publicdata/nih-gov
2
0
Fork 0
Code Issues Pull requests Projects Releases Packages Wiki Activity Actions
nih-gov/www.ncbi.nlm.nih.gov/books/NBK1473/index.html
Scott Williams f361c7df98 Incremental update
2025-03-17 02:05:34 +00:00

687 lines
No EOL
158 KiB
HTML
Raw Blame History

This file contains invisible Unicode characters

This file contains invisible Unicode characters that are indistinguishable to humans but may be processed differently by a computer. If you think that this is intentional, you can safely ignore this warning. Use the Escape button to reveal them.

This file contains Unicode characters that might be confused with other characters. If you think that this is intentional, you can safely ignore this warning. Use the Escape button to reveal them.

<?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="NBK1473" /><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="/NBK1473/" /><meta name="ncbi_pagename" content="Costeff Syndrome - GeneReviews® - NCBI Bookshelf" /><meta name="ncbi_bookparttype" content="chapter" /><meta name="ncbi_app" content="bookshelf" />
<!-- Logger end -->
<title>Costeff Syndrome - 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="Costeff Syndrome" /><meta name="citation_publisher" content="University of Washington, Seattle" /><meta name="citation_date" content="2020/04/30" /><meta name="citation_author" content="Yair Anikster" /><meta name="citation_pmid" content="20301646" /><meta name="citation_fulltext_html_url" content="https://www.ncbi.nlm.nih.gov/books/NBK1473/" /><meta name="citation_keywords" content="3-Methylglutaconic Aciduria Type 3" /><meta name="citation_keywords" content="OPA3 Defect" /><meta name="citation_keywords" content="3-Methylglutaconic Aciduria Type 3" /><meta name="citation_keywords" content="OPA3 Defect" /><meta name="citation_keywords" content="Optic atrophy 3 protein" /><meta name="citation_keywords" content="OPA3" /><meta name="citation_keywords" content="Costeff Syndrome" /><link rel="schema.DC" href="http://purl.org/DC/elements/1.0/" /><meta name="DC.Title" content="Costeff Syndrome" /><meta name="DC.Type" content="Text" /><meta name="DC.Publisher" content="University of Washington, Seattle" /><meta name="DC.Contributor" content="Yair Anikster" /><meta name="DC.Date" content="2020/04/30" /><meta name="DC.Identifier" content="https://www.ncbi.nlm.nih.gov/books/NBK1473/" /><meta name="description" content="Costeff syndrome is characterized by optic atrophy and/or choreoathetoid movement disorder with onset before age ten years. Optic atrophy is associated with progressive decrease in visual acuity within the first years of life, sometimes associated with infantile-onset horizontal nystagmus. Most individuals have chorea, often severe enough to restrict ambulation. Some are confined to a wheelchair from an early age. Although most individuals develop spastic paraparesis, mild ataxia, and occasional mild cognitive deficit in their second decade, the course of the disease is relatively stable." /><meta name="og:title" content="Costeff Syndrome" /><meta name="og:type" content="book" /><meta name="og:description" content="Costeff syndrome is characterized by optic atrophy and/or choreoathetoid movement disorder with onset before age ten years. Optic atrophy is associated with progressive decrease in visual acuity within the first years of life, sometimes associated with infantile-onset horizontal nystagmus. Most individuals have chorea, often severe enough to restrict ambulation. Some are confined to a wheelchair from an early age. Although most individuals develop spastic paraparesis, mild ataxia, and occasional mild cognitive deficit in their second decade, the course of the disease is relatively stable." /><meta name="og:url" content="https://www.ncbi.nlm.nih.gov/books/NBK1473/" /><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/mga3/" /><link rel="canonical" href="https://www.ncbi.nlm.nih.gov/books/NBK1473/" /><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="CE8EC4E27D2A3B210000000000AB008A.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="#__NBK1473_dtls__">Show details</a><div style="display:none" class="ui-widget" id="__NBK1473_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&amp;targetsite=external&amp;targetcat=link&amp;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/cdls/" title="Previous page in this title">&lt; Prev</a><a class="active page_link next" href="/books/n/gene/ce-dysp/" title="Next page in this title">Next &gt;</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="_NBK1473_"><span class="title" itemprop="name">Costeff Syndrome</span></h1><div itemprop="alternativeHeadline" class="subtitle whole_rhythm">Synonyms: 3-Methylglutaconic Aciduria Type 3, <i>OPA3</i> Defect</div><p class="contrib-group"><span itemprop="author">Yair Anikster</span>, MD, PhD.</p><a data-jig="ncbitoggler" href="#__NBK1473_ai__" style="border:0;text-decoration:none">Author Information and Affiliations</a><div style="display:none" class="ui-widget" id="__NBK1473_ai__"><div class="contrib half_rhythm"><span itemprop="author">Yair Anikster</span>, MD, PhD<div class="affiliation small">Head of Metabolic Disease Unit
Edmond and Lily Safra Children's Hospital
Sheba Medical Center
Tel Hashomer, Israel<div><span class="email-label">Email: </span><a href="mailto:dev@null" data-email="li.vog.htlaeh.abehs@retskina.riay" class="oemail">li.vog.htlaeh.abehs@retskina.riay</a></div></div></div></div><p class="small">Initial Posting: <span itemprop="datePublished">July 28, 2006</span>; Last Update: <span itemprop="dateModified">April 30, 2020</span>.</p><p><em>Estimated reading time: 21 minutes</em></p></div><div class="jig-ncbiinpagenav body-content whole_rhythm" data-jigconfig="allHeadingLevels: ['h2'],smoothScroll: false" itemprop="text"><div id="mga3.Summary" itemprop="description"><h2 id="_mga3_Summary_">Summary</h2><div><h4 class="inline">Clinical characteristics.</h4><p>Costeff syndrome is characterized by optic atrophy and/or choreoathetoid movement disorder with onset before age ten years. Optic atrophy is associated with progressive decrease in visual acuity within the first years of life, sometimes associated with infantile-onset horizontal nystagmus. Most individuals have chorea, often severe enough to restrict ambulation. Some are confined to a wheelchair from an early age. Although most individuals develop spastic paraparesis, mild ataxia, and occasional mild cognitive deficit in their second decade, the course of the disease is relatively stable.</p></div><div><h4 class="inline">Diagnosis/testing.</h4><p>The diagnosis of Costeff syndrome is established in a <a class="def" href="/books/n/gene/glossary/def-item/proband/">proband</a> with suggestive findings by identification of <a class="def" href="/books/n/gene/glossary/def-item/biallelic/">biallelic</a> <i>OPA3</i> pathogenic variants 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>: Supportive and often provided by a multidisciplinary team; treatment of visual impairment, spasticity, and movement disorder as in the general population.</p><p><i>Agents/circumstances to avoid</i>: Use of tobacco, alcohol, and medications known to impair mitochondrial function.</p></div><div><h4 class="inline">Genetic counseling.</h4><p>Costeff syndrome 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 <i>OPA3</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 being affected, a 50% chance of being an unaffected <a class="def" href="/books/n/gene/glossary/def-item/carrier/">carrier</a>, and a 25% chance of being unaffected and not a carrier. When both <i>OPA3</i> pathogenic variants have been identified in an affected family member, <a class="def" href="/books/n/gene/glossary/def-item/carrier-testing/">carrier testing</a> for at-risk family members, <a class="def" href="/books/n/gene/glossary/def-item/prenatal-testing/">prenatal testing</a> for pregnancies at increased risk, and <a class="def" href="/books/n/gene/glossary/def-item/preimplantation-genetic-testing/">preimplantation genetic testing</a> are possible.</p></div></div><div id="mga3.Diagnosis"><h2 id="_mga3_Diagnosis_">Diagnosis</h2><div id="mga3.Suggestive_Findings"><h3>Suggestive Findings</h3><p>The diagnosis of Costeff syndrome <b>is suspected</b> in a child with the following <a href="#mga3.Clinical_Findings">clinical</a> and <a href="#mga3.Laboratory_Findings">laboratory</a> findings and family history consistent with <a class="def" href="/books/n/gene/glossary/def-item/autosomal-recessive/">autosomal recessive</a> inheritance.</p><div id="mga3.Clinical_Findings"><h4>Clinical Findings</h4><p>
<b>Early in the disease course</b>
</p><ul><li class="half_rhythm"><div>Relatively normal early development and growth</div></li><li class="half_rhythm"><div>Bilateral early-onset optic atrophy (pathologically pale optic discs, attenuated papillary vasculature, and visual evoked potentials that show bilateral prolonged latencies consistent with optic atrophy)</div></li><li class="half_rhythm"><div>Choreoathetoid movement disorder</div></li></ul><p>
<b>Later in the disease course</b>
</p><ul><li class="half_rhythm"><div>Progressive spasticity</div></li><li class="half_rhythm"><div>Cerebellar ataxia</div></li><li class="half_rhythm"><div>Cognitive deterioration (in a minority of individuals)</div></li></ul></div><div id="mga3.Laboratory_Findings"><h4>Laboratory Findings</h4><p><b>Increased urinary excretion of 3-methylglutaconate</b>
<b>(3-MGC) and 3-methylglutaric acid (3-MGA).</b> In Costeff syndrome, urinary 3-MGC and 3-MGA (measured using gas chromatography-mass spectrometry) are mildly increased. Note: (1) In Costeff syndrome, the excretion of 3-MGC and 3-MGA is variable, sometimes even overlapping that of normal controls; furthermore, 3-MGC and 3-MGA are not always easy to detect on urine organic acid analysis. (2) Because laboratories both within and between countries use different methods, they have very different reference ranges; thus, <b>the sex- and age-specific reference range determined by each reference laboratory should be used</b>.</p></div></div><div id="mga3.Establishing_the_Diagnosis"><h3>Establishing the Diagnosis</h3><p>The <b>diagnosis</b> of Costeff syndrome <b>is established</b> in a <a class="def" href="/books/n/gene/glossary/def-item/proband/">proband</a> with suggestive findings and <a class="def" href="/books/n/gene/glossary/def-item/biallelic/">biallelic</a> <i>OPA3</i> pathogenic variants identified by <a class="def" href="/books/n/gene/glossary/def-item/molecular-genetic-testing/">molecular genetic testing</a> (<a href="/books/NBK1473/table/mga3.T.molecular_genetic_testing_used_in/?report=objectonly" target="object" rid-ob="figobmga3Tmoleculargenetictestingusedin">Table 1</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> (single-gene testing or <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> and <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. Because the <a class="def" href="/books/n/gene/glossary/def-item/phenotype/">phenotype</a> of Costeff syndrome is broad, individuals with the distinctive findings described in <a href="#mga3.Suggestive_Findings">Suggestive Findings</a> are likely to be diagnosed using gene-targeted testing (see <a href="#mga3.Option_1">Option 1</a>), whereas those in whom the diagnosis of Costeff syndrome has not been considered are more likely to be diagnosed using genomic testing (see <a href="#mga3.Option_2">Option 2</a>).</p><div id="mga3.Option_1"><h4>Option 1</h4><p><b>Single-<a class="def" href="/books/n/gene/glossary/def-item/gene/">gene</a> testing.</b> Sequence analysis of <i>OPA3</i> is performed first to detect 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. Note: Depending on the sequencing method used, single-<a class="def" href="/books/n/gene/glossary/def-item/exon/">exon</a>, multiexon, or whole-gene deletions/duplications may not be detected. If no variant is detected by the sequencing method used, the next step could be to perform gene-targeted <a class="def" href="/books/n/gene/glossary/def-item/deletion-duplication-analysis/">deletion/duplication analysis</a> to detect (multi)exon and whole-gene deletions or duplications; to date, however, deletions/duplications have not been identified as a cause of Costeff syndrome.</p><p>Note: <b>Targeted analysis</b> for the <a href="/books/NBK1473/table/mga3.T.notable_opa3_pathogenic_variants/?report=objectonly" target="object" rid-ob="figobmga3Tnotableopa3pathogenicvariants">c.143-1G&#x0003e;C</a> <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a>, which has been identified in all affected individuals of Iraqi Jewish descent, can be performed first in this population.