1036 lines
No EOL
182 KiB
HTML
1036 lines
No EOL
182 KiB
HTML
<?xml version="1.0" encoding="utf-8"?>
|
||
<!DOCTYPE html PUBLIC "-//W3C//DTD XHTML 1.0 Transitional//EN" "http://www.w3.org/TR/xhtml1/DTD/xhtml1-transitional.dtd">
|
||
<html xmlns="http://www.w3.org/1999/xhtml" xml:lang="en" lang="en">
|
||
|
||
<head><meta http-equiv="Content-Type" content="text/html; charset=utf-8" />
|
||
<!-- AppResources meta begin -->
|
||
<meta name="paf-app-resources" content="" />
|
||
<script type="text/javascript">var ncbi_startTime = new Date();</script>
|
||
|
||
<!-- AppResources meta end -->
|
||
|
||
<!-- TemplateResources meta begin -->
|
||
<meta name="paf_template" content="" />
|
||
|
||
<!-- TemplateResources meta end -->
|
||
|
||
<!-- Logger begin -->
|
||
<meta name="ncbi_db" content="books" /><meta name="ncbi_pdid" content="book-part" /><meta name="ncbi_acc" content="NBK1515" /><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="/NBK1515/" /><meta name="ncbi_pagename" content="Tyrosinemia Type I - GeneReviews® - NCBI Bookshelf" /><meta name="ncbi_bookparttype" content="chapter" /><meta name="ncbi_app" content="bookshelf" />
|
||
<!-- Logger end -->
|
||
|
||
<title>Tyrosinemia Type I - 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="Tyrosinemia Type I" /><meta name="citation_publisher" content="University of Washington, Seattle" /><meta name="citation_date" content="2017/05/25" /><meta name="citation_author" content="Lisa Sniderman King" /><meta name="citation_author" content="Cristine Trahms" /><meta name="citation_author" content="C Ronald Scott" /><meta name="citation_pmid" content="20301688" /><meta name="citation_fulltext_html_url" content="https://www.ncbi.nlm.nih.gov/books/NBK1515/" /><meta name="citation_keywords" content="FAH Deficiency" /><meta name="citation_keywords" content="Fumarylacetoacetase Deficiency" /><meta name="citation_keywords" content="Fumarylacetoacetate Hydrolase Deficiency" /><meta name="citation_keywords" content="Hepatorenal Tyrosinemia" /><meta name="citation_keywords" content="FAH Deficiency" /><meta name="citation_keywords" content="Hepatorenal Tyrosinemia" /><meta name="citation_keywords" content="Hereditary Tyrosinemia Type I" /><meta name="citation_keywords" content="Fumarylacetoacetase Deficiency" /><meta name="citation_keywords" content="Fumarylacetoacetate Hydrolase Deficiency" /><meta name="citation_keywords" content="Fumarylacetoacetase" /><meta name="citation_keywords" content="FAH" /><meta name="citation_keywords" content="Tyrosinemia Type I" /><link rel="schema.DC" href="http://purl.org/DC/elements/1.0/" /><meta name="DC.Title" content="Tyrosinemia Type I" /><meta name="DC.Type" content="Text" /><meta name="DC.Publisher" content="University of Washington, Seattle" /><meta name="DC.Contributor" content="Lisa Sniderman King" /><meta name="DC.Contributor" content="Cristine Trahms" /><meta name="DC.Contributor" content="C Ronald Scott" /><meta name="DC.Date" content="2017/05/25" /><meta name="DC.Identifier" content="https://www.ncbi.nlm.nih.gov/books/NBK1515/" /><meta name="description" content="Untreated tyrosinemia type I usually presents either in young infants with severe liver involvement or later in the first year with liver dysfunction and renal tubular dysfunction associated with growth failure and rickets. Untreated children may have repeated, often unrecognized, neurologic crises lasting one to seven days that can include change in mental status, abdominal pain, peripheral neuropathy, and/or respiratory failure requiring mechanical ventilation. Death in the untreated child usually occurs before age ten years, typically from liver failure, neurologic crisis, or hepatocellular carcinoma. Combined treatment with nitisinone and a low-tyrosine diet has resulted in a greater than 90% survival rate, normal growth, improved liver function, prevention of cirrhosis, correction of renal tubular acidosis, and improvement in secondary rickets." /><meta name="og:title" content="Tyrosinemia Type I" /><meta name="og:type" content="book" /><meta name="og:description" content="Untreated tyrosinemia type I usually presents either in young infants with severe liver involvement or later in the first year with liver dysfunction and renal tubular dysfunction associated with growth failure and rickets. Untreated children may have repeated, often unrecognized, neurologic crises lasting one to seven days that can include change in mental status, abdominal pain, peripheral neuropathy, and/or respiratory failure requiring mechanical ventilation. Death in the untreated child usually occurs before age ten years, typically from liver failure, neurologic crisis, or hepatocellular carcinoma. Combined treatment with nitisinone and a low-tyrosine diet has resulted in a greater than 90% survival rate, normal growth, improved liver function, prevention of cirrhosis, correction of renal tubular acidosis, and improvement in secondary rickets." /><meta name="og:url" content="https://www.ncbi.nlm.nih.gov/books/NBK1515/" /><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/tyrosinemia/" /><link rel="canonical" href="https://www.ncbi.nlm.nih.gov/books/NBK1515/" /><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="CE8B89EC7D2A97D10000000000810067.