="text-align:left;vertical-align:middle;">Gene <sup>1</sup></th><th id="hd_h_riboflavin-tn.T.molecular_genetic_testin_1_1_1_2" rowspan="2" scope="col" colspan="1" headers="hd_h_riboflavin-tn.T.molecular_genetic_testin_1_1_1_2" style="text-align:left;vertical-align:middle;">Proportion of RTD<br />Attributed to<br />Pathogenic<br />Variants in Gene <sup>2</sup></th><th id="hd_h_riboflavin-tn.T.molecular_genetic_testin_1_1_1_3" colspan="2" scope="colgroup" rowspan="1" style="text-align:left;vertical-align:middle;">Proportion of Probands with a Pathogenic Variant <sup>3</sup> Detectable by Method</th></tr><tr><th headers="hd_h_riboflavin-tn.T.molecular_genetic_testin_1_1_1_3" id="hd_h_riboflavin-tn.T.molecular_genetic_testin_1_1_2_1" colspan="1" scope="colgroup" rowspan="1" style="text-align:left;vertical-align:middle;">Sequence analysis <sup>4</sup></th><th headers="hd_h_riboflavin-tn.T.molecular_genetic_testin_1_1_1_3" id="hd_h_riboflavin-tn.T.molecular_genetic_testin_1_1_2_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Gene-targeted <a class="def" href="/books/n/gene/glossary/def-item/deletion-duplication-analysis/">deletion/duplication analysis</a> <sup>5</sup></th></tr></thead><tbody><tr><td headers="hd_h_riboflavin-tn.T.molecular_genetic_testin_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<i>SLC52A2</i>
|
||
</td><td headers="hd_h_riboflavin-tn.T.molecular_genetic_testin_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">~44%</td><td headers="hd_h_riboflavin-tn.T.molecular_genetic_testin_1_1_1_3 hd_h_riboflavin-tn.T.molecular_genetic_testin_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">60/60 probands <sup>7</sup></td><td headers="hd_h_riboflavin-tn.T.molecular_genetic_testin_1_1_1_3 hd_h_riboflavin-tn.T.molecular_genetic_testin_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">No large deletions/duplications <sup>8</sup></td></tr><tr><td headers="hd_h_riboflavin-tn.T.molecular_genetic_testin_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<i>SLC52A3</i>
|
||
</td><td headers="hd_h_riboflavin-tn.T.molecular_genetic_testin_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">~56%</td><td headers="hd_h_riboflavin-tn.T.molecular_genetic_testin_1_1_1_3 hd_h_riboflavin-tn.T.molecular_genetic_testin_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">76/76 probands <sup>9</sup></td><td headers="hd_h_riboflavin-tn.T.molecular_genetic_testin_1_1_1_3 hd_h_riboflavin-tn.T.molecular_genetic_testin_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">No large deletions/duplications <sup>8</sup></td></tr></tbody></table></div><div><div><dl class="temp-labeled-list small"><dt>1. </dt><dd><div id="riboflavin-tn.TF.1.1"><p class="no_margin">See <a href="/books/NBK299312/#riboflavin-tn.molgen.TA">Table A. Genes and Databases</a> for <a class="def" href="/books/n/gene/glossary/def-item/chromosome/">chromosome</a> <a class="def" href="/books/n/gene/glossary/def-item/locus/">locus</a> and protein.</p></div></dd><dt>2. </dt><dd><div id="riboflavin-tn.TF.1.2"><p class="no_margin"><a class="bk_pop" href="#riboflavin-tn.REF.abbas.2018.bcr2018224958">Abbas et al [2018]</a>, <a class="bk_pop" href="#riboflavin-tn.REF.bamaga.2018.938">Bamaga et al [2018]</a>, <a class="bk_pop" href="#riboflavin-tn.REF.garg.2018.471">Garg et al [2018]</a>, <a class="bk_pop" href="#riboflavin-tn.REF.gorcenco.2019.245">Gorcenco et al [2019]</a>, <a class="bk_pop" href="#riboflavin-tn.REF.mutlu.2019.201">Mutlu et al [2019]</a>, <a class="bk_pop" href="#riboflavin-tn.REF.ocallaghan.2019.598">O'Callaghan et al [2019]</a>, <a class="bk_pop" href="#riboflavin-tn.REF.shi.2019.76">Shi et al [2019]</a>, <a class="bk_pop" href="#riboflavin-tn.REF.carreau.2020">Carreau et al [2020]</a>, <a class="bk_pop" href="#riboflavin-tn.REF.kranthi.2020.1217">Kranthi et al [2020]</a>, <a class="bk_pop" href="#riboflavin-tn.REF.pillai.2020.2781">Pillai et al [2020]</a>, <a class="bk_pop" href="#riboflavin-tn.REF.rabbani.2020.342">Rabbani et al [2020]</a>, <a class="bk_pop" href="#riboflavin-tn.REF.gayathri.2021.945">Gayathri et al [2021]</a>, <a class="bk_pop" href="#riboflavin-tn.REF.khani.2021.102.e1">Khani et al [2021]</a></p></div></dd><dt>3. </dt><dd><div id="riboflavin-tn.TF.1.3"><p class="no_margin">See <a href="#riboflavin-tn.Molecular_Genetics">Molecular Genetics</a> for information on variants.</p></div></dd><dt>4. </dt><dd><div id="riboflavin-tn.TF.1.4"><p class="no_margin">Sequence analysis detects variants that are benign, <a class="def" href="/books/n/gene/glossary/def-item/likely-benign/">likely benign</a>, of <a class="def" href="/books/n/gene/glossary/def-item/uncertain-significance/">uncertain significance</a>, <a class="def" href="/books/n/gene/glossary/def-item/likely-pathogenic/">likely pathogenic</a>, or pathogenic. Variants may include small intragenic deletions/insertions and <a class="def" href="/books/n/gene/glossary/def-item/missense/">missense</a>, <a class="def" href="/books/n/gene/glossary/def-item/nonsense-variant/">nonsense</a>, and <a class="def" href="/books/n/gene/glossary/def-item/splice-site/">splice site</a> variants; typically, <a class="def" href="/books/n/gene/glossary/def-item/exon/">exon</a> or whole-<a class="def" href="/books/n/gene/glossary/def-item/gene/">gene</a> deletions/duplications are not detected. For issues to consider in interpretation of <a class="def" href="/books/n/gene/glossary/def-item/sequence-analysis/">sequence analysis</a> results, click <a href="/books/n/gene/app2/">here</a>.</p></div></dd><dt>5. </dt><dd><div id="riboflavin-tn.TF.1.5"><p class="no_margin">Gene-targeted <a class="def" href="/books/n/gene/glossary/def-item/deletion-duplication-analysis/">deletion/duplication analysis</a> detects intragenic deletions or duplications. Methods used may include a range of techniques such as <a class="def" href="/books/n/gene/glossary/def-item/quantitative-pcr/">quantitative PCR</a>, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and <a class="def" href="/books/n/gene/glossary/def-item/gene/">gene</a>-targeted microarray designed to detect single-<a class="def" href="/books/n/gene/glossary/def-item/exon/">exon</a> deletions or duplications.</p></div></dd><dt>6. </dt><dd><div id="riboflavin-tn.TF.1.6"><p class="no_margin">
|
||
<a class="bk_pop" href="#riboflavin-tn.REF.kang.2020.160">Kang et al [2020]</a>
|
||
</p></div></dd><dt>7. </dt><dd><div id="riboflavin-tn.TF.1.7"><p class="no_margin"><a class="bk_pop" href="#riboflavin-tn.REF.bamaga.2018.938">Bamaga et al [2018]</a>, <a class="bk_pop" href="#riboflavin-tn.REF.gorcenco.2019.245">Gorcenco et al [2019]</a>, <a class="bk_pop" href="#riboflavin-tn.REF.ocallaghan.2019.598">O'Callaghan et al [2019]</a>, <a class="bk_pop" href="#riboflavin-tn.REF.shi.2019.76">Shi et al [2019]</a>, <a class="bk_pop" href="#riboflavin-tn.REF.carreau.2020">Carreau et al [2020]</a>, <a class="bk_pop" href="#riboflavin-tn.REF.kranthi.2020.1217">Kranthi et al [2020]</a>, <a class="bk_pop" href="#riboflavin-tn.REF.pillai.2020.2781">Pillai et al [2020]</a></p></div></dd><dt>8. </dt><dd><div id="riboflavin-tn.TF.1.8"><p class="no_margin">No large deletions/duplications have been identified using <a class="def" href="/books/n/gene/glossary/def-item/chromosome/">chromosome</a> microarray analysis (CMA) [<a class="bk_pop" href="#riboflavin-tn.REF.amir.2020.283">Amir et al 2020</a>].</p></div></dd><dt>9. </dt><dd><div id="riboflavin-tn.TF.1.9"><p class="no_margin"><a class="bk_pop" href="#riboflavin-tn.REF.abbas.2018.bcr2018224958">Abbas et al [2018]</a>, <a class="bk_pop" href="#riboflavin-tn.REF.garg.2018.471">Garg et al [2018]</a>, <a class="bk_pop" href="#riboflavin-tn.REF.mutlu.2019.201">Mutlu et al [2019]</a>, <a class="bk_pop" href="#riboflavin-tn.REF.ocallaghan.2019.598">O'Callaghan et al [2019]</a>, <a class="bk_pop" href="#riboflavin-tn.REF.carreau.2020">Carreau et al [2020]</a>, <a class="bk_pop" href="#riboflavin-tn.REF.rabbani.2020.342">Rabbani et al [2020]</a>, <a class="bk_pop" href="#riboflavin-tn.REF.gayathri.2021.945">Gayathri et al [2021]</a>, <a class="bk_pop" href="#riboflavin-tn.REF.khani.2021.102.e1">Khani et al [2021]</a></p></div></dd></dl></div></div></div></div></div></div><div id="riboflavin-tn.Clinical_Characteristics"><h2 id="_riboflavin-tn_Clinical_Characteristics_">Clinical Characteristics</h2><div id="riboflavin-tn.Clinical_Description"><h3>Clinical Description</h3><p>Riboflavin transporter deficiency 2 (caused by <a class="def" href="/books/n/gene/glossary/def-item/biallelic/">biallelic</a> <i>SLC52A2</i> pathogenic variants) and riboflavin transporter deficiency 3 (caused by biallelic <i>SLC52A3</i> pathogenic variants) are clinically characterized by motor neuropathy, sensory neuropathy, and cranial neuronopathy [<a class="bk_pop" href="#riboflavin-tn.REF.bandettini_di_poggio.2014.141">Bandettini Di Poggio et al 2014</a>, <a class="bk_pop" href="#riboflavin-tn.REF.foley.2014.44">Foley et al 2014</a>, <a class="bk_pop" href="#riboflavin-tn.REF.manole.2014.506">Manole et al 2014</a>]. Motor neuropathy manifests as proximal and distal limb weakness (often with severe distal wasting and breathing problems due to paralysis of the diaphragm), sensory neuropathy as gait ataxia, and cranial neuronopathy as optic atrophy, sensorineural hearing loss, and bulbar palsy.</p><p>In contrast, RTD1 (possibly caused by <a class="def" href="/books/n/gene/glossary/def-item/biallelic/">biallelic</a> <i>SLC52A1</i> pathogenic variants), reported in a single case report, may manifest in infancy as generalized or focal tonic-clonic seizures, metabolic acidosis, and hyperammonemia, responsive to riboflavin supplementation [<a class="bk_pop" href="#riboflavin-tn.REF.kang.2020.160">Kang et al 2020</a>].</p><div id="riboflavin-tn.Riboflavin_De_ciency_2_and"><h4>Riboflavin Deficiency 2 and 3</h4><p>While most individuals with RTD2 or RTD3 (caused by <a class="def" href="/books/n/gene/glossary/def-item/biallelic/">biallelic</a> pathogenic variants in <i>SLC52A2</i> or <i>SLC52A3</i>, respectively) present early in life, late onset (ages 10-30 years) has been reported in persons with RTD3. Males and females are equally affected. <a href="/books/NBK299312/table/riboflavin-tn.T.riboflavin_transporter_d/?report=objectonly" target="object" rid-ob="figobriboflavintnTriboflavintransporterd">Table 2</a> summarizes the frequency of select features in 136 individuals with molecularly confirmed RTD2 and RTD3.</p><div id="riboflavin-tn.T.riboflavin_transporter_d" class="table"><h3><span class="label">Table 2. </span></h3><div class="caption"><p>Riboflavin Transporter Deficiency 2 and 3: Select Features</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK299312/table/riboflavin-tn.T.riboflavin_transporter_d/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__riboflavin-tn.T.riboflavin_transporter_d_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_riboflavin-tn.T.riboflavin_transporter_d_1_1_1_1" rowspan="2" colspan="2" scope="colgroup" headers="hd_h_riboflavin-tn.T.riboflavin_transporter_d_1_1_1_1" style="text-align:left;vertical-align:middle;">Feature</th><th id="hd_h_riboflavin-tn.T.riboflavin_transporter_d_1_1_1_2" colspan="3" scope="colgroup" rowspan="1" style="text-align:center;vertical-align:middle;">% of Persons w/Feature</th></tr><tr><th headers="hd_h_riboflavin-tn.T.riboflavin_transporter_d_1_1_1_2" id="hd_h_riboflavin-tn.T.riboflavin_transporter_d_1_1_2_1" colspan="1" scope="colgroup" rowspan="1" style="text-align:left;vertical-align:middle;">RTD2 (n=60)</th><th headers="hd_h_riboflavin-tn.T.riboflavin_transporter_d_1_1_1_2" id="hd_h_riboflavin-tn.T.riboflavin_transporter_d_1_1_2_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">RTD3 (n=76)</th><th headers="hd_h_riboflavin-tn.T.riboflavin_transporter_d_1_1_1_2" id="hd_h_riboflavin-tn.T.riboflavin_transporter_d_1_1_2_3" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">RTD2 & RTD3 (n=136)</th></tr></thead><tbody><tr><td headers="hd_h_riboflavin-tn.T.riboflavin_transporter_d_1_1_1_1" colspan="2" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Age of onset</b>
|
||
</td><td headers="hd_h_riboflavin-tn.T.riboflavin_transporter_d_1_1_1_2 hd_h_riboflavin-tn.T.riboflavin_transporter_d_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Mean 3.2 yrs</td><td headers="hd_h_riboflavin-tn.T.riboflavin_transporter_d_1_1_1_2 hd_h_riboflavin-tn.T.riboflavin_transporter_d_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Mean 8.5 yrs</td><td headers="hd_h_riboflavin-tn.T.riboflavin_transporter_d_1_1_1_2 hd_h_riboflavin-tn.T.riboflavin_transporter_d_1_1_2_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr><tr><td headers="hd_h_riboflavin-tn.T.riboflavin_transporter_d_1_1_1_1" colspan="2" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Peripheral neuropathy</b>
|
||
</td><td headers="hd_h_riboflavin-tn.T.riboflavin_transporter_d_1_1_1_2 hd_h_riboflavin-tn.T.riboflavin_transporter_d_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">92%</td><td headers="hd_h_riboflavin-tn.T.riboflavin_transporter_d_1_1_1_2 hd_h_riboflavin-tn.T.riboflavin_transporter_d_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">84%</td><td headers="hd_h_riboflavin-tn.T.riboflavin_transporter_d_1_1_1_2 hd_h_riboflavin-tn.T.riboflavin_transporter_d_1_1_2_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">80%-90%</td></tr><tr><td headers="hd_h_riboflavin-tn.T.riboflavin_transporter_d_1_1_1_1" colspan="2" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Motor neuropathy (weakness, hypotonia)</b>
|
||
</td><td headers="hd_h_riboflavin-tn.T.riboflavin_transporter_d_1_1_1_2 hd_h_riboflavin-tn.T.riboflavin_transporter_d_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">77%</td><td headers="hd_h_riboflavin-tn.T.riboflavin_transporter_d_1_1_1_2 hd_h_riboflavin-tn.T.riboflavin_transporter_d_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">80%</td><td headers="hd_h_riboflavin-tn.T.riboflavin_transporter_d_1_1_1_2 hd_h_riboflavin-tn.T.riboflavin_transporter_d_1_1_2_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">80%</td></tr><tr><td headers="hd_h_riboflavin-tn.T.riboflavin_transporter_d_1_1_1_1" colspan="2" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Sensory neuropathy (gait abnormality, ataxia)</b>
|
||
</td><td headers="hd_h_riboflavin-tn.T.riboflavin_transporter_d_1_1_1_2 hd_h_riboflavin-tn.T.riboflavin_transporter_d_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">60%</td><td headers="hd_h_riboflavin-tn.T.riboflavin_transporter_d_1_1_1_2 hd_h_riboflavin-tn.T.riboflavin_transporter_d_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">13%</td><td headers="hd_h_riboflavin-tn.T.riboflavin_transporter_d_1_1_1_2 hd_h_riboflavin-tn.T.riboflavin_transporter_d_1_1_2_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">34%</td></tr><tr><td headers="hd_h_riboflavin-tn.T.riboflavin_transporter_d_1_1_1_1" rowspan="4" scope="row" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Cranial neuronopathy</b>
|
||
</td><td headers="hd_h_riboflavin-tn.T.riboflavin_transporter_d_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Optic nerve atrophy / ophthalmoplegia</b>
|
||
</td><td headers="hd_h_riboflavin-tn.T.riboflavin_transporter_d_1_1_1_2 hd_h_riboflavin-tn.T.riboflavin_transporter_d_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">43%</td><td headers="hd_h_riboflavin-tn.T.riboflavin_transporter_d_1_1_1_2 hd_h_riboflavin-tn.T.riboflavin_transporter_d_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">19%</td><td headers="hd_h_riboflavin-tn.T.riboflavin_transporter_d_1_1_1_2 hd_h_riboflavin-tn.T.riboflavin_transporter_d_1_1_2_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr><tr><td headers="hd_h_riboflavin-tn.T.riboflavin_transporter_d_1_1_1_1" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Facial weakness</b>
|
||
</td><td headers="hd_h_riboflavin-tn.T.riboflavin_transporter_d_1_1_1_2 hd_h_riboflavin-tn.T.riboflavin_transporter_d_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">34%</td><td headers="hd_h_riboflavin-tn.T.riboflavin_transporter_d_1_1_1_2 hd_h_riboflavin-tn.T.riboflavin_transporter_d_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">55%</td><td headers="hd_h_riboflavin-tn.T.riboflavin_transporter_d_1_1_1_2 hd_h_riboflavin-tn.T.riboflavin_transporter_d_1_1_2_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr><tr><td headers="hd_h_riboflavin-tn.T.riboflavin_transporter_d_1_1_1_1" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Hearing loss</b>
|
||
</td><td headers="hd_h_riboflavin-tn.T.riboflavin_transporter_d_1_1_1_2 hd_h_riboflavin-tn.T.riboflavin_transporter_d_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">85%</td><td headers="hd_h_riboflavin-tn.T.riboflavin_transporter_d_1_1_1_2 hd_h_riboflavin-tn.T.riboflavin_transporter_d_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">82%</td><td headers="hd_h_riboflavin-tn.T.riboflavin_transporter_d_1_1_1_2 hd_h_riboflavin-tn.T.riboflavin_transporter_d_1_1_2_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr><tr><td headers="hd_h_riboflavin-tn.T.riboflavin_transporter_d_1_1_1_1" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Bulbar palsy</b>
|
||
</td><td headers="hd_h_riboflavin-tn.T.riboflavin_transporter_d_1_1_1_2 hd_h_riboflavin-tn.T.riboflavin_transporter_d_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">55%</td><td headers="hd_h_riboflavin-tn.T.riboflavin_transporter_d_1_1_1_2 hd_h_riboflavin-tn.T.riboflavin_transporter_d_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">62%</td><td headers="hd_h_riboflavin-tn.T.riboflavin_transporter_d_1_1_1_2 hd_h_riboflavin-tn.T.riboflavin_transporter_d_1_1_2_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr><tr><td headers="hd_h_riboflavin-tn.T.riboflavin_transporter_d_1_1_1_1" colspan="2" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Respiratory involvement</b>
|
||
</td><td headers="hd_h_riboflavin-tn.T.riboflavin_transporter_d_1_1_1_2 hd_h_riboflavin-tn.T.riboflavin_transporter_d_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">48%</td><td headers="hd_h_riboflavin-tn.T.riboflavin_transporter_d_1_1_1_2 hd_h_riboflavin-tn.T.riboflavin_transporter_d_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">57%</td><td headers="hd_h_riboflavin-tn.T.riboflavin_transporter_d_1_1_1_2 hd_h_riboflavin-tn.T.riboflavin_transporter_d_1_1_2_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr><tr><td headers="hd_h_riboflavin-tn.T.riboflavin_transporter_d_1_1_1_1" colspan="2" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Feeding difficulties</b>
|
||
</td><td headers="hd_h_riboflavin-tn.T.riboflavin_transporter_d_1_1_1_2 hd_h_riboflavin-tn.T.riboflavin_transporter_d_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">23%</td><td headers="hd_h_riboflavin-tn.T.riboflavin_transporter_d_1_1_1_2 hd_h_riboflavin-tn.T.riboflavin_transporter_d_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">41%</td><td headers="hd_h_riboflavin-tn.T.riboflavin_transporter_d_1_1_1_2 hd_h_riboflavin-tn.T.riboflavin_transporter_d_1_1_2_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr><tr><td headers="hd_h_riboflavin-tn.T.riboflavin_transporter_d_1_1_1_1" colspan="2" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Abnormal cranial MRI</b>
|
||