</p><p><b>A <a class="def" href="/books/n/gene/glossary/def-item/multigene-panel/">multigene panel</a></b> that includes <i>OPA3</i> and other genes of interest (see <a href="#mga3.Differential_Diagnosis">Differential Diagnosis</a>) is 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="mga3.Option_2"><h4>Option 2</h4><p><b>Comprehensive <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>(s) are 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>If <a class="def" href="/books/n/gene/glossary/def-item/exome-sequencing/">exome sequencing</a> is not diagnostic, <b><a class="def" href="/books/n/gene/glossary/def-item/exome-array/">exome array</a></b> (when clinically available) may be considered to detect (multi)<a class="def" href="/books/n/gene/glossary/def-item/exon/">exon</a> deletions or duplications that cannot be detected by <a class="def" href="/books/n/gene/glossary/def-item/sequence-analysis/">sequence analysis</a>; to date, however, deletions/duplications have not been identified as a cause of Costeff syndrome.</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="mga3.T.molecular_genetic_testing_used_in" class="table"><h3><span class="label">Table 1. </span></h3><div class="caption"><p>Molecular Genetic Testing Used in Costeff Syndrome</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK1473/table/mga3.T.molecular_genetic_testing_used_in/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__mga3.T.molecular_genetic_testing_used_in_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_mga3.T.molecular_genetic_testing_used_in_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Gene&#x000a0;<sup>1</sup></th><th id="hd_h_mga3.T.molecular_genetic_testing_used_in_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Method</th><th id="hd_h_mga3.T.molecular_genetic_testing_used_in_1_1_1_3" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Proportion of Pathogenic Variants&#x000a0;<sup>2</sup> Detectable by Method</th></tr></thead><tbody><tr><td headers="hd_h_mga3.T.molecular_genetic_testing_used_in_1_1_1_1" rowspan="3" scope="row" colspan="1" style="text-align:left;vertical-align:middle;">
<i>OPA3</i>
</td><td headers="hd_h_mga3.T.molecular_genetic_testing_used_in_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Targeted analysis for the <a href="/books/NBK1473/table/mga3.T.notable_opa3_pathogenic_variants/?report=objectonly" target="object" rid-ob="figobmga3Tnotableopa3pathogenicvariants">c.143-1G&#x0003e;C</a> <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a> in the Iraqi Jewish population&#x000a0;<sup>3</sup></td><td headers="hd_h_mga3.T.molecular_genetic_testing_used_in_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">100%</td></tr><tr><td headers="hd_h_mga3.T.molecular_genetic_testing_used_in_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">Sequence analysis&#x000a0;<sup>4</sup></td><td headers="hd_h_mga3.T.molecular_genetic_testing_used_in_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">100%&#x000a0;<sup>5</sup></td></tr><tr><td headers="hd_h_mga3.T.molecular_genetic_testing_used_in_1_1_1_2" colspan="1" scope="row" rowspan="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>&#x000a0;<sup>6</sup></td><td headers="hd_h_mga3.T.molecular_genetic_testing_used_in_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Unknown&#x000a0;<sup>7</sup></td></tr></tbody></table></div><div><div><dl class="temp-labeled-list small"><dt>1. </dt><dd><div id="mga3.TF.1.1"><p class="no_margin">See <a href="/books/NBK1473/#mga3.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="mga3.TF.1.2"><p class="no_margin">See <a href="#mga3.Molecular_Genetics">Molecular Genetics</a> for information on variants detected in this <a class="def" href="/books/n/gene/glossary/def-item/gene/">gene</a>.</p></div></dd><dt>3. </dt><dd><div id="mga3.TF.1.3"><p class="no_margin">The variant <a href="/books/NBK1473/table/mga3.T.notable_opa3_pathogenic_variants/?report=objectonly" target="object" rid-ob="figobmga3Tnotableopa3pathogenicvariants">c.143-1G&#x0003e;C</a> accounts for 100% of pathogenic variants in the Iraqi Jewish population [<a class="bk_pop" href="#mga3.REF.anikster.2001.1218">Anikster et al 2001</a>].</p></div></dd><dt>4. </dt><dd><div id="mga3.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="mga3.TF.1.5"><p class="no_margin">Data derived from the subscription-based professional view of Human Gene Mutation Database [<a class="bk_pop" href="#mga3.REF.stenson.2020.1197">Stenson et al 2020</a>]</p></div></dd><dt>6. </dt><dd><div id="mga3.TF.1.6"><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 <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>7. </dt><dd><div id="mga3.TF.1.7"><p class="no_margin">No data on detection rate of <a class="def" href="/books/n/gene/glossary/def-item/gene/">gene</a>-targeted <a class="def" href="/books/n/gene/glossary/def-item/deletion-duplication-analysis/">deletion/duplication analysis</a> are available.</p></div></dd></dl></div></div></div></div></div></div><div id="mga3.Clinical_Characteristics"><h2 id="_mga3_Clinical_Characteristics_">Clinical Characteristics</h2><div id="mga3.Clinical_Description"><h3>Clinical Description</h3><p>Most individuals with Costeff syndrome present within the first ten years of life with decreased visual acuity and/or choreoathetoid movement disorder. Although most develop spastic paraparesis, mild ataxia, and occasional mild cognitive deficit in their second decade, the course of the disease is relatively stable.</p><p>The following description of the phenotypic features of Costeff syndrome is based on two reports:</p><ul><li class="half_rhythm"><div><a class="bk_pop" href="#mga3.REF.elpeleg.1994.167">Elpeleg et al [1994]</a> reported on 36 affected individuals, 11 of whom were previously unreported and 25 of whom had been previously reported.</div></li><li class="half_rhythm"><div><a class="bk_pop" href="#mga3.REF.yahalom.2014.2275">Yahalom et al [2014]</a> reported on 28 individuals (age range: 6 months &#x02013; 68 years) six of whom were previously unreported and 22 of whom had been previously reported by <a class="bk_pop" href="#mga3.REF.elpeleg.1994.167">Elpeleg et al [1994]</a>.</div></li></ul><div id="mga3.Optic_Atrophy"><h4>Optic Atrophy</h4><p>Optic atrophy manifests as decreased visual acuity within the first years of life, sometimes associated with infantile-onset horizontal nystagmus.</p><p>In 36 individuals with Costeff syndrome, visual acuity decreased with age:</p><ul><li class="half_rhythm"><div>In two children age two years, visual acuity appeared to be normal.</div></li><li class="half_rhythm"><div>In 14 individuals age three to 21 years (14.2&#x000b1;5.5), visual acuity was 6/21 or less.</div></li><li class="half_rhythm"><div>In 20 individuals age five to 37 years (18&#x000b1;9.5), visual acuity was 3/60 or less.</div></li></ul><p>Some children have strabismus and gaze apraxia.</p></div><div id="mga3.Motor_Disability"><h4>Motor Disability</h4><p>Motor disability is primarily caused by extrapyramidal dysfunction and spasticity.</p><p><b>Extrapyramidal dysfunction.</b> Most individuals have chorea, often severe enough to restrict ambulation. Some are confined to a wheelchair from an early age. In 36 individuals with Costeff syndrome, extrapyramidal involvement caused the following in 32 individuals:</p><ul><li class="half_rhythm"><div>Major disability in 17 individuals age two to 37 years (mean 16.1&#x000b1;17.8)</div></li><li class="half_rhythm"><div>Minor disability in maintaining stable posture and fine motor activities in 12 individuals age two to 26 years (11.7&#x000b1;8.1)</div></li><li class="half_rhythm"><div>Mild manifestations with no resulting disability in three individuals age 15 to 36 years</div></li></ul><p>No extrapyramidal involvement was observed in four individuals ages 13 to 32 years.</p><p><b>Spasticity.</b> Unstable spastic gait, increased tendon reflexes, and Babinski sign may be seen. In 36 individuals with Costeff syndrome, spasticity was age-related:</p><ul><li class="half_rhythm"><div>Nine individuals age two to 12 years (5.9&#x000b1;3.5) did not have spasticity.</div></li><li class="half_rhythm"><div>Four individuals age 11 to 26 years had mild spasticity but no related disability.</div></li><li class="half_rhythm"><div>Eleven individuals age 13 to 37 years (21.4&#x000b1;9.3) had mild spasticity-related disability.</div></li><li class="half_rhythm"><div>Twelve individuals age nine to 26 years (17.0&#x000b1;4.8) had severe spasticity-related disability.</div></li></ul><p><b>Cerebellar dysfunction</b> is usually mild. Ataxia and dysarthria caused mostly mild disability in 18 of the 36 individuals reported by <a class="bk_pop" href="#mga3.REF.elpeleg.1994.167">Elpeleg et al [1994]</a>.</p></div><div id="mga3.Cognitive_Impairment"><h4>Cognitive Impairment</h4><p>Cognitive impairment was previously noted in some individuals. Of 36 individuals:</p><ul><li class="half_rhythm"><div>Nineteen individuals age two to 36 years (16&#x000b1;18.7) had an IQ of 71 or higher.</div></li><li class="half_rhythm"><div>Thirteen individuals age two to 37 years (14.7&#x000b1;9.2) had an IQ between 55 and 71.</div></li><li class="half_rhythm"><div>Four individuals age nine to 26 years had an IQ between 40 and 54.</div></li></ul><p>More recently, however, a study of the neuropsychological profile of 16 adults with Costeff syndrome reported intact global cognition and learning abilities and strong auditory memory performance [<a class="bk_pop" href="#mga3.REF.sofer.2015.197">Sofer et al 2015</a>].</p></div><div id="mga3.Other"><h4>Other</h4><p>Several affected individuals were reported to have married, four of whom (all female) had healthy offspring [<a class="bk_pop" href="#mga3.REF.yahalom.2014.2275">Yahalom et al 2014</a>].</p><p>Affected adults in the seventh decade of life have been reported [<a class="bk_pop" href="#mga3.REF.yahalom.2014.2275">Yahalom et al 2014</a>]; life expectancy beyond the seventh decade is unknown.</p><p>Seizures are not typical in Costeff syndrome. Partial seizures were reported in one individual. In addition, two individuals with Costeff syndrome were reported with electrical status epilepticus during slow-wave sleep (ESESS) (also known as continuous spike-wave of slow sleep (CSWSS) [<a class="bk_pop" href="#mga3.REF.carmi.2015.733">Carmi et al 2015</a>, <a class="bk_pop" href="#mga3.REF.kessi.2018.40">Kessi et al 2018</a>].</p><p>Cranial nerve functions, sensation, and muscle tone are normal.</p><p>No cardiac or structural brain abnormalities have been reported.</p><p>The level of 3-methylglutaconate (3-MGC) or 3-methylglutaric acid (3-MGA) in urine does not correlate with the degree of neurologic damage.</p><p>Electroretinogram is normal.</p></div></div><div id="mga3.GenotypePhenotype_Correlations"><h3>Genotype-Phenotype Correlations</h3><p>Genotype-<a class="def" href="/books/n/gene/glossary/def-item/phenotype/">phenotype</a> correlations cannot be made due to the limited number of <i>OPA3</i> pathogenic variants identified to date.</p><p>All individuals of Iraqi Jewish origin with Costeff syndrome have the same <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a> (<a href="/books/NBK1473/table/mga3.T.notable_opa3_pathogenic_variants/?report=objectonly" target="object" rid-ob="figobmga3Tnotableopa3pathogenicvariants">c.143-1G&#x0003e;C</a>); however, phenotypic severity varies, even within the same family.</p></div><div id="mga3.Nomenclature"><h3>Nomenclature</h3><p>Costeff syndrome has also been referred to as "optic atrophy plus syndrome" and "Costeff optic atrophy syndrome."</p></div><div id="mga3.Prevalence"><h3>Prevalence</h3><p>Costeff syndrome has been reported in more than 40 individuals of Iraqi Jewish origin [<a class="bk_pop" href="#mga3.REF.anikster.2001.1218">Anikster et al 2001</a>], but also in families of Kurdish-Turkish descent [<a class="bk_pop" href="#mga3.REF.kleta.2002.201">Kleta et al 2002</a>], Afghani descent [<a class="bk_pop" href="#mga3.REF.gaier.2019.570">Gaier et al 2019</a>], and others. Of note, as the vast majority of affected individuals are still of Iraqi Jewish descent residing in Israel, it must be underscored that some families originate from the Iraqi area, including Iran and Syria. Individuals with Costeff syndrome have also been diagnosed from outside of Israel, including recently in the United States [Author, personal observation].</p><p>The <a class="def" href="/books/n/gene/glossary/def-item/carrier-rate/">carrier rate</a> in Iraqi Jews was initially estimated at 1:10 [<a class="bk_pop" href="#mga3.REF.anikster.2001.1218">Anikster et al 2001</a>]; however, subsequent screening tests showed the carrier rate to be 1:20-1:30 [Author, personal observation].</p></div></div><div id="mga3.Genetically_Related_Allelic_Disorde"><h2 id="_mga3_Genetically_Related_Allelic_Disorde_">Genetically Related (Allelic) Disorders</h2><p>The <a class="def" href="/books/n/gene/glossary/def-item/heterozygous/">heterozygous</a> <i>OPA3</i> pathogenic variants p.Gly93Ser and p.Gln105Glu were reported in two families with <a class="def" href="/books/n/gene/glossary/def-item/autosomal-dominant/">autosomal dominant</a> optic atrophy and cataract (OMIM <a href="https://omim.org/entry/165300" ref="pagearea=body&amp;targetsite=external&amp;targetcat=link&amp;targettype=uri">165300</a>).</p><p>Another <a class="def" href="/books/n/gene/glossary/def-item/autosomal-dominant/">autosomal dominant</a> <a class="def" href="/books/n/gene/glossary/def-item/phenotype/">phenotype</a> of optic atrophy, cataracts, lipodystrophy/lipoatrophy, and peripheral neuropathy was associated with a <a class="def" href="/books/n/gene/glossary/def-item/de-novo/"><i>de novo</i></a>