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="#__NBK1515_dtls__">Show details</a><div style="display:none" class="ui-widget" id="__NBK1515_dtls__"><div>Adam MP, Feldman J, Mirzaa GM, et al., editors.</div><div>Seattle (WA): <a href="http://www.washington.edu" ref="pagearea=page-banner&targetsite=external&targetcat=link&targettype=publisher">University of Washington, Seattle</a>; 1993-2025.</div></div><div class="half_rhythm"><ul class="inline_list"><li style="margin-right:1em"><a class="bk_cntns" href="/books/n/gene/">GeneReviews by Title</a></li></ul></div><div class="bk_noprnt"><form method="get" action="/books/n/gene/" id="bk_srch"><div class="bk_search"><label for="bk_term" class="offscreen_noflow">Search term</label><input type="text" title="Search GeneReviews" id="bk_term" name="term" value="" data-jig="ncbiclearbutton" /> <input type="submit" class="jig-ncbibutton" value="Search GeneReviews" submit="false" style="padding: 0.1em 0.4em;" /></div></form><div><ul class="inline_list"><li><a href="/books/n/gene/advanced/">GeneReviews Advanced Search</a></li><li style="margin-left:.5em"><a href="/books/n/gene/helpadvsearch/">Help</a></li></ul></div></div></div><div class="icnblk_cntnt two_col"><div class="pagination bk_noprnt"><a class="active page_link prev" href="/books/n/gene/thdrd/" title="Previous page in this title">< Prev</a><a class="active page_link next" href="/books/n/gene/tyrosinemia-2/" title="Next page in this title">Next ></a></div></div></div></div></div>
|
||
<div class="main-content lit-style" itemscope="itemscope" itemtype="http://schema.org/CreativeWork"><div class="meta-content fm-sec"><h1 id="_NBK1515_"><span class="title" itemprop="name">Tyrosinemia Type I</span></h1><div itemprop="alternativeHeadline" class="subtitle whole_rhythm">Synonyms: FAH Deficiency, Fumarylacetoacetase Deficiency, Fumarylacetoacetate Hydrolase Deficiency, Hepatorenal Tyrosinemia</div><p class="contrib-group"><span itemprop="author">Lisa Sniderman King</span>, MSc, CGC, <span itemprop="author">Cristine Trahms</span>, MS, RD, and <span itemprop="author">C Ronald Scott</span>, MD.</p><a data-jig="ncbitoggler" href="#__NBK1515_ai__" style="border:0;text-decoration:none">Author Information and Affiliations</a><div style="display:none" class="ui-widget" id="__NBK1515_ai__"><div class="contrib half_rhythm"><span itemprop="author">Lisa Sniderman King</span>, MSc, CGC<div class="affiliation small">Genzyme Corporation<br />Cambridge, Massachusetts<div><span class="email-label">Email: </span><a href="mailto:dev@null" data-email="moc.emyzneg@gniknamredins.asil" class="oemail">moc.emyzneg@gniknamredins.asil</a></div></div></div><div class="contrib half_rhythm"><span itemprop="author">Cristine Trahms</span>, MS, RD<div class="affiliation small">Department of Nutrition<br />University of Washington<br />Seattle, Washington<div><span class="email-label">Email: </span><a href="mailto:dev@null" data-email="ude.notgnihsaw.u@smhartc" class="oemail">ude.notgnihsaw.u@smhartc</a></div></div></div><div class="contrib half_rhythm"><span itemprop="author">C Ronald Scott</span>, MD<div class="affiliation small">Department of Pediatrics<br />University of Washington<br />Seattle, Washington<div><span class="email-label">Email: </span><a href="mailto:dev@null" data-email="ude.notgnihsaw.u@ttocsrc" class="oemail">ude.notgnihsaw.u@ttocsrc</a></div></div></div></div><p class="small">Initial Posting: <span itemprop="datePublished">July 24, 2006</span>; Last Update: <span itemprop="dateModified">May 25, 2017</span>.</p><p><em>Estimated reading time: 27 minutes</em></p></div><div class="jig-ncbiinpagenav body-content whole_rhythm" data-jigconfig="allHeadingLevels: ['h2'],smoothScroll: false" itemprop="text"><div id="tyrosinemia.Summary" itemprop="description"><h2 id="_tyrosinemia_Summary_">Summary</h2><div><h4 class="inline">Clinical characteristics.</h4><p>Untreated tyrosinemia type I usually presents either in young infants with severe liver involvement or later in the first year with liver dysfunction and renal tubular dysfunction associated with growth failure and rickets. Untreated children may have repeated, often unrecognized, neurologic crises lasting one to seven days that can include change in mental status, abdominal pain, peripheral neuropathy, and/or respiratory failure requiring mechanical ventilation. Death in the untreated child usually occurs before age ten years, typically from liver failure, neurologic crisis, or hepatocellular carcinoma. Combined treatment with nitisinone and a low-tyrosine diet has resulted in a greater than 90% survival rate, normal growth, improved liver function, prevention of cirrhosis, correction of renal tubular acidosis, and improvement in secondary rickets.</p></div><div><h4 class="inline">Diagnosis/testing.