</td><td headers="hd_h_riboflavin-tn.T.riboflavin_transporter_d_1_1_1_2 hd_h_riboflavin-tn.T.riboflavin_transporter_d_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">19% (7/37)</td><td headers="hd_h_riboflavin-tn.T.riboflavin_transporter_d_1_1_1_2 hd_h_riboflavin-tn.T.riboflavin_transporter_d_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">22% (13/60)</td><td headers="hd_h_riboflavin-tn.T.riboflavin_transporter_d_1_1_1_2 hd_h_riboflavin-tn.T.riboflavin_transporter_d_1_1_2_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr></tbody></table></div><div><div><dl class="temp-labeled-list small"><dt></dt><dd><div><p class="no_margin">Based on <a class="bk_pop" href="#riboflavin-tn.REF.ocallaghan.2019.598">O'Callaghan et al [2019]</a></p></div></dd><dt></dt><dd><div><p class="no_margin">RTD2 = riboflavin transporter deficiency caused by <a class="def" href="/books/n/gene/glossary/def-item/biallelic/">biallelic</a> <i>SLC52A2</i> pathogenic variants; RTD3 = riboflavin transporter deficiency caused by biallelic <i>SLC52A3</i> pathogenic variants</p></div></dd></dl></div></div></div><p>The <a class="def" href="/books/n/gene/glossary/def-item/phenotype/">phenotype</a> of individuals with riboflavin deficiency 2 and 3 at onset usually includes hearing impairment and/or sensory ataxia, followed by progressive upper limb weakness, optic atrophy, bulbar weakness, and respiratory failure.The time between the disease onset and the development of other manifestations varies but is usually one to two years. In some individuals an intercurrent event, usually an injury or infection, appears to precipitate the initial manifestations or worsen existing findings [<a class="bk_pop" href="#riboflavin-tn.REF.bandettini_di_poggio.2014.141">Bandettini Di Poggio et al 2014</a>].</p><p>Note: When the onset occurs in infancy, after a symptom-free first few weeks (or in some cases months) of life, infants become floppy with failure to thrive and rapidly developing respiratory insufficiency due to paralysis of the diaphragm, followed (in order of appearance) by:</p><ul><li class="half_rhythm"><div>Infantile- or early childhood-onset nystagmus</div></li><li class="half_rhythm"><div>Early childhood-onset sensory (gait) ataxia</div></li><li class="half_rhythm"><div>Early-childhood onset progressive and severe sensorineural hearing loss</div></li><li class="half_rhythm"><div>Weakness and atrophy of the upper limbs (first distally then proximally)</div></li><li class="half_rhythm"><div>Weakness of neck extensors and later trunk muscles</div></li><li class="half_rhythm"><div>Tongue fasciculations and atrophy with increased swallowing problems</div></li><li class="half_rhythm"><div>Respiratory insufficiency due to muscle weakness</div></li></ul><p>Other initial presenting features can include stridor, slurring of speech, and facial weakness. Visual problems due to optic atrophy are common [<a class="bk_pop" href="#riboflavin-tn.REF.bandettini_di_poggio.2014.141">Bandettini Di Poggio et al 2014</a>, <a class="bk_pop" href="#riboflavin-tn.REF.foley.2014.44">Foley et al 2014</a>, <a class="bk_pop" href="#riboflavin-tn.REF.manole.2014.506">Manole et al 2014</a>, <a class="bk_pop" href="#riboflavin-tn.REF.srour.2014.775">Srour et al 2014</a>, <a class="bk_pop" href="#riboflavin-tn.REF.bamaga.2018.938">Bamaga et al 2018</a>, <a class="bk_pop" href="#riboflavin-tn.REF.amir.2020.283">Amir et al 2020</a>, <a class="bk_pop" href="#riboflavin-tn.REF.kranthi.2020.1217">Kranthi et al 2020</a>].</p><p><b>Motor neuropathy</b> has been described in 80% of affected individuals. Limb weakness is frequently accompanied by atrophy and involves the upper extremities more than the lower extremities in RTD2. Many also developed axial weakness, with severe weakness of neck extensor and trunk muscles.</p><p>Electrophysiologic studies, when performed, were suggestive of peripheral neuropathy in most individuals with RTD, showing chronic denervation and anterior horn dysfunction. Nerve conduction studies suggest an axonal rather than demyelinating neuropathy.</p><p><b>Sensory neuropathy</b> was reported in 34% of individuals. However, most individuals with gait abnormalities/ataxia had RTD2, while only 13% of those with RTD3 had sensory symptoms. Vibration and proprioception are the most severely affected.</p><p><b>Ophthalmologic involvement,</b> the result of optic nerve atrophy, usually manifests as reduced visual acuity and visual field impairment; a few individuals also experience color blindness. Vision loss can progress rapidly or slowly [<a class="bk_pop" href="#riboflavin-tn.REF.bamaga.2018.938">Bamaga et al 2018</a>, <a class="bk_pop" href="#riboflavin-tn.REF.gorcenco.2019.245">Gorcenco et al 2019</a>, <a class="bk_pop" href="#riboflavin-tn.REF.kranthi.2020.1217">Kranthi et al 2020</a>].</p><p>When present, torsional/horizontal nystagmus is one of the early signs of optic atrophy prior to vision loss; thus, RTD should be considered in children with new-onset nystagmus [<a class="bk_pop" href="#riboflavin-tn.REF.amir.2020.283">Amir et al 2020</a>].</p><p><b>Facial weakness.</b> Fifty-five per cent of individuals with RTD3 presented with facial weakness caused by degeneration of cranial nerve VII; this feature was rarely observed in RTD2.</p><p><b>Hearing loss,</b> a presenting manifestation in many individuals, falls within the auditory neuropathy spectrum disorder (ANSD) and is a consequence of cranial nerve VIII degeneration. Otoacoustic emissions (OAE) are usually present while auditory brain stem reflexes (ABR) are abnormal or absent. The hearing loss is usually progressive and severe and can result in complete bilateral deafness (hearing loss >81 decibels). The time between the onset of ANSD and the development of other manifestations of RTD varies but is usually one to two years. Very rarely affected individuals do not develop any hearing impairment, and sometimes it appears later in the disease course [<a class="bk_pop" href="#riboflavin-tn.REF.anderson.2019.31">Anderson et al 2019</a>, <a class="bk_pop" href="#riboflavin-tn.REF.mutlu.2019.201">Mutlu et al 2019</a>, <a class="bk_pop" href="#riboflavin-tn.REF.amir.2020.283">Amir et al 2020</a>].</p><p><b>Bulbar palsy.</b> Signs and symptoms of bulbar palsy are common, being reported in more than 50% of individuals. Most individuals report dysarthria and feeding difficulties resulting from dysphagia. Tongue wasting/fasciculations are common on neurologic examination.</p><p><b>Respiratory involvement,</b> a consequence of neurogenic diaphragm paralysis, is often an early manifestation. Many affected individuals present with breath-holding spells within the first year of the disease course. Therefore, respiratory insufficiency, secondary to muscle weakness, can also be one of the late manifestations of untreated RTD. Artificial respiratory support may be required.</p><p>Other features variably seen:</p><ul><li class="half_rhythm"><div><b>Epilepsy.</b> Some affected individuals had a single seizure-like episode that resolved before the diagnosis of RTD was established and before beginning treatment with riboflavin [<a class="bk_pop" href="#riboflavin-tn.REF.pillai.2020.2781">Pillai et al 2020</a>, <a class="bk_pop" href="#riboflavin-tn.REF.rabbani.2020.342">Rabbani et al 2020</a>].</div></li><li class="half_rhythm"><div><b>Progressive mental and motor</b>
|
||
<b>regression</b> [<a class="bk_pop" href="#riboflavin-tn.REF.shi.2019.76">Shi et al 2019</a>, <a class="bk_pop" href="#riboflavin-tn.REF.pillai.2020.2781">Pillai et al 2020</a>]</div></li><li class="half_rhythm"><div><b>Anemia.</b> Although two individuals had riboflavin-responsive severe macrocytic anemia, riboflavin deficiency had been previously associated with mild-moderate anemia [<a class="bk_pop" href="#riboflavin-tn.REF.amir.2020.283">Amir et al 2020</a>, <a class="bk_pop" href="#riboflavin-tn.REF.pillai.2020.2781">Pillai et al 2020</a>].</div></li><li class="half_rhythm"><div><b>Depression.</b> To date, only associated with RTD3 [<a class="bk_pop" href="#riboflavin-tn.REF.rabbani.2020.342">Rabbani et al 2020</a>, <a class="bk_pop" href="#riboflavin-tn.REF.khani.2021.102.e1">Khani et al 2021</a>]</div></li></ul><p>While the RTD2 and RTD3 phenotypes are difficult to differentiate, in RTD2 early-onset weakness in the upper limbs and neck is almost invariable, in contrast to RTD3 or genetically unclassified Brown-Vialetto-Van Laere (BVVL) syndrome, in which the onset of weakness is often more generalized [<a class="bk_pop" href="#riboflavin-tn.REF.green.2010.485">Green et al 2010</a>, <a class="bk_pop" href="#riboflavin-tn.REF.bosch.2011.159">Bosch et al 2011</a>, <a class="bk_pop" href="#riboflavin-tn.REF.bosch.2012.83">Bosch et al 2012</a>, <a class="bk_pop" href="#riboflavin-tn.REF.foley.2014.44">Foley et al 2014</a>].</p><p><b>Life expectancy.</b> Untreated, most infants diagnosed with RTD rapidly become ventilator dependent (often for some years at home or in intensive care units) and most die before age 12 years [<a class="bk_pop" href="#riboflavin-tn.REF.bandettini_di_poggio.2014.141">Bandettini Di Poggio et al 2014</a>, <a class="bk_pop" href="#riboflavin-tn.REF.foley.2014.44">Foley et al 2014</a>, <a class="bk_pop" href="#riboflavin-tn.REF.manole.2014.506">Manole et al 2014</a>].</p><p>Previous data suggest that in 70% of individuals receiving riboflavin supplementation, muscle strength, motor abilities, respiratory function, and cranial nerve deficits improve [<a class="bk_pop" href="#riboflavin-tn.REF.ocallaghan.2019.598">O'Callaghan et al 2019</a>]. Death was reported in some individuals if the treatment was discontinued or started too late in the disease course [<a class="bk_pop" href="#riboflavin-tn.REF.jaeger.2016.559">Jaeger & Bosch 2016</a>].</p><p>With improved disease management and riboflavin treatment (see <a href="#riboflavin-tn.Management">Management</a>), life span is likely to increase; however, the experience with riboflavin supplementation has only been since 2010 [<a class="bk_pop" href="#riboflavin-tn.REF.bosch.2011.159">Bosch et al 2011</a>, <a class="bk_pop" href="#riboflavin-tn.REF.horvath.2012.679">Horvath 2012</a>, <a class="bk_pop" href="#riboflavin-tn.REF.bandettini_di_poggio.2014.141">Bandettini Di Poggio et al 2014</a>, <a class="bk_pop" href="#riboflavin-tn.REF.foley.2014.44">Foley et al 2014</a>, <a class="bk_pop" href="#riboflavin-tn.REF.manole.2014.506">Manole et al 2014</a>].</p><p><b>Pathology.</b> Few pathologic descriptions are available. Sural nerve biopsies in individuals with RTD2 and RTD3 previously showed axonal neuropathy and degeneration. In one study, clinical manifestations and MRI findings supported neuronal loss and degeneration in cranial nerve nuclei and tracts and in the brain stem, cerebellum, and spinal cord of individuals with RTD3 [<a class="bk_pop" href="#riboflavin-tn.REF.ocallaghan.2019.598">O'Callaghan et al 2019</a>].</p></div></div><div id="riboflavin-tn.GenotypePhenotype_Correlat"><h3>Genotype-Phenotype Correlations</h3><p>See <a href="/books/NBK299312/table/riboflavin-tn.T.riboflavin_transporter_d/?report=objectonly" target="object" rid-ob="figobriboflavintnTriboflavintransporterd">Table 2</a> for a comparison of select clinical findings by <a class="def" href="/books/n/gene/glossary/def-item/gene/">gene</a>.</p></div><div id="riboflavin-tn.Nomenclature"><h3>Nomenclature</h3><p>Other terms used to refer to riboflavin transporter deficiency:</p><ul><li class="half_rhythm"><div>Brown-Vialetto-Van Laere (BVVL) syndrome (corresponding with either <i>SLC52A3-</i> or <i>SLC52A2</i>-related disease) and Fazio-Londe syndrome (a BVVL-like syndrome without deafness caused by <i>SLC52A3</i> pathogenic variants)</div></li><li class="half_rhythm"><div><i>SLC52A2</i>-related riboflavin transporter deficiency may be referred to as spinocerebellar ataxia with blindness and deafness type 2 (SCABD2)[<a class="bk_pop" href="#riboflavin-tn.REF.babanejad.2018.195">Babanejad et al 2018</a>].</div></li></ul></div><div id="riboflavin-tn.Prevalence"><h3>Prevalence</h3><p>Although riboflavin transporter deficiency (RTD) is relatively rare, the advent of <a class="def" href="/books/n/gene/glossary/def-item/molecular-genetic-testing/">molecular genetic testing</a> has improved diagnostic capabilities, making RTD appear more prevalent than previously thought [<a class="bk_pop" href="#riboflavin-tn.REF.foley.2014.44">Foley et al 2014</a>].</p><p>It is difficult to establish the prevalence of RTD. It may be underdiagnosed and misdiagnosed; however, it is estimated that RTD affects one in 1,000,000 people in the general population.</p><p><b><i>SLC52A2.</i></b> The founder <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a> <a href="/books/NBK299312/table/riboflavin-tn.T.riboflavin_transporter_d_2/?report=objectonly" target="object" rid-ob="figobriboflavintnTriboflavintransporterd2">c.916G>A;p.Gly306Arg</a> has been described in the Lebanese population [<a class="bk_pop" href="#riboflavin-tn.REF.foley.2014.44">Foley et al 2014</a>, <a class="bk_pop" href="#riboflavin-tn.REF.srour.2014.775">Srour et al 2014</a>].</p><p><b><i>SLC52A3.</i></b> No founder variants have been reported.</p></div></div><div id="riboflavin-tn.Genetically_Related_Alleli"><h2 id="_riboflavin-tn_Genetically_Related_Alleli_">Genetically Related (Allelic) Disorders</h2><p>No phenotypes other than those discussed in this <i>GeneReview</i> are known (or presumed) to be associated with <a class="def" href="/books/n/gene/glossary/def-item/biallelic/">biallelic</a> <a class="def" href="/books/n/gene/glossary/def-item/germline/">germline</a> pathogenic variants in <i>SLC52A1</i>, <i>SLC52A2,</i> or <i>SLC52A3</i>.</p><p>Sporadic tumors (including esophageal squamous cell carcinomas) occurring as single tumors in the absence of any other findings of riboflavin transporter deficiency frequently harbor somatic pathogenic variants in <i>SLC52A3</i> that are <b>not</b> present in the <a class="def" href="/books/n/gene/glossary/def-item/germline/">germline</a>; thus, predisposition to these tumors is not heritable.</p></div><div id="riboflavin-tn.Differential_Diagnosis"><h2 id="_riboflavin-tn_Differential_Diagnosis_">Differential Diagnosis</h2><div id="riboflavin-tn.T.genes_and_disorders_of_i" class="table"><h3><span class="label">Table 3. </span></h3><div class="caption"><p>Genes and Disorders of Interest in the Differential Diagnosis of Riboflavin Transporter Deficiency</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK299312/table/riboflavin-tn.T.genes_and_disorders_of_i/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__riboflavin-tn.T.genes_and_disorders_of_i_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_riboflavin-tn.T.genes_and_disorders_of_i_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Gene(s)</th><th id="hd_h_riboflavin-tn.T.genes_and_disorders_of_i_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Disorder</th><th id="hd_h_riboflavin-tn.T.genes_and_disorders_of_i_1_1_1_3" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">MOI</th><th id="hd_h_riboflavin-tn.T.genes_and_disorders_of_i_1_1_1_4" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Clinical Features</th><th id="hd_h_riboflavin-tn.T.genes_and_disorders_of_i_1_1_1_5" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Distinguishing Features</th></tr></thead><tbody><tr><td headers="hd_h_riboflavin-tn.T.genes_and_disorders_of_i_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<i>AAAS</i>
|
||
</td><td headers="hd_h_riboflavin-tn.T.genes_and_disorders_of_i_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Achalasia-addisonianism-alacrimia syndrome (AAAS) (OMIM <a href="https://omim.org/entry/231550" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">231550</a>)</td><td headers="hd_h_riboflavin-tn.T.genes_and_disorders_of_i_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">AR</td><td headers="hd_h_riboflavin-tn.T.genes_and_disorders_of_i_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Prominent bulbar features; however, achalasia, alacrimia, adrenal problems & autonomic symptoms are the primary manifestations. <sup>1</sup></td><td headers="hd_h_riboflavin-tn.T.genes_and_disorders_of_i_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Persons w/AAAS have an abnormal, small fissured tongue similar to that in ALS. <sup>2</sup></td></tr><tr><td headers="hd_h_riboflavin-tn.T.genes_and_disorders_of_i_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<i>BSCL2</i>
|
||
<br />
|
||
<i>GARS1</i>
|
||
</td><td headers="hd_h_riboflavin-tn.T.genes_and_disorders_of_i_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><a href="/books/n/gene/spg17/"><i>BSCL2</i></a>- or <a href="/books/n/gene/cmt2d/"><i>GARS1</i></a>-related distal hereditary motor neuropathy (HMN)</td><td headers="hd_h_riboflavin-tn.T.genes_and_disorders_of_i_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">AD</td><td headers="hd_h_riboflavin-tn.T.genes_and_disorders_of_i_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Axonal neuropathy w/upper limb-predominant involvement</td><td headers="hd_h_riboflavin-tn.T.genes_and_disorders_of_i_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><i>BSCL2</i>- & <i>GARS1</i>-related distal HMN are not assoc w/optic atrophy, hearing loss, or bulbar dysfunction. <sup>3</sup></td></tr><tr><td headers="hd_h_riboflavin-tn.T.genes_and_disorders_of_i_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><a href="/books/n/gene/als-ftd/"><i>C9orf72</i></a><br /><i>FUS</i><br /><i>SOD1</i><br /><a href="/books/n/gene/tardbp-als/"><i>TARDBP</i></a><br /><i>UBQLN2</i> <sup>4</sup><br />(~30 genes <sup>5</sup>)</td><td headers="hd_h_riboflavin-tn.T.genes_and_disorders_of_i_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><a href="/books/n/gene/als-overview/">Amyotrophic lateral sclerosis</a> (ALS)</td><td headers="hd_h_riboflavin-tn.T.genes_and_disorders_of_i_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">AD<br />AR<br />XL <sup>6</sup></td><td headers="hd_h_riboflavin-tn.T.genes_and_disorders_of_i_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<p>Progressive, fatal, neurodegenerative disease involving both brain & spinal cord. Death most often results from failure of respiratory muscles. RTD has been described as an AR juvenile form of ALS since both RTD & ALS have bulbar & LMN involvement.</p>
|
||
</td><td headers="hd_h_riboflavin-tn.T.genes_and_disorders_of_i_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">ALS features that differentiate it from RTD: absence of hearing loss, less prominent bulbar presentations, later onset, asymmetric early presentations, & usually more rapid progression <sup>7</sup></td></tr><tr><td headers="hd_h_riboflavin-tn.T.genes_and_disorders_of_i_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<i>ETFA</i>
|
||
<br />
|
||
<i>ETFB</i>
|
||
<br />
|
||
<i>ETFDH</i>
|
||
</td><td headers="hd_h_riboflavin-tn.T.genes_and_disorders_of_i_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Neonatal-onset <a href="/books/n/gene/madd/">multiple acyl-CoA dehydrogenase deficiency</a> (MADD)</td><td headers="hd_h_riboflavin-tn.T.genes_and_disorders_of_i_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">AR</td><td headers="hd_h_riboflavin-tn.T.genes_and_disorders_of_i_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Usually fatal; severe hypoketotic hypoglycemia, metabolic acidosis, multisystem involvement, & excretion of large amts of fatty acid- & amino acid-derived metabolites (biochemical profile similar to RTD)</td><td headers="hd_h_riboflavin-tn.T.genes_and_disorders_of_i_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">MADD usually presents w/metabolic decompensation or muscle weakness. Hearing loss has not been described in MADD.</td></tr><tr><td headers="hd_h_riboflavin-tn.T.genes_and_disorders_of_i_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<i>IGHMBP2</i>
|
||
</td><td headers="hd_h_riboflavin-tn.T.genes_and_disorders_of_i_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Spinal muscular atrophy with respiratory distress 1 (SMARD1) (OMIM <a href="https://omim.org/entry/604320" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">604320</a>)</td><td headers="hd_h_riboflavin-tn.T.genes_and_disorders_of_i_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">AR</td><td headers="hd_h_riboflavin-tn.T.genes_and_disorders_of_i_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Typically early-onset (infantile onset is most common) severe axonal polyneuronopathy w/distal muscle & lower-limb weakness & respiratory failure due to diaphragmatic paralysis; ± autonomic involvement, pneumonia, & hypotonia</td><td headers="hd_h_riboflavin-tn.T.genes_and_disorders_of_i_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Deafness has not been described in SMARD1. <sup>8</sup></td></tr><tr><td headers="hd_h_riboflavin-tn.T.genes_and_disorders_of_i_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<i>SMN1</i>
|
||
</td><td headers="hd_h_riboflavin-tn.T.genes_and_disorders_of_i_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<a href="/books/n/gene/sma/">Spinal muscular atrophy</a>
|
||
</td><td headers="hd_h_riboflavin-tn.T.genes_and_disorders_of_i_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">AR</td><td headers="hd_h_riboflavin-tn.T.genes_and_disorders_of_i_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Muscle weakness & atrophy due to progressive degeneration & irreversible loss of anterior horn cells in spinal cord & brain stem nuclei. Onset of weakness ranges from before birth to adulthood; weakness is symmetric, proximal > distal, & progressive.</td><td headers="hd_h_riboflavin-tn.T.genes_and_disorders_of_i_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">RTD is limited to lower cranial nerves & progresses to death in 1-5 yrs if not treated.</td></tr><tr><td headers="hd_h_riboflavin-tn.T.genes_and_disorders_of_i_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<i>VWA1</i>
|
||
</td><td headers="hd_h_riboflavin-tn.T.genes_and_disorders_of_i_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">10-bp repeat expansion in <i>VWA1</i> assoc w/HMN</td><td headers="hd_h_riboflavin-tn.T.genes_and_disorders_of_i_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">AR</td><td headers="hd_h_riboflavin-tn.T.genes_and_disorders_of_i_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Axonal motor neuropathy w/upper & lower limb involvement, distal & proximal wasting, & tongue fasciculations/atrophy <sup>9</sup></td><td headers="hd_h_riboflavin-tn.T.genes_and_disorders_of_i_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Unlike RTD, which has predominantly upper limb involvement, <i>VWA1-</i>assoc HMN more frequently affects lower limbs (upper limb involvement is usually secondary) & most affected persons present w/foot deformities. <i>VWA1</i>-assoc HMN is not assoc w/other bulbar manifestations, optic atrophy, or hearing loss. <sup>9</sup></td></tr></tbody></table></div><div><div><dl class="temp-labeled-list small"><dt></dt><dd><div><p class="no_margin">AD = <a class="def" href="/books/n/gene/glossary/def-item/autosomal-dominant/">autosomal dominant</a>; ALS = amyotrophic lateral sclerosis; AR = <a class="def" href="/books/n/gene/glossary/def-item/autosomal-recessive/">autosomal recessive</a>; LMN = lower motor neuron; MOI = <a class="def" href="/books/n/gene/glossary/def-item/mode-of-inheritance/">mode of inheritance</a>; RTD = riboflavin transporter deficiency; XL = <a class="def" href="/books/n/gene/glossary/def-item/x-linked/">X-linked</a></p></div></dd><dt>1. </dt><dd><div id="riboflavin-tn.TF.3.1"><p class="no_margin">
|
||
<a class="bk_pop" href="#riboflavin-tn.REF.flokas.2019.99">Flokas et al [2019]</a>
|
||
</p></div></dd><dt>2. </dt><dd><div id="riboflavin-tn.TF.3.2"><p class="no_margin">
|
||
<a class="bk_pop" href="#riboflavin-tn.REF.manole.2014.506">Manole et al [2014]</a>
|
||
</p></div></dd><dt>3. </dt><dd><div id="riboflavin-tn.TF.3.3"><p class="no_margin">
|
||
<a class="bk_pop" href="#riboflavin-tn.REF.rossor.2012.6">Rossor et al [2012]</a>
|
||