<i>OPA3</i> variant [<a class="bk_pop" href="#mga3.REF.bourne.2017.a001156">Bourne et al 2017</a>].</p></div><div id="mga3.Differential_Diagnosis"><h2 id="_mga3_Differential_Diagnosis_">Differential Diagnosis</h2><div id="mga3.3Methylglutaconic_Aciduria"><h3>3-Methylglutaconic Aciduria</h3><p>Increased urinary excretion of the branched-chain organic acid 3-methylglutaconate (3-MGC) is a relatively common finding in children investigated for suspected inborn errors of metabolism [<a class="bk_pop" href="#mga3.REF.gunayaygun.2005.1">Gunay-Aygun 2005</a>]. 3-MGC is an intermediate of leucine degradation and the mevalonate shunt pathway that links sterol synthesis with mitochondrial acetyl-CoA metabolism (<a class="figpopup" href="/books/NBK1473/figure/mga3.F1/?report=objectonly" target="object" rid-figpopup="figmga3F1" rid-ob="figobmga3F1">Figure 1</a>).</p><div class="iconblock whole_rhythm clearfix ten_col fig" id="figmga3F1" co-legend-rid="figlgndmga3F1"><a href="/books/NBK1473/figure/mga3.F1/?report=objectonly" target="object" title="Figure 1. " class="img_link icnblk_img figpopup" rid-figpopup="figmga3F1" rid-ob="figobmga3F1"><img class="small-thumb" src="/books/NBK1473/bin/mga3-Image001.gif" src-large="/books/NBK1473/bin/mga3-Image001.jpg" alt="Figure 1. " /></a><div class="icnblk_cntnt" id="figlgndmga3F1"><h4 id="mga3.F1"><a href="/books/NBK1473/figure/mga3.F1/?report=objectonly" target="object" rid-ob="figobmga3F1">Figure 1. </a></h4><p class="float-caption no_bottom_margin">Metabolic pathway diagram showing branched-chain organic acid 3-MGC as an intermediate of leucine degradation and the mevalonate shunt pathway that links sterol synthesis with mitochondrial acetyl-CoA </p></div></div><p>A classification of inborn errors of metabolism with 3-methylglutaconic aciduria (3-MGCA) as the discriminative feature was published by <a class="bk_pop" href="#mga3.REF.wortmann.2013a.923">Wortmann et al [2013a]</a> and <a class="bk_pop" href="#mga3.REF.wortmann.2013b.913">Wortmann et al [2013b]</a>. Clinical features (<a href="/books/NBK1473/table/mga3.T.inborn_errors_of_metabolism_assoc/?report=objectonly" target="object" rid-ob="figobmga3Tinbornerrorsofmetabolismassoc">Table 2</a>) and biochemical findings of syndromes associated with 3-MGCA vary. Tissues with higher requirements for oxidative metabolism, such as the central nervous system and cardiac and skeletal muscle, are predominantly affected. The only disorder in which the exact source of 3-MGC is known (a block of leucine degradation) is <i>AUH</i> defect, the rarest 3-MGCA, caused by primary deficiency of the mitochondrial enzyme 3-methylglutaconyl-CoA hydratase (3-MGCH).</p><div id="mga3.T.inborn_errors_of_metabolism_assoc" class="table"><h3><span class="label">Table 2. </span></h3><div class="caption"><p>Inborn Errors of Metabolism Associated with 3-Methylglutaconic Aciduria</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK1473/table/mga3.T.inborn_errors_of_metabolism_assoc/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__mga3.T.inborn_errors_of_metabolism_assoc_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_mga3.T.inborn_errors_of_metabolism_assoc_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">3-MGCA</th><th id="hd_h_mga3.T.inborn_errors_of_metabolism_assoc_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Gene</th><th id="hd_h_mga3.T.inborn_errors_of_metabolism_assoc_1_1_1_3" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">MOI</th><th id="hd_h_mga3.T.inborn_errors_of_metabolism_assoc_1_1_1_4" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Disorder</th><th id="hd_h_mga3.T.inborn_errors_of_metabolism_assoc_1_1_1_5" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Key Clinical Characteristics in Addition to 3-MGCA&#x000a0;<sup>1</sup></th></tr></thead><tbody><tr><td headers="hd_h_mga3.T.inborn_errors_of_metabolism_assoc_1_1_1_1" rowspan="10" scope="row" colspan="1" style="text-align:left;vertical-align:middle;">
<b>Discriminating feature&#x000a0;<sup>2</sup></b>
</td><td headers="hd_h_mga3.T.inborn_errors_of_metabolism_assoc_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
<i>AGK</i>
</td><td headers="hd_h_mga3.T.inborn_errors_of_metabolism_assoc_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">AR</td><td headers="hd_h_mga3.T.inborn_errors_of_metabolism_assoc_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Sengers syndrome<br />(See <a href="/books/n/gene/mtdna-md-ov/">Mitochondrial DNA Maintenance Defects Overview</a>.)</td><td headers="hd_h_mga3.T.inborn_errors_of_metabolism_assoc_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Cataracts; cardiomyopathy (DD)</td></tr><tr><td headers="hd_h_mga3.T.inborn_errors_of_metabolism_assoc_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">
<i>AUH</i>
</td><td headers="hd_h_mga3.T.inborn_errors_of_metabolism_assoc_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">AR</td><td headers="hd_h_mga3.T.inborn_errors_of_metabolism_assoc_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">AUH defect<br />(OMIM <a href="https://omim.org/entry/250950" ref="pagearea=body&amp;targetsite=external&amp;targetcat=link&amp;targettype=uri">250950</a>)</td><td headers="hd_h_mga3.T.inborn_errors_of_metabolism_assoc_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
<ul><li class="half_rhythm"><div>Nonspecific speech &#x00026; language delay w/o metabolic derangement in some individuals &#x00026; w/hypoglycemia &#x00026; metabolic acidosis in others</div></li><li class="half_rhythm"><div>Failure to thrive, ID, &#x00026; DD common</div></li><li class="half_rhythm"><div>Microcephaly &#x00026; progressive neurologic impairment w/spastic quadriplegia, seizures, &#x00026; dystonia reported&#x000a0;<sup>3</sup></div></li></ul>
</td></tr><tr><td headers="hd_h_mga3.T.inborn_errors_of_metabolism_assoc_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">
<i>CLPB</i>
</td><td headers="hd_h_mga3.T.inborn_errors_of_metabolism_assoc_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">AR</td><td headers="hd_h_mga3.T.inborn_errors_of_metabolism_assoc_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
<a href="/books/n/gene/clpb-def/">CLPB deficiency</a>
</td><td headers="hd_h_mga3.T.inborn_errors_of_metabolism_assoc_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Cataracts; central hypopnea; DD &#x00026; ID; movement disorder; neutropenia (epilepsy)</td></tr><tr><td headers="hd_h_mga3.T.inborn_errors_of_metabolism_assoc_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">
<i>DNAJC19</i>
</td><td headers="hd_h_mga3.T.inborn_errors_of_metabolism_assoc_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">AR</td><td headers="hd_h_mga3.T.inborn_errors_of_metabolism_assoc_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">DNAJC19 defect (DCMA syndrome)<br />(OMIM <a href="https://omim.org/entry/610198" ref="pagearea=body&amp;targetsite=external&amp;targetcat=link&amp;targettype=uri">610198</a>)</td><td headers="hd_h_mga3.T.inborn_errors_of_metabolism_assoc_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
<ul><li class="half_rhythm"><div>Cardiomyopathy; DD &#x00026; ID; growth restriction; cerebellar ataxia; may be assoc w/optic atrophy</div></li><li class="half_rhythm"><div>Seen in Dariusleut Hutterite population of Canada.&#x000a0;<sup>4</sup></div></li></ul>
</td></tr><tr><td headers="hd_h_mga3.T.inborn_errors_of_metabolism_assoc_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">
<i>HTRA2</i>
</td><td headers="hd_h_mga3.T.inborn_errors_of_metabolism_assoc_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">AR</td><td headers="hd_h_mga3.T.inborn_errors_of_metabolism_assoc_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">MGCA8<br />(OMIM <a href="https://omim.org/entry/617248" ref="pagearea=body&amp;targetsite=external&amp;targetcat=link&amp;targettype=uri">617248</a>)</td><td headers="hd_h_mga3.T.inborn_errors_of_metabolism_assoc_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Cataracts; central hypopnea; DD &#x00026; ID; epilepsy; movement disorder; neutropenia</td></tr><tr><td headers="hd_h_mga3.T.inborn_errors_of_metabolism_assoc_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">
<b>
<i>OPA3</i>
</b>
</td><td headers="hd_h_mga3.T.inborn_errors_of_metabolism_assoc_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
<b>AR</b>
</td><td headers="hd_h_mga3.T.inborn_errors_of_metabolism_assoc_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
<b>Costeff syndrome</b>
</td><td headers="hd_h_mga3.T.inborn_errors_of_metabolism_assoc_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
<b>DD; movement disorders; optic atrophy</b>
</td></tr><tr><td headers="hd_h_mga3.T.inborn_errors_of_metabolism_assoc_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">
<i>SERAC1</i>
</td><td headers="hd_h_mga3.T.inborn_errors_of_metabolism_assoc_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">AR</td><td headers="hd_h_mga3.T.inborn_errors_of_metabolism_assoc_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><i>SERAC1</i> defect<br />(<a href="/books/n/gene/megdel/">MEGDEL syndrome</a>)</td><td headers="hd_h_mga3.T.inborn_errors_of_metabolism_assoc_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">DD &#x00026; ID; deafness; movement disorder (epilepsy &#x00026; optic atrophy)</td></tr><tr><td headers="hd_h_mga3.T.inborn_errors_of_metabolism_assoc_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;"><i>TAFAZZIN</i> (<i>TAZ</i>)</td><td headers="hd_h_mga3.T.inborn_errors_of_metabolism_assoc_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">XL</td><td headers="hd_h_mga3.T.inborn_errors_of_metabolism_assoc_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><i>TAFAZZIN</i> defect<br />(<a href="/books/n/gene/barth/">Barth syndrome</a>)</td><td headers="hd_h_mga3.T.inborn_errors_of_metabolism_assoc_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Cardiomyopathy;&#x000a0;<sup>5</sup> skeletal myopathy; DD; growth restriction; neutropenia</td></tr><tr><td headers="hd_h_mga3.T.inborn_errors_of_metabolism_assoc_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">
<i>TIMM50</i>
</td><td headers="hd_h_mga3.T.inborn_errors_of_metabolism_assoc_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">AR</td><td headers="hd_h_mga3.T.inborn_errors_of_metabolism_assoc_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">MGCA9<br />(OMIM <a href="https://omim.org/entry/617698" ref="pagearea=body&amp;targetsite=external&amp;targetcat=link&amp;targettype=uri">617698</a>)</td><td headers="hd_h_mga3.T.inborn_errors_of_metabolism_assoc_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">DD &#x00026; ID; epilepsy</td></tr><tr><td headers="hd_h_mga3.T.inborn_errors_of_metabolism_assoc_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">
<i>TMEM70</i>
</td><td headers="hd_h_mga3.T.inborn_errors_of_metabolism_assoc_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">AR</td><td headers="hd_h_mga3.T.inborn_errors_of_metabolism_assoc_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><i>TMEM70</i> defect</td><td headers="hd_h_mga3.T.inborn_errors_of_metabolism_assoc_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Cardiomyopathy; DD &#x00026; ID</td></tr><tr><td headers="hd_h_mga3.T.inborn_errors_of_metabolism_assoc_1_1_1_1" rowspan="3" scope="row" colspan="1" style="text-align:left;vertical-align:middle;">
<b>Occasional feature</b>
</td><td headers="hd_h_mga3.T.inborn_errors_of_metabolism_assoc_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
<i>POLG</i>
</td><td headers="hd_h_mga3.T.inborn_errors_of_metabolism_assoc_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td><td headers="hd_h_mga3.T.inborn_errors_of_metabolism_assoc_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
<a href="/books/n/gene/alpers/"><i>POLG</i> disorders</a>