</h4><p>Tyrosinemia type I results from deficiency of the enzyme fumarylacetoacetase (FAH). The diagnosis is established in a <a class="def" href="/books/n/gene/glossary/def-item/proband/">proband</a> with typical biochemical findings (increased succinylacetone concentration in the blood and urine; elevated plasma concentrations of tyrosine, methionine, and phenylalanine; and elevated urinary concentration of tyrosine metabolites and the compound δ-ALA) and/or by the identification of <a class="def" href="/books/n/gene/glossary/def-item/biallelic/">biallelic</a> pathogenic variants in <i>FAH</i> 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> Nitisinone (Orfadin<sup>®</sup>), 2-(2-nitro-4-trifluoro-methylbenzyol)-1,3 cyclohexanedione (NTBC), which blocks parahydroxyphenylpyruvic acid dioxygenase <i>(p</i>-HPPD), the second step in the tyrosine degradation pathway, prevents the accumulation of fumarylacetoacetate and its conversion to succinylacetone. Nitisinone treatment should begin as soon as the diagnosis of tyrosinemia type I is confirmed. Because nitisinone increases the blood concentration of tyrosine, dietary management with controlled intake of phenylalanine and tyrosine should be started immediately after diagnosis to prevent tyrosine crystals from forming in the cornea. If the blood concentration of phenylalanine becomes too low (<20 μmol/L), additional natural protein should be added to the diet. Prior to the availability of nitisinone, the only definitive therapy for tyrosinemia type I was liver transplantation, which now should be reserved for those children who have severe liver failure at presentation and fail to respond to nitisinone therapy or have documented evidence of malignant changes in hepatic tissue.</p><p><i>Prevention of primary manifestations:</i> Initiation of treatment with nitisinone as soon as the diagnosis is confirmed.</p><p><i>Prevention of secondary complications:</i> Treatment of early signs of carnitine deficiency, osteoporosis, and rickets that are secondary to renal tubular Fanconi syndrome.</p><p><i>Surveillance:</i> Guidelines for routine surveillance of individuals with tyrosinemia type I have been established.</p><p><i>Agents/circumstances to avoid:</i> Inappropriate protein intake.</p><p><i>Evaluation of relatives at risk:</i> All subsequent children of the parents of a child with tyrosinemia type I should have urine and blood succinylacetone analyzed as soon as possible after birth to enable the earliest possible diagnosis and initiation of therapy. If the pathogenic variants in the family are known, prenatal <a class="def" href="/books/n/gene/glossary/def-item/molecular-genetic-testing/">molecular genetic testing</a> of an at-risk pregnancy may be considered.</p><p><i>Pregnancy management:</i> Little data exist on the use of nitisinone during human pregnancy; however, at least two women have given birth to healthy infants while receiving therapeutic doses of nitisinone.</p></div><div><h4 class="inline">Genetic counseling.</h4><p>Tyrosinemia type I is inherited in an <a class="def" href="/books/n/gene/glossary/def-item/autosomal-recessive/">autosomal recessive</a> manner. At conception, each sib of an affected individual has 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. Carrier testing for at-risk relatives and <a class="def" href="/books/n/gene/glossary/def-item/prenatal-testing/">prenatal testing</a> for a pregnancy at increased risk are possible if both pathogenic variants in a family are known.</p></div></div><div id="tyrosinemia.Diagnosis"><h2 id="_tyrosinemia_Diagnosis_">Diagnosis</h2><p>Tyrosinemia type I is caused by deficiency of the enzyme fumarylacetoacetase (FAH) (<a href="https://enzyme.expasy.org/EC/3.7.1.2" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">EC 3.7.1.2</a>) (see <a class="figpopup" href="/books/NBK1515/figure/tyrosinemia.F1/?report=objectonly" target="object" rid-figpopup="figtyrosinemiaF1" rid-ob="figobtyrosinemiaF1">Figure 1</a> and <a href="#tyrosinemia.Pathophysiology">Pathophysiology</a>).</p><div class="iconblock whole_rhythm clearfix ten_col fig" id="figtyrosinemiaF1" co-legend-rid="figlgndtyrosinemiaF1"><a href="/books/NBK1515/figure/tyrosinemia.F1/?report=objectonly" target="object" title="Figure 1. " class="img_link icnblk_img figpopup" rid-figpopup="figtyrosinemiaF1" rid-ob="figobtyrosinemiaF1"><img class="small-thumb" src="/books/NBK1515/bin/tyrosinemia-Image001.gif" src-large="/books/NBK1515/bin/tyrosinemia-Image001.jpg" alt="Figure 1. " /></a><div class="icnblk_cntnt" id="figlgndtyrosinemiaF1"><h4 id="tyrosinemia.F1"><a href="/books/NBK1515/figure/tyrosinemia.F1/?report=objectonly" target="object" rid-ob="figobtyrosinemiaF1">Figure 1. </a></h4><p class="float-caption no_bottom_margin">The tyrosine catabolic pathway </p></div></div><div id="tyrosinemia.Suggestive_Findings"><h3>Suggestive Findings</h3><p>Tyrosinemia type I <b>should be suspected</b> in individuals with the following newborn screening results, clinical features, and supportive laboratory findings.</p><p>
|
||
<b>Newborn screening</b>
|
||