</p></div></dd><dt>4. </dt><dd><div id="riboflavin-tn.TF.3.4"><p class="no_margin">Of note, a <i>UBQLN1</i> variant was identified in an individual with a clinical diagnosis of Brown-Vialetto-Van Laere (BVVL) syndrome and atypical early-onset ALS with bulbar palsy & hearing loss. Although the pathogenicity of this variant is uncertain, this finding highlights the overlap of the BVVL and ALS phenotypes [<a class="bk_pop" href="#riboflavin-tn.REF.gonz_lezp_rez.2012.391">González-Pérez et al 2012</a>].</p></div></dd><dt>5. </dt><dd><div id="riboflavin-tn.TF.3.5"><p class="no_margin">The ALS-related genes that have been identified and that account for at least half of ALS that occurs in families with a history of more than one affected relative. Thirty genes have been associated with genetic ALS; <i>C9orf72</i>, <i>FUS</i>, <i>SOD1</i>, and <i>TARDBP</i> are the four most robust and common genes.</p></div></dd><dt>6. </dt><dd><div id="riboflavin-tn.TF.3.6"><p class="no_margin">Determination of the <a class="def" href="/books/n/gene/glossary/def-item/mode-of-inheritance/">mode of inheritance</a> is based on family history and <a class="def" href="/books/n/gene/glossary/def-item/molecular-genetic-testing/">molecular genetic testing</a>.</p></div></dd><dt>7. </dt><dd><div id="riboflavin-tn.TF.3.7"><p class="no_margin"><a class="bk_pop" href="#riboflavin-tn.REF.yedavalli.2018.53">Yedavalli et al [2018]</a>, <a class="bk_pop" href="#riboflavin-tn.REF.khani.2021.102.e1">Khani et al [2021]</a></p></div></dd><dt>8. </dt><dd><div id="riboflavin-tn.TF.3.8"><p class="no_margin">
|
||
<a class="bk_pop" href="#riboflavin-tn.REF.saladini.2020.1169">Saladini et al [2020]</a>
|
||
</p></div></dd><dt>9. </dt><dd><div id="riboflavin-tn.TF.3.9"><p class="no_margin">
|
||
<a class="bk_pop" href="#riboflavin-tn.REF.pagnamenta.2021">Pagnamenta et al [2021]</a>
|
||
</p></div></dd></dl></div></div></div><p><b>Transient neonatal riboflavin deficiency.</b> In the reports of transient riboflavin deficiency in two newborns of mothers <a class="def" href="/books/n/gene/glossary/def-item/heterozygous/">heterozygous</a> for an <i>SLC52A1</i> <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a>, the mothers were asymptomatic whereas the infants had clinical and biochemical features of <a href="/books/n/gene/madd/">multiple acyl-CoA dehydrogenase deficiency</a> (MADD) that resolved with riboflavin supplementation. When riboflavin supplementation was discontinued, children both showed normal psychomotor development. In the report of <a class="bk_pop" href="#riboflavin-tn.REF.ho.2011.e1976">Ho et al [2011]</a> only the mother was heterozygous for the <i>SLC52A1</i> variant, whereas in the report of <a class="bk_pop" href="#riboflavin-tn.REF.mosegaard.2017.182">Mosegaard et al [2017]</a>, both the mother and infant were heterozygous.</p><p><b>Disorders of unknown cause</b> to consider in the differential diagnosis of riboflavin transporter deficiency include the following:</p><ul><li class="half_rhythm"><div><b>Nathalie syndrome</b> (OMIM <a href="https://omim.org/entry/255990" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">255990</a>) has no lower cranial nerve signs but includes deafness and weakness in addition to spinal muscular atrophy (SMA), cataracts, hypogonadism, and cardiac conduction defects.</div></li><li class="half_rhythm"><div><b>Madras motor neuron disease (MMND)</b> (also referred to as Madras pattern motor neuron disease), a rare disorder with early-onset progressive neuromuscular disease with a relatively benign course, has predominantly been observed in southern India. Multiple cranial nerve palsies involve predominately the seventh and ninth to 12th cranial nerves. Hearing impairment is present in all; optic atrophy is present in some. While the majority are <a class="def" href="/books/n/gene/glossary/def-item/simplex/">simplex</a> cases (i.e., a single occurrence in a family), a few <a class="def" href="/books/n/gene/glossary/def-item/familial/">familial</a> cases have been reported. The etiology is unknown; pathogenic variants in <i>SLC52A2</i> and <i>SLC52A3</i> as well as <i>C9orf72</i> have been excluded [<a class="bk_pop" href="#riboflavin-tn.REF.nalini.2013.119">Nalini et al 2013</a>].</div></li><li class="half_rhythm"><div><b>Facial-onset sensory motor neuronopathy (FOSMN)</b> is a rare, slowly progressive, lower motor neuron disease with sensory compromise, involving mainly the face, bulbar region, and upper limbs. FOSMN syndrome represents a primary neurodegenerative variant of motor neuron disease with TAR DNA-binding protein (TDP)-43 aggregation. While most individuals have an insidious clinical course over the fifth to seventh decades of life, childhood and juvenile onset have been reported [<a class="bk_pop" href="#riboflavin-tn.REF.pinto.2019.238">Pinto et al 2019</a>].</div></li></ul></div><div id="riboflavin-tn.Management"><h2 id="_riboflavin-tn_Management_">Management</h2><p>No clinical practice guidelines for riboflavin transporter deficiency have been published.</p><p>Note: Because <i>SLC25A1</i>-related riboflavin-responsive hyperammonemic seizures have been described in a single individual to date [<a class="bk_pop" href="#riboflavin-tn.REF.kang.2020.160">Kang et al 2020</a>], current information is insufficient to provide management recommendations.</p><p>When riboflavin transporter deficiency is suspected during the diagnostic evaluation, begin oral riboflavin supplementation (see <a href="#riboflavin-tn.Treatment_of_Manifestation">Treatment of Manifestations</a>) immediately and continue it lifelong unless the diagnosis is excluded by <a class="def" href="/books/n/gene/glossary/def-item/molecular-genetic-testing/">molecular genetic testing</a>.</p><div id="riboflavin-tn.Evaluations_Following_Init"><h3>Evaluations Following Initial Diagnosis</h3><p>To establish the extent of disease and needs in an individual diagnosed with riboflavin transporter deficiency, the evaluations summarized in <a href="/books/NBK299312/table/riboflavin-tn.T.recommended_evaluations/?report=objectonly" target="object" rid-ob="figobriboflavintnTrecommendedevaluations">Table 4</a> (if not performed as part of the evaluation that led to the diagnosis) are recommended.</p><div id="riboflavin-tn.T.recommended_evaluations" class="table"><h3><span class="label">Table 4. </span></h3><div class="caption"><p>Recommended Evaluations Following Initial Diagnosis in Individuals with Riboflavin Transporter Deficiency 2 and 3</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK299312/table/riboflavin-tn.T.recommended_evaluations/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__riboflavin-tn.T.recommended_evaluations_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_riboflavin-tn.T.recommended_evaluations_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">System/Concern</th><th id="hd_h_riboflavin-tn.T.recommended_evaluations_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Evaluation</th><th id="hd_h_riboflavin-tn.T.recommended_evaluations_1_1_1_3" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Comment</th></tr></thead><tbody><tr><td headers="hd_h_riboflavin-tn.T.recommended_evaluations_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Constitutional</b>
|
||
</td><td headers="hd_h_riboflavin-tn.T.recommended_evaluations_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Measure height, weight, & head circumference.</td><td headers="hd_h_riboflavin-tn.T.recommended_evaluations_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Weight loss reported in some persons</td></tr><tr><td headers="hd_h_riboflavin-tn.T.recommended_evaluations_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Motor/sensory</b>
|
||
<br />
|
||
<b>neuropathy</b>
|
||
</td><td headers="hd_h_riboflavin-tn.T.recommended_evaluations_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Neuromuscular specialist</td><td headers="hd_h_riboflavin-tn.T.recommended_evaluations_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Assess proximal & distal muscle strength (Rankins scale, MRC strength scale), sensory loss, & gait disturbance (SARA ataxia scale).</td></tr><tr><td headers="hd_h_riboflavin-tn.T.recommended_evaluations_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Epilepsy</b>
|
||
</td><td headers="hd_h_riboflavin-tn.T.recommended_evaluations_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Medical history; EEG</td><td headers="hd_h_riboflavin-tn.T.recommended_evaluations_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr><tr><td headers="hd_h_riboflavin-tn.T.recommended_evaluations_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Musculoskeletal</b>
|
||
</td><td headers="hd_h_riboflavin-tn.T.recommended_evaluations_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Orthopedics / physical medicine & rehab / PT & OT eval</td><td headers="hd_h_riboflavin-tn.T.recommended_evaluations_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">To assess:
|
||
<ul><li class="half_rhythm"><div>Gross motor & fine motor skills</div></li><li class="half_rhythm"><div>Spine for scoliosis</div></li><li class="half_rhythm"><div>Mobility, ADL, & need for bracing &/or adaptive devices</div></li><li class="half_rhythm"><div>Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills)</div></li></ul></td></tr><tr><td headers="hd_h_riboflavin-tn.T.recommended_evaluations_1_1_1_1" rowspan="2" scope="row" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Optic atrophy</b>
|
||
</td><td headers="hd_h_riboflavin-tn.T.recommended_evaluations_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Experienced ophthalmologist</td><td headers="hd_h_riboflavin-tn.T.recommended_evaluations_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Assess extraocular movement, best corrected visual acuity, color vision testing (Farnsworth test), visual field testing (Goldman perimetry), visual evoked potentials, OCT, fundus exam</td></tr><tr><td headers="hd_h_riboflavin-tn.T.recommended_evaluations_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">Vision specialist</td><td headers="hd_h_riboflavin-tn.T.recommended_evaluations_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Assess for need for visual aids, preferential seating in school.</td></tr><tr><td headers="hd_h_riboflavin-tn.T.recommended_evaluations_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Sensorineural</b>
|
||
<br />
|
||
<b>hearing</b>
|
||
<br />
|
||
<b>impairment</b>
|
||
</td><td headers="hd_h_riboflavin-tn.T.recommended_evaluations_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Audiologic exam</td><td headers="hd_h_riboflavin-tn.T.recommended_evaluations_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Incl:
|
||
<ul><li class="half_rhythm"><div>ABRs to confirm pathology & provide baseline</div></li><li class="half_rhythm"><div>Evoked OAEs to identify type of hearing impairment</div></li><li class="half_rhythm"><div>Speech discrimination tests</div></li><li class="half_rhythm"><div>Behavioral tests</div></li></ul></td></tr><tr><td headers="hd_h_riboflavin-tn.T.recommended_evaluations_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Speech & language</b>
|
||
</td><td headers="hd_h_riboflavin-tn.T.recommended_evaluations_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Speech & language assessment</td><td headers="hd_h_riboflavin-tn.T.recommended_evaluations_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">As indicated</td></tr><tr><td headers="hd_h_riboflavin-tn.T.recommended_evaluations_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Bulbar dysfunction</b>
|
||
</td><td headers="hd_h_riboflavin-tn.T.recommended_evaluations_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td><td headers="hd_h_riboflavin-tn.T.recommended_evaluations_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Assess for swallowing disorder (dysphagia).</td></tr><tr><td headers="hd_h_riboflavin-tn.T.recommended_evaluations_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Gastrointestinal/</b>
|
||
<br />
|
||
<b>Feeding</b>
|
||
</td><td headers="hd_h_riboflavin-tn.T.recommended_evaluations_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Gastroenterology / nutrition / feeding team eval</td><td headers="hd_h_riboflavin-tn.T.recommended_evaluations_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Assess aspiration risk & nutritional status; consider eval for gastric tube placement in those w/dysphagia &/or aspiration risk.</td></tr><tr><td headers="hd_h_riboflavin-tn.T.recommended_evaluations_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Autonomic</b>
|
||
<br />
|
||
<b>dysfunction</b>
|
||
</td><td headers="hd_h_riboflavin-tn.T.recommended_evaluations_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Physical exam, medical history</td><td headers="hd_h_riboflavin-tn.T.recommended_evaluations_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Assess heart rate, temperature, medical history for syncope.</td></tr><tr><td headers="hd_h_riboflavin-tn.T.recommended_evaluations_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Respiratory</b>
|
||
<br />
|
||
<b>involvement</b>
|
||
</td><td headers="hd_h_riboflavin-tn.T.recommended_evaluations_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Pulmonary consultation</td><td headers="hd_h_riboflavin-tn.T.recommended_evaluations_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Sleep study / polysomnography</td></tr><tr><td headers="hd_h_riboflavin-tn.T.recommended_evaluations_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Depression</b>
|
||
</td><td headers="hd_h_riboflavin-tn.T.recommended_evaluations_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Psychiatric consultation</td><td headers="hd_h_riboflavin-tn.T.recommended_evaluations_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">If present</td></tr><tr><td headers="hd_h_riboflavin-tn.T.recommended_evaluations_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Genetic</b>
|
||
<br />
|
||
<b>counseling</b>
|
||
</td><td headers="hd_h_riboflavin-tn.T.recommended_evaluations_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">By genetics professionals <sup>1</sup></td><td headers="hd_h_riboflavin-tn.T.recommended_evaluations_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">To inform affected persons & their families re nature, MOI, & implications of riboflavin transporter deficiency in order to facilitate medical & personal decision making</td></tr><tr><td headers="hd_h_riboflavin-tn.T.recommended_evaluations_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Family support</b>
|
||
<br />
|
||
<b>& resources</b>
|
||
</td><td headers="hd_h_riboflavin-tn.T.recommended_evaluations_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Assess need for:
|
||
<ul><li class="half_rhythm"><div>Community or <a href="#riboflavin-tn.Resources">online resources</a> such as <a href="https://www.p2pusa.org/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">Parent to Parent</a>;</div></li><li class="half_rhythm"><div>Social work involvement for parental support;</div></li><li class="half_rhythm"><div>Home nursing referral.</div></li></ul></td><td headers="hd_h_riboflavin-tn.T.recommended_evaluations_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr></tbody></table></div><div><div><dl class="temp-labeled-list small"><dt></dt><dd><div><p class="no_margin">ABR = auditory evoked brain stem response; ADL = activities of daily living; MOI = <a class="def" href="/books/n/gene/glossary/def-item/mode-of-inheritance/">mode of inheritance</a>; OAE = otoacoustic emission; OCT = optical coherence tomography; OT = occupational therapy; PT = physical therapy</p></div></dd><dt>1. </dt><dd><div id="riboflavin-tn.TF.4.1"><p class="no_margin">Medical geneticist, certified genetic counselor, certified advanced genetic nurse</p></div></dd></dl></div></div></div></div><div id="riboflavin-tn.Treatment_of_Manifestation"><h3>Treatment of Manifestations</h3><p><b>High-dose supplementation</b>
|
||
<b>of</b>
|
||
<b>riboflavin (vitamin B<sub>2</sub>).</b> Riboflavin supplementation is effective and possibly lifesaving. It is recommended that treatment begin as soon as RTD is suspected and continue lifelong unless <a class="def" href="/books/n/gene/glossary/def-item/molecular-genetic-testing/">molecular genetic testing</a> fails to identify <a class="def" href="/books/n/gene/glossary/def-item/biallelic/">biallelic</a> pathogenic variants in either <i>SLC52A2</i> or <i>SLC52A3</i>. Before initiating riboflavin supplementation, perform the assessments in <a href="/books/NBK299312/table/riboflavin-tn.T.recommended_evaluations/?report=objectonly" target="object" rid-ob="figobriboflavintnTrecommendedevaluations">Table 4</a>.</p><p>High-dose supplementation of riboflavin (10-50 mg/kg/day) has been effective in individuals with molecularly confirmed riboflavin transporter deficiency and, also in some individuals in whom the genetic basis of riboflavin transporter deficiency has not been established.</p><p>The amount of riboflavin given varies depending on the severity and response of the individual to the treatment. It has been reported that doses <10 mg/kg/day are ineffective [<a class="bk_pop" href="#riboflavin-tn.REF.ocallaghan.2019.598">O'Callaghan et al 2019</a>], whereas doses >80 mg/kg/day may have minimal side effects.</p><p>Oral riboflavin supplementation should be given in gradually increasing doses in order to establish the optimal dose:</p><dl class="temp-labeled-list"><dt>1.</dt><dd><p class="no_top_margin">Riboflavin 10 mg/kg/day in 3 doses for 1 month</p></dd><dt>2.</dt><dd><p class="no_top_margin">Riboflavin 20 mg/kg/day in 3 doses for 1 month</p></dd><dt>3.</dt><dd><p class="no_top_margin">Riboflavin 30 mg/kg/day in 3 doses for 1 month</p></dd><dt>4.</dt><dd><p class="no_top_margin">Riboflavin 40 mg/kg/day in 3 doses for 1 month</p></dd><dt>5.</dt><dd><p class="no_top_margin">Riboflavin 50 mg/kg/day in 3 doses for 1 month</p></dd></dl><p>Note: Theoretically, parenteral administration of riboflavin may increase uptake and effect [<a class="bk_pop" href="#riboflavin-tn.REF.gorcenco.2019.245">Gorcenco et al 2019</a>].</p><p>Side effects reported after high-dose riboflavin supplementation, when present, can include diarrhea, increased urination, and urine discoloration. Allergic reactions have been described rarely. Side effects, problems, or deterioration at any point require discussion with the treating clinician.</p><p>Open-label studies have reported improvement of motor symptoms or neurophysiologic measurements or hearing level in a third of individuals treated with up to 500 mg riboflavin three times per day. However, no randomized controlled trials have been performed [<a class="bk_pop" href="#riboflavin-tn.REF.foley.2014.44">Foley et al 2014</a>, <a class="bk_pop" href="#riboflavin-tn.REF.jaeger.2016.559">Jaeger & Bosch 2016</a>].</p><p>Positive clinical response to the treatment could occur with some latency; thus, riboflavin therapy should be continued in all suspected or genetically diagnosed RTD cases even when there is no apparent initial clinical improvement [<a class="bk_pop" href="#riboflavin-tn.REF.ocallaghan.2019.598">O'Callaghan et al 2019</a>].</p><p>Better response to the treatment is reported when given earlier in life or in the disease course. Adulthood-onset or late treatment are frequently associated with non-improvement, likely reflecting neuronal damage.</p><p><b>Supportive care</b> by multidisciplinary specialists including the following are recommended: pulmonology; orthopedics, rehabilitation medicine, physical therapy and occupational therapy; speech and language therapy; feeding team including gastroenterology, nutritionists; low vision specialist; and mental health specialists (see <a href="/books/NBK299312/table/riboflavin-tn.T.supportive_care_for_indi/?report=objectonly" target="object" rid-ob="figobriboflavintnTsupportivecareforindi">Table 5</a>).</p><div id="riboflavin-tn.T.supportive_care_for_indi" class="table"><h3><span class="label">Table 5. </span></h3><div class="caption"><p>Supportive Care for Individuals with Riboflavin Transporter Deficiency 2 and 3</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK299312/table/riboflavin-tn.T.supportive_care_for_indi/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__riboflavin-tn.T.supportive_care_for_indi_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_riboflavin-tn.T.supportive_care_for_indi_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Manifestation/<br />Concern</th><th id="hd_h_riboflavin-tn.T.supportive_care_for_indi_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Treatment</th><th id="hd_h_riboflavin-tn.T.supportive_care_for_indi_1_1_1_3" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Considerations/Other</th></tr></thead><tbody><tr><td headers="hd_h_riboflavin-tn.T.supportive_care_for_indi_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Poor weight gain / Failure to thrive</b>
|
||
</td><td headers="hd_h_riboflavin-tn.T.supportive_care_for_indi_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Feeding therapy; gastrostomy tube placement may be required for persistent feeding issues.</td><td headers="hd_h_riboflavin-tn.T.supportive_care_for_indi_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Low threshold for clinical feeding eval &/or radiographic swallowing study if clinical signs or symptoms of dysphagia</td></tr><tr><td headers="hd_h_riboflavin-tn.T.supportive_care_for_indi_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Dysphagia</b>
|
||