</td><td headers="hd_h_mga3.T.inborn_errors_of_metabolism_assoc_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Encephalopathy w/intractable epilepsy &#x00026; hepatic failure; DD or dementia, lactic acidosis, &#x00026; myopathy</td></tr><tr><td headers="hd_h_mga3.T.inborn_errors_of_metabolism_assoc_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">
<i>SUCLA2</i>
</td><td headers="hd_h_mga3.T.inborn_errors_of_metabolism_assoc_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">AR</td><td headers="hd_h_mga3.T.inborn_errors_of_metabolism_assoc_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
<a href="/books/n/gene/sucla2-def/"><i>SUCLA2</i> mtDNA depletion syndrome, encephalomyopathic form w/methylmalonic aciduria</a>
</td><td headers="hd_h_mga3.T.inborn_errors_of_metabolism_assoc_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Hypotonia; epilepsy; muscular atrophy; movement disorder; growth retardation</td></tr><tr><td headers="hd_h_mga3.T.inborn_errors_of_metabolism_assoc_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">
<i>SUCLG1</i>
</td><td headers="hd_h_mga3.T.inborn_errors_of_metabolism_assoc_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">AR</td><td headers="hd_h_mga3.T.inborn_errors_of_metabolism_assoc_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
<a href="/books/n/gene/suclg1-mtddepl/"><i>SUCLG1</i> mtDNA depletion syndrome, encephalomyopathic form w/methylmalonic aciduria</a>
</td><td headers="hd_h_mga3.T.inborn_errors_of_metabolism_assoc_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Hypotonia; uncontrolled movement; hearing loss; DD</td></tr></tbody></table></div><div><div><dl class="temp-labeled-list small"><dt></dt><dd><div><p class="no_margin">3-MGCA = 3-methylglutaconic aciduria; DD = developmental delay; ID = intellectual disability; MOI = <a class="def" href="/books/n/gene/glossary/def-item/mode-of-inheritance/">mode of inheritance</a>; 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="mga3.TF.2.1"><p class="no_margin">Features shown in ( )s are rare.</p></div></dd><dt>2. </dt><dd><div id="mga3.TF.2.2"><p class="no_margin">Adapted from <a class="bk_pop" href="#mga3.REF.kovacsnagy.2018.373">Kovacs-Nagy et al [2018]</a>, Table 1</p></div></dd><dt>3. </dt><dd><div id="mga3.TF.2.3"><p class="no_margin"><a class="bk_pop" href="#mga3.REF.sweetman.2001">Sweetman &#x00026; Williams [2001]</a>, <a class="bk_pop" href="#mga3.REF.ijlst.2002.1463">Ijlst et al [2002]</a>, <a class="bk_pop" href="#mga3.REF.illsinger.2004.213">Illsinger et al [2004]</a></p></div></dd><dt>4. </dt><dd><div id="mga3.TF.2.4"><p class="no_margin">
<a class="bk_pop" href="#mga3.REF.davey.2006.385">Davey et al [2006]</a>
</p></div></dd><dt>5. </dt><dd><div id="mga3.TF.2.5"><p class="no_margin">Dilated cardiomyopathy presents within the first year of life or even prenatally [<a class="bk_pop" href="#mga3.REF.barth.2004.349">Barth et al 2004</a>].</p></div></dd></dl></div></div></div></div><div id="mga3.Clinical_Findings_of_Costeff_Syndro"><h3>Clinical Findings of Costeff Syndrome</h3><p><b>Behr syndrome.</b> The clinical picture of Behr syndrome is most similar to Costeff syndrome [<a class="bk_pop" href="#mga3.REF.copeliovitch.2001.512">Copeliovitch et al 2001</a>]. Behr syndrome is an <a class="def" href="/books/n/gene/glossary/def-item/autosomal-recessive/">autosomal recessive</a> disorder caused by pathogenic variants in <i>OPA1</i> (OMIM <a href="https://omim.org/entry/210000" ref="pagearea=body&amp;targetsite=external&amp;targetcat=link&amp;targettype=uri">210000</a>) associated with childhood-onset optic atrophy and spinocerebellar degeneration characterized by ataxia, spasticity, intellectual disability, posterior column sensory loss, and peripheral neuropathy.</p><p>Ataxia, an obligatory finding in Behr syndrome, is not seen in approximately half of individuals with Costeff syndrome; conversely, most individuals with Behr syndrome do not manifest extrapyramidal dysfunction, one of the major features of Costeff syndrome. Given that some individuals with Costeff syndrome do not have extrapyramidal dysfunction, it is not possible to distinguish Behr syndrome from Costeff syndrome based on clinical findings alone. Costeff syndrome can be distinguished from Behr syndrome by the presence of elevated excretion of 3-MGC and 3-MGA in urine.</p></div></div><div id="mga3.Management"><h2 id="_mga3_Management_">Management</h2><div id="mga3.Evaluations_Following_Initial_Diagn"><h3>Evaluations Following Initial Diagnosis</h3><p>To establish the extent of disease and needs in an individual diagnosed with Costeff syndrome, the evaluations summarized in <a href="/books/NBK1473/table/mga3.T.recommended_evaluations_following/?report=objectonly" target="object" rid-ob="figobmga3Trecommendedevaluationsfollowing">Table 3</a> (if not performed as part of the evaluation that led to the diagnosis) are recommended.</p><div id="mga3.T.recommended_evaluations_following" class="table"><h3><span class="label">Table 3. </span></h3><div class="caption"><p>Recommended Evaluations Following Initial Diagnosis in Individuals with Costeff Syndrome</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK1473/table/mga3.T.recommended_evaluations_following/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__mga3.T.recommended_evaluations_following_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_mga3.T.recommended_evaluations_following_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">System/Concern</th><th id="hd_h_mga3.T.recommended_evaluations_following_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Evaluation</th><th id="hd_h_mga3.T.recommended_evaluations_following_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_mga3.T.recommended_evaluations_following_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
<b>Optic atrophy</b>
</td><td headers="hd_h_mga3.T.recommended_evaluations_following_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Complete ophthalmologic exam</td><td headers="hd_h_mga3.T.recommended_evaluations_following_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Assess:
<ul><li class="half_rhythm"><div>Extraocular movement, best corrected visual acuity, color vision testing, visual field testing, visual evoked potentials, fundus exam;</div></li><li class="half_rhythm"><div>Need for visual aids.</div></li></ul></td></tr><tr><td headers="hd_h_mga3.T.recommended_evaluations_following_1_1_1_1" rowspan="2" scope="row" colspan="1" style="text-align:left;vertical-align:middle;">
<b>Motor disability</b>
</td><td headers="hd_h_mga3.T.recommended_evaluations_following_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Complete neurologic exam</td><td headers="hd_h_mga3.T.recommended_evaluations_following_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Assess for extrapyramidal dysfunction, spasticity, cerebellar dysfunction</td></tr><tr><td headers="hd_h_mga3.T.recommended_evaluations_following_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">Refer to neuromuscular clinic (OT/PT / rehab specialist).</td><td headers="hd_h_mga3.T.recommended_evaluations_following_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 &#x00026; fine motor skills</div></li><li class="half_rhythm"><div>Mobility, activities of daily living, &#x00026; need for adaptive devices</div></li><li class="half_rhythm"><div>Need for PT (to improve gross motor skills) &#x00026;/or OT (to improve fine motor skills)</div></li></ul></td></tr><tr><td headers="hd_h_mga3.T.recommended_evaluations_following_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
<b>Feeding</b>
<br />
<b>difficulties</b>
</td><td headers="hd_h_mga3.T.recommended_evaluations_following_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_mga3.T.recommended_evaluations_following_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">To incl eval of aspiration risk &#x00026; nutritional status</td></tr><tr><td headers="hd_h_mga3.T.recommended_evaluations_following_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
<b>Development</b>
<br />
<b>(children)</b>
</td><td headers="hd_h_mga3.T.recommended_evaluations_following_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Developmental assessment</td><td headers="hd_h_mga3.T.recommended_evaluations_following_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
<ul><li class="half_rhythm"><div>To incl motor, adaptive, cognitive, &#x00026; speech/language eval</div></li><li class="half_rhythm"><div>Eval for early intervention / special education</div></li></ul>
</td></tr><tr><td headers="hd_h_mga3.T.recommended_evaluations_following_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
<b>Cognitive</b>
<br />
<b>impairment</b>
<br />
<b>(older children</b>
<br />
<b>&#x00026; adults)</b>
</td><td headers="hd_h_mga3.T.recommended_evaluations_following_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">To incl motor, speech/language eval; general cognitive skills</td><td headers="hd_h_mga3.T.recommended_evaluations_following_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Frontotemporal &#x00026; executive deficits; perform formal neuropsychological eval.</td></tr><tr><td headers="hd_h_mga3.T.recommended_evaluations_following_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_mga3.T.recommended_evaluations_following_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">By genetics professionals&#x000a0;<sup>1</sup></td><td headers="hd_h_mga3.T.recommended_evaluations_following_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">To inform affected persons &#x00026; families re nature, MOI, &#x00026; implications of Costeff syndrome to facilitate medical &#x00026; personal decision making</td></tr><tr><td headers="hd_h_mga3.T.recommended_evaluations_following_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
<b>Family support</b>
<br />
<b>&#x00026; resources</b>
</td><td headers="hd_h_mga3.T.recommended_evaluations_following_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
<ul><li class="half_rhythm"><div>Contact w/a <a href="#mga3.Resources">patient advocacy organization</a> may provide additional benefit.</div></li><li class="half_rhythm"><div>Assess need for social work involvement for caregiver support and help coordinating multidisciplinary care.</div></li></ul>
</td><td headers="hd_h_mga3.T.recommended_evaluations_following_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">MOI = <a class="def" href="/books/n/gene/glossary/def-item/mode-of-inheritance/">mode of inheritance</a>; OT = occupational therapy; PT = physical therapy</p></div></dd><dt>1. </dt><dd><div id="mga3.TF.3.1"><p class="no_margin">Medical geneticist, certified genetic counselor, or certified advanced genetic nurse</p></div></dd></dl></div></div></div></div><div id="mga3.Treatment_of_Manifestations"><h3>Treatment of Manifestations</h3><p>Treatment is supportive. A multidisciplinary team including a neurologist, orthopedic surgeon, ophthalmologist, biochemical geneticist, and physical therapist is required for the care of affected individuals.</p><div id="mga3.T.treatment_of_manifestations_in_in" class="table"><h3><span class="label">Table 4. </span></h3><div class="caption"><p>Treatment of Manifestations in Individuals with Costeff Syndrome</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK1473/table/mga3.T.treatment_of_manifestations_in_in/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__mga3.T.treatment_of_manifestations_in_in_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_mga3.T.treatment_of_manifestations_in_in_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Manifestation/Concern</th><th id="hd_h_mga3.T.treatment_of_manifestations_in_in_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Treatment</th><th id="hd_h_mga3.T.treatment_of_manifestations_in_in_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_mga3.T.treatment_of_manifestations_in_in_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
<b>Visual impairment</b>
</td><td headers="hd_h_mga3.T.treatment_of_manifestations_in_in_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Standard treatment(s) as recommended by ophthalmologist</td><td headers="hd_h_mga3.T.treatment_of_manifestations_in_in_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
<ul><li class="half_rhythm"><div>Eval for visual aids</div></li><li class="half_rhythm"><div>Community vision services through early intervention or school district</div></li></ul>
</td></tr><tr><td headers="hd_h_mga3.T.treatment_of_manifestations_in_in_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
<b>Spasticity</b>
</td><td headers="hd_h_mga3.T.treatment_of_manifestations_in_in_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Orthopedics / physical medicine &#x00026; rehab / PT&#x00026;OT incl stretching to help avoid contractures &#x00026; falls</td><td headers="hd_h_mga3.T.treatment_of_manifestations_in_in_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Consider need for positioning &#x00026; mobility devices, disability parking placard.</td></tr><tr><td headers="hd_h_mga3.T.treatment_of_manifestations_in_in_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