</p><ul><li class="half_rhythm"><div><b>Presence of succinylacetone,</b> measured directly from the newborn blood spot by tandem mass spectroscopy, is pathognomonic for tyrosinemia type 1.</div></li><li class="half_rhythm"><div><b>Elevated tyrosine or methionine concentration</b> in the blood suggests liver disease, which can be from a variety of causes; the diagnosis of tyrosinemia type I should be further evaluated by quantification of plasma or urinary succinylacetone.</div><ul><li class="half_rhythm"><div>Infants with tyrosinemia type I may have only modestly elevated or normal blood concentrations of tyrosine and methionine when the first newborn screening sample is collected.</div></li><li class="half_rhythm"><div>Elevated tyrosine concentration on newborn screening can be the result of transient tyrosinemia of the newborn, <a href="/books/n/gene/tyrosinemia-2/">tyrosinemia type II</a> or III, or other liver disease.</div></li><li class="half_rhythm"><div>Elevated methionine concentration can indicate liver dysfunction, defects in methionine metabolism, or homocystinuria (see <a href="/books/n/gene/homocystinuria/">Homocystinuria Caused by Cystathionine Beta-Synthetase Deficiency</a>).</div></li></ul></li><li class="half_rhythm"><div><b>Low delta-ALA-dehydratase (PBG synthase) enzyme activity.</b> This is measured in the newborn screening program in Quebec, Canada [<a class="bk_pop" href="#tyrosinemia.REF.gigu_re.2005">Giguère et al 2005</a>]. Succinylacetone is then measured in the urine of infants with apparent δ-ALA dehydratase deficiency [<a class="bk_pop" href="#tyrosinemia.REF.schulze.2001.1424">Schulze et al 2001</a>].</div></li></ul><p>
|
||
<b>Clinical features (in untreated individuals)</b>
|
||
</p><ul><li class="half_rhythm"><div class="half_rhythm">Severe liver disease in young infants</div></li><li class="half_rhythm"><div class="half_rhythm">Signs of kidney disease, rickets, and/or neurologic crises in children older than age six months</div><div class="half_rhythm">Untreated children may have repeated neurologic crises lasting one to seven days that can include change in mental status, abdominal pain, peripheral neuropathy, and/or respiratory failure requiring mechanical ventilation.</div></li></ul><p>
|
||
<b>Supportive laboratory findings</b>
|
||
</p><ul><li class="half_rhythm"><div class="half_rhythm">
|
||
<b>Increased succinylacetone concentration in the blood and excretion in the urine</b>
|
||
</div><div class="half_rhythm">Note: (1) Increased excretion of succinylacetone in the urine of a child with liver failure or severe kidney disease is a pathognomonic sign of tyrosinemia type I. (2) Many laboratories require that measurement of succinylacetone be specifically requested when ordering urine organic acids.</div></li><li class="half_rhythm"><div class="half_rhythm">
|
||
<b>Elevated plasma concentration of tyrosine, methionine, and phenylalanine</b>
|
||
</div><div class="half_rhythm">Note: (1) Plasma tyrosine concentration in affected infants can be normal in cord blood and during the newborn period. (2) Elevated plasma tyrosine concentration can also be a nonspecific indicator of liver damage or immaturity; for example, in infants taking a high-protein formula [<a class="bk_pop" href="#tyrosinemia.REF.techakittiroj.2005.281">Techakittiroj et al 2005</a>], including undiluted goat's milk [<a class="bk_pop" href="#tyrosinemia.REF.hendriksz.2004.552">Hendriksz & Walter 2004</a>].</div></li><li class="half_rhythm"><div class="half_rhythm"><b>Elevated urinary concentration of tyrosine metabolites</b>
|
||
<i>p</i>-hydroxyphenylpyruvate, <i>p</i>-hydroxyphenyllactate, and <i>p</i>-hydroxyphenylacetate detected on urine organic acid testing</div></li><li class="half_rhythm"><div class="half_rhythm"><b>Increased urinary excretion of the compound δ-ALA</b> secondary to inhibition of the enzyme δ-ALA dehydratase by succinylacetone in the liver and circulating red blood cells [<a class="bk_pop" href="#tyrosinemia.REF.sassa.1983.625">Sassa & Kappas 1983</a>]</div></li><li class="half_rhythm"><div class="half_rhythm">
|
||
<b>Changes in liver function (in untreated tyrosinemia type 1)</b>
|
||
</div><ul><li class="half_rhythm"><div><b>Markedly elevated serum concentration of alpha-fetoprotein (average 160,000 ng/mL)</b> (normal: <1,000 ng/mL for infants age 1-3 months; <12 ng/mL for children age 3 months to 18 years)</div></li><li class="half_rhythm"><div>Prolonged prothrombin and partial thromboplastin times</div></li></ul></li></ul><p>Note: (1) Changes in serum concentration of alpha-fetoprotein (AFP) and prothrombin time / partial thromboplastin time (PT/PTT) are more severe in tyrosinemia type I than in nonspecific liver disease and are often the presenting findings in tyrosinemia type I. (2) Transaminases and bilirubin are only modestly elevated, if at all. (3) An individual with liver disease and normal serum concentration of AFP and normal PT/PTT has a low probability of having tyrosinemia type I.