</td><td headers="hd_h_riboflavin-tn.T.supportive_care_for_indi_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td><td headers="hd_h_riboflavin-tn.T.supportive_care_for_indi_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<ul><li class="half_rhythm"><div>Determine exact cause of swallowing malfunction; modify food types & consistency, head positioning during swallowing, & exercises to improve swallowing.</div></li><li class="half_rhythm"><div>Attn to oral hygiene & dental care, as dysphagia may → impaired clearance of organisms & pathogenic colonization</div></li></ul>
|
||
</td></tr><tr><td headers="hd_h_riboflavin-tn.T.supportive_care_for_indi_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Musculoskeletal</b>
|
||
</td><td headers="hd_h_riboflavin-tn.T.supportive_care_for_indi_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Orthopedics / physical medicine & rehab / PT & OT incl stretching to help avoid contractures & falls</td><td headers="hd_h_riboflavin-tn.T.supportive_care_for_indi_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Consider need for orthotics for limb & trunk bracing, positioning & mobility devices, & disability parking placard.</td></tr><tr><td headers="hd_h_riboflavin-tn.T.supportive_care_for_indi_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Reduced vision</b>
|
||
</td><td headers="hd_h_riboflavin-tn.T.supportive_care_for_indi_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Low vision aids; per ophthalmologist & low vision specialist</td><td headers="hd_h_riboflavin-tn.T.supportive_care_for_indi_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Community vision services through early intervention or school district</td></tr><tr><td headers="hd_h_riboflavin-tn.T.supportive_care_for_indi_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Ptosis</b>
|
||
</td><td headers="hd_h_riboflavin-tn.T.supportive_care_for_indi_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Per treating ophthalmologist</td><td headers="hd_h_riboflavin-tn.T.supportive_care_for_indi_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr><tr><td headers="hd_h_riboflavin-tn.T.supportive_care_for_indi_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Sensorineural</b>
|
||
<br />
|
||
<b>hearing impairment</b>
|
||
</td><td headers="hd_h_riboflavin-tn.T.supportive_care_for_indi_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Treatment of SNHL depends on degree of hearing impairment. <sup>1</sup></td><td headers="hd_h_riboflavin-tn.T.supportive_care_for_indi_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Educational intervention for the hearing impaired; cochlear implants or hearing aids may be required.</td></tr><tr><td headers="hd_h_riboflavin-tn.T.supportive_care_for_indi_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Dysarthria</b>
|
||
</td><td headers="hd_h_riboflavin-tn.T.supportive_care_for_indi_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Speech-language pathologist</td><td headers="hd_h_riboflavin-tn.T.supportive_care_for_indi_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Help maintain vocal control; improve speech, breathing techniques, & communication in general</td></tr><tr><td headers="hd_h_riboflavin-tn.T.supportive_care_for_indi_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Depression</b>
|
||
</td><td headers="hd_h_riboflavin-tn.T.supportive_care_for_indi_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Depending on severity, treatment may be required.</td><td headers="hd_h_riboflavin-tn.T.supportive_care_for_indi_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr><tr><td headers="hd_h_riboflavin-tn.T.supportive_care_for_indi_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Epilepsy</b>
|
||
</td><td headers="hd_h_riboflavin-tn.T.supportive_care_for_indi_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Standardized treatment w/ASM by experienced neurologist</td><td headers="hd_h_riboflavin-tn.T.supportive_care_for_indi_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<ul><li class="half_rhythm"><div>Many ASMs may be effective; no one ASM has been demonstrated effective specifically for RTD.</div></li><li class="half_rhythm"><div>Education of parents/caregivers <sup>2</sup></div></li></ul>
|
||
</td></tr><tr><td headers="hd_h_riboflavin-tn.T.supportive_care_for_indi_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Family needs /</b>
|
||
<br />
|
||
<b>social support</b>
|
||
</td><td headers="hd_h_riboflavin-tn.T.supportive_care_for_indi_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Educational services; home nursing care; palliative care consultation</td><td headers="hd_h_riboflavin-tn.T.supportive_care_for_indi_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr></tbody></table></div><div><div><dl class="temp-labeled-list small"><dt></dt><dd><div><p class="no_margin">ASM = anti-seizure medication; OT = occupational therapy; PT = physical therapy; SNHL = sensorineural hearing loss</p></div></dd><dt>1. </dt><dd><div id="riboflavin-tn.TF.5.1"><p class="no_margin">See <a href="/books/n/gene/deafness-overview/">Hereditary Hearing Loss and Deafness Overview</a> for details about treatment options.</p></div></dd><dt>2. </dt><dd><div id="riboflavin-tn.TF.5.2"><p class="no_margin">Education of parents/caregivers regarding common seizure presentations is appropriate. For information on non-medical interventions and coping strategies for children diagnosed with epilepsy, see <a href="https://www.epilepsy.com/tools-resources/forms-resources#Epilepsy-Foundation-Toolbox" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">Epilepsy Foundation Toolbox</a>.</p></div></dd></dl></div></div></div><div id="riboflavin-tn.Educational_Services_for_T"><h4>Educational Services for Those with Motor and Language Disabilities</h4><p><b>Ages 0-3 years.</b> Referral to an early intervention program is recommended for access to occupational, physical, speech, and feeding therapy as well as infant mental health services, special educators, and sensory impairment specialists. In the US, early intervention is a federally funded program available in all states that provides in-home services to target individual therapy needs.</p><p><b>Ages 3-5 years.</b> In the US, developmental preschool through the local public school district is recommended. Before placement, an evaluation is made to determine needed services and therapies and an individualized education plan (IEP) is developed for those who qualify based on established motor, language, social, or cognitive delay. The early intervention program typically assists with this transition. Developmental preschool is center based; for children too medically unstable to attend, home-based services are provided.</p><p><b>All ages.</b> Consultation with a developmental pediatrician is recommended to ensure the involvement of appropriate community, state, and educational agencies (US) and to support parents in maximizing quality of life. Some issues to consider:</p><ul><li class="half_rhythm"><div>IEP services:</div><ul><li class="half_rhythm"><div>An IEP provides specially designed instruction and related services to children who qualify.</div></li><li class="half_rhythm"><div>IEP services will be reviewed annually to determine whether any changes are needed.</div></li><li class="half_rhythm"><div>Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.</div></li><li class="half_rhythm"><div>Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.</div></li><li class="half_rhythm"><div>PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.</div></li><li class="half_rhythm"><div>As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.</div></li></ul></li><li class="half_rhythm"><div>A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.</div></li><li class="half_rhythm"><div>Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.</div></li><li class="half_rhythm"><div>Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.</div></li></ul></div></div><div id="riboflavin-tn.Surveillance"><h3>Surveillance</h3><div id="riboflavin-tn.T.recommended_surveillance" class="table"><h3><span class="label">Table 6. </span></h3><div class="caption"><p>Recommended Surveillance for Individuals with Riboflavin Transporter Deficiency 2 and 3</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK299312/table/riboflavin-tn.T.recommended_surveillance/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__riboflavin-tn.T.recommended_surveillance_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_riboflavin-tn.T.recommended_surveillance_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">System/Concern</th><th id="hd_h_riboflavin-tn.T.recommended_surveillance_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Evaluation</th><th id="hd_h_riboflavin-tn.T.recommended_surveillance_1_1_1_3" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Frequency</th></tr></thead><tbody><tr><td headers="hd_h_riboflavin-tn.T.recommended_surveillance_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Riboflavin</b>
|
||
<br />
|
||
<b>supplementation</b>
|
||
</td><td headers="hd_h_riboflavin-tn.T.recommended_surveillance_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<ul><li class="half_rhythm"><div>Discussion of any problems w/riboflavin supplementation</div></li><li class="half_rhythm"><div>Blood sample for riboflavin/FAD/FMN; acylcarnitine analysis (if previous/y abnormal) to determine if they are normalizing</div></li></ul>
|
||
</td><td headers="hd_h_riboflavin-tn.T.recommended_surveillance_1_1_1_3" rowspan="7" colspan="1" style="text-align:left;vertical-align:middle;">3 mos, 6 mos, &<br />12 mos after<br />initiation of<br />riboflavin<br />supplementation,<br />then annually or<br />as needed</td></tr><tr><td headers="hd_h_riboflavin-tn.T.recommended_surveillance_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Neurologic exam</b>
|
||
</td><td headers="hd_h_riboflavin-tn.T.recommended_surveillance_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Focused on motor/sensory findings</td></tr><tr><td headers="hd_h_riboflavin-tn.T.recommended_surveillance_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Musculoskeletal</b>
|
||
</td><td headers="hd_h_riboflavin-tn.T.recommended_surveillance_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<ul><li class="half_rhythm"><div>Orthopedic eval of spine/scoliosis</div></li><li class="half_rhythm"><div>Physical medicine & rehab; OT/PT eval of fine & gross motor skills, ADL</div></li></ul>
|
||
</td></tr><tr><td headers="hd_h_riboflavin-tn.T.recommended_surveillance_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Sensorineural</b>
|
||
<br />
|
||
<b>hearing</b>
|
||
<br />
|
||
<b>impairment</b>
|
||
</td><td headers="hd_h_riboflavin-tn.T.recommended_surveillance_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Audiogram</td></tr><tr><td headers="hd_h_riboflavin-tn.T.recommended_surveillance_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Epilepsy</b>
|
||
</td><td headers="hd_h_riboflavin-tn.T.recommended_surveillance_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Assess new episodes; EEG.</td></tr><tr><td headers="hd_h_riboflavin-tn.T.recommended_surveillance_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Autonomic</b>
|
||
<br />
|
||
<b>dysfunction</b>
|
||
</td><td headers="hd_h_riboflavin-tn.T.recommended_surveillance_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Physical exam</td></tr><tr><td headers="hd_h_riboflavin-tn.T.recommended_surveillance_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Vision loss</b>
|
||
</td><td headers="hd_h_riboflavin-tn.T.recommended_surveillance_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Ophthalmologic exam</td></tr><tr><td headers="hd_h_riboflavin-tn.T.recommended_surveillance_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Speech &</b>
|
||
<br />
|
||
<b>language</b>
|
||
</td><td headers="hd_h_riboflavin-tn.T.recommended_surveillance_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Eval by speech-language pathologist; consider need for alternative communication.</td><td headers="hd_h_riboflavin-tn.T.recommended_surveillance_1_1_1_3" rowspan="5" colspan="1" style="text-align:left;vertical-align:middle;">As needed</td></tr><tr><td headers="hd_h_riboflavin-tn.T.recommended_surveillance_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Bulbar</b>
|
||
<br />
|
||
<b>dysfunction</b>
|
||
</td><td headers="hd_h_riboflavin-tn.T.recommended_surveillance_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Assess safety of oral feeding vs need for gastrostomy tube.</td></tr><tr><td headers="hd_h_riboflavin-tn.T.recommended_surveillance_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Feeding</b>
|
||
</td><td headers="hd_h_riboflavin-tn.T.recommended_surveillance_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Assess nutrition, dietary needs.</td></tr><tr><td headers="hd_h_riboflavin-tn.T.recommended_surveillance_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Respiratory</b>
|
||
<br />
|
||
<b>involvement</b>
|
||
</td><td headers="hd_h_riboflavin-tn.T.recommended_surveillance_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Assess need for ventilation.</td></tr><tr><td headers="hd_h_riboflavin-tn.T.recommended_surveillance_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Family support/</b>
|
||
<br />
|
||
<b>resources</b>
|
||
</td><td headers="hd_h_riboflavin-tn.T.recommended_surveillance_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Discussion of any problems</td></tr></tbody></table></div><div><div><dl class="temp-labeled-list small"><dt></dt><dd><div><p class="no_margin">ADL = activities of daily living; FAD = flavin adenine dinucleotide; FMN = flavin mononucleotide; OT = occupational therapy; PT = physical therapy</p></div></dd></dl></div></div></div></div><div id="riboflavin-tn.AgentsCircumstances_to_Avo"><h3>Agents/Circumstances to Avoid</h3><p>Avoid dietary restriction of riboflavin and consume riboflavin-rich foods such as meat, eggs, and milk.</p><p>Metabolic stress caused by increased physical activity can decrease levels of riboflavin; therefore, excessive exercise should be limited.</p></div><div id="riboflavin-tn.Evaluation_of_Relatives_at"><h3>Evaluation of Relatives at Risk</h3><p>When the <i>SLC52A2</i> or <i>SLC52A3</i> pathogenic variants in the family are known (or if a <a class="def" href="/books/n/gene/glossary/def-item/proband/">proband</a> is found to have <a class="def" href="/books/n/gene/glossary/def-item/biallelic/">biallelic</a> <i>SLC52A1</i> pathogenic variants presumed to be associated with RTD1), it is appropriate to perform <a class="def" href="/books/n/gene/glossary/def-item/molecular-genetic-testing/">molecular genetic testing</a> on the older and younger sibs of a proband with RTD to identify those with biallelic pathogenic variants who would benefit from early treatment with riboflavin supplementation and monitoring for potential complications of the disorder.</p><p>If the pathogenic variants are not known, riboflavin should be administered for both diagnostic and therapeutic purposes if a younger sib of a <a class="def" href="/books/n/gene/glossary/def-item/proband/">proband</a> presents with typical symptoms or signs of RTD.</p><p>See <a href="#riboflavin-tn.Pregnancy_Management">Pregnancy Management</a> for information about riboflavin supplementation in women who are <a class="def" href="/books/n/gene/glossary/def-item/heterozygous/">heterozygous</a> for an <i>SLC52A1, SLC52A2,</i> or <i>SLC52A3</i> <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a>.</p><p>See <a href="#riboflavin-tn.Related_Genetic_Counseling">Genetic Counseling</a> for issues related to testing of at-risk relatives for <a class="def" href="/books/n/gene/glossary/def-item/genetic-counseling/">genetic counseling</a> purposes.</p></div><div id="riboflavin-tn.Pregnancy_Management"><h3>Pregnancy Management</h3><p><b>Females with <a class="def" href="/books/n/gene/glossary/def-item/biallelic/">biallelic</a> RTD-causing pathogenic variants.</b> Females who have riboflavin transporter deficiency with biallelic pathogenic variants in either <i>SLC52A2</i> or <i>SLC52A3</i> should take riboflavin supplements before and during pregnancy and when breast feeding to avoid inducing riboflavin deficiency in the fetus and infant. Recommended dose during pregnancy is 10 mg/kg/day.</p><p><b>Females <a class="def" href="/books/n/gene/glossary/def-item/heterozygous/">heterozygous</a> for an RTD-causing <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a>.</b> The authors recommend a diet rich in riboflavin during pregnancy for females who are heterozygous for an RTD-related pathogenic variant. Young women heterozygous for an RTD-causing pathogenic variant should also receive counseling regarding the possibility of further riboflavin supplementation, if necessary, during pregnancy and when breastfeeding, to avoid risks of riboflavin deficiency in both mother and offspring.</p><ul><li class="half_rhythm"><div>Transient neonatal riboflavin deficiency (see <a href="#riboflavin-tn.Differential_Diagnosis">Differential Diagnosis</a>) has been reported in offspring of a mother <a class="def" href="/books/n/gene/glossary/def-item/heterozygous/">heterozygous</a> for an <i>SLC52A1</i> <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a> who became riboflavin deficient during pregnancy; her riboflavin-deficient newborn experienced neonatal seizures responsive to riboflavin supplementation. It is unknown if the offspring of females heterozygous for a <i>SLC52A2</i> or <i>SLC52A3</i> pathogenic variant may also be at increased risk for neonatal riboflavin deficiency.</div></li><li class="half_rhythm"><div>Although no data are available, <a class="def" href="/books/n/gene/glossary/def-item/heterozygous/">heterozygous</a> females may be at increased risk of developing symptoms due to an increased demand for riboflavin during pregnancy.</div></li></ul><p>Few studies have evaluated for adverse fetal outcomes after excessive maternal riboflavin intake during pregnancy. Riboflavin deficiency during pregnancy, however, has been associated with an increased risk of maternal preeclampsia and preterm delivery [<a class="bk_pop" href="#riboflavin-tn.REF.carmichael.2013.579">Carmichael et al 2013</a>].</p></div><div id="riboflavin-tn.Therapies_Under_Investigat"><h3>Therapies Under Investigation</h3><p>Search <a href="https://clinicaltrials.gov/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">ClinicalTrials.gov</a> in the US and <a href="https://www.clinicaltrialsregister.eu/ctr-search/search" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">EU Clinical Trials Register</a> in Europe for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.</p></div></div><div id="riboflavin-tn.Genetic_Counseling"><h2 id="_riboflavin-tn_Genetic_Counseling_">Genetic Counseling</h2><p>
|
||
<i>Genetic counseling is the process of providing individuals and families with
|
||
information on the nature, mode(s) of inheritance, and implications of genetic disorders to help them
|
||
make informed medical and personal decisions. The following section deals with genetic
|
||
risk assessment and the use of family history and genetic testing to clarify genetic
|
||
status for family members; it is not meant to address all personal, cultural, or
|
||
ethical issues that may arise or to substitute for consultation with a genetics
|
||
professional</i>. —ED.</p><div id="riboflavin-tn.Mode_of_Inheritance"><h3>Mode of Inheritance</h3><p>Riboflavin transporter deficiency 2 (RTD2) and RTD3 – caused by <a class="def" href="/books/n/gene/glossary/def-item/biallelic/">biallelic</a> pathogenic variants in <i>SLC52A2</i> or <i>SLC52A3</i>, respectively – are inherited in an <a class="def" href="/books/n/gene/glossary/def-item/autosomal-recessive/">autosomal recessive</a> manner.</p><p>Preliminary data from a single case report suggests that RTD1 is caused by <a class="def" href="/books/n/gene/glossary/def-item/biallelic/">biallelic</a> pathogenic variants in <i>SLC25A1</i> and inherited in an <a class="def" href="/books/n/gene/glossary/def-item/autosomal-recessive/">autosomal recessive</a> manner [<a class="bk_pop" href="#riboflavin-tn.REF.kang.2020.160">Kang et al 2020</a>]. Because further study is needed to confirm this observation, RTD1 is not discussed further in this section.</p></div><div id="riboflavin-tn.Risk_to_Family_Members"><h3>Risk to Family Members</h3><p>
|
||
<b>Parents of a <a class="def" href="/books/n/gene/glossary/def-item/proband/">proband</a></b>
|
||
</p><ul><li class="half_rhythm"><div>The parents of an affected child are obligate heterozygotes (i.e., presumed to be carriers of one <i>SLC52A2</i> or one <i>SLC52A3</i> <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a> based on family history).</div></li><li class="half_rhythm"><div>Molecular genetic testing is recommended for the parents of a <a class="def" href="/books/n/gene/glossary/def-item/proband/">proband</a> to confirm that both parents are <a class="def" href="/books/n/gene/glossary/def-item/heterozygous/">heterozygous</a> for an <i>SLC52A2</i> or <i>SLC52A3</i> <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a> and to allow reliable <a class="def" href="/books/n/gene/glossary/def-item/recurrence-risk/">recurrence risk</a> assessment. If a pathogenic variant is detected in only one parent, the following possibilities should be considered:</div><ul><li class="half_rhythm"><div>One of the pathogenic variants identified in the <a class="def" href="/books/n/gene/glossary/def-item/proband/">proband</a> occurred as a <a class="def" href="/books/n/gene/glossary/def-item/de-novo/"><i>de novo</i></a> event in the proband or as a <a class="def" href="/books/n/gene/glossary/def-item/postzygotic/">postzygotic</a> <i>de novo</i> event in a mosaic parent [<a class="bk_pop" href="#riboflavin-tn.REF.j_nsson.2017.519">Jónsson et al 2017</a>].</div></li><li class="half_rhythm"><div>Uniparental isodisomy for the parental <a class="def" href="/books/n/gene/glossary/def-item/chromosome/">chromosome</a> with the <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a> resulted in homozygosity for the pathogenic variant in the <a class="def" href="/books/n/gene/glossary/def-item/proband/">proband</a>.</div></li></ul></li><li class="half_rhythm"><div>Most <a class="def" href="/books/n/gene/glossary/def-item/heterozygous/">heterozygous</a> individuals do not have manifestations of RTD. Theoretically, heterozygotes may have manifestations of RTD if other conditions that lead to riboflavin depletion (e.g., dietary restriction, malnourishment, pregnancy, and/or illness) co-occur (see <a href="#riboflavin-tn.Pregnancy_Management">Pregnancy Management</a>). Preliminary research data suggest that in some individuals heterozygous pathogenic variants in <i>SLC52A3</i> may be associated with RTD in the absence of conditions that lead to riboflavin depletion; however, this hypothesis requires further research [<a class="bk_pop" href="#riboflavin-tn.REF.khani.2021.102.e1">Khani et al 2021</a>].</div></li></ul><p>