<b>Poor weight gain /</b>
<br />
<b>Failure to thrive</b>
</td><td headers="hd_h_mga3.T.treatment_of_manifestations_in_in_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Feeding therapy</td><td headers="hd_h_mga3.T.treatment_of_manifestations_in_in_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Low threshold for clinical feeding eval &#x00026;/or radiographic swallowing study if clinical signs or symptoms of dysphagia</td></tr><tr><td headers="hd_h_mga3.T.treatment_of_manifestations_in_in_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
<b>DD</b>
</td><td headers="hd_h_mga3.T.treatment_of_manifestations_in_in_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">See <a href="#mga3.Developmental_Delay__Intellectual_D">DD/ID Management Issues</a>.</td><td headers="hd_h_mga3.T.treatment_of_manifestations_in_in_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr><tr><td headers="hd_h_mga3.T.treatment_of_manifestations_in_in_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
<b>Family/Community</b>
</td><td headers="hd_h_mga3.T.treatment_of_manifestations_in_in_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
<ul><li class="half_rhythm"><div>Ensure appropriate social work involvement to connect families w/local resources, respite, &#x00026; support.</div></li><li class="half_rhythm"><div>Coordination of care to manage multiple subspecialty appointments, equipment, medications, &#x00026; supplies</div></li></ul>
</td><td headers="hd_h_mga3.T.treatment_of_manifestations_in_in_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
<ul><li class="half_rhythm"><div>Ongoing assessment of need for palliative care involvement &#x00026;/or home nursing</div></li><li class="half_rhythm"><div>Consider involvement in adaptive sports or Special Olympics.</div></li></ul>
</td></tr></tbody></table></div><div><div><dl class="temp-labeled-list small"><dt></dt><dd><div><p class="no_margin">DD = developmental delay; ID = intellectual disability; OT = occupational therapy; PT = physical therapy</p></div></dd></dl></div></div></div><div id="mga3.Developmental_Delay__Intellectual_D"><h4>Developmental Delay / Intellectual Disability Management Issues</h4><p>The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country.</p><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 id="mga3.Motor_Dysfunction"><h4>Motor Dysfunction</h4><p>
<b>Gross motor dysfunction</b>
</p><ul><li class="half_rhythm"><div>Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation).</div></li><li class="half_rhythm"><div>Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).</div></li><li class="half_rhythm"><div>For muscle tone abnormalities including hypertonia or dystonia, consider involving appropriate specialists to aid in management of baclofen, tizanidine, Botox<sup>&#x000ae;</sup>, anti-parkinsonian medications, or orthopedic procedures.</div></li></ul><p><b>Fine motor dysfunction.</b> Occupational therapy is recommended for difficulty with fine motor skills that affect adaptive function such as feeding, grooming, dressing, and writing.</p><p><b>Oral motor dysfunction</b> should be assessed at each visit and clinical feeding evaluations and/or radiographic swallowing studies should be obtained for choking/gagging during feeds, poor weight gain, frequent respiratory illnesses or feeding refusal that is not otherwise explained. Assuming that the individual is safe to eat by mouth, feeding therapy (typically from an occupational or speech therapist) is recommended to help improve coordination or sensory-related feeding issues. Feeds can be thickened or chilled for safety. When feeding dysfunction is severe, an NG-tube or G-tube may be necessary.</p><p><b>Communication issues.</b> Consider evaluation for alternative means of communication (e.g., <a href="https://www.asha.org/NJC/AAC/" ref="pagearea=body&amp;targetsite=external&amp;targetcat=link&amp;targettype=uri">augmentative and alternative communication</a> [AAC]) for individuals who have expressive language difficulties. An AAC evaluation can be completed by a speech-language pathologist who has expertise in the area. The evaluation will consider cognitive abilities and sensory impairments to determine the most appropriate form of communication. AAC devices can range from low-tech, such as picture exchange communication, to high-tech, such as voice-generating devices. Contrary to popular belief, AAC devices do not hinder verbal development of speech, but rather support optimal speech and language development.</p></div></div><div id="mga3.Surveillance"><h3>Surveillance</h3><div id="mga3.T.recommended_surveillance_for_indi" class="table"><h3><span class="label">Table 5. </span></h3><div class="caption"><p>Recommended Surveillance for Individuals with Costeff Syndrome</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK1473/table/mga3.T.recommended_surveillance_for_indi/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__mga3.T.recommended_surveillance_for_indi_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_mga3.T.recommended_surveillance_for_indi_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">System/Concern</th><th id="hd_h_mga3.T.recommended_surveillance_for_indi_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Evaluation</th><th id="hd_h_mga3.T.recommended_surveillance_for_indi_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_mga3.T.recommended_surveillance_for_indi_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
<b>Visual impairment</b>
</td><td headers="hd_h_mga3.T.recommended_surveillance_for_indi_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
<ul><li class="half_rhythm"><div>Ophthalmologic exam incl best corrected visual acuity, color vision testing, &#x00026; visual field testing</div></li><li class="half_rhythm"><div>Appropriateness of visual aids</div></li></ul>
</td><td headers="hd_h_mga3.T.recommended_surveillance_for_indi_1_1_1_3" rowspan="2" colspan="1" style="text-align:left;vertical-align:middle;">Annually</td></tr><tr><td headers="hd_h_mga3.T.recommended_surveillance_for_indi_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
<b>Pyramidal dysfunction / Spasticity / Cerebellar dysfunction</b>
</td><td headers="hd_h_mga3.T.recommended_surveillance_for_indi_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
<ul><li class="half_rhythm"><div>Neurologic exam for progression of findings</div></li><li class="half_rhythm"><div>Orthopedics (eval of Achilles tendon shortening); OT/PT eval</div></li><li class="half_rhythm"><div>Speech &#x00026; language assessment</div></li></ul>
</td></tr><tr><td headers="hd_h_mga3.T.recommended_surveillance_for_indi_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
<b>Feeding &#x00026; nutrition</b>
</td><td headers="hd_h_mga3.T.recommended_surveillance_for_indi_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">By feeding team</td><td headers="hd_h_mga3.T.recommended_surveillance_for_indi_1_1_1_3" rowspan="2" colspan="1" style="text-align:left;vertical-align:middle;">As needed</td></tr><tr><td headers="hd_h_mga3.T.recommended_surveillance_for_indi_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
<b>Orthopedic involvement&#x000a0;<sup>1</sup></b>
</td><td headers="hd_h_mga3.T.recommended_surveillance_for_indi_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Eval by orthopedic surgeon</td></tr><tr><td headers="hd_h_mga3.T.recommended_surveillance_for_indi_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
<b>Family/Community</b>
</td><td headers="hd_h_mga3.T.recommended_surveillance_for_indi_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Assess family need for social work support (e.g., palliative/respite care, home nursing, other local resources) &#x00026; care coordination.</td><td headers="hd_h_mga3.T.recommended_surveillance_for_indi_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">At each visit</td></tr></tbody></table></div><div><div><dl class="temp-labeled-list small"><dt></dt><dd><div><p class="no_margin">OT = occupational therapy; PT = physical therapy</p></div></dd><dt>1. </dt><dd><div id="mga3.TF.5.1"><p class="no_margin">Shortening of Achilles tendon</p></div></dd></dl></div></div></div></div><div id="mga3.AgentsCircumstances_to_Avoid"><h3>Agents/Circumstances to Avoid</h3><p>The following should be avoided:</p><ul><li class="half_rhythm"><div>Tobacco and alcohol use</div></li><li class="half_rhythm"><div>Medications known to impair mitochondrial function</div></li></ul></div><div id="mga3.Evaluation_of_Relatives_at_Risk"><h3>Evaluation of Relatives at Risk</h3><p>See <a href="#mga3.Related_Genetic_Counseling_Issues">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="mga3.Therapies_Under_Investigation"><h3>Therapies Under Investigation</h3><p>Search <a href="https://clinicaltrials.gov/" ref="pagearea=body&amp;targetsite=external&amp;targetcat=link&amp;targettype=uri">ClinicalTrials.gov</a> in the US and <a href="https://www.clinicaltrialsregister.eu/ctr-search/search" ref="pagearea=body&amp;targetsite=external&amp;targetcat=link&amp;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="mga3.Genetic_Counseling"><h2 id="_mga3_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>. &#x02014;ED.</p><div id="mga3.Mode_of_Inheritance"><h3>Mode of Inheritance</h3><p>Costeff syndrome is inherited in an <a class="def" href="/books/n/gene/glossary/def-item/autosomal-recessive/">autosomal recessive</a> manner.</p></div><div id="mga3.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>OPA3</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>OPA3</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. (<i>De novo</i> variants are known to occur at a low but appreciable rate in <a class="def" href="/books/n/gene/glossary/def-item/autosomal-recessive/">autosomal recessive</a> disorders [<a class="bk_pop" href="#mga3.REF.j_nsson.2017.519">J&#x000f3;nsson et al 2017</a>].)</div></li><li class="half_rhythm"><div>Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.</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>OPA3</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 being affected, a 50% chance of being an asymptomatic <a class="def" href="/books/n/gene/glossary/def-item/carrier/">carrier</a>, and a 25% chance of being unaffected and not a carrier. Note: Intrafamilial clinical variability is observed in Costeff syndrome; a sib who inherits <a class="def" href="/books/n/gene/glossary/def-item/biallelic/">biallelic</a> <i>OPA3</i> pathogenic variants may be more or less severely affected than the <a class="def" href="/books/n/gene/glossary/def-item/proband/">proband</a>.</div></li><li class="half_rhythm"><div>Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.</div></li></ul><p>
<b>Offspring of a <a class="def" href="/books/n/gene/glossary/def-item/proband/">proband</a></b>
</p><ul><li class="half_rhythm"><div>Unless an individual with Costeff syndrome has children with an affected individual or a <a class="def" href="/books/n/gene/glossary/def-item/carrier/">carrier</a>, the offspring of a <a class="def" href="/books/n/gene/glossary/def-item/proband/">proband</a> will be obligate heterozygotes (carriers) for a <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a> in <i>OPA3</i>.</div></li><li class="half_rhythm"><div>Note: The <a class="def" href="/books/n/gene/glossary/def-item/carrier/">carrier</a> frequency in individuals of Iraqi Jewish descent was formerly estimated at 1:10 [<a class="bk_pop" href="#mga3.REF.anikster.2001.1218">Anikster et al 2001</a>]; it now appears to be 1:20-1:30.</div></li></ul><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>OPA3</i> <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a>.</p></div><div id="mga3.Carrier_Heterozygote_Detection"><h3>Carrier (Heterozygote) Detection</h3><p>Carrier testing for at-risk relatives requires prior identification of the <i>OPA3</i> pathogenic variants in the family.</p><p>Carrier testing in individuals of Iraqi Jewish origin relies on targeted analysis for the <a href="/books/NBK1473/table/mga3.T.notable_opa3_pathogenic_variants/?report=objectonly" target="object" rid-ob="figobmga3Tnotableopa3pathogenicvariants">c.143-1G&#x0003e;C</a> <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a>.</p><p>Note: Because carriers have normal urinary excretion of 3-methylglutaric acid (3-MGA) and 3-methylglutaconate (3-MGC), <a class="def" href="/books/n/gene/glossary/def-item/carrier/">carrier</a> status cannot be determined using biochemical genetic testing.</p></div><div id="mga3.Related_Genetic_Counseling_Issues"><h3>Related Genetic Counseling Issues</h3><p>