</p></div><div id="tyrosinemia.Establishing_the_Diagnosis"><h3>Establishing the Diagnosis</h3><p>The diagnosis of tyrosinemia type I <b>is established</b> in a <a class="def" href="/books/n/gene/glossary/def-item/proband/">proband</a> with characteristic biochemical findings (increased succinylacetone concentration in the blood and urine; elevated plasma concentrations of tyrosine, methionine, and phenylalanine; and elevated urinary concentration of tyrosine metabolites and the compound δ-ALA) and/or by identification of <a class="def" href="/books/n/gene/glossary/def-item/biallelic/">biallelic</a> pathogenic (or <a class="def" href="/books/n/gene/glossary/def-item/likely-pathogenic/">likely pathogenic</a>) variants in <i>FAH</i> on <a class="def" href="/books/n/gene/glossary/def-item/molecular-genetic-testing/">molecular genetic testing</a> (see <a href="/books/NBK1515/table/tyrosinemia.T.molecular_genetic_testing/?report=objectonly" target="object" rid-ob="figobtyrosinemiaTmoleculargenetictesting">Table 1</a>).</p><p>Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "<a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a>" and "<a class="def" href="/books/n/gene/glossary/def-item/likely-pathogenic/">likely pathogenic</a> variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [<a class="bk_pop" href="#tyrosinemia.REF.richards.2015.405">Richards et al 2015</a>]. Reference to "pathogenic variants" in this <i>GeneReview</i> is understood to include likely pathogenic variants. (2) Identification of <a class="def" href="/books/n/gene/glossary/def-item/biallelic/">biallelic</a> <i>FAH</i> variants of <a class="def" href="/books/n/gene/glossary/def-item/uncertain-significance/">uncertain significance</a> (or of one known <i>FAH</i> pathogenic variant and one <i>FAH</i> variant of uncertain significance) does not establish or rule out the diagnosis.</p><div id="tyrosinemia.Molecular_Genetic_Testing"><h4>Molecular Genetic Testing</h4><p><b>Single-<a class="def" href="/books/n/gene/glossary/def-item/gene/">gene</a> testing.</b> Sequence analysis of <i>FAH</i> is performed first and followed by gene-targeted <a class="def" href="/books/n/gene/glossary/def-item/deletion-duplication-analysis/">deletion/duplication analysis</a> if only one or no <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a> is found.</p><ul><li class="half_rhythm"><div>Targeted analysis for the <a href="/books/NBK1515/table/tyrosinemia.T.fah_variants_discussed_in/?report=objectonly" target="object" rid-ob="figobtyrosinemiaTfahvariantsdiscussedin">p.Pro261Leu</a> <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a> can be performed first in individuals of Ashkenzai Jewish ancestry; this variant accounts for more than 99% of the pathogenic variants in this population [<a class="bk_pop" href="#tyrosinemia.REF.elpeleg.2002.80">Elpeleg et al 2002</a>].</div></li><li class="half_rhythm"><div>The <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a> <a href="/books/NBK1515/table/tyrosinemia.T.fah_variants_discussed_in/?report=objectonly" target="object" rid-ob="figobtyrosinemiaTfahvariantsdiscussedin">c.1062+5G>A (IVS12+5 G>A)</a> accounts for 87.9% of pathogenic variants in the French Canadian population [<a class="bk_pop" href="#tyrosinemia.REF.poudrier.1996.59">Poudrier et al 1996</a>].</div></li><li class="half_rhythm"><div>The four common <i>FAH</i> pathogenic variants – c.1062+5G>A (IVS12+5 G>A), <a href="/books/NBK1515/table/tyrosinemia.T.fah_variants_discussed_in/?report=objectonly" target="object" rid-ob="figobtyrosinemiaTfahvariantsdiscussedin">c.554-1G>T</a> (IVS6-1 G>T), <a href="/books/NBK1515/table/tyrosinemia.T.fah_variants_discussed_in/?report=objectonly" target="object" rid-ob="figobtyrosinemiaTfahvariantsdiscussedin">c.607-6T>G</a> (IVS7-6 T>G), and p.Pro261Leu – account for approximately 60% of pathogenic variants in tyrosinemia type I in the general US population [CR Scott, unpublished data].</div></li></ul><div id="tyrosinemia.T.molecular_genetic_testing" class="table"><h3><span class="label">Table 1. </span></h3><div class="caption"><p>Molecular Genetic Testing Used in Tyrosinemia Type I</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK1515/table/tyrosinemia.T.molecular_genetic_testing/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__tyrosinemia.T.molecular_genetic_testing_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_tyrosinemia.T.molecular_genetic_testing_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Gene <sup>1</sup></th><th id="hd_h_tyrosinemia.T.molecular_genetic_testing_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Method</th><th id="hd_h_tyrosinemia.T.molecular_genetic_testing_1_1_1_3" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Proportion of Pathogenic Variants <sup>2</sup> Identified by Method</th></tr></thead><tbody><tr><td headers="hd_h_tyrosinemia.T.molecular_genetic_testing_1_1_1_1" rowspan="2" scope="row" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<i>FAH</i>
|
||