|
||
<b>Sibs of a <a class="def" href="/books/n/gene/glossary/def-item/proband/">proband</a></b>
|
||
</p><ul><li class="half_rhythm"><div>If both parents are known to be <a class="def" href="/books/n/gene/glossary/def-item/heterozygous/">heterozygous</a> for an <i>SLC52A2</i> or <i>SLC52A3</i> <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a>, each sib of an affected individual has at conception a 25% chance of inheriting <a class="def" href="/books/n/gene/glossary/def-item/biallelic/">biallelic</a> pathogenic variants and being affected, a 50% chance of inheriting one pathogenic variant and being heterozygous, and a 25% chance of inheriting neither of the <a class="def" href="/books/n/gene/glossary/def-item/familial/">familial</a> RTD-related pathogenic variants.</div></li><li class="half_rhythm"><div>Most <a class="def" href="/books/n/gene/glossary/def-item/heterozygous/">heterozygous</a> individuals do not have manifestations of RTD. Theoretically, heterozygotes may have manifestations of RTD if other conditions that lead to riboflavin depletion (e.g., dietary restriction, malnourishment, pregnancy, and/or illness) co-occur (see <a href="#riboflavin-tn.Pregnancy_Management">Pregnancy Management</a>).Preliminary research data suggest that in some individuals heterozygous pathogenic variants in <i>SLC52A3</i> may be associated with RTD in the absence of conditions that lead to riboflavin depletion; however, this hypothesis requires further research [<a class="bk_pop" href="#riboflavin-tn.REF.khani.2021.102.e1">Khani et al 2021</a>].</div></li></ul><p><b>Offspring of a <a class="def" href="/books/n/gene/glossary/def-item/proband/">proband</a>.</b> Unless an affected individual's reproductive partner also has RTD or is a <a class="def" href="/books/n/gene/glossary/def-item/carrier/">carrier</a>, offspring will be obligate heterozygotes (carriers) for an <i>SLC52A2</i> or <i>SLC52A3</i> <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a>.</p><p><b>Other family members.</b> Each sib of the <a class="def" href="/books/n/gene/glossary/def-item/proband/">proband</a>'s parents is at a 50% risk of being a <a class="def" href="/books/n/gene/glossary/def-item/carrier/">carrier</a> of an <i>SLC52A2</i> or <i>SLC52A3</i> <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a>.</p></div><div id="riboflavin-tn.Carrier_Detection"><h3>Carrier Detection</h3><p>Carrier testing for at-risk relatives requires prior identification of the <i>SLC52A2</i> or <i>SLC52A3</i> pathogenic variants in the family.</p></div><div id="riboflavin-tn.Related_Genetic_Counseling"><h3>Related Genetic Counseling Issues</h3><p>See Management, <a href="#riboflavin-tn.Evaluation_of_Relatives_at">Evaluation of Relatives at Risk</a> for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.</p><p>
|
||
<b>Family planning</b>
|
||
</p><ul><li class="half_rhythm"><div>Young women with RTD should receive counseling regarding riboflavin supplementation both before and during pregnancy and when breast feeding to avoid inducing riboflavin deficiency in the fetus and infant (see <a href="#riboflavin-tn.Pregnancy_Management">Pregnancy Management</a>).</div></li><li class="half_rhythm"><div>Women found to be <a class="def" href="/books/n/gene/glossary/def-item/heterozygous/">heterozygous</a> (carriers) for a <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a> in <i>SLC52A1</i> are recommended a diet rich in riboflavin during pregnancy, and should receive counseling regarding the possibility of riboflavin supplementation before and during pregnancy and when breastfeeding to avoid neonatal riboflavin deficiency. Although no data are available, the same approach should be considered in women who are heterozygous for a pathogenic variant in <i>SLC52A2</i> or <i>SLC52A3</i> to avoid the possibility of riboflavin deficiency in the fetus and infant.</div></li><li class="half_rhythm"><div>The optimal time for determination of genetic risk and discussion of the availability of prenatal/<a class="def" href="/books/n/gene/glossary/def-item/preimplantation-genetic-testing/">preimplantation genetic testing</a> is before pregnancy.</div></li><li class="half_rhythm"><div>It is appropriate to offer <a class="def" href="/books/n/gene/glossary/def-item/genetic-counseling/">genetic counseling</a> (including discussion of potential risks to offspring and reproductive options) to young adults who are carriers or are at risk of being carriers.</div></li></ul></div><div id="riboflavin-tn.Prenatal_Testing_and_Preim"><h3>Prenatal Testing and Preimplantation Genetic Testing</h3><p>Once the <i>SLC52A2</i> or <i>SLC52A3</i> pathogenic variants have been identified in an affected family member, prenatal and <a class="def" href="/books/n/gene/glossary/def-item/preimplantation-genetic-testing/">preimplantation genetic testing</a> are possible.</p><p>Differences in perspective may exist among medical professionals and within families regarding the use of <a class="def" href="/books/n/gene/glossary/def-item/prenatal-testing/">prenatal testing</a>. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.</p></div></div><div id="riboflavin-tn.Resources"><h2 id="_riboflavin-tn_Resources_">Resources</h2><p>
|
||
<i>GeneReviews staff has selected the following disease-specific and/or umbrella
|
||
support organizations and/or registries for the benefit of individuals with this disorder
|
||
and their families. GeneReviews is not responsible for the information provided by other
|
||
organizations. For information on selection criteria, click <a href="/books/n/gene/app4/">here</a>.</i></p>
|
||
<ul><li class="half_rhythm"><div>
|
||
<b>Cure RTD Foundation</b>
|
||
</div><div><b>Phone:</b> 403-244-4549</div><div><b>Email:</b> info@cureRTD.org</div><div>
|
||
<a href="http://curertd.org/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">www.curertd.org</a>
|
||
</div></li><li class="half_rhythm"><div>
|
||
<b>MedlinePlus</b>
|
||
</div><div>
|
||
<a href="https://medlineplus.gov/genetics/condition/riboflavin-transporter-deficiency-neuronopathy/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">Riboflavin transporter deficiency neuronopathy</a>
|
||
</div></li><li class="half_rhythm"><div>
|
||
<b>Cure RTD Registry</b>
|
||
</div><div>
|
||
<a href="http://curertd.org/research/rtdregistry/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">www.curertd.org/research/rtdregistry</a>
|
||
</div></li></ul>
|
||
</div><div id="riboflavin-tn.Molecular_Genetics"><h2 id="_riboflavin-tn_Molecular_Genetics_">Molecular Genetics</h2><p><i>Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —</i>ED.</p><div id="riboflavin-tn.molgen.TA" class="table"><h3><span class="label">Table A.</span></h3><div class="caption"><p>Riboflavin Transporter Deficiency: Genes and Databases</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK299312/table/riboflavin-tn.molgen.TA/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__riboflavin-tn.molgen.TA_lrgtbl__"><table class="no_bottom_margin"><tbody><tr><th id="hd_b_riboflavin-tn.molgen.TA_1_1_1_1" rowspan="1" colspan="1" style="vertical-align:top;">Gene</th><th id="hd_b_riboflavin-tn.molgen.TA_1_1_1_2" rowspan="1" colspan="1" style="vertical-align:top;">Chromosome Locus</th><th id="hd_b_riboflavin-tn.molgen.TA_1_1_1_3" rowspan="1" colspan="1" style="vertical-align:top;">Protein</th><th id="hd_b_riboflavin-tn.molgen.TA_1_1_1_4" rowspan="1" colspan="1" style="vertical-align:top;">Locus-Specific Databases</th><th id="hd_b_riboflavin-tn.molgen.TA_1_1_1_5" rowspan="1" colspan="1" style="vertical-align:top;">HGMD</th><th id="hd_b_riboflavin-tn.molgen.TA_1_1_1_6" rowspan="1" colspan="1" style="vertical-align:top;">ClinVar</th></tr><tr><td headers="hd_b_riboflavin-tn.molgen.TA_1_1_1_1" rowspan="1" colspan="1" style="vertical-align:top;">
|
||
<a href="/gene/55065" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=gene">
|
||
<i>SLC52A1</i>
|
||
</a>
|
||
</td><td headers="hd_b_riboflavin-tn.molgen.TA_1_1_1_2" rowspan="1" colspan="1" style="vertical-align:top;">
|
||
<a href="https://www.ncbi.nlm.nih.gov/genome/gdv/?context=gene&acc=55065" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">17p13<wbr style="display:inline-block"></wbr>.2</a>
|
||
</td><td headers="hd_b_riboflavin-tn.molgen.TA_1_1_1_3" rowspan="1" colspan="1" style="vertical-align:top;">
|
||
<a href="http://www.uniprot.org/uniprot/Q9NWF4" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">Solute carrier family 52, riboflavin transporter, member 1</a>
|
||
</td><td headers="hd_b_riboflavin-tn.molgen.TA_1_1_1_4" rowspan="1" colspan="1" style="vertical-align:top;">
|
||
<a href="https://www.lovd.nl/SLC52A1" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">SLC52A1 @ LOVD</a>
|
||
</td><td headers="hd_b_riboflavin-tn.molgen.TA_1_1_1_5" rowspan="1" colspan="1" style="vertical-align:top;">
|
||
<a href="http://www.hgmd.cf.ac.uk/ac/gene.php?gene=SLC52A1" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">SLC52A1</a>
|
||
</td><td headers="hd_b_riboflavin-tn.molgen.TA_1_1_1_6" rowspan="1" colspan="1" style="vertical-align:top;">
|
||
<a href="https://www.ncbi.nlm.nih.gov/clinvar/?term=SLC52A1[gene]" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">SLC52A1</a>
|
||
</td></tr><tr><td headers="hd_b_riboflavin-tn.molgen.TA_1_1_1_1" rowspan="1" colspan="1" style="vertical-align:top;">
|
||
<a href="/gene/79581" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=gene">
|
||
<i>SLC52A2</i>
|
||
</a>
|
||
</td><td headers="hd_b_riboflavin-tn.molgen.TA_1_1_1_2" rowspan="1" colspan="1" style="vertical-align:top;">
|
||
<a href="https://www.ncbi.nlm.nih.gov/genome/gdv/?context=gene&acc=79581" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">8q24<wbr style="display:inline-block"></wbr>.3</a>
|
||
</td><td headers="hd_b_riboflavin-tn.molgen.TA_1_1_1_3" rowspan="1" colspan="1" style="vertical-align:top;">
|
||
<a href="http://www.uniprot.org/uniprot/Q9HAB3" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">Solute carrier family 52, riboflavin transporter, member 2</a>
|
||
</td><td headers="hd_b_riboflavin-tn.molgen.TA_1_1_1_4" rowspan="1" colspan="1" style="vertical-align:top;">
|
||
<a href="https://databases.lovd.nl/shared/genes/SLC52A2" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">SLC52A2 database</a>
|
||
</td><td headers="hd_b_riboflavin-tn.molgen.TA_1_1_1_5" rowspan="1" colspan="1" style="vertical-align:top;">
|
||
<a href="http://www.hgmd.cf.ac.uk/ac/gene.php?gene=SLC52A2" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">SLC52A2</a>
|
||
</td><td headers="hd_b_riboflavin-tn.molgen.TA_1_1_1_6" rowspan="1" colspan="1" style="vertical-align:top;">
|
||
<a href="https://www.ncbi.nlm.nih.gov/clinvar/?term=SLC52A2[gene]" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">SLC52A2</a>
|
||
</td></tr><tr><td headers="hd_b_riboflavin-tn.molgen.TA_1_1_1_1" rowspan="1" colspan="1" style="vertical-align:top;">
|
||
<a href="/gene/113278" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=gene">
|
||
<i>SLC52A3</i>
|
||
</a>
|
||
</td><td headers="hd_b_riboflavin-tn.molgen.TA_1_1_1_2" rowspan="1" colspan="1" style="vertical-align:top;">
|
||
<a href="https://www.ncbi.nlm.nih.gov/genome/gdv/?context=gene&acc=113278" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">20p13</a>
|
||
</td><td headers="hd_b_riboflavin-tn.molgen.TA_1_1_1_3" rowspan="1" colspan="1" style="vertical-align:top;">
|
||
<a href="http://www.uniprot.org/uniprot/Q9NQ40" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">Solute carrier family 52, riboflavin transporter, member 3</a>
|
||
</td><td headers="hd_b_riboflavin-tn.molgen.TA_1_1_1_4" rowspan="1" colspan="1" style="vertical-align:top;">
|
||
<a href="http://databases.lovd.nl/shared/genes/SLC52A3" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">SLC52A3 database</a>
|
||
</td><td headers="hd_b_riboflavin-tn.molgen.TA_1_1_1_5" rowspan="1" colspan="1" style="vertical-align:top;">
|
||
<a href="http://www.hgmd.cf.ac.uk/ac/gene.php?gene=SLC52A3" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">SLC52A3</a>
|
||
</td><td headers="hd_b_riboflavin-tn.molgen.TA_1_1_1_6" rowspan="1" colspan="1" style="vertical-align:top;">
|
||
<a href="https://www.ncbi.nlm.nih.gov/clinvar/?term=SLC52A3[gene]" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">SLC52A3</a>
|
||
</td></tr></tbody></table></div><div><div><dl class="temp-labeled-list small"><dt></dt><dd><div id="riboflavin-tn.TFA.1"><p class="no_margin">Data are compiled from the following standard references: <a class="def" href="/books/n/gene/glossary/def-item/gene/">gene</a> from
|
||
<a href="http://www.genenames.org/index.html" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">HGNC</a>;
|
||
<a class="def" href="/books/n/gene/glossary/def-item/chromosome/">chromosome</a> <a class="def" href="/books/n/gene/glossary/def-item/locus/">locus</a> from
|
||
<a href="http://www.omim.org/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">OMIM</a>;
|
||
protein from <a href="http://www.uniprot.org/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">UniProt</a>.
|
||
For a description of databases (Locus Specific, HGMD, ClinVar) to which links are provided, click
|
||
<a href="/books/n/gene/app1/">here</a>.</p></div></dd></dl></div></div></div><div id="riboflavin-tn.molgen.TB" class="table"><h3><span class="label">Table B.</span></h3><div class="caption"><p>OMIM Entries for Riboflavin Transporter Deficiency (<a href="/omim/211500,211530,607882,607883,613350,614707,615026" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=omim">View All in OMIM</a>) </p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK299312/table/riboflavin-tn.molgen.TB/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__riboflavin-tn.molgen.TB_lrgtbl__"><table><tbody><tr><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
||
<a href="/omim/211500" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=omim">211500</a></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">FAZIO-LONDE DISEASE</td></tr><tr><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
||
<a href="/omim/211530" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=omim">211530</a></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">BROWN-VIALETTO-VAN LAERE SYNDROME 1; BVVLS1</td></tr><tr><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
||
<a href="/omim/607882" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=omim">607882</a></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">SOLUTE CARRIER FAMILY 52 (RIBOFLAVIN TRANSPORTER), MEMBER 2; SLC52A2</td></tr><tr><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
||
<a href="/omim/607883" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=omim">607883</a></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">SOLUTE CARRIER FAMILY 52 (RIBOFLAVIN TRANSPORTER), MEMBER 1; SLC52A1</td></tr><tr><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
||
<a href="/omim/613350" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=omim">613350</a></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">SOLUTE CARRIER FAMILY 52 (RIBOFLAVIN TRANSPORTER), MEMBER 3; SLC52A3</td></tr><tr><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
||
<a href="/omim/614707" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=omim">614707</a></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">BROWN-VIALETTO-VAN LAERE SYNDROME 2; BVVLS2</td></tr><tr><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
||
<a href="/omim/615026" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=omim">615026</a></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">RIBOFLAVIN DEFICIENCY; RBFVD</td></tr></tbody></table></div></div><div id="riboflavin-tn.Molecular_Pathogenesis"><h3>Molecular Pathogenesis</h3><p><i>SLC52A1, SLC52A2</i>, and <i>SLC52A3</i> encode the transmembrane proteins (hRFVT1, hRFVT2, and hRFVT3, respectively) that mediate cellular uptake of riboflavin (vitamin B<sub>2</sub>) in the intestine (as well as in the stomach, duodenum, colon, and rectum) and reabsorption in the kidney [<a class="bk_pop" href="#riboflavin-tn.REF.subramanian.2015.13">Subramanian et al 2015</a>, <a class="bk_pop" href="#riboflavin-tn.REF.udhayabanu.2016.210">Udhayabanu et al 2016</a>, <a class="bk_pop" href="#riboflavin-tn.REF.mosegaard.2020.3847">Mosegaard et al 2020</a>]. <i>SLC52A1</i> is highly expressed in the placenta and hRFVT1 is the only one of the three proteins to transport riboflavin to the fetus. The water-soluble vitamin riboflavin is then converted to the coenzymes flavin mononucleotide (FMN) and flavin adenine dinucleotide (FAD), which are essential for mitochondrial function and electron transfer in oxidation-reduction reactions [<a class="bk_pop" href="#riboflavin-tn.REF.udhayabanu.2016.210">Udhayabanu et al 2016</a>].</p><p><b>Mechanism of disease causation</b>. Loss of function. The pathogenic variants in <i>SLC52A2</i> and <i>SLC52A3</i> that cause loss of function may include <a class="def" href="/books/n/gene/glossary/def-item/missense/">missense</a>, <a class="def" href="/books/n/gene/glossary/def-item/nonsense-variant/">nonsense</a>, frameshift, and <a class="def" href="/books/n/gene/glossary/def-item/splice-site/">splice site</a> variants that reduce riboflavin uptake or riboflavin transporter protein expression [<a class="bk_pop" href="#riboflavin-tn.REF.haack.2012.943">Haack et al 2012</a>, <a class="bk_pop" href="#riboflavin-tn.REF.foley.2014.44">Foley et al 2014</a>, <a class="bk_pop" href="#riboflavin-tn.REF.manole.2017.2820">Manole et al 2017</a>].</p><div id="riboflavin-tn.T.riboflavin_transporter_d_1" class="table"><h3><span class="label">Table 7. </span></h3><div class="caption"><p>Riboflavin Transporter Deficiency: Gene-Specific Laboratory Technical Considerations</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK299312/table/riboflavin-tn.T.riboflavin_transporter_d_1/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__riboflavin-tn.T.riboflavin_transporter_d_1_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_riboflavin-tn.T.riboflavin_transporter_d_1_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Gene <sup>1</sup></th><th id="hd_h_riboflavin-tn.T.riboflavin_transporter_d_1_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Special Consideration</th></tr></thead><tbody><tr><td headers="hd_h_riboflavin-tn.T.riboflavin_transporter_d_1_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<i>SLC52A1</i>
|
||
</td><td headers="hd_h_riboflavin-tn.T.riboflavin_transporter_d_1_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">While a <a class="def" href="/books/n/gene/glossary/def-item/heterozygous/">heterozygous</a> multiexon <a class="def" href="/books/n/gene/glossary/def-item/deletion/">deletion</a> combined w/<a class="def" href="/books/n/gene/glossary/def-item/homozygous/">homozygous</a> <a class="def" href="/books/n/gene/glossary/def-item/exon/">exon</a> 3 <a class="def" href="/books/n/gene/glossary/def-item/deletion/">deletion</a> was reported in association w/RTD1, this observation may require further investigation [<a class="bk_pop" href="#riboflavin-tn.REF.kang.2020.160">Kang et al 2020</a>].</td></tr><tr><td headers="hd_h_riboflavin-tn.T.riboflavin_transporter_d_1_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<i>SLC52A2</i>
|
||
</td><td headers="hd_h_riboflavin-tn.T.riboflavin_transporter_d_1_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">To date only nonsynonymous pathogenic variants in the <a class="def" href="/books/n/gene/glossary/def-item/homozygous/">homozygous</a> or <a class="def" href="/books/n/gene/glossary/def-item/compound-heterozygous/">compound heterozygous</a> state have been reported in RTD2 [<a class="bk_pop" href="#riboflavin-tn.REF.bosch.2012.83">Bosch et al 2012</a>, <a class="bk_pop" href="#riboflavin-tn.REF.spagnoli.2014.231">Spagnoli et al 2014</a>].</td></tr><tr><td headers="hd_h_riboflavin-tn.T.riboflavin_transporter_d_1_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<i>SLC52A3</i>
|
||