<b>Family planning</b>
</p><ul><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 affected, are carriers, or are at risk of being carriers.</div></li></ul></div><div id="mga3.Prenatal_Testing_and_Preimplantatio"><h3>Prenatal Testing and Preimplantation Genetic Testing</h3><p><b>Molecular genetic testing.</b> Once the <i>OPA3</i> pathogenic variants have been identified in an affected family member, <a class="def" href="/books/n/gene/glossary/def-item/prenatal-testing/">prenatal testing</a> for a pregnancy at increased risk and <a class="def" href="/books/n/gene/glossary/def-item/preimplantation-genetic-testing/">preimplantation genetic testing</a> are possible.</p><p><b>Biochemical genetic testing.</b> Measurement of 3-MGC and 3-MGA in amniotic fluid is not reliable.</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="mga3.Resources"><h2 id="_mga3_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>Costeff Support Group</b>
</div><div>Sheba Medical Center</div><div>Tel Hashomer 52621</div><div>Israel</div><div><b>Phone:</b> +9723530 5017</div><div><b>Fax:</b> +9723530 2658</div><div><b>Email:</b> roma40@012.net.il</div></li><li class="half_rhythm"><div>
<b>National Library of Medicine Genetics Home Reference</b>
</div><div>
<a href="https://ghr.nlm.nih.gov/condition/costeff-syndrome" ref="pagearea=body&amp;targetsite=external&amp;targetcat=link&amp;targettype=uri">Costeff syndrome</a>
</div></li><li class="half_rhythm"><div>
<b>Metabolic Support UK</b>
</div><div>United Kingdom</div><div><b>Phone:</b> 0845 241 2173</div><div>
<a href="https://metabolicsupportuk.org/" ref="pagearea=body&amp;targetsite=external&amp;targetcat=link&amp;targettype=uri">metabolicsupportuk.org</a>
</div></li><li class="half_rhythm"><div>
<b>Organic Acidemia Association</b>
</div><div><b>Phone:</b> 763-559-1797</div><div><b>Email:</b> info@oaanews.org</div><div>
<a href="https://oaanews.org/" ref="pagearea=body&amp;targetsite=external&amp;targetcat=link&amp;targettype=uri">oaanews.org</a>
</div></li></ul>
</div><div id="mga3.Molecular_Genetics"><h2 id="_mga3_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. &#x02014;</i>ED.</p><div id="mga3.molgen.TA" class="table"><h3><span class="label">Table A.</span></h3><div class="caption"><p>Costeff Syndrome: Genes and Databases</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK1473/table/mga3.molgen.TA/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__mga3.molgen.TA_lrgtbl__"><table class="no_bottom_margin"><tbody><tr><th id="hd_b_mga3.molgen.TA_1_1_1_1" rowspan="1" colspan="1" style="vertical-align:top;">Gene</th><th id="hd_b_mga3.molgen.TA_1_1_1_2" rowspan="1" colspan="1" style="vertical-align:top;">Chromosome Locus</th><th id="hd_b_mga3.molgen.TA_1_1_1_3" rowspan="1" colspan="1" style="vertical-align:top;">Protein</th><th id="hd_b_mga3.molgen.TA_1_1_1_4" rowspan="1" colspan="1" style="vertical-align:top;">Locus-Specific Databases</th><th id="hd_b_mga3.molgen.TA_1_1_1_5" rowspan="1" colspan="1" style="vertical-align:top;">HGMD</th><th id="hd_b_mga3.molgen.TA_1_1_1_6" rowspan="1" colspan="1" style="vertical-align:top;">ClinVar</th></tr><tr><td headers="hd_b_mga3.molgen.TA_1_1_1_1" rowspan="1" colspan="1" style="vertical-align:top;">
<a href="/gene/80207" ref="pagearea=body&amp;targetsite=entrez&amp;targetcat=link&amp;targettype=gene">
<i>OPA3</i>
</a>
</td><td headers="hd_b_mga3.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&#x00026;acc=80207" ref="pagearea=body&amp;targetsite=external&amp;targetcat=link&amp;targettype=uri">19q13<wbr style="display:inline-block"></wbr>​.32</a>
</td><td headers="hd_b_mga3.molgen.TA_1_1_1_3" rowspan="1" colspan="1" style="vertical-align:top;">
<a href="http://www.uniprot.org/uniprot/Q9H6K4" ref="pagearea=body&amp;targetsite=external&amp;targetcat=link&amp;targettype=uri">Optic atrophy 3 protein</a>
</td><td headers="hd_b_mga3.molgen.TA_1_1_1_4" rowspan="1" colspan="1" style="vertical-align:top;">
<a href="https://databases.lovd.nl/shared/genes/OPA3" ref="pagearea=body&amp;targetsite=external&amp;targetcat=link&amp;targettype=uri">OPA3 @ LOVD</a>
</td><td headers="hd_b_mga3.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=OPA3" ref="pagearea=body&amp;targetsite=external&amp;targetcat=link&amp;targettype=uri">OPA3</a>
</td><td headers="hd_b_mga3.molgen.TA_1_1_1_6" rowspan="1" colspan="1" style="vertical-align:top;">
<a href="https://www.ncbi.nlm.nih.gov/clinvar/?term=OPA3[gene]" ref="pagearea=body&amp;targetsite=external&amp;targetcat=link&amp;targettype=uri">OPA3</a>
</td></tr></tbody></table></div><div><div><dl class="temp-labeled-list small"><dt></dt><dd><div id="mga3.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&amp;targetsite=external&amp;targetcat=link&amp;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&amp;targetsite=external&amp;targetcat=link&amp;targettype=uri">OMIM</a>;
protein from <a href="http://www.uniprot.org/" ref="pagearea=body&amp;targetsite=external&amp;targetcat=link&amp;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="mga3.molgen.TB" class="table"><h3><span class="label">Table B.</span></h3><div class="caption"><p>OMIM Entries for Costeff Syndrome (<a href="/omim/258501,606580" ref="pagearea=body&amp;targetsite=entrez&amp;targetcat=term&amp;targettype=omim">View All in OMIM</a>) </p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK1473/table/mga3.molgen.TB/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__mga3.molgen.TB_lrgtbl__"><table><tbody><tr><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
<a href="/omim/258501" ref="pagearea=body&amp;targetsite=entrez&amp;targetcat=term&amp;targettype=omim">258501</a></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">3-METHYLGLUTACONIC ACIDURIA, TYPE III; MGCA3</td></tr><tr><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
<a href="/omim/606580" ref="pagearea=body&amp;targetsite=entrez&amp;targetcat=term&amp;targettype=omim">606580</a></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">OUTER MITOCHONDRIAL MEMBRANE LIPID METABOLISM REGULATOR OPA3; OPA3</td></tr></tbody></table></div></div><div id="mga3.Molecular_Pathogenesis"><h3>Molecular Pathogenesis</h3><p><i>OPA3</i> encodes a 179-amino acid (20-kd) protein that contains a mitochondrial targeting peptide, NRIKE, at amino acid residues 25-29 and is predicted to be exported to the mitochondrion [<a class="bk_pop" href="#mga3.REF.anikster.2001.1218">Anikster et al 2001</a>]. It is ubiquitously expressed, with highest expression in skeletal muscle and kidney. In the brain, the cerebral cortex, medulla, cerebellum, and frontal lobe have slightly increased expression [<a class="bk_pop" href="#mga3.REF.anikster.2001.1218">Anikster et al 2001</a>].</p><p>The resulting lack of <a class="def" href="/books/n/gene/glossary/def-item/mrna/">mRNA</a> expression manifests as the absence of an <i>OPA3</i> band on a northern blotting of fibroblasts from affected individuals and as an inability to amplify <i>OPA3</i> from the blood of affected individuals [<a class="bk_pop" href="#mga3.REF.anikster.2001.1218">Anikster et al 2001</a>].</p><p>The effect of the <i>OPA3</i> pathogenic variants on cell function is unknown. Homozygous acceptor <a class="def" href="/books/n/gene/glossary/def-item/splice-site/">splice site</a> variant c.143-1G&#x0003e;C in <i>OPA3</i> with loss of function leads to typical Costeff syndrome.</p><p><b>Mechanism of disease causation.</b>
<i>OPA3</i> loss of function</p><p><b><i>OPA3</i>-specific laboratory technical considerations.</b> In the literature, the number of exons of <i>OPA3</i> may be given as two or three. The issue is one of alternative <a class="def" href="/books/n/gene/glossary/def-item/splicing/">splicing</a>; see <a class="bk_pop" href="#mga3.REF.lam.2014.114">Lam et al [2014]</a> for a succinct explanation.</p><div id="mga3.T.notable_opa3_pathogenic_variants" class="table"><h3><span class="label">Table 6. </span></h3><div class="caption"><p>Notable <i>OPA3</i> Pathogenic Variants</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK1473/table/mga3.T.notable_opa3_pathogenic_variants/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__mga3.T.notable_opa3_pathogenic_variants_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_mga3.T.notable_opa3_pathogenic_variants_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Reference Sequences</th><th id="hd_h_mga3.T.notable_opa3_pathogenic_variants_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">DNA Nucleotide Change (Alias&#x000a0;<sup>1</sup>)</th><th id="hd_h_mga3.T.notable_opa3_pathogenic_variants_1_1_1_3" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Predicted Protein Change</th><th id="hd_h_mga3.T.notable_opa3_pathogenic_variants_1_1_1_4" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Comment [Reference]</th></tr></thead><tbody><tr><td headers="hd_h_mga3.T.notable_opa3_pathogenic_variants_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
<a href="https://www.ncbi.nlm.nih.gov/nuccore/156151425" ref="pagearea=body&amp;targetsite=external&amp;targetcat=link&amp;targettype=uri">NM_025136<wbr style="display:inline-block"></wbr>​.2</a>
</td><td headers="hd_h_mga3.T.notable_opa3_pathogenic_variants_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">c.143-1G&#x0003e;C<br />(IVS1-1G&#x0003e;C)</td><td headers="hd_h_mga3.T.notable_opa3_pathogenic_variants_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">--</td><td headers="hd_h_mga3.T.notable_opa3_pathogenic_variants_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Accounts for 100% of pathogenic variants of individuals of Iraqi Jewish origin w/Costeff syndrome [<a class="bk_pop" href="#mga3.REF.anikster.2001.1218">Anikster et al 2001</a>]</td></tr><tr><td headers="hd_h_mga3.T.notable_opa3_pathogenic_variants_1_1_1_1" rowspan="2" scope="row" colspan="1" style="text-align:left;vertical-align:middle;">
<a href="https://www.ncbi.nlm.nih.gov/nuccore/156151425" ref="pagearea=body&amp;targetsite=external&amp;targetcat=link&amp;targettype=uri">NM_025136<wbr style="display:inline-block"></wbr>​.2</a>
<br />
<a href="https://www.ncbi.nlm.nih.gov/protein/13376717" ref="pagearea=body&amp;targetsite=external&amp;targetcat=link&amp;targettype=uri">NP_079412<wbr style="display:inline-block"></wbr>​.1</a>
</td><td headers="hd_h_mga3.T.notable_opa3_pathogenic_variants_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">c.322_339del<br />(320_337del)</td><td headers="hd_h_mga3.T.notable_opa3_pathogenic_variants_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">p.Gln108_Glu113del</td><td headers="hd_h_mga3.T.notable_opa3_pathogenic_variants_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Found in an individual of Turkish-Kurdish origin w/Costeff syndrome [<a class="bk_pop" href="#mga3.REF.kleta.2002.201">Kleta et al 2002</a>]&#x000a0;<sup>2</sup></td></tr><tr><td headers="hd_h_mga3.T.notable_opa3_pathogenic_variants_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">c.415C&#x0003e;T</td><td headers="hd_h_mga3.T.notable_opa3_pathogenic_variants_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">p.Gln139Ter</td><td headers="hd_h_mga3.T.notable_opa3_pathogenic_variants_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Found in an individual of Indian origin w/Costeff syndrome [<a class="bk_pop" href="#mga3.REF.ho.2008.s419">Ho et al 2008</a>]&#x000a0;<sup>3</sup></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 author. <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&amp;targetsite=external&amp;targetcat=link&amp;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><dt>1. </dt><dd><div id="mga3.TF.6.1"><p class="no_margin">Variant designation that does not conform to current naming conventions</p></div></dd><dt>2. </dt><dd><div id="mga3.TF.6.2"><p class="no_margin">First <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a> found to date in an individual of non-Iraqi Jewish origin</p></div></dd><dt>3. </dt><dd><div id="mga3.TF.6.3"><p class="no_margin">Homozygous <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a>; the second pathogenic variant found to date in an individual of non-Iraqi Jewish origin</p></div></dd></dl></div></div></div></div></div><div id="mga3.References"><h2 id="_mga3_References_">References</h2><div id="mga3.Literature_Cited"><h3>Literature Cited</h3><ul class="simple-list"><li class="half_rhythm"><div class="bk_ref" id="mga3.REF.anikster.2001.1218">Anikster Y, Kleta R, Shaag A, Gahl WA, Elpeleg O. Type III 3-methylglutaconic aciduria (optic atrophy plus syndrome, or Costeff optic atrophy syndrome): identification of the OPA3 gene and its founder mutation in Iraqi Jews. <span><span class="ref-journal">Am J Hum Genet. </span>2001;<span class="ref-vol">69</span>:1218–24.