</td><td headers="hd_h_tyrosinemia.T.molecular_genetic_testing_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Sequence analysis <sup>3</sup></td><td headers="hd_h_tyrosinemia.T.molecular_genetic_testing_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">>95%</td></tr><tr><td headers="hd_h_tyrosinemia.T.molecular_genetic_testing_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> <sup>4</sup></td><td headers="hd_h_tyrosinemia.T.molecular_genetic_testing_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Unknown; one reported large <a class="def" href="/books/n/gene/glossary/def-item/deletion/">deletion</a> <sup>5</sup></td></tr></tbody></table></div><div><div><dl class="temp-labeled-list small"><dt>1. </dt><dd><div id="tyrosinemia.TF.1.1"><p class="no_margin">See <a href="/books/NBK1515/#tyrosinemia.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="tyrosinemia.TF.1.2"><p class="no_margin">See <a href="#tyrosinemia.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="tyrosinemia.TF.1.3"><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 <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 and small intragenic deletions/insertions; 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>4. </dt><dd><div id="tyrosinemia.TF.1.4"><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>5. </dt><dd><div id="tyrosinemia.TF.1.5"><p class="no_margin"><a class="bk_pop" href="#tyrosinemia.REF.park.2009.930">Park et al [2009]</a> reported a large <a class="def" href="/books/n/gene/glossary/def-item/deletion/">deletion</a> involving <i>FAH.</i></p></div></dd></dl></div></div></div></div></div></div><div id="tyrosinemia.Clinical_Characteristics"><h2 id="_tyrosinemia_Clinical_Characteristics_">Clinical Characteristics</h2><div id="tyrosinemia.Clinical_Description"><h3>Clinical Description</h3><p><b>For children who were not detected by newborn screening, tyrosinemia type I</b> usually presents either in young infants with severe liver involvement or later in the first year with liver dysfunction and significant renal involvement, growth failure, and rickets. Growth failure results from chronic illness with poor nutritional intake, liver involvement, and/or chronic kidney disease. Death in the undetected or untreated child usually occurs before age ten years, typically from liver failure, neurologic crisis, or hepatocellular carcinoma.</p><ul><li class="half_rhythm"><div class="half_rhythm"><b>Liver involvement.</b> Undetected or untreated children presenting before age six months typically have acute liver failure with initial loss of synthetic function for clotting factors. PT and PTT are markedly prolonged and not corrected by vitamin K supplementation; factor II, VII, IX, XI, and XII levels are decreased; factor V and factor VIII levels are preserved. Paradoxically, serum transaminase levels may be only modestly elevated; serum bilirubin concentration may be normal or only slightly elevated, in contrast to most forms of severe liver disease in which marked elevation of transaminases and serum bilirubin concentration occur <b>concomitantly</b> with prolongation of PT and PTT. Resistance of affected liver cells to cell death may explain the observed discrepancy in liver function [<a class="bk_pop" href="#tyrosinemia.REF.vogel.2004.433">Vogel et al 2004</a>].</div><div class="half_rhythm">This early phase can progress to liver failure with ascites, jaundice, and gastrointestinal bleeding. Children may have a characteristic odor of "boiled cabbage" or "rotten mushrooms." Infants occasionally have persistent hypoglycemia; some have hyperinsulinism [<a class="bk_pop" href="#tyrosinemia.REF.baumann.2005.131">Baumann et al 2005</a>]. Others have chronic low-grade acidosis [CR Scott, unpublished data]. Untreated affected infants may die from liver failure within weeks or months of first symptoms [<a class="bk_pop" href="#tyrosinemia.REF.hegarty.2015.1387">Hegarty et al 2015</a>].</div></li><li class="half_rhythm"><div class="half_rhythm"><b>Renal tubular involvement.</b> In the more chronic form of the untreated disorder, symptoms develop after age six months; renal tubular involvement is the major manifestation. The renal tubular dysfunction involves a Fanconi-like renal syndrome with generalized aminoaciduria, phosphate loss, and, for many, renal tubular acidosis. The continued renal loss of phosphate is believed to account for rickets; serum calcium concentrations are usually normal.</div></li><li class="half_rhythm"><div class="half_rhythm"><b>Neurologic crises.</b> Untreated children may have repeated neurologic crises similar to those seen in older individuals with <a href="/books/n/gene/aip/">acute intermittent porphyria</a>. These crises include change in mental status, abdominal pain, peripheral neuropathy, and/or respiratory failure requiring mechanical ventilation. Crises can last one to seven days. Repeated neurologic crises often go unrecognized:</div><ul><li class="half_rhythm"><div><a class="bk_pop" href="#tyrosinemia.REF.mitchell.1990.432">Mitchell et al [1990]</a> reported that 42% of untreated French Canadian children with tyrosinemia type I had experienced such episodes.</div></li><li class="half_rhythm"><div>In an international survey, <a class="bk_pop" href="#tyrosinemia.REF.van_spronsen.1994.1187">van Spronsen et al [1994]</a> reported that 10% of deaths in untreated children occurred during a neurologic crisis.</div></li></ul></li><li class="half_rhythm"><div class="half_rhythm"><b>Hepatocellular carcinoma.</b> Those children who are not treated with nitisinone and a low-tyrosine diet and who survive the acute onset of liver failure are at high risk of developing and succumbing to hepatocellular carcinoma.