</td><td headers="hd_h_riboflavin-tn.T.riboflavin_transporter_d_1_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Numerous pathogenic variants have been reported in the <a class="def" href="/books/n/gene/glossary/def-item/homozygous/">homozygous</a> & <a class="def" href="/books/n/gene/glossary/def-item/compound-heterozygous/">compound heterozygous</a> state in RTD3. Preliminary data suggest that in some persons <a class="def" href="/books/n/gene/glossary/def-item/heterozygous/">heterozygous</a> pathogenic variants in <i>SLC52A3</i> may be assoc w/RTD in the absence of conditions that lead to riboflavin depletion; however, this hypothesis requires further investigation [<a class="bk_pop" href="#riboflavin-tn.REF.khani.2021.102.e1">Khani et al 2021</a>].</td></tr></tbody></table></div><div><div><dl class="temp-labeled-list small"><dt></dt><dd><div><p class="no_margin">RTD1 = riboflavin transporter deficiency 1; RTD2 = RTD caused by <a class="def" href="/books/n/gene/glossary/def-item/biallelic/">biallelic</a> <i>SLC52A2</i> pathogenic variants; RTD3 = RTD caused by biallelic <i>SLC52A3</i> pathogenic variants</p></div></dd></dl></div></div></div><div id="riboflavin-tn.T.riboflavin_transporter_d_2" class="table"><h3><span class="label">Table 8. </span></h3><div class="caption"><p>Riboflavin Transporter Deficiency: Notable Pathogenic Variants by Gene</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK299312/table/riboflavin-tn.T.riboflavin_transporter_d_2/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__riboflavin-tn.T.riboflavin_transporter_d_2_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_riboflavin-tn.T.riboflavin_transporter_d_2_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Gene</th><th id="hd_h_riboflavin-tn.T.riboflavin_transporter_d_2_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Reference Sequences</th><th id="hd_h_riboflavin-tn.T.riboflavin_transporter_d_2_1_1_1_3" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">DNA Nucleotide Change</th><th id="hd_h_riboflavin-tn.T.riboflavin_transporter_d_2_1_1_1_4" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Predicted<br />Protein Change</th><th id="hd_h_riboflavin-tn.T.riboflavin_transporter_d_2_1_1_1_5" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Comment [Reference]</th></tr></thead><tbody><tr><td headers="hd_h_riboflavin-tn.T.riboflavin_transporter_d_2_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<i>SLC52A2</i>
|
||
</td><td headers="hd_h_riboflavin-tn.T.riboflavin_transporter_d_2_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<a href="https://www.ncbi.nlm.nih.gov/nuccore/NM_024531.4" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">NM_024531<wbr style="display:inline-block"></wbr>.4</a>
|
||
<br />
|
||
<a href="https://www.ncbi.nlm.nih.gov/protein/NP_078807.1" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">NP_078807<wbr style="display:inline-block"></wbr>.1</a>
|
||
</td><td headers="hd_h_riboflavin-tn.T.riboflavin_transporter_d_2_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">c.916G>A</td><td headers="hd_h_riboflavin-tn.T.riboflavin_transporter_d_2_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">p.Gly306Arg</td><td headers="hd_h_riboflavin-tn.T.riboflavin_transporter_d_2_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Founder variant in the Lebanese population [<a class="bk_pop" href="#riboflavin-tn.REF.foley.2014.44">Foley et al 2014</a>, <a class="bk_pop" href="#riboflavin-tn.REF.srour.2014.775">Srour et al 2014</a>]</td></tr><tr><td headers="hd_h_riboflavin-tn.T.riboflavin_transporter_d_2_1_1_1_1" rowspan="2" scope="row" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<i>SLC52A3</i>
|
||
</td><td headers="hd_h_riboflavin-tn.T.riboflavin_transporter_d_2_1_1_1_2" rowspan="2" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<a href="https://www.ncbi.nlm.nih.gov/nuccore/NM_033409.3" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">NM_033409<wbr style="display:inline-block"></wbr>.3</a>
|
||
<br />
|
||
<a href="https://www.ncbi.nlm.nih.gov/protein/NP_212134.3" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">NP_212134<wbr style="display:inline-block"></wbr>.3</a>
|
||
</td><td headers="hd_h_riboflavin-tn.T.riboflavin_transporter_d_2_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">c.710C>T</td><td headers="hd_h_riboflavin-tn.T.riboflavin_transporter_d_2_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">p.Ala237Val</td><td headers="hd_h_riboflavin-tn.T.riboflavin_transporter_d_2_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Variant w/an unusual pattern of inheritance in 2 related persons of Indian ancestry [<a class="bk_pop" href="#riboflavin-tn.REF.gayathri.2021.945">Gayathri et al 2021</a>]</td></tr><tr><td headers="hd_h_riboflavin-tn.T.riboflavin_transporter_d_2_1_1_1_3" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">c.986A>G</td><td headers="hd_h_riboflavin-tn.T.riboflavin_transporter_d_2_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">p.Tyr329Cys</td><td headers="hd_h_riboflavin-tn.T.riboflavin_transporter_d_2_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Preliminary data suggest that some persons <a class="def" href="/books/n/gene/glossary/def-item/heterozygous/">heterozygous</a> for this variant may manifest RTD in the absence of circumstances that cause riboflavin depletion, but this hypothesis requires further investigation [<a class="bk_pop" href="#riboflavin-tn.REF.khani.2021.102.e1">Khani et al 2021</a>].</td></tr></tbody></table></div><div><div><dl class="temp-labeled-list small"><dt></dt><dd><div><p class="no_margin">Variants listed in the table have been provided by the authors. <i>GeneReviews</i> staff have not independently verified the classification of variants.</p></div></dd><dt></dt><dd><div><p class="no_margin"><i>GeneReviews</i> follows the standard naming conventions of the Human Genome Variation Society (<a href="https://varnomen.hgvs.org/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">varnomen<wbr style="display:inline-block"></wbr>.hgvs.org</a>). See <a href="/books/n/gene/app3/">Quick Reference</a> for an explanation of nomenclature.</p></div></dd></dl></div></div></div></div></div><div id="riboflavin-tn.Chapter_Notes"><h2 id="_riboflavin-tn_Chapter_Notes_">Chapter Notes</h2><div id="riboflavin-tn.Author_Notes"><h3>Author Notes</h3><p>
|
||
<a href="https://www.cnmd.ac.uk/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">MRC Centre for Neuromuscular Diseases</a>
|
||
</p><p>The authors are interested in neuromuscular diseases, channelopathies, and neurodevelopmental disorders; their work involves both the genetics and the functional aspects of these disorders.</p><p>Emails for correspondence: <a href="mailto:dev@null" data-email="ku.ca.lcu@ilac.e" class="oemail">ku.ca.lcu@ilac.e</a> and <a href="mailto:dev@null" data-email="ku.ca.lcu@nedluoh.h" class="oemail">ku.ca.lcu@nedluoh.h</a></p></div><div id="riboflavin-tn.Acknowledgments"><h3>Acknowledgments</h3><p>The authors would like to thank the patients and their families for their essential help with this work. This study was supported by the Medical Research Council UK, the Wellcome Trust, and the Brain Research Trust (BRT). This study was also supported by the National Institute for Health Research University College London Hospitals Biomedical Research Centre (NIHR-UCLH-BRC).</p></div><div id="riboflavin-tn.Revision_History"><h3>Revision History</h3><ul><li class="half_rhythm"><div>8 April 2021 (bp) Comprehensive update posted live</div></li><li class="half_rhythm"><div>11 June 2015 (me) Review posted live</div></li><li class="half_rhythm"><div>2 September 2014 (am) Original submission</div></li></ul></div></div><div id="riboflavin-tn.References"><h2 id="_riboflavin-tn_References_">References</h2><div id="riboflavin-tn.Literature_Cited"><h3>Literature Cited</h3><ul class="simple-list"><li class="half_rhythm"><div class="bk_ref" id="riboflavin-tn.REF.abbas.2018.bcr2018224958">Abbas Q, Jafri SK, Ishaque S, Rahman AJ. Brown-Vialetto-Van Laere syndrome: a novel diagnosis to a common presentation. <span><span class="ref-journal">BMJ Case Rep. </span>2018;<span class="ref-vol">2018</span>:bcr2018224958. </span> [<a href="/pmc/articles/PMC6040568/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC6040568</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/29950502" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 29950502</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="riboflavin-tn.REF.amir.2020.283">Amir F, Atzinger C, Massey K, Greinwald J, Hunter LL, Ulm E, Kettler M. The clinical journey of patients with riboflavin transporter deficiency type 2. <span><span class="ref-journal">J Child Neurol. </span>2020;<span class="ref-vol">35</span>:283–90.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/31868069" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 31868069</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="riboflavin-tn.REF.anderson.2019.31">Anderson P, Schaefer S, Henderson L, Bruce IA. Cochlear implantation in children with auditory neuropathy: lessons from Brown-Vialetto-Van Laere syndrome. <span><span class="ref-journal">Cochlear Implants International. </span>2019;<span class="ref-vol">20</span>:31–8.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/30332915" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 30332915</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="riboflavin-tn.REF.babanejad.2018.195">Babanejad M, Adeli OA, Nikzat N, Beheshtian M, Azarafra H, Sadeghnia F, Mohseni M, Najmabadi H, Kahrizi K. SLC52A2 mutations cause SCABD2 phenotype: a second report. <span><span class="ref-journal">Int J Pediatr Otorhinolaryngol. </span>2018;<span class="ref-vol">104</span>:195–9.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/29287867" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 29287867</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="riboflavin-tn.REF.bamaga.2018.938">Bamaga AK, Maamari RN, Culican SM, Shinawi M, Golumbek PT. Child neurology: Brown-Vialetto-Van Laere syndrome: dramatic visual recovery after delayed riboflavin therapy. <span><span class="ref-journal">Neurology. </span>2018;<span class="ref-vol">91</span>:938–41.</span> [<a href="/pmc/articles/PMC6260193/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC6260193</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/30420458" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 30420458</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="riboflavin-tn.REF.bandettini_di_poggio.2014.141">Bandettini Di Poggio M, Monti Bragadin M, Reni L, Doria-Lamba L, Cereda C, Pardini M, Roccatagliata L, Rossi A, Schenone A. Brown-Vialetto-Van Laere syndrome: clinical and neuroradiological findings of a genetically proven patient. <span><span class="ref-journal">Amyotroph Lateral Scler Frontotemporal Degener. </span>2014;<span class="ref-vol">15</span>:141–4.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/24079556" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 24079556</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="riboflavin-tn.REF.bosch.2011.159">Bosch AM, Abeling NG, Ijlst L, Knoester H, van der Pol WL, Stroomer AE, Wanders RJ, Visser G, Wijburg FA, Duran M, Waterham HR. Brown-Vialetto-Van Laere and Fazio Londe syndrome is associated with a riboflavin transporter defect mimicking mild MADD: a new inborn error of metabolism with potential treatment. <span><span class="ref-journal">J Inherit Metab Dis. </span>2011;<span class="ref-vol">34</span>:159–64.</span> [<a href="/pmc/articles/PMC3026695/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC3026695</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/21110228" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 21110228</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="riboflavin-tn.REF.bosch.2012.83">Bosch AM, Stroek K, Abeling NG, Waterham HR, Ijlst L, Wanders RJ. The Brown-Vialetto-Van Laere and Fazio Londe syndrome revisited: natural history, genetics, treatment and future perspectives. <span><span class="ref-journal">Orphanet J Rare Dis. </span>2012;<span class="ref-vol">7</span>:83.</span> [<a href="/pmc/articles/PMC3517535/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC3517535</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/23107375" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 23107375</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="riboflavin-tn.REF.carmichael.2013.579">Carmichael SL, Yang W, Shaw GM. National Birth Defects Prevention Study: maternal dietary nutrient intake and risk of preterm delivery. <span><span class="ref-journal">Am J Perinatol. </span>2013;<span class="ref-vol">30</span>:579–88.</span> [<a href="/pmc/articles/PMC4041277/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC4041277</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/23208764" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 23208764</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="riboflavin-tn.REF.carreau.2020">Carreau C, Benoit C, Ahle G, Cauquil C, Roubertie A, Lenglet T, Cosgrove J, Meunier I, Veauville-Merllié A, Acquaviva-Bourdain C, Nadjar Y. Late-onset riboflavin transporter deficiency: a treatable mimic of various motor neuropathy aetiologies. <span><span class="ref-journal">J Neurol Neurosurg Psychiatry. </span>2020.</span> Epub ahead of print. [<a href="https://pubmed.ncbi.nlm.nih.gov/33087424" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 33087424</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="riboflavin-tn.REF.flokas.2019.99">Flokas ME, Tomani M, Agdere L, Brown B. Triple A syndrome (Allgrove syndrome): improving outcomes with a multidisciplinary approach. <span><span class="ref-journal">Pediatric Health Med Ther. </span>2019;<span class="ref-vol">10</span>:99–106.</span> [<a href="/pmc/articles/PMC6718240/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC6718240</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/31695556" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 31695556</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="riboflavin-tn.REF.foley.2014.44">Foley AR, Menezes MP, Pandraud A, Gonzalez MA, Al-Odaib A, Abrams AJ, Sugano K, Yonezawa A, Manzur AY, Burns J, Hughes I, McCullagh BG, Jungbluth H, Lim MJ, Lin JP, Megarbane A, Urtizberea JA, Shah AH, Antony J, Webster R, Broomfield A, Ng J, Mathew AA, O'Byrne JJ, Forman E, Scoto M, Prasad M, O'Brien K, Olpin S, Oppenheim M, Hargreaves I, Land JM, Wang MX, Carpenter K, Horvath R, Straub V, Lek M, Gold W, Farrell MO, Brandner S, Phadke R, Matsubara K, McGarvey ML, Scherer SS, Baxter PS, King MD, Clayton P, Rahman S, Reilly MM, Ouvrier RA, Christodoulou J, Züchner S, Muntoni F, Houlden H. Treatable childhood neuronopathy caused by mutations in riboflavin transporter RFVT2. <span><span class="ref-journal">Brain. </span>2014;<span class="ref-vol">137</span>:44–56.</span> [<a href="/pmc/articles/PMC3891447/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC3891447</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/24253200" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 24253200</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="riboflavin-tn.REF.garg.2018.471">Garg M, Kulkarni SD, Hegde AU, Shah KN. Riboflavin treatment in genetically proven Brown-Vialetto-Van Laere syndrome. <span><span class="ref-journal">J Pediatr Neurosci. </span>2018;<span class="ref-vol">13</span>:471–3.</span> [<a href="/pmc/articles/PMC6413615/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC6413615</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/30937093" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 30937093</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="riboflavin-tn.REF.gayathri.2021.945">Gayathri S, Gowda VK, Udhayabanu T, O'Callaghan B, Efthymiou S, Varalakshmi P, Benakappa N, Houlden H, Ashokkumar B. Brown-Vialetto-Van Laere and Fazio-Londe syndromes: SLC52A3 mutations with puzzling phenotypes and inheritance. <span><span class="ref-journal">Eur J Neurol. </span>2021;<span class="ref-vol">28</span>:945–54.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/33325104" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 33325104</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="riboflavin-tn.REF.gonz_lezp_rez.2012.391">González-Pérez P, Lu Y, Chian RJ, Sapp PC, Tanzi RE, Bertram L, McKenna-Yasek D, Gao FB, Brown RH Jr. Association of UBQLN1 mutation with Brown-Vialetto-Van Laere syndrome but not typical ALS. <span><span class="ref-journal">Neurobiol Dis. </span>2012;<span class="ref-vol">48</span>:391–8.</span> [<a href="/pmc/articles/PMC4245016/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC4245016</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/22766032" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 22766032</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="riboflavin-tn.REF.gorcenco.2019.245">Gorcenco S, Vaz FM, Tracewska-Siemiatkowska A, Tranebjærg L, Cremers FPM, Ygland E, Kicsi J, Rendtorff ND, Möller C, Kjellström U, Andréasson S, Puschmann A. Oral therapy for riboflavin transporter deficiency - what is the regimen of choice? <span><span class="ref-journal">Parkinsonism Relat Disord. </span>2019;<span class="ref-vol">61</span>:245–7.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/30343981" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 30343981</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="riboflavin-tn.REF.green.2010.485">Green P, Wiseman M, Crow YJ, Houlden H, Riphagen S, Lin JP, Raymond FL, Childs AM, Sheridan E, Edwards S, Josifova DJ. Brown-Vialetto-Van Laere syndrome, a ponto-bulbar palsy with deafness, is caused by mutations in c20orf54. <span><span class="ref-journal">Am J Hum Genet. </span>2010;<span class="ref-vol">86</span>:485–9.</span> [<a href="/pmc/articles/PMC2833371/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC2833371</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/20206331" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 20206331</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="riboflavin-tn.REF.haack.2012.943">Haack TB, Makowski C, Yao Y, Graf E, Hempel M, Wieland T, Tauer U, Ahting U, Mayr JA, Freisinger P, Yoshimatsu H, Inui K, Strom TM, Meitinger T, Yonezawa A, Prokisch H. Impaired riboflavin transport due to missense mutations in SLC52A2 causes Brown-Vialetto-Van Laere syndrome. <span><span class="ref-journal">J Inherit Metab Dis. </span>2012;<span class="ref-vol">35</span>:943–8.</span> [<a href="/pmc/articles/PMC3470687/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC3470687</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/22864630" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 22864630</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="riboflavin-tn.REF.ho.2011.e1976">Ho G, Yonezawa A, Masuda S, Inui K, Sim KG, Carpenter K, Olsen RK, Mitchell JJ, Rhead WJ, Peters G, Christodoulou J. Maternal riboflavin deficiency, resulting in transient neonatal-onset glutaric aciduria Type 2, is caused by a microdeletion in the riboflavin transporter gene GPR172B. <span><span class="ref-journal">Hum Mutat. </span>2011;<span class="ref-vol">32</span>:E1976–84.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/21089064" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 21089064</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="riboflavin-tn.REF.horvath.2012.679">Horvath R. Update on clinical aspects and treatment of selected vitamin-responsive disorders II (riboflavin and CoQ 10). <span><span class="ref-journal">J Inherit Metab Dis. </span>2012;<span class="ref-vol">35</span>:679–87.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/22231380" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 22231380</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="riboflavin-tn.REF.jaeger.2016.559">Jaeger B, Bosch AM. Clinical presentation and outcome of riboflavin transporter deficiency: mini review after five years of experience. <span><span class="ref-journal">J Inherit Metab Dis. </span>2016;<span class="ref-vol">39</span>:559–64.</span> [<a href="/pmc/articles/PMC4920840/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC4920840</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/26973221" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 26973221</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="riboflavin-tn.REF.johnson.2012.2875">Johnson JO, Gibbs JR, Megarbane A, Urtizberea JA, Hernandez DG, Foley AR, Arepalli S, Pandraud A, Simón-Sánchez J, Clayton P, Reilly MM, Muntoni F, Abramzon Y, Houlden H, Singleton AB. Exome sequencing reveals riboflavin transporter mutations as a cause of motor neuron disease. <span><span class="ref-journal">Brain. </span>2012;<span class="ref-vol">135</span>:2875–82.</span> [<a href="/pmc/articles/PMC3437022/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC3437022</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/22740598" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 22740598</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="riboflavin-tn.REF.johnson.2010.567">Johnson JO, Gibbs JR, Van Maldergem L, Houlden H, Singleton AB. Exome sequencing in Brown-Vialetto-van Laere syndrome. <span><span class="ref-journal">Am J Hum Genet. </span>2010;<span class="ref-vol">87</span>:567–9.</span> [<a href="/pmc/articles/PMC2948797/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC2948797</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/20920669" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 20920669</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="riboflavin-tn.REF.j_nsson.2017.519">Jónsson H, Sulem P, Kehr B, Kristmundsdottir S, Zink F, Hjartarson E, Hardarson MT, Hjorleifsson KE, Eggertsson HP, Gudjonsson SA, Ward LD, Arnadottir GA, Helgason EA, Helgason H, Gylfason A, Jonasdottir A, Jonasdottir A, Rafnar T, Frigge M, Stacey SN, Th Magnusson O, Thorsteinsdottir U, Masson G, Kong A, Halldorsson BV, Helgason A, Gudbjartsson DF, Stefansson K. Parental influence on human germline de novo mutations in 1,548 trios from Iceland. <span><span class="ref-journal">Nature. </span>2017;<span class="ref-vol">549</span>:519–22.