</span> [<a href="/pmc/articles/PMC1235533/" ref="pagearea=cite-ref&amp;targetsite=entrez&amp;targetcat=link&amp;targettype=pmc">PMC free article<span class="bk_prnt">: PMC1235533</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/11668429" ref="pagearea=cite-ref&amp;targetsite=entrez&amp;targetcat=link&amp;targettype=pubmed">PubMed<span class="bk_prnt">: 11668429</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="mga3.REF.barth.2004.349">Barth PG, Valianpour F, Bowen VM, Lam J, Duran M, Vaz FM, Wanders RJ. X-linked cardioskeletal myopathy and neutropenia (Barth syndrome): an update. <span><span class="ref-journal">Am J Med Genet A. </span>2004;<span class="ref-vol">126A</span>:349–54.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/15098233" ref="pagearea=cite-ref&amp;targetsite=entrez&amp;targetcat=link&amp;targettype=pubmed">PubMed<span class="bk_prnt">: 15098233</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="mga3.REF.bourne.2017.a001156">Bourne SC, Townsend KN, Shyr C, Matthews A, Lear SA, Attariwala R, Lehman A, Wasserman WW, van Karnebeek C, Sinclair G, Vallance H, Gibson WT. Optic atrophy, cataracts, lipodystrophy/lipoatrophy, and peripheral neuropathy caused by a de novo OPA3 mutation. <span><span class="ref-journal">Cold Spring Harb Mol Case Stud. </span>2017;<span class="ref-vol">3</span>:a001156. </span> [<a href="/pmc/articles/PMC5171695/" ref="pagearea=cite-ref&amp;targetsite=entrez&amp;targetcat=link&amp;targettype=pmc">PMC free article<span class="bk_prnt">: PMC5171695</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/28050599" ref="pagearea=cite-ref&amp;targetsite=entrez&amp;targetcat=link&amp;targettype=pubmed">PubMed<span class="bk_prnt">: 28050599</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="mga3.REF.carmi.2015.733">Carmi N, Lev D, Leshinsky-Silver E, Anikster Y, Blumkin L, Kivity S, Lerman-Sagie T, Zerem A. Atypical presentation of Costeff syndrome-severe psychomotor involvement and electrical status epilepticus during slow wave sleep. <span><span class="ref-journal">Eur J Paediatr Neurol. </span>2015;<span class="ref-vol">19</span>:733–6.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/26190011" ref="pagearea=cite-ref&amp;targetsite=entrez&amp;targetcat=link&amp;targettype=pubmed">PubMed<span class="bk_prnt">: 26190011</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="mga3.REF.copeliovitch.2001.512">Copeliovitch L, Katz K, Arbel N, Harries N, Bar-On E, Soudry M. Musculoskeletal deformities in Behr syndrome. <span><span class="ref-journal">J Pediatr Orthop. </span>2001;<span class="ref-vol">21</span>:512–4.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/11433166" ref="pagearea=cite-ref&amp;targetsite=entrez&amp;targetcat=link&amp;targettype=pubmed">PubMed<span class="bk_prnt">: 11433166</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="mga3.REF.davey.2006.385">Davey KM, Parboosingh JS, McLeod DR, Chan A, Casey R, Ferreira P, Snyder FF, Bridge PJ, Bernier FP. Mutation of DNAJC19, a human homologue of yeast inner mitochondrial membrane co-chaperones, causes DCMA syndrome, a novel autosomal recessive Barth syndrome-like condition. <span><span class="ref-journal">J Med Genet. </span>2006;<span class="ref-vol">43</span>:385–93.</span> [<a href="/pmc/articles/PMC2564511/" ref="pagearea=cite-ref&amp;targetsite=entrez&amp;targetcat=link&amp;targettype=pmc">PMC free article<span class="bk_prnt">: PMC2564511</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/16055927" ref="pagearea=cite-ref&amp;targetsite=entrez&amp;targetcat=link&amp;targettype=pubmed">PubMed<span class="bk_prnt">: 16055927</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="mga3.REF.elpeleg.1994.167">Elpeleg ON, Costeff H, Joseph A, Shental Y, Weitz R, Gibson KM. 3-Methylglutaconic aciduria in the Iraqi-Jewish "optic atrophy plus" (Costeff) syndrome. <span><span class="ref-journal">Dev Med Child Neurol. </span>1994;<span class="ref-vol">36</span>:167–72.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/7510656" ref="pagearea=cite-ref&amp;targetsite=entrez&amp;targetcat=link&amp;targettype=pubmed">PubMed<span class="bk_prnt">: 7510656</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="mga3.REF.gaier.2019.570">Gaier ED, Sahai I, Wiggs JL, McGeeney B, Hoffman J, Peeler CE. Novel homozygous OPA3 mutation in an Afghani family with 3-methylglutaconic aciduria type III and optic atrophy. <span><span class="ref-journal">Ophthalmic Genet. </span>2019;<span class="ref-vol">40</span>:570–3.</span> [<a href="/pmc/articles/PMC7050282/" ref="pagearea=cite-ref&amp;targetsite=entrez&amp;targetcat=link&amp;targettype=pmc">PMC free article<span class="bk_prnt">: PMC7050282</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/31928268" ref="pagearea=cite-ref&amp;targetsite=entrez&amp;targetcat=link&amp;targettype=pubmed">PubMed<span class="bk_prnt">: 31928268</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="mga3.REF.gunayaygun.2005.1">Gunay-Aygun M. 3-Methylglutaconic aciduria: a common biochemical marker in various syndromes with diverse clinical features. <span><span class="ref-journal">Mol Genet Metab. </span>2005;<span class="ref-vol">84</span>:1–3.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/15719488" ref="pagearea=cite-ref&amp;targetsite=entrez&amp;targetcat=link&amp;targettype=pubmed">PubMed<span class="bk_prnt">: 15719488</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="mga3.REF.ho.2008.s419">Ho G, Walter JH, Christodoulou J. Costeff optic atrophy syndrome: New clinical case and novel molecular findings. <span><span class="ref-journal">J Inherit Metab Dis. </span>2008;<span class="ref-vol">31</span> Suppl 2:S419–23.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/18985435" ref="pagearea=cite-ref&amp;targetsite=entrez&amp;targetcat=link&amp;targettype=pubmed">PubMed<span class="bk_prnt">: 18985435</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="mga3.REF.ijlst.2002.1463">Ijlst L, Loupatty FJ, Ruiter JP, Duran M, Lehnert W, Wanders RJ. 3-Methylglutaconic aciduria type I is caused by mutations in AUH. <span><span class="ref-journal">Am J Hum Genet. </span>2002;<span class="ref-vol">71</span>:1463–6.</span> [<a href="/pmc/articles/PMC378594/" ref="pagearea=cite-ref&amp;targetsite=entrez&amp;targetcat=link&amp;targettype=pmc">PMC free article<span class="bk_prnt">: PMC378594</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/12434311" ref="pagearea=cite-ref&amp;targetsite=entrez&amp;targetcat=link&amp;targettype=pubmed">PubMed<span class="bk_prnt">: 12434311</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="mga3.REF.illsinger.2004.213">Illsinger S, Lucke T, Zschocke J, Gibson KM, Das AM. 3-methylglutaconic aciduria type I in a boy with fever-associated seizures. <span><span class="ref-journal">Pediatr Neurol. </span>2004;<span class="ref-vol">30</span>:213–5.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/15033206" ref="pagearea=cite-ref&amp;targetsite=entrez&amp;targetcat=link&amp;targettype=pubmed">PubMed<span class="bk_prnt">: 15033206</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="mga3.REF.j_nsson.2017.519">J&#x000f3;nsson 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&amp;targetsite=entrez&amp;targetcat=link&amp;targettype=pubmed">PubMed<span class="bk_prnt">: 28959963</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="mga3.REF.kessi.2018.40">Kessi M, Peng J, Yang L, Xiong J, Duan H, Pang N, Yin F. Genetic etiologies of the electrical status epilepticus during slow wave sleep: systematic review. <span><span class="ref-journal">BMC Genet. </span>2018;<span class="ref-vol">19</span>:40.</span> [<a href="/pmc/articles/PMC6034250/" ref="pagearea=cite-ref&amp;targetsite=entrez&amp;targetcat=link&amp;targettype=pmc">PMC free article<span class="bk_prnt">: PMC6034250</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/29976148" ref="pagearea=cite-ref&amp;targetsite=entrez&amp;targetcat=link&amp;targettype=pubmed">PubMed<span class="bk_prnt">: 29976148</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="mga3.REF.kleta.2002.201">Kleta R, Skovby F, Christensen E, Rosenberg T, Gahl WA, Anikster Y. 3-Methylglutaconic aciduria type III in a non-Iraqi-Jewish kindred: clinical and molecular findings. <span><span class="ref-journal">Mol Genet Metab. </span>2002;<span class="ref-vol">76</span>:201–6.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/12126933" ref="pagearea=cite-ref&amp;targetsite=entrez&amp;targetcat=link&amp;targettype=pubmed">PubMed<span class="bk_prnt">: 12126933</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="mga3.REF.kovacsnagy.2018.373">Kovacs-Nagy R, Morin G, Nouri MA, Brandau O, Saadi NW, Nouri MA, van den Broek F, Prokisch H, Mayr JA, Wortmann SB. HTRA2 defect: a recognizable inborn error of metabolism with 3-methylglutaconic aciduria as discriminating feature characterized by neonatal movement disorder and epilepsy-report of 11 patients. <span><span class="ref-journal">Neuropediatrics. </span>2018;<span class="ref-vol">49</span>:373–8.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/30114719" ref="pagearea=cite-ref&amp;targetsite=entrez&amp;targetcat=link&amp;targettype=pubmed">PubMed<span class="bk_prnt">: 30114719</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="mga3.REF.lam.2014.114">Lam C, Gallo LK, Dineen R, Ciccone C, Dorward H, Hoganson GE, Wolfe L, Gahl WA, Huizing M. Two novel compound heterozygous mutations in OPA3 in two siblings with OPA3-related 3-methylglutaconic aciduria. <span><span class="ref-journal">Mol Genet Metab Rep. </span>2014;<span class="ref-vol">1</span>:114–23.</span> [<a href="/pmc/articles/PMC3987911/" ref="pagearea=cite-ref&amp;targetsite=entrez&amp;targetcat=link&amp;targettype=pmc">PMC free article<span class="bk_prnt">: PMC3987911</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/24749080" ref="pagearea=cite-ref&amp;targetsite=entrez&amp;targetcat=link&amp;targettype=pubmed">PubMed<span class="bk_prnt">: 24749080</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="mga3.REF.sofer.2015.197">Sofer S, Schweiger A, Blumkin L, Yahalom G, Anikster Y, Lev D, Ben-Zeev B, Lerman-Sagie T, Hassin-Baer S. The neuropsychological profile of patients with 3-methylglutaconic aciduria type III, Costeff syndrome. <span><span class="ref-journal">Am J Med Genet B Neuropsychiatr Genet. </span>2015;<span class="ref-vol">168B</span>:197–203.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/25657044" ref="pagearea=cite-ref&amp;targetsite=entrez&amp;targetcat=link&amp;targettype=pubmed">PubMed<span class="bk_prnt">: 25657044</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="mga3.REF.stenson.2020.1197">Stenson PD, Mort M, Ball EV, Chapman M, Evans K, Azevedo L, Hayden M, Heywood S, Millar DS, Phillips AD, Cooper DN. The Human Gene Mutation Database (HGMD&#x000ae;): optimizing its use in a clinical diagnostic or research setting. <span><span class="ref-journal">Hum Genet. </span>2020;<span class="ref-vol">139</span>:1197–207.</span> [<a href="/pmc/articles/PMC7497289/" ref="pagearea=cite-ref&amp;targetsite=entrez&amp;targetcat=link&amp;targettype=pmc">PMC free article<span class="bk_prnt">: PMC7497289</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/32596782" ref="pagearea=cite-ref&amp;targetsite=entrez&amp;targetcat=link&amp;targettype=pubmed">PubMed<span class="bk_prnt">: 32596782</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="mga3.REF.sweetman.2001">Sweetman L, Williams JC. Branched chain organic acidurias. In: Scriver CR, Beaudet AL, Sly WS, Valle D, eds. <em>The Metabolic and Molecular Basis of Inherited Disease</em>. Vol 2. New York, NY: McGraw-Hill; 2001:2137-40.</div></li><li class="half_rhythm"><div class="bk_ref" id="mga3.REF.wortmann.2013a.923">Wortmann SB, Duran M, Anikster Y, Barth PG, Sperl W, Zschocke J, Morava E, Wevers RA. Inborn errors of metabolism with 3-methylglutaconic aciduria as discriminative feature: proper classification and nomenclature. <span><span class="ref-journal">J Inherit Metab Dis. </span>2013a;<span class="ref-vol">36</span>:923–8.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/23296368" ref="pagearea=cite-ref&amp;targetsite=entrez&amp;targetcat=link&amp;targettype=pubmed">PubMed<span class="bk_prnt">: 23296368</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="mga3.REF.wortmann.2013b.913">Wortmann SB, Kluijtmans LA, Rodenburg RJ, Sass JO, Nouws J, van Kaauwen EP, Kleefstra T, Tranebjaerg L, de Vries MC, Isohanni P, Walter K, Alkuraya FS, Smuts I, Reinecke CJ, van der Westhuizen FH, Thorburn D, Smeitink JA, Morava E, Wevers RA. 3-Methylglutaconic aciduria-lessons from 50 genes and 977 patients. <span><span class="ref-journal">J Inherit Metab Dis. </span>2013b;<span class="ref-vol">36</span>:913–21.