</div></li><li class="half_rhythm"><div class="half_rhythm"><b>Survival in untreated children.</b> Untreated infants diagnosed before age two months had a two-year survival rate of 29% [<a class="bk_pop" href="#tyrosinemia.REF.van_spronsen.1994.1187">van Spronsen et al 1994</a>].</div><ul><li class="half_rhythm"><div>Those diagnosed between ages two and six months had a 74% two-year survival rate; those diagnosed after age six months had a 96% two-year survival rate.</div></li><li class="half_rhythm"><div>After more than five years the survival rate of the group diagnosed between ages two and six months dropped to approximately 30% and that of the group diagnosed after age six months dropped to approximately 60% (<a class="figpopup" href="/books/NBK1515/figure/tyrosinemia.F2/?report=objectonly" target="object" rid-figpopup="figtyrosinemiaF2" rid-ob="figobtyrosinemiaF2">Figure 2</a>).</div></li></ul></li></ul><div class="iconblock whole_rhythm clearfix ten_col fig" id="figtyrosinemiaF2" co-legend-rid="figlgndtyrosinemiaF2"><a href="/books/NBK1515/figure/tyrosinemia.F2/?report=objectonly" target="object" title="Figure 2. " class="img_link icnblk_img figpopup" rid-figpopup="figtyrosinemiaF2" rid-ob="figobtyrosinemiaF2"><img class="small-thumb" src="/books/NBK1515/bin/tyrosinemia-Image002.gif" src-large="/books/NBK1515/bin/tyrosinemia-Image002.jpg" alt="Figure 2. " /></a><div class="icnblk_cntnt" id="figlgndtyrosinemiaF2"><h4 id="tyrosinemia.F2"><a href="/books/NBK1515/figure/tyrosinemia.F2/?report=objectonly" target="object" rid-ob="figobtyrosinemiaF2">Figure 2. </a></h4><p class="float-caption no_bottom_margin">Survival of children with tyrosinemia before 1992 [van Spronsen et al 1994] </p></div></div><p><b>Treated tyrosinemia type I.</b> The natural history in children who are treated with nitisinone is different from that in untreated children. Affected children younger than age two years who are treated with a combination of nitisinone and low-tyrosine diet are markedly improved compared to those children treated with low-tyrosine diet alone. The combined nitisinone and low-tyrosine diet treatment has resulted in a greater than 90% survival rate, normal growth, improved liver function, prevention of cirrhosis, correction of renal tubular acidosis, and improvement in secondary rickets [<a class="bk_pop" href="#tyrosinemia.REF.mckiernan.2006.743">McKiernan 2006</a>, <a class="bk_pop" href="#tyrosinemia.REF.masurelpaulet.2008.81">Masurel-Paulet et al 2008</a>, <a class="bk_pop" href="#tyrosinemia.REF.larochelle.2012.49">Larochelle et al 2012</a>].</p><ul><li class="half_rhythm"><div class="half_rhythm"><b>Neurologic crises</b> observed in treated children have always been associated with a prolonged interruption in nitisinone treatment [CR Scott, unpublished data].</div></li><li class="half_rhythm"><div class="half_rhythm">Children with <b>acute liver failure</b> require support prior to and during the initiation of treatment with nitisinone. Improvement generally occurs within one week of starting nitisinone treatment.</div></li><li class="half_rhythm"><div class="half_rhythm"><b>Corneal crystals.</b> Nitisinone blocks the tyrosine catabolic pathway such that succinylacetone is not produced but tissue tyrosine levels are raised. Blood tyrosine concentration greater than 600 mol/L confers risk of precipitation of tyrosine as bilateral, linear, branching subepithelial corneal opacities [<a class="bk_pop" href="#tyrosinemia.REF.ahmad.2002.266">Ahmad et al 2002</a>], causing photophobia and itchy, sensitive eyes. The crystals resolve once tyrosine levels are reduced.</div></li><li class="half_rhythm"><div class="half_rhythm"><b>Hepatocellular carcinoma.</b> Although <a class="bk_pop" href="#tyrosinemia.REF.holme.2000.805">Holme & Lindstedt [2000]</a> and <a class="bk_pop" href="#tyrosinemia.REF.van_spronsen.2005.90">van Spronsen et al [2005]</a> reported hepatocellular carcinoma in individuals after years of nitisinone therapy, it is estimated that fewer than 5% of children placed on nitisinone therapy before age two years develop hepatocellular carcinoma by age ten years [<a class="bk_pop" href="#tyrosinemia.REF.larochelle.2012.49">Larochelle et al 2012</a>].</div><div class="half_rhythm">In Quebec, where tyrosinemia type I is included in the newborn screening program, no affected individuals have been hospitalized for manifestations of tyrosinemia type I, and hepatocellular carcinoma has not been reported in individuals who were placed on nitisinone therapy prior to age 30 days. The longest period of treatment reported in this group is 12 years [<a class="bk_pop" href="#tyrosinemia.REF.larochelle.2012.49">Larochelle et al 2012</a>].