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/28959963" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 28959963</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="riboflavin-tn.REF.kang.2020.160">Kang U, Yang DH, Nam SO, Lee Y-J, Yeon GM. Riboflavin transporter 1 deficiency caused by a homozygous single exonal deletion of SLC52A1. <span><span class="ref-journal">Ann Child Neurol. </span>2020;<span class="ref-vol">28</span>:160–3.</span></div></li><li class="half_rhythm"><div class="bk_ref" id="riboflavin-tn.REF.khani.2021.102.e1">Khani M, Shamshiri H, Taheri H, Hardy J, Bras JT, Carmona S, Moazzeni H, Alavi A, Heshmati A, Taghizadeh P, Nilipour Y, Ghazanfari T, Shahabi M, Okhovat AA, Rohani M, Valle G, Boostani R, Abdi S, Eshghi S, Nafissi S, Elahi E. BVVL/ FL: features caused by SLC52A3 mutations; WDFY4 and TNFSF13B may be novel causative genes. <span><span class="ref-journal">Neurobiol Aging. </span>2021;<span class="ref-vol">99</span>:102.e1–102.e10.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/33189404" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 33189404</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="riboflavin-tn.REF.kranthi.2020.1217">Kranthi P, Garuda BR, Gopi S, Kumar TS. Brown-Vialetto-Van Laere syndrome: a rare case report of MND mimic. <span><span class="ref-journal">Neurol India. </span>2020;<span class="ref-vol">68</span>:1217–9.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/33109881" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 33109881</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="riboflavin-tn.REF.manole.2014.506">Manole A, Fratta P, Houlden H. Recent advances in bulbar syndromes: genetic causes and disease mechanisms. <span><span class="ref-journal">Curr Opin Neurol. </span>2014;<span class="ref-vol">27</span>:506–14.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/25159929" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 25159929</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="riboflavin-tn.REF.manole.2017.2820">Manole A, Jaunmuktane Z, Hargreaves I, Ludtmann MHR, Salpietro V, Bello OD, Pope S, Pandraud A, Horga A, Scalco RS, Li A, Ashokkumar B, Lourenço CM, Heales S, Horvath R, Chinnery PF, Toro C, Singleton AB, Jacques TS, Abramov AY, Muntoni F, Hanna MG, Reilly MM, Revesz T, Kullmann DM, Jepson JEC, Houlden H. Clinical, pathological and functional characterization of riboflavin-responsive neuropathy. <span><span class="ref-journal">Brain. </span>2017;<span class="ref-vol">140</span>:2820–37.</span> [<a href="/pmc/articles/PMC5808726/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC5808726</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/29053833" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 29053833</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="riboflavin-tn.REF.mosegaard.2017.182">Mosegaard S, Bruun GH, Flyvbjerg KF, Bliksrud YT, Gregersen N, Dembic M, Annexstad E, Tangeraas T, Olsen RKJ, Andresen BS. An intronic variation in SLC52A1 causes exon skipping and transient riboflavin-responsive multiple acyl-CoA dehydrogenation deficiency. <span><span class="ref-journal">Mol Genet Metab. </span>2017;<span class="ref-vol">122</span>:182–8.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/29122468" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 29122468</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="riboflavin-tn.REF.mosegaard.2020.3847">Mosegaard S, Dipace G, Bross P, Carlsen J, Gregersen N, Olsen RKJ. Riboflavin deficiency-implications for general human health and inborn errors of metabolism. <span><span class="ref-journal">Int J Mol Sci. </span>2020;<span class="ref-vol">21</span>:3847.</span> [<a href="/pmc/articles/PMC7312377/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC7312377</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/32481712" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 32481712</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="riboflavin-tn.REF.mutlu.2019.201">Mutlu B, Topçu MT, Çiprut A. A case with Brown-Vialetto-Van Laere syndrome: a sudden onset auditory neuropathy spectrum disorder. <span><span class="ref-journal">Turk Arch Otorhinolaryngol. </span>2019;<span class="ref-vol">57</span>:201–5.</span> [<a href="/pmc/articles/PMC7032554/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC7032554</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/32128519" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 32128519</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="riboflavin-tn.REF.nalini.2013.119">Nalini A, Pandraud A, Mok K, Houlden H. Madras motor neuron disease (MMND) is distinct from the riboflavin transporter genetic defects that cause Brown-Vialetto-Van Laere syndrome. <span><span class="ref-journal">J Neurol Sci. </span>2013;<span class="ref-vol">334</span>:119–22.</span> [<a href="/pmc/articles/PMC4068726/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC4068726</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/24139842" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 24139842</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="riboflavin-tn.REF.ocallaghan.2019.598">O'Callaghan B, Bosch AM, Houlden H. An update on the genetics, clinical presentation, and pathomechanisms of human riboflavin transporter deficiency. <span><span class="ref-journal">J Inherit Metab Dis. </span>2019;<span class="ref-vol">42</span>:598–607.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/30793323" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 30793323</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="riboflavin-tn.REF.pagnamenta.2021">Pagnamenta AT, Kaiyrzhanov R, Zou Y, Da'as SI, Maroofian R, Donkervoort S, Dominik N, Lauffer M, Ferla MP, Orioli A, Giess A, Tucci A, Beetz C, Sedghi M, Ansari B, Barresi R, Basiri K, Cortese A, Elgar G, Fernandez-Garcia MA, Yip J, Foley AR, Gutowski N, Jungbluth H, Lassche S, Lavin T, Marcelis C, Marks P, Marini-Bettolo C, Medne L, Moslemi AR, Sarkozy A, Reilly MM, Muntoni F, Millan F, Muraresku CC, Need AC, Nemeth AH, Neuhaus SB, Norwood F, O'Donnell M, O'Driscoll M, Rankin J, Yum SW, Zolkipli-Cunningham Z, Brusius I, Wunderlich G; Genomics England Research Consortium, Karakaya M, Wirth B, Fakhro KA, Tajsharghi H, Bönnemann CG, Taylor JC, Houlden H. An ancestral 10-bp repeat expansion in VWA1 causes recessive hereditary motor neuropathy. 2021;144:584-600. [<a href="/pmc/articles/PMC8263055/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC8263055</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/33559681" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 33559681</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="riboflavin-tn.REF.pillai.2020.2781">Pillai NR, Amin H, Gijavanekar C, Liu N, Issaq N, Broniowska KA, Bertuch AA, Sutton VR, Elsea SH, Scaglia F. Hematologic presentation and the role of untargeted metabolomics analysis in monitoring treatment for riboflavin transporter deficiency. <span><span class="ref-journal">Am J Med Genet A. </span>2020;<span class="ref-vol">182</span>:2781–7.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/32909658" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 32909658</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="riboflavin-tn.REF.pinto.2019.238">Pinto WBVR, Naylor FGM, Chieia MAT, de Souza PVS, Oliveira ASB. New findings in facial-onset sensory and motor neuronopathy (FOSMN) syndrome. <span><span class="ref-journal">Rev Neurol (Paris). </span>2019;<span class="ref-vol">175</span>:238–46.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/30293881" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 30293881</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="riboflavin-tn.REF.rabbani.2020.342">Rabbani B, Bakhshandeh MK, Navaeifar MR, Abbaskhanian A, Soveizi M, Geravandpoor S, Mahdieh N. Brown-Vialetto-Van Laere syndrome and Fazio-Londe syndrome: a novel mutation and in silico analyses. <span><span class="ref-journal">J Clin Neurosci. </span>2020;<span class="ref-vol">72</span>:342–9.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/31959559" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 31959559</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="riboflavin-tn.REF.richards.2015.405">Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. <span><span class="ref-journal">Genet Med. </span>2015;<span class="ref-vol">17</span>:405–24.</span> [<a href="/pmc/articles/PMC4544753/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC4544753</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/25741868" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 25741868</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="riboflavin-tn.REF.rosemberg.1982.84">Rosemberg S, Lancellotti CL, Arita F, Campos C, de Castro NP Jr. Progressive bulbar paralysis of childhood (Fazio-Londe disease) with deafness. Case report with clinicopathologic correlation. <span><span class="ref-journal">Eur Neurol. </span>1982;<span class="ref-vol">21</span>:84–9.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/7094955" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 7094955</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="riboflavin-tn.REF.rossor.2012.6">Rossor AM, Kalmar B, Greensmith L, Reilly MM. The distal hereditary motor neuropathies. <span><span class="ref-journal">J Neurol Neurosurg Psychiatry. </span>2012;<span class="ref-vol">83</span>:6–14.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/22028385" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 22028385</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="riboflavin-tn.REF.saladini.2020.1169">Saladini M, Nizzardo M, Govoni A, Taiana M, Bresolin N, Comi GP, Corti S. Spinal muscular atrophy with respiratory distress type 1: clinical phenotypes, molecular pathogenesis and therapeutic insights. <span><span class="ref-journal">J Cell Mol Med. </span>2020;<span class="ref-vol">24</span>:1169–78.</span> [<a href="/pmc/articles/PMC6991628/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC6991628</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/31802621" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 31802621</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="riboflavin-tn.REF.shi.2019.76">Shi K, Shi Z, Yan H, Wang X, Yang Y, Xiong H, Gu Q, Wu Y, Jiang Y, Wang J. A Chinese pedigree with Brown-Vialetto-Van Laere syndrome due to two novel mutations of SLC52A2 gene: clinical course and response to riboflavin. <span><span class="ref-journal">BMC Med Genet. </span>2019;<span class="ref-vol">20</span>:76.</span> [<a href="/pmc/articles/PMC6505200/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC6505200</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/31064337" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 31064337</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="riboflavin-tn.REF.spagnoli.2014.231">Spagnoli C, Pitt MC, Rahman S, de Sousa C. Brown-Vialetto-van Laere syndrome: a riboflavin responsive neuronopathy of infancy with singular features. <span><span class="ref-journal">Eur J Paediatr Neurol. </span>2014;<span class="ref-vol">18</span>:231–4.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/24206674" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 24206674</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="riboflavin-tn.REF.srour.2014.775">Srour M, Putorti ML, Schwartzentruber J, Bolduc V, Shevell MI, Poulin C, O'ferrall E, Buhas D, Majewski J, Brais B, et al. Mutations in riboflavin transporter present with severe sensory loss and deafness in childhood. <span><span class="ref-journal">Muscle Nerve. </span>2014;<span class="ref-vol">50</span>:775–9.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/24616084" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 24616084</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="riboflavin-tn.REF.subramanian.2015.13">Subramanian VS, Kapadia R, Ghosal A, Said HM. Identification of residues/sequences in the human riboflavin transporter-2 that is important for function and cell biology. <span><span class="ref-journal">Nutr Metab (Lond). </span>2015;<span class="ref-vol">12</span>:13.</span> [<a href="/pmc/articles/PMC4367879/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC4367879</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/25798182" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 25798182</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="riboflavin-tn.REF.udhayabanu.2016.210">Udhayabanu T, Subramanian VS, Teafatiller T, Gowda VK, Raghavan VS, Varalakshmi P, Said HM, Ashokkumar B. SLC52A2 [p.P141T] and SLC52A3 [p.N21S] causing Brown-Vialetto-Van Laere syndrome in an Indian patient: first genetically proven case with mutations in two riboflavin transporters. <span><span class="ref-journal">Clin Chim Acta. </span>2016;<span class="ref-vol">462</span>:210–4.</span> [<a href="/pmc/articles/PMC5521005/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC5521005</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/27702554" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 27702554</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="riboflavin-tn.REF.yedavalli.2018.53">Yedavalli VS, Patil A, Shah P. Amyotrophic lateral sclerosis and its mimics/variants: a comprehensive review. <span><span class="ref-journal">J Clin Imaging Sci. </span>2018;<span class="ref-vol">8</span>:53.</span> [<a href="/pmc/articles/PMC6302559/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC6302559</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/30652056" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 30652056</span></a>]</div></li></ul></div></div><div id="bk_toc_contnr"></div></div></div>
|
||
<div class="post-content"><div><div class="half_rhythm"><a href="/books/about/copyright/">Copyright</a> © 1993-2025, University of Washington, Seattle. GeneReviews is
|
||
a registered trademark of the University of Washington, Seattle. All rights
|
||
reserved.<p class="small">GeneReviews® chapters are owned by the University of Washington. Permission is
|
||
hereby granted to reproduce, distribute, and translate copies of content materials for
|
||
noncommercial research purposes only, provided that (i) credit for source (<a href="http://www.genereviews.org/" ref="pagearea=meta&targetsite=external&targetcat=link&targettype=uri">http://www.genereviews.org/</a>) and copyright (© 1993-2025 University of
|
||
Washington) are included with each copy; (ii) a link to the original material is provided
|
||
whenever the material is published elsewhere on the Web; and (iii) reproducers,
|
||
distributors, and/or translators comply with the <a href="https://www.ncbi.nlm.nih.gov/books/n/gene/GRcopyright_permiss/" ref="pagearea=meta&targetsite=external&targetcat=link&targettype=uri">GeneReviews® Copyright Notice and Usage
|
||
Disclaimer</a>. No further modifications are allowed. For clarity, excerpts
|
||
of GeneReviews chapters for use in lab reports and clinic notes are a permitted
|
||
use.</p><p class="small">For more information, see the <a href="https://www.ncbi.nlm.nih.gov/books/n/gene/GRcopyright_permiss/" ref="pagearea=meta&targetsite=external&targetcat=link&targettype=uri">GeneReviews® Copyright Notice and Usage
|
||
Disclaimer</a>.</p><p class="small">For questions regarding permissions or whether a specified use is allowed,
|
||
contact: <a href="mailto:dev@null" data-email="ude.wu@tssamda" class="oemail">ude.wu@tssamda</a>.</p></div><div class="small"><span class="label">Bookshelf ID: NBK299312</span><span class="label">PMID: <a href="https://pubmed.ncbi.nlm.nih.gov/26072523" title="PubMed record of this page" ref="pagearea=meta&targetsite=entrez&targetcat=link&targettype=pubmed">26072523</a></span></div><div style="margin-top:2em" class="bk_noprnt"><a class="bk_cntns" href="/books/n/gene/">GeneReviews by Title</a><div class="pagination bk_noprnt"><a class="active page_link prev" href="/books/n/gene/rcdp/" title="Previous page in this title">< Prev</a><a class="active page_link next" href="/books/n/gene/ritscher-schinzel/" title="Next page in this title">Next ></a></div></div></div></div>
|
||
|
||
</div>
|
||
|
||
<!-- Custom content below content -->
|
||
<div class="col4">
|
||
|
||
</div>
|
||
|
||
|
||
<!-- Book content -->
|
||
|
||
<!-- Custom contetnt below bottom nav -->
|
||
<div class="col5">
|
||
|
||
</div>
|
||
</div>
|
||
|
||
<div id="rightcolumn" class="four_col col last">
|
||
<!-- Custom content above discovery portlets -->
|
||
<div class="col6">
|
||
<div id="ncbi_share_book"><a href="#" class="ncbi_share" data-ncbi_share_config="popup:false,shorten:true" ref="id=NBK299312&db=books">Share</a></div>
|
||
|
||
</div>
|
||
<div xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"></div><div class="portlet"><div class="portlet_head"><div class="portlet_title"><h3><span>Views</span></h3></div><a name="Shutter" sid="1" href="#" class="portlet_shutter" title="Show/hide content" remembercollapsed="true" pgsec_name="PDF_download" id="Shutter"></a></div><div class="portlet_content"><ul xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="simple-list"><li><a href="/books/NBK299312/?report=reader">PubReader</a></li><li><a href="/books/NBK299312/?report=printable">Print View</a></li><li><a data-jig="ncbidialog" href="#_ncbi_dlg_citbx_NBK299312" data-jigconfig="width:400,modal:true">Cite this Page</a><div id="_ncbi_dlg_citbx_NBK299312" style="display:none" title="Cite this Page"><div class="bk_tt">Cali E, Dominik N, Manole A, et al. Riboflavin Transporter Deficiency. 2015 Jun 11 [Updated 2021 Apr 8]. In: Adam MP, Feldman J, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2025. <span class="bk_cite_avail"></span></div></div></li><li><a href="/books/NBK299312/pdf/Bookshelf_NBK299312.pdf">PDF version of this page</a> (600K)</li><li><a href="#" class="toggle-glossary-link" title="Enable/disable links to the glossary">Disable Glossary Links</a></li></ul></div></div><div class="portlet"><div class="portlet_head"><div class="portlet_title"><h3><span>In this GeneReview</span></h3></div><a name="Shutter" sid="1" href="#" class="portlet_shutter" title="Show/hide content" remembercollapsed="true" pgsec_name="page-toc" id="Shutter"></a></div><div class="portlet_content"><ul xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="simple-list"><li><a href="#riboflavin-tn.Summary" ref="log$=inpage&link_id=inpage">Summary</a></li><li><a href="#riboflavin-tn.GeneReview_Scope" ref="log$=inpage&link_id=inpage"><i>GeneReview</i> Scope</a></li><li><a href="#riboflavin-tn.Diagnosis" ref="log$=inpage&link_id=inpage">Diagnosis</a></li><li><a href="#riboflavin-tn.Clinical_Characteristics" ref="log$=inpage&link_id=inpage">Clinical Characteristics</a></li><li><a href="#riboflavin-tn.Genetically_Related_Alleli" ref="log$=inpage&link_id=inpage">Genetically Related (Allelic) Disorders</a></li><li><a href="#riboflavin-tn.Differential_Diagnosis" ref="log$=inpage&link_id=inpage">Differential Diagnosis</a></li><li><a href="#riboflavin-tn.Management" ref="log$=inpage&link_id=inpage">Management</a></li><li><a href="#riboflavin-tn.Genetic_Counseling" ref="log$=inpage&link_id=inpage">Genetic Counseling</a></li><li><a href="#riboflavin-tn.Resources" ref="log$=inpage&link_id=inpage">Resources</a></li><li><a href="#riboflavin-tn.Molecular_Genetics" ref="log$=inpage&link_id=inpage">Molecular Genetics</a></li><li><a href="#riboflavin-tn.Chapter_Notes" ref="log$=inpage&link_id=inpage">Chapter Notes</a></li><li><a href="#riboflavin-tn.References" ref="log$=inpage&link_id=inpage">References</a></li></ul></div></div><div class="portlet"><div class="portlet_head"><div class="portlet_title"><h3><span>Bulk Download</span></h3></div><a name="Shutter" sid="1" href="#" class="portlet_shutter" title="Show/hide content" remembercollapsed="true" pgsec_name="source-links" id="Shutter"></a></div><div class="portlet_content"><ul xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="simple-list"><li><a href="https://ftp.ncbi.nlm.nih.gov/pub/litarch/ca/84/" ref="pagearea=source-links&targetsite=external&targetcat=link&targettype=uri">Bulk download GeneReviews data from FTP</a></li></ul></div></div><div class="portlet"><div class="portlet_head"><div class="portlet_title"><h3><span>GeneReviews Links</span></h3></div><a name="Shutter" sid="1" href="#" class="portlet_shutter" title="Show/hide content" remembercollapsed="true" pgsec_name="source-links" id="Shutter"></a></div><div class="portlet_content"><ul xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="simple-list"><li><a href="/books/n/gene/advanced/"><i>GeneReviews</i> Advanced Search</a></li><li><a href="/books/n/gene/glossary/"><i>GeneReviews</i> Glossary</a></li><li><a href="/books/n/gene/resource_mats/">Resource Materials</a> <span class="bk_hlight1">NEW FEATURE</span></li><li><a href="/books/n/gene/updates/">New in <i>GeneReviews</i></a></li><li><a href="/books/n/gene/authors/">Author List</a></li><li><a href="/books/n/gene/prospective_authors/">For Current/Prospective Authors</a></li><li><a href="/books/n/gene/GRpersonnel/"><i>GeneReviews</i> Personnel</a></li><li><a href="/books/n/gene/howto_linkin/">Download/Link to <i>GeneReviews</i></a></li><li><a href="/books/n/gene/contact_us/">Contact Us</a></li></ul></div></div><div class="portlet"><div class="portlet_head"><div class="portlet_title"><h3><span>Tests in GTR by Gene</span></h3></div><a name="Shutter" sid="1" href="#" class="portlet_shutter" title="Show/hide content" remembercollapsed="true" pgsec_name="document-links" id="Shutter"></a></div><div class="portlet_content"><ul xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="simple-list"><li>
|
||