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/23355087" ref="pagearea=cite-ref&amp;targetsite=entrez&amp;targetcat=link&amp;targettype=pubmed">PubMed<span class="bk_prnt">: 23355087</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="mga3.REF.yahalom.2014.2275">Yahalom G, Anikster Y, Huna-Baron R, Hoffmann C, Blumkin L, Lev D, Tsabari R, Nitsan Z, Lerman SF, Ben-Zeev B, Pode-Shakked B, Sofer S, Schweiger A, Lerman-Sagie T, Hassin-Baer S. Costeff syndrome: clinical features and natural history. <span><span class="ref-journal">J Neurol. </span>2014;<span class="ref-vol">261</span>:2275–82.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/25201222" ref="pagearea=cite-ref&amp;targetsite=entrez&amp;targetcat=link&amp;targettype=pubmed">PubMed<span class="bk_prnt">: 25201222</span></a>]</div></li></ul></div></div><div id="mga3.Chapter_Notes"><h2 id="_mga3_Chapter_Notes_">Chapter Notes</h2><div id="mga3.Author_Notes"><h3>Author Notes</h3><p>Readers are welcome to contact Dr Anikster with questions at the <a href="https://eng.sheba.co.il/pediatric_metabolic_disease" ref="pagearea=body&amp;targetsite=external&amp;targetcat=link&amp;targettype=uri">Metabolic Disease Unit</a>.<br />Phone: +97235305017<br />Fax: +97235305018</p></div><div id="mga3.Author_History"><h3>Author History</h3><p>Yair Anikster, MD, PhD (2006-present)<br />William A Gahl, MD, PhD; National Institutes of Health (2006-2013)<br />Meral Gunay-Aygun, MD; National Institutes of Health (2006-2020)<br />Marian Huizing, PhD; National Institutes of Health (2013-2020)</p></div><div id="mga3.Revision_History"><h3>Revision History</h3><ul><li class="half_rhythm"><div>30 April 2020 (bp) Comprehensive update posted live</div></li><li class="half_rhythm"><div>19 December 2013 (me) Comprehensive update posted live</div></li><li class="half_rhythm"><div>31 March 2009 (me) Comprehensive update posted live</div></li><li class="half_rhythm"><div>28 July 2006 (me) Review posted live</div></li><li class="half_rhythm"><div>27 April 2006 (mga) Original submission</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&amp;targetsite=external&amp;targetcat=link&amp;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&amp;targetsite=external&amp;targetcat=link&amp;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&amp;targetsite=external&amp;targetcat=link&amp;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: NBK1473</span><span class="label">PMID: <a href="https://pubmed.ncbi.nlm.nih.gov/20301646" title="PubMed record of this page" ref="pagearea=meta&amp;targetsite=entrez&amp;targetcat=link&amp;targettype=pubmed">20301646</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/cdls/" title="Previous page in this title">&lt; Prev</a><a class="active page_link next" href="/books/n/gene/ce-dysp/" title="Next page in this title">Next &gt;</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=NBK1473&amp;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/NBK1473/?report=reader">PubReader</a></li><li><a href="/books/NBK1473/?report=printable">Print View</a></li><li><a data-jig="ncbidialog" href="#_ncbi_dlg_citbx_NBK1473" data-jigconfig="width:400,modal:true">Cite this Page</a><div id="_ncbi_dlg_citbx_NBK1473" style="display:none" title="Cite this Page"><div class="bk_tt">Anikster Y. Costeff Syndrome. 2006 Jul 28 [Updated 2020 Apr 30]. 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/NBK1473/pdf/Bookshelf_NBK1473.pdf">PDF version of this page</a> (522K)</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="#mga3.Summary" ref="log$=inpage&amp;link_id=inpage">Summary</a></li><li><a href="#mga3.Diagnosis" ref="log$=inpage&amp;link_id=inpage">Diagnosis</a></li><li><a href="#mga3.Clinical_Characteristics" ref="log$=inpage&amp;link_id=inpage">Clinical Characteristics</a></li><li><a href="#mga3.Genetically_Related_Allelic_Disorde" ref="log$=inpage&amp;link_id=inpage">Genetically Related (Allelic) Disorders</a></li><li><a href="#mga3.Differential_Diagnosis" ref="log$=inpage&amp;link_id=inpage">Differential Diagnosis</a></li><li><a href="#mga3.Management" ref="log$=inpage&amp;link_id=inpage">Management</a></li><li><a href="#mga3.Genetic_Counseling" ref="log$=inpage&amp;link_id=inpage">Genetic Counseling</a></li><li><a href="#mga3.Resources" ref="log$=inpage&amp;link_id=inpage">Resources</a></li><li><a href="#mga3.Molecular_Genetics" ref="log$=inpage&amp;link_id=inpage">Molecular Genetics</a></li><li><a href="#mga3.References" ref="log$=inpage&amp;link_id=inpage">References</a></li><li><a href="#mga3.Chapter_Notes" ref="log$=inpage&amp;link_id=inpage">Chapter Notes</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&amp;targetsite=external&amp;targetcat=link&amp;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=80207[geneid]" ref="pagearea=document-links&amp;targetsite=external&amp;targetcat=link&amp;targettype=uri&amp;link_id=tests_in_gtr_by_gene">OPA3</a>
</li></ul></div></div><div class="portlet"><div class="portlet_head"><div class="portlet_title"><h3><span>Variations in ClinVar</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/clinvar/?term=NBK1473+AND+genereviews[submitter]" ref="pagearea=document-links&amp;targetsite=external&amp;targetcat=link&amp;targettype=uri">Variations from this GeneReview in ClinVar</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=medgen&amp;DbFrom=books&amp;Cmd=Link&amp;LinkName=books_medgen&amp;IdsFromResult=1474142" ref="log$=recordlinks">MedGen</a><div class="brieflinkpop offscreen_noflow">Related information in MedGen</div></li><li class="brieflinkpopper"><a class="brieflinkpopperctrl" href="/books/?Db=omim&amp;DbFrom=books&amp;Cmd=Link&amp;LinkName=books_omim&amp;IdsFromResult=1474142" ref="log$=recordlinks">OMIM</a><div class="brieflinkpop offscreen_noflow">Related OMIM records</div></li><li class="brieflinkpopper"><a class="brieflinkpopperctrl" href="/books/?Db=pmc&amp;DbFrom=books&amp;Cmd=Link&amp;LinkName=books_pmc_refs&amp;IdsFromResult=1474142" ref="log$=recordlinks">PMC</a><div class="brieflinkpop offscreen_noflow">PubMed Central citations</div></li><li class="brieflinkpopper"><a class="brieflinkpopperctrl" href="/books/?Db=pubmed&amp;DbFrom=books&amp;Cmd=Link&amp;LinkName=books_pubmed_refs&amp;IdsFromResult=1474142" ref="log$=recordlinks">PubMed</a><div class="brieflinkpop offscreen_noflow">Links to PubMed</div></li><li class="brieflinkpopper"><a class="brieflinkpopperctrl" href="/books/?Db=gene&amp;DbFrom=books&amp;Cmd=Link&amp;LinkName=books_gene&amp;IdsFromResult=1474142" ref="log$=recordlinks">Gene</a><div class="brieflinkpop offscreen_noflow">Locus Links</div></li></ul></div></div><div class="portlet"><div class="portlet_head"><div class="portlet_title"><h3><span>Similar articles in PubMed</span></h3></div><a name="Shutter" sid="1" href="#" class="portlet_shutter" title="Show/hide content" remembercollapsed="true" pgsec_name="PBooksDiscovery_RA" id="Shutter"></a></div><div class="portlet_content"><ul><li class="brieflinkpopper two_line"><a class="brieflinkpopperctrl" href="/pubmed/20301656" ref="ordinalpos=1&amp;linkpos=1&amp;log$=relatedreviews&amp;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/20301790" ref="ordinalpos=1&amp;linkpos=2&amp;log$=relatedreviews&amp;logdbfrom=pubmed"><span xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="invert">Review</span> Ataxia-Telangiectasia.</a><span class="source">[GeneReviews(®). 1993]</span><div class="brieflinkpop offscreen_noflow"><span xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="invert">Review</span> Ataxia-Telangiectasia.<div class="brieflinkpopdesc"><em xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="author">Veenhuis S, van Os N, Weemaes C, Kamsteeg EJ, Willemsen M. </em><em xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="cit">GeneReviews(®). 1993</em></div></div></li><li class="brieflinkpopper two_line"><a class="brieflinkpopperctrl" href="/pubmed/20301497" ref="ordinalpos=1&amp;linkpos=3&amp;log$=relatedreviews&amp;logdbfrom=pubmed"><span xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="invert">Review</span> Biotinidase 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> Biotinidase Deficiency.<div class="brieflinkpopdesc"><em xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="author">Wolf B. </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/20301601" ref="ordinalpos=1&amp;linkpos=4&amp;log$=relatedreviews&amp;logdbfrom=pubmed"><span xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="invert">Review</span> Neuronal Ceroid-Lipofuscinoses – RETIRED CHAPTER, FOR HISTORICAL REFERENCE ONLY.</a><span class="source">[GeneReviews(®). 1993]</span><div class="brieflinkpop offscreen_noflow"><span xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="invert">Review</span> Neuronal Ceroid-Lipofuscinoses – RETIRED CHAPTER, FOR HISTORICAL REFERENCE ONLY.<div class="brieflinkpopdesc"><em xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="author">Mole SE, Williams RE. </em><em xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="cit">GeneReviews(®). 1993</em></div></div></li><li class="brieflinkpopper two_line"><a class="brieflinkpopperctrl" href="/pubmed/20301599" ref="ordinalpos=1&amp;linkpos=5&amp;log$=relatedreviews&amp;logdbfrom=pubmed"><span xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="invert">Review</span> Beta-Thalassemia.</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> Beta-Thalassemia.<div class="brieflinkpopdesc"><em xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="author">Langer AL. </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&amp;cmd=link&amp;linkname=pubmed_pubmed_reviews&amp;uid=20301646" ref="ordinalpos=1&amp;log$=relatedreviews_seeall&amp;logdbfrom=pubmed">See reviews...</a><a class="seemore" href="/sites/entrez?db=pubmed&amp;cmd=link&amp;linkname=pubmed_pubmed&amp;uid=20301646" ref="ordinalpos=1&amp;log$=relatedarticles_seeall&amp;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$=activity&amp;linkpos=1" href="/portal/utils/pageresolver.fcgi?recordid=67d2aaf4a68b6b5afc7a2afd">Costeff Syndrome - GeneReviews®</a><div class="ralinkpop offscreen_noflow">Costeff Syndrome - GeneReviews®<div class="brieflinkpopdesc"></div></div><div class="tertiary"></div></li><li class="ra_rcd ralinkpopper two_line"><a class="htb ralinkpopperctrl" ref="log$=activity&amp;linkpos=2" href="/portal/utils/pageresolver.fcgi?recordid=67d2aaf1b15b832ebc149485">Cornelia de Lange Syndrome - GeneReviews®</a><div class="ralinkpop offscreen_noflow">Cornelia de Lange 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$=activity&amp;linkpos=3" href="/portal/utils/pageresolver.fcgi?recordid=67d2aaeeb15b832ebc147dcf">Congenital Stromal Corneal Dystrophy - GeneReviews®</a><div class="ralinkpop offscreen_noflow">Congenital Stromal Corneal Dystrophy - GeneReviews®<div class="brieflinkpopdesc"></div></div><div class="tertiary"></div></li><li class="ra_rcd ralinkpopper two_line"><a class="htb ralinkpopperctrl" ref="log$=activity&amp;linkpos=4" href="/portal/utils/pageresolver.fcgi?recordid=67d2aaeba68b6b5afc79fab2">Congenital NAD Deficiency Disorder - GeneReviews®</a><div class="ralinkpop offscreen_noflow">Congenital NAD Deficiency Disorder - GeneReviews®<div class="brieflinkpopdesc"></div></div><div class="tertiary"></div></li><li class="ra_rcd ralinkpopper two_line"><a class="htb ralinkpopperctrl" ref="log$=activity&amp;linkpos=5" href="/portal/utils/pageresolver.fcgi?recordid=67d2aae7a68b6b5afc79e596">Congenital Mirror Movements - GeneReviews®</a><div class="ralinkpop offscreen_noflow">Congenital Mirror Movements - GeneReviews®<div class="brieflinkpopdesc"></div></div><div class="tertiary"></div></li></ul><p class="HTOn">Your browsing activity is empty.</p><p class="HTOff">Activity recording is turned off.</p><p id="turnOn" class="HTOff"><a href="javascript:historyDisplayState('HTOn')">Turn recording back on</a></p><a class="seemore" href="/sites/myncbi/recentactivity">See more...</a></div></div></div>
<!-- Custom content below discovery portlets -->
<div class="col7">
</div>
</div>
</div>
<!-- Custom content after all -->
<div class="col8">
</div>
<div class="col9">
</div>
<script type="text/javascript" src="/corehtml/pmc/js/jquery.scrollTo-1.4.2.js"></script>
<script type="text/javascript">
(function($){
$('.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&amp;ncbi_db=books&amp;ncbi_pdid=book-part&amp;ncbi_acc=NBK1473&amp;ncbi_domain=gene&amp;ncbi_report=record&amp;ncbi_type=fulltext&amp;ncbi_objectid=&amp;ncbi_pcid=/NBK1473/&amp;ncbi_pagename=Costeff Syndrome - GeneReviews® - NCBI Bookshelf&amp;ncbi_bookparttype=chapter&amp;ncbi_app=bookshelf" /></noscript>
<!-- usually for JS scripts at page bottom -->
<!--<component id="PageFixtures" label="styles"></component>-->
<!-- CE8B5AF87C7FFCB1_0191SID /projects/books/PBooks@9.11 portal107 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>
Reference in a new issue View git blame Copy permalink