<a href="https://www.ncbi.nlm.nih.gov/gtr/tests/?term=113278[geneid]" ref="pagearea=document-links&targetsite=external&targetcat=link&targettype=uri&link_id=tests_in_gtr_by_gene">SLC52A3</a>
|
||
</li><li>
|
||
<a href="https://www.ncbi.nlm.nih.gov/gtr/tests/?term=79581[geneid]" ref="pagearea=document-links&targetsite=external&targetcat=link&targettype=uri&link_id=tests_in_gtr_by_gene">SLC52A2</a>
|
||
</li><li>
|
||
<a href="https://www.ncbi.nlm.nih.gov/gtr/tests/?term=55065[geneid]" ref="pagearea=document-links&targetsite=external&targetcat=link&targettype=uri&link_id=tests_in_gtr_by_gene">SLC52A1</a>
|
||
</li></ul></div></div><div class="portlet"><div class="portlet_head"><div class="portlet_title"><h3><span>Related information</span></h3></div><a name="Shutter" sid="1" href="#" class="portlet_shutter" title="Show/hide content" remembercollapsed="true" pgsec_name="discovery_db_links" id="Shutter"></a></div><div class="portlet_content"><ul><li class="brieflinkpopper"><a class="brieflinkpopperctrl" href="/books/?Db=omim&DbFrom=books&Cmd=Link&LinkName=books_omim&IdsFromResult=4077796" ref="log$=recordlinks">OMIM</a><div class="brieflinkpop offscreen_noflow">Related OMIM records</div></li><li class="brieflinkpopper"><a class="brieflinkpopperctrl" href="/books/?Db=pmc&DbFrom=books&Cmd=Link&LinkName=books_pmc_refs&IdsFromResult=4077796" ref="log$=recordlinks">PMC</a><div class="brieflinkpop offscreen_noflow">PubMed Central citations</div></li><li class="brieflinkpopper"><a class="brieflinkpopperctrl" href="/books/?Db=pubmed&DbFrom=books&Cmd=Link&LinkName=books_pubmed_refs&IdsFromResult=4077796" ref="log$=recordlinks">PubMed</a><div class="brieflinkpop offscreen_noflow">Links to PubMed</div></li><li class="brieflinkpopper"><a class="brieflinkpopperctrl" href="/books/?Db=gene&DbFrom=books&Cmd=Link&LinkName=books_gene&IdsFromResult=4077796" ref="log$=recordlinks">Gene</a><div class="brieflinkpop offscreen_noflow">Locus Links</div></li></ul></div></div><div class="portlet"><div class="portlet_head"><div class="portlet_title"><h3><span>Similar articles in PubMed</span></h3></div><a name="Shutter" sid="1" href="#" class="portlet_shutter" title="Show/hide content" remembercollapsed="true" pgsec_name="PBooksDiscovery_RA" id="Shutter"></a></div><div class="portlet_content"><ul><li class="brieflinkpopper two_line"><a class="brieflinkpopperctrl" href="/pubmed/20301656" ref="ordinalpos=1&linkpos=1&log$=relatedreviews&logdbfrom=pubmed"><span xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="invert">Review</span> Adenosine Deaminase Deficiency.</a><span class="source">[GeneReviews(®). 1993]</span><div class="brieflinkpop offscreen_noflow"><span xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="invert">Review</span> Adenosine Deaminase Deficiency.<div class="brieflinkpopdesc"><em xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="author">Hershfield M, Tarrant T. </em><em xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="cit">GeneReviews(®). 1993</em></div></div></li><li class="brieflinkpopper two_line"><a class="brieflinkpopperctrl" href="/pubmed/20301631" ref="ordinalpos=1&linkpos=2&log$=relatedreviews&logdbfrom=pubmed"><span xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="invert">Review</span> Citrullinemia Type I.</a><span class="source">[GeneReviews(®). 1993]</span><div class="brieflinkpop offscreen_noflow"><span xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="invert">Review</span> Citrullinemia Type I.<div class="brieflinkpopdesc"><em xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="author">Quinonez SC, Lee KN. </em><em xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="cit">GeneReviews(®). 1993</em></div></div></li><li class="brieflinkpopper two_line"><a class="brieflinkpopperctrl" href="/pubmed/24404629" ref="ordinalpos=1&linkpos=3&log$=relatedreviews&logdbfrom=pubmed"><span xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="invert">Review</span> Familial Hypercholesterolemia.</a><span class="source">[GeneReviews(®). 1993]</span><div class="brieflinkpop offscreen_noflow"><span xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="invert">Review</span> Familial Hypercholesterolemia.<div class="brieflinkpopdesc"><em xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="author">Ison HE, Clarke SL, Knowles JW. </em><em xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="cit">GeneReviews(®). 1993</em></div></div></li><li class="brieflinkpopper two_line"><a class="brieflinkpopperctrl" href="/pubmed/20301409" ref="ordinalpos=1&linkpos=4&log$=relatedreviews&logdbfrom=pubmed"><span xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="invert">Review</span> Isolated Methylmalonic Acidemia.</a><span class="source">[GeneReviews(®). 1993]</span><div class="brieflinkpop offscreen_noflow"><span xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="invert">Review</span> Isolated Methylmalonic Acidemia.<div class="brieflinkpopdesc"><em xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="author">Manoli I, Sloan JL, Venditti CP. </em><em xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="cit">GeneReviews(®). 1993</em></div></div></li><li class="brieflinkpopper two_line"><a class="brieflinkpopperctrl" href="/pubmed/35862567" ref="ordinalpos=1&linkpos=5&log$=relatedreviews&logdbfrom=pubmed"><span xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="invert">Review</span> Carnitine-Acylcarnitine Translocase Deficiency.</a><span class="source">[GeneReviews(®). 1993]</span><div class="brieflinkpop offscreen_noflow"><span xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="invert">Review</span> Carnitine-Acylcarnitine Translocase Deficiency.<div class="brieflinkpopdesc"><em xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="author">Morales Corado JA, Lee CU, Enns GM. </em><em xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="cit">GeneReviews(®). 1993</em></div></div></li></ul><a class="seemore" href="/sites/entrez?db=pubmed&cmd=link&linkname=pubmed_pubmed_reviews&uid=26072523" ref="ordinalpos=1&log$=relatedreviews_seeall&logdbfrom=pubmed">See reviews...</a><a class="seemore" href="/sites/entrez?db=pubmed&cmd=link&linkname=pubmed_pubmed&uid=26072523" ref="ordinalpos=1&log$=relatedarticles_seeall&logdbfrom=pubmed">See all...</a></div></div><div class="portlet"><div class="portlet_head"><div class="portlet_title"><h3><span>Recent Activity</span></h3></div><a name="Shutter" sid="1" href="#" class="portlet_shutter" title="Show/hide content" remembercollapsed="true" pgsec_name="recent_activity" id="Shutter"></a></div><div class="portlet_content"><div xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" id="HTDisplay" class=""><div class="action"><a href="javascript:historyDisplayState('ClearHT')">Clear</a><a href="javascript:historyDisplayState('HTOff')" class="HTOn">Turn Off</a><a href="javascript:historyDisplayState('HTOn')" class="HTOff">Turn On</a></div><ul id="activity"><li class="ra_rcd ralinkpopper two_line"><a class="htb ralinkpopperctrl" ref="log$=activity&linkpos=1" href="/portal/utils/pageresolver.fcgi?recordid=67d2afc5a68b6b5afc989ed4">Riboflavin Transporter Deficiency - GeneReviews®</a><div class="ralinkpop offscreen_noflow">Riboflavin Transporter Deficiency - GeneReviews®<div class="brieflinkpopdesc"></div></div><div class="tertiary"></div></li><li class="ra_rcd ralinkpopper two_line"><a class="htb ralinkpopperctrl" ref="log$=activity&linkpos=2" href="/portal/utils/pageresolver.fcgi?recordid=67d2afc384f3725e594f2c1a">Rhizomelic Chondrodysplasia Punctata Type 1 - GeneReviews®</a><div class="ralinkpop offscreen_noflow">Rhizomelic Chondrodysplasia Punctata Type 1 - GeneReviews®<div class="brieflinkpopdesc"></div></div><div class="tertiary"></div></li><li class="ra_rcd ralinkpopper two_line"><a class="htb ralinkpopperctrl" ref="log$=activity&linkpos=3" href="/portal/utils/pageresolver.fcgi?recordid=67d2afc0b15b832ebc32095c">Rhabdoid Tumor Predisposition Syndrome - GeneReviews®</a><div class="ralinkpop offscreen_noflow">Rhabdoid Tumor Predisposition Syndrome - GeneReviews®<div class="brieflinkpopdesc"></div></div><div class="tertiary"></div></li><li class="ra_rcd ralinkpopper two_line"><a class="htb ralinkpopperctrl" ref="log$=activity&linkpos=4" href="/portal/utils/pageresolver.fcgi?recordid=67d2afbda68b6b5afc986290">Retinoblastoma - GeneReviews®</a><div class="ralinkpop offscreen_noflow">Retinoblastoma - GeneReviews®<div class="brieflinkpopdesc"></div></div><div class="tertiary"></div></li><li class="ra_rcd ralinkpopper two_line"><a class="htb ralinkpopperctrl" ref="log$=activity&linkpos=5" href="/portal/utils/pageresolver.fcgi?recordid=67d2afba84f3725e594eed3b">Retinal Vasculopathy with Cerebral Leukoencephalopathy and Systemic Manifestatio...</a><div class="ralinkpop offscreen_noflow">Retinal Vasculopathy with Cerebral Leukoencephalopathy and Systemic Manifestations - GeneReviews®<div class="brieflinkpopdesc"></div></div><div class="tertiary"></div></li></ul><p class="HTOn">Your browsing activity is empty.</p><p class="HTOff">Activity recording is turned off.</p><p id="turnOn" class="HTOff"><a href="javascript:historyDisplayState('HTOn')">Turn recording back on</a></p><a class="seemore" href="/sites/myncbi/recentactivity">See more...</a></div></div></div>
|
||
|
||
<!-- Custom content below discovery portlets -->
|
||
<div class="col7">
|
||
|
||
</div>
|
||
</div>
|
||
</div>
|
||
|
||
<!-- Custom content after all -->
|
||
<div class="col8">
|
||
|
||
</div>
|
||
<div class="col9">
|
||
|
||
</div>
|
||
|
||
<script type="text/javascript" src="/corehtml/pmc/js/jquery.scrollTo-1.4.2.js"></script>
|
||
<script type="text/javascript">
|
||
(function($){
|
||
$('.skiplink').each(function(i, item){
|
||
var href = $($(item).attr('href'));
|
||
href.attr('tabindex', '-1').addClass('skiptarget'); // ensure the target can receive focus
|
||
$(item).on('click', function(event){
|
||
event.preventDefault();
|
||
$.scrollTo(href, 0, {
|
||
onAfter: function(){
|
||
href.focus();
|
||
}
|
||
});
|
||
});
|
||
});
|
||
})(jQuery);
|
||
</script>
|
||
</div>
|
||
<div class="bottom">
|
||
|
||
<div id="NCBIFooter_dynamic">
|
||
<!--<component id="Breadcrumbs" label="breadcrumbs"/>
|
||
<component id="Breadcrumbs" label="helpdesk"/>-->
|
||
|
||
</div>
|
||
|
||
<div class="footer" id="footer">
|
||
<section class="icon-section">
|
||
<div id="icon-section-header" class="icon-section_header">Follow NCBI</div>
|
||
<div class="grid-container container">
|
||
<div class="icon-section_container">
|
||
<a class="footer-icon" id="footer_twitter" href="https://twitter.com/ncbi" aria-label="Twitter"><svg xmlns="http://www.w3.org/2000/svg" data-name="Layer 1" viewBox="0 0 300 300">
|
||
<defs>
|
||
<style>
|
||
.cls-11 {
|
||
fill: #737373;
|
||
}
|
||
</style>
|
||
</defs>
|
||
<title>Twitter</title>
|
||
<path class="cls-11" d="M250.11,105.48c-7,3.14-13,3.25-19.27.14,8.12-4.86,8.49-8.27,11.43-17.46a78.8,78.8,0,0,1-25,9.55,39.35,39.35,0,0,0-67,35.85,111.6,111.6,0,0,1-81-41.08A39.37,39.37,0,0,0,81.47,145a39.08,39.08,0,0,1-17.8-4.92c0,.17,0,.33,0,.5a39.32,39.32,0,0,0,31.53,38.54,39.26,39.26,0,0,1-17.75.68,39.37,39.37,0,0,0,36.72,27.3A79.07,79.07,0,0,1,56,223.34,111.31,111.31,0,0,0,116.22,241c72.3,0,111.83-59.9,111.83-111.84,0-1.71,0-3.4-.1-5.09C235.62,118.54,244.84,113.37,250.11,105.48Z">
|
||
</path>
|
||
</svg></a>
|
||
<a class="footer-icon" id="footer_facebook" href="https://www.facebook.com/ncbi.nlm" aria-label="Facebook"><svg xmlns="http://www.w3.org/2000/svg" data-name="Layer 1" viewBox="0 0 300 300">
|
||
<title>Facebook</title>
|
||
<path class="cls-11" d="M210.5,115.12H171.74V97.82c0-8.14,5.39-10,9.19-10h27.14V52l-39.32-.12c-35.66,0-42.42,26.68-42.42,43.77v19.48H99.09v36.32h27.24v109h45.41v-109h35Z">
|
||
</path>
|
||
</svg></a>
|
||
<a class="footer-icon" id="footer_linkedin" href="https://www.linkedin.com/company/ncbinlm" aria-label="LinkedIn"><svg xmlns="http://www.w3.org/2000/svg" data-name="Layer 1" viewBox="0 0 300 300">
|
||
<title>LinkedIn</title>
|
||
<path class="cls-11" d="M101.64,243.37H57.79v-114h43.85Zm-22-131.54h-.26c-13.25,0-21.82-10.36-21.82-21.76,0-11.65,8.84-21.15,22.33-21.15S101.7,78.72,102,90.38C102,101.77,93.4,111.83,79.63,111.83Zm100.93,52.61A17.54,17.54,0,0,0,163,182v61.39H119.18s.51-105.23,0-114H163v13a54.33,54.33,0,0,1,34.54-12.66c26,0,44.39,18.8,44.39,55.29v58.35H198.1V182A17.54,17.54,0,0,0,180.56,164.44Z">
|
||
</path>
|
||
</svg></a>
|
||
<a class="footer-icon" id="footer_github" href="https://github.com/ncbi" aria-label="GitHub"><svg xmlns="http://www.w3.org/2000/svg" data-name="Layer 1" viewBox="0 0 300 300">
|
||
<defs>
|
||
<style>
|
||
.cls-11,
|
||
.cls-12 {
|
||
fill: #737373;
|
||
}
|
||
|
||
.cls-11 {
|
||
fill-rule: evenodd;
|
||
}
|
||
</style>
|
||
</defs>
|
||
<title>GitHub</title>
|
||
<path class="cls-11" d="M151.36,47.28a105.76,105.76,0,0,0-33.43,206.1c5.28,1,7.22-2.3,7.22-5.09,0-2.52-.09-10.85-.14-19.69-29.42,6.4-35.63-12.48-35.63-12.48-4.81-12.22-11.74-15.47-11.74-15.47-9.59-6.56.73-6.43.73-6.43,10.61.75,16.21,10.9,16.21,10.9,9.43,16.17,24.73,11.49,30.77,8.79,1-6.83,3.69-11.5,6.71-14.14C108.57,197.1,83.88,188,83.88,147.51a40.92,40.92,0,0,1,10.9-28.39c-1.1-2.66-4.72-13.42,1-28,0,0,8.88-2.84,29.09,10.84a100.26,100.26,0,0,1,53,0C198,88.3,206.9,91.14,206.9,91.14c5.76,14.56,2.14,25.32,1,28a40.87,40.87,0,0,1,10.89,28.39c0,40.62-24.74,49.56-48.29,52.18,3.79,3.28,7.17,9.71,7.17,19.58,0,14.15-.12,25.54-.12,29,0,2.82,1.9,6.11,7.26,5.07A105.76,105.76,0,0,0,151.36,47.28Z">
|
||
</path>
|
||
<path class="cls-12" d="M85.66,199.12c-.23.52-1.06.68-1.81.32s-1.2-1.06-.95-1.59,1.06-.69,1.82-.33,1.21,1.07.94,1.6Zm-1.3-1">
|
||
</path>
|
||
<path class="cls-12" d="M90,203.89c-.51.47-1.49.25-2.16-.49a1.61,1.61,0,0,1-.31-2.19c.52-.47,1.47-.25,2.17.49s.82,1.72.3,2.19Zm-1-1.08">
|
||
</path>
|
||
<path class="cls-12" d="M94.12,210c-.65.46-1.71,0-2.37-.91s-.64-2.07,0-2.52,1.7,0,2.36.89.65,2.08,0,2.54Zm0,0"></path>
|
||
<path class="cls-12" d="M99.83,215.87c-.58.64-1.82.47-2.72-.41s-1.18-2.06-.6-2.7,1.83-.46,2.74.41,1.2,2.07.58,2.7Zm0,0">
|
||
</path>
|
||
<path class="cls-12" d="M107.71,219.29c-.26.82-1.45,1.2-2.64.85s-2-1.34-1.74-2.17,1.44-1.23,2.65-.85,2,1.32,1.73,2.17Zm0,0">
|
||
</path>
|
||
<path class="cls-12" d="M116.36,219.92c0,.87-1,1.59-2.24,1.61s-2.29-.68-2.3-1.54,1-1.59,2.26-1.61,2.28.67,2.28,1.54Zm0,0">
|
||
</path>
|
||
<path class="cls-12" d="M124.42,218.55c.15.85-.73,1.72-2,1.95s-2.37-.3-2.52-1.14.73-1.75,2-2,2.37.29,2.53,1.16Zm0,0"></path>
|
||
</svg></a>
|
||
<a class="footer-icon" id="footer_blog" href="https://ncbiinsights.ncbi.nlm.nih.gov/" aria-label="Blog">
|
||
<svg xmlns="http://www.w3.org/2000/svg" id="Layer_1" data-name="Layer 1" viewBox="0 0 40 40">
|
||
<defs><style>.cls-1{fill:#737373;}</style></defs>
|
||
<title>NCBI Insights Blog</title>
|
||
<path class="cls-1" d="M14,30a4,4,0,1,1-4-4,4,4,0,0,1,4,4Zm11,3A19,19,0,0,0,7.05,15a1,1,0,0,0-1,1v3a1,1,0,0,0,.93,1A14,14,0,0,1,20,33.07,1,1,0,0,0,21,34h3a1,1,0,0,0,1-1Zm9,0A28,28,0,0,0,7,6,1,1,0,0,0,6,7v3a1,1,0,0,0,1,1A23,23,0,0,1,29,33a1,1,0,0,0,1,1h3A1,1,0,0,0,34,33Z"></path>
|
||
</svg>
|
||
</a>
|
||
</div>
|
||
</div>
|
||
</section>
|
||
|
||
<section class="container-fluid bg-primary">
|
||
<div class="container pt-5">
|
||
<div class="row mt-3">
|
||
<div class="col-lg-3 col-12">
|
||
<p><a class="text-white" href="https://www.nlm.nih.gov/socialmedia/index.html">Connect with NLM</a></p>
|
||
<ul class="list-inline social_media">
|
||
<li class="list-inline-item"><a href="https://twitter.com/NLM_NIH" aria-label="Twitter" target="_blank" rel="noopener noreferrer"><svg xmlns="http://www.w3.org/2000/svg" xmlns:xlink="http://www.w3.org/1999/xlink" version="1.1" x="0px" y="0px" viewBox="0 0 249 249" style="enable-background:new 0 0 249 249;" xml:space="preserve">
|
||
<style type="text/css">
|
||
.st20 {
|
||
fill: #FFFFFF;
|
||
}
|
||
|
||
.st30 {
|
||
fill: none;
|
||
stroke: #FFFFFF;
|
||
stroke-width: 8;
|
||
stroke-miterlimit: 10;
|
||
}
|
||
</style>
|
||
<title>Twitter</title>
|
||
<g>
|
||
<g>
|
||
<g>
|
||
<path class="st20" d="M192.9,88.1c-5,2.2-9.2,2.3-13.6,0.1c5.7-3.4,6-5.8,8.1-12.3c-5.4,3.2-11.4,5.5-17.6,6.7 c-10.5-11.2-28.1-11.7-39.2-1.2c-7.2,6.8-10.2,16.9-8,26.5c-22.3-1.1-43.1-11.7-57.2-29C58,91.6,61.8,107.9,74,116 c-4.4-0.1-8.7-1.3-12.6-3.4c0,0.1,0,0.2,0,0.4c0,13.2,9.3,24.6,22.3,27.2c-4.1,1.1-8.4,1.3-12.5,0.5c3.6,11.3,14,19,25.9,19.3 c-11.6,9.1-26.4,13.2-41.1,11.5c12.7,8.1,27.4,12.5,42.5,12.5c51,0,78.9-42.2,78.9-78.9c0-1.2,0-2.4-0.1-3.6 C182.7,97.4,189.2,93.7,192.9,88.1z"></path>
|
||
</g>
|
||
</g>
|
||
<circle class="st30" cx="124.4" cy="128.8" r="108.2"></circle>
|
||
</g>
|
||
</svg></a></li>
|
||
<li class="list-inline-item"><a href="https://www.facebook.com/nationallibraryofmedicine" aria-label="Facebook" rel="noopener noreferrer" target="_blank">
|
||
<svg xmlns="http://www.w3.org/2000/svg" xmlns:xlink="http://www.w3.org/1999/xlink" version="1.1" x="0px" y="0px" viewBox="0 0 249 249" style="enable-background:new 0 0 249 249;" xml:space="preserve">
|
||
<style type="text/css">
|
||
.st10 {
|
||
fill: #FFFFFF;
|
||
}
|
||
|
||
.st110 {
|
||
fill: none;
|
||
stroke: #FFFFFF;
|
||
stroke-width: 8;
|
||
stroke-miterlimit: 10;
|
||
}
|
||
</style>
|
||
<title>Facebook</title>
|
||
<g>
|
||
<g>
|
||
<path class="st10" d="M159,99.1h-24V88.4c0-5,3.3-6.2,5.7-6.2h16.8V60l-24.4-0.1c-22.1,0-26.2,16.5-26.2,27.1v12.1H90v22.5h16.9 v67.5H135v-67.5h21.7L159,99.1z"></path>
|
||
</g>
|
||
</g>
|
||
<circle class="st110" cx="123.6" cy="123.2" r="108.2"></circle>
|
||
</svg>
|
||
</a></li>
|
||
<li class="list-inline-item"><a href="https://www.youtube.com/user/NLMNIH" aria-label="Youtube" target="_blank" rel="noopener noreferrer"><svg xmlns="http://www.w3.org/2000/svg" xmlns:xlink="http://www.w3.org/1999/xlink" version="1.1" x="0px" y="0px" viewBox="0 0 249 249" style="enable-background:new 0 0 249 249;" xml:space="preserve">
|
||
<title>Youtube</title>
|
||
<style type="text/css">
|
||
.st4 {
|
||
fill: none;
|
||
stroke: #FFFFFF;
|
||
stroke-width: 8;
|
||
stroke-miterlimit: 10;
|
||
}
|
||
|
||
.st5 {
|
||
fill: #FFFFFF;
|
||
}
|
||
</style>
|
||
<circle class="st4" cx="124.2" cy="123.4" r="108.2"></circle>
|
||
<g transform="translate(0,-952.36218)">
|
||
<path class="st5" d="M88.4,1037.4c-10.4,0-18.7,8.3-18.7,18.7v40.1c0,10.4,8.3,18.7,18.7,18.7h72.1c10.4,0,18.7-8.3,18.7-18.7 v-40.1c0-10.4-8.3-18.7-18.7-18.7H88.4z M115.2,1058.8l29.4,17.4l-29.4,17.4V1058.8z"></path>
|
||
</g>
|
||
</svg></a></li>
|
||
</ul>
|
||
</div>
|
||
<div class="col-lg-3 col-12">
|
||
<p class="address_footer text-white">National Library of Medicine<br />
|
||
<a href="https://www.google.com/maps/place/8600+Rockville+Pike,+Bethesda,+MD+20894/@38.9959508,-77.101021,17z/data=!3m1!4b1!4m5!3m4!1s0x89b7c95e25765ddb:0x19156f88b27635b8!8m2!3d38.9959508!4d-77.0988323" class="text-white" target="_blank" rel="noopener noreferrer">8600 Rockville Pike<br />
|
||
Bethesda, MD 20894</a></p>
|
||
</div>
|
||
<div class="col-lg-3 col-12 centered-lg">
|
||
<p><a href="https://www.nlm.nih.gov/web_policies.html" class="text-white">Web Policies</a><br />
|
||
<a href="https://www.nih.gov/institutes-nih/nih-office-director/office-communications-public-liaison/freedom-information-act-office" class="text-white">FOIA</a><br />
|
||
<a href="https://www.hhs.gov/vulnerability-disclosure-policy/index.html" class="text-white" id="vdp">HHS Vulnerability Disclosure</a></p>
|
||
</div>
|
||
<div class="col-lg-3 col-12 centered-lg">
|
||
<p><a class="supportLink text-white" href="https://support.nlm.nih.gov/">Help</a><br />
|
||
<a href="https://www.nlm.nih.gov/accessibility.html" class="text-white">Accessibility</a><br />
|
||
<a href="https://www.nlm.nih.gov/careers/careers.html" class="text-white">Careers</a></p>
|
||
</div>
|
||
</div>
|
||
<div class="row">
|
||
<div class="col-lg-12 centered-lg">
|
||
<nav class="bottom-links">
|
||
<ul class="mt-3">
|
||
<li>
|
||
<a class="text-white" href="//www.nlm.nih.gov/">NLM</a>
|
||
</li>
|
||
<li>
|
||
<a class="text-white" href="https://www.nih.gov/">NIH</a>
|
||
</li>
|
||
<li>
|
||
<a class="text-white" href="https://www.hhs.gov/">HHS</a>
|
||
</li>
|
||
<li>
|
||
<a class="text-white" href="https://www.usa.gov/">USA.gov</a>
|
||
</li>
|
||
</ul>
|
||
</nav>
|
||
</div>
|
||
</div>
|
||
</div>
|
||
</section>
|
||
<script type="text/javascript" src="/portal/portal3rc.fcgi/rlib/js/InstrumentOmnitureBaseJS/InstrumentNCBIConfigJS/InstrumentNCBIBaseJS/InstrumentPageStarterJS.js?v=1"> </script>
|
||
<script type="text/javascript" src="/portal/portal3rc.fcgi/static/js/hfjs2.js"> </script>
|
||
</div>
|
||
</div>
|
||
</div>
|
||
<!--/.page-->
|
||
</div>
|
||
<!--/.wrap-->
|
||
</div><!-- /.twelve_col -->
|
||
</div>
|
||
<!-- /.grid -->
|
||
|
||
<span class="PAFAppResources"></span>
|
||
|
||
<!-- BESelector tab -->
|
||
|
||
|
||
|
||
<noscript><img alt="statistics" src="/stat?jsdisabled=true&ncbi_db=books&ncbi_pdid=book-part&ncbi_acc=NBK299312&ncbi_domain=gene&ncbi_report=record&ncbi_type=fulltext&ncbi_objectid=&ncbi_pcid=/NBK299312/&ncbi_pagename=Riboflavin Transporter Deficiency - GeneReviews® - NCBI Bookshelf&ncbi_bookparttype=chapter&ncbi_app=bookshelf" /></noscript>
|
||
|
||
|
||
<!-- usually for JS scripts at page bottom -->
|
||
<!--<component id="PageFixtures" label="styles"></component>-->
|
||
|
||
|
||
<!-- CE8B5AF87C7FFCB1_0191SID /projects/books/PBooks@9.11 portal104 v4.1.r689238 Tue, Oct 22 2024 16:10:51 -->
|
||
<span id="portal-csrf-token" style="display:none" data-token="CE8B5AF87C7FFCB1_0191SID"></span>
|
||
|
||
<script type="text/javascript" src="//static.pubmed.gov/portal/portal3rc.fcgi/4216699/js/3879255/4121861/3501987/4008961/3893018/3821238/4062932/4209313/4212053/4076480/3921943/3400083/3426610.js" snapshot="books"></script></body>
|
||
</html> |