</div></li></ul></div><div id="tyrosinemia.Pathophysiology"><h3>Pathophysiology</h3><p>Fumarylacetoacetase (FAH) is the terminal enzyme in the tyrosine catabolic pathway (<a class="figpopup" href="/books/NBK1515/figure/tyrosinemia.F1/?report=objectonly" target="object" rid-figpopup="figtyrosinemiaF1" rid-ob="figobtyrosinemiaF1">Figure 1</a>). In FAH deficiency, fumarylacetoacetate (FAA), the immediate precursor:</p><ul><li class="half_rhythm"><div>Appears to accumulate in hepatocytes, causing cellular damage and apoptosis (identified in an animal model by <a class="bk_pop" href="#tyrosinemia.REF.endo.2002.227">Endo & Sun [2002]</a>);</div></li><li class="half_rhythm"><div>Is diverted into succinylacetoacetate and succinylacetone. Succinylacetone interferes with the activity of the following hepatic enzymes:</div><ul><li class="half_rhythm"><div>Parahydroxyphenylpyruvic acid dioxygenase <i>(p</i>-HPPD), resulting in elevation of plasma tyrosine concentration;</div></li><li class="half_rhythm"><div>PBG synthase, resulting in (1) reduced activity of the enzyme δ-ALA dehydratase in liver and circulating red blood cells; (2) reduced heme synthesis; (3) increased δ-aminolevulinic acid (δ-ALA), which may induce acute neurologic episodes; and (4) increased urinary excretion of δ-ALA.</div></li></ul></li></ul></div><div id="tyrosinemia.GenotypePhenotype_Correlatio"><h3>Genotype-Phenotype Correlations</h3><p>In general, no correlation is observed between clinical presentation and <a class="def" href="/books/n/gene/glossary/def-item/genotype/">genotype</a>. Acute and chronic forms have been seen in the same families, as well as in unrelated individuals with the same genotype [<a class="bk_pop" href="#tyrosinemia.REF.poudrier.1998.119">Poudrier et al 1998</a>].</p><p>One mechanism that explains this clinical variation is <a class="def" href="/books/n/gene/glossary/def-item/gene/">gene</a> reversion. Hepatic nodules removed from livers of individuals with the chronic form of tyrosinemia type I have been shown to have cells that are immunologically positive for FAH protein and to have enzymatic activity for FAH [<a class="bk_pop" href="#tyrosinemia.REF.kvittingen.1994.1657">Kvittingen et al 1994</a>, <a class="bk_pop" href="#tyrosinemia.REF.grompe.2001.563">Grompe 2001</a>]. These seemingly "normal" cells appear to have arisen by gene reversion – that is, the spontaneous self-correction (i.e., reversion or "back-mutation") of the <a class="def" href="/books/n/gene/glossary/def-item/germline/">germline</a> <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a> to the normal gene sequence during somatic cell division.</p><p>Spontaneous somatic variants that suppress the effects of the pathogenic variants and allow for normal or near-normal <a class="def" href="/books/n/gene/glossary/def-item/gene/">gene</a> expression in these cells have also been reported [<a class="bk_pop" href="#tyrosinemia.REF.bliksrud.2005.406">Bliksrud et al 2005</a>]. This is a true reversion of the mutated sequence and not the result of maternal cell colonization or maternal cell fusion [<a class="bk_pop" href="#tyrosinemia.REF.bergeron.2004.1381">Bergeron et al 2004</a>]. The "normal" (i.e., reverted) cells have a selective growth advantage because they are no longer at risk for apoptosis from the accumulation of FAA. These foci of revertant "normal" cell colonies comprise many of the liver nodules in untreated individuals with chronic tyrosinemia type I who have a milder biochemical and clinical <a class="def" href="/books/n/gene/glossary/def-item/phenotype/">phenotype</a> [<a class="bk_pop" href="#tyrosinemia.REF.kim.2000.791">Kim et al 2000</a>, <a class="bk_pop" href="#tyrosinemia.REF.demers.2003.1313">Demers et al 2003</a>]. However, the continued production of FAA by the nonrevertant mutated cells places the individual at continued risk for hepatocellular carcinoma [<a class="bk_pop" href="#tyrosinemia.REF.kim.2000.791">Kim et al 2000</a>].</p><p>A rare and atypical form of tyrosinemia type I has been reported in a four-month-old Belgian infant with severe liver disease. Liver function studies were abnormal with markedly elevated alpha-fetoprotein, prolonged PT and PTT, and undetectable succinylacetone in urine. Fumarylacetoacetase (FAH) protein and activity was decreased, but not absent. Homozygosity for a unique <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a>, <a href="/books/NBK1515/table/tyrosinemia.T.fah_variants_discussed_in/?report=objectonly" target="object" rid-ob="figobtyrosinemiaTfahvariantsdiscussedin">c.103G>A (p.Ala35Thr)</a>, was identified [<a class="bk_pop" href="#tyrosinemia.REF.cassiman.2009.28">Cassiman et al 2009</a>].</p><p>Similarly, three sibs who developed chronic liver disease and HCC without detectable blood or urine succinylacetone had deficient FAH activity. The family was of Middle Eastern background and each child was <a class="def" href="/books/n/gene/glossary/def-item/homozygous/">homozygous</a> for <a href="/books/NBK1515/table/tyrosinemia.T.fah_variants_discussed_in/?report=objectonly" target="object" rid-ob="figobtyrosinemiaTfahvariantsdiscussedin">c.424A>G</a> in <i>FAH</i> [<a class="bk_pop" href="#tyrosinemia.REF.blackburn.2016.1097">Blackburn et al 2016</a>].</p></div><div id="tyrosinemia.Nomenclature"><h3>Nomenclature</h3><p>The term " tyrosinosis" was previously used to refer to tyrosinemia type I include tyrosinosis.</p></div><div id="tyrosinemia.Prevalence"><h3>Prevalence</h3><p>In geographic areas without newborn screening, tyrosinemia type I affects approximately one in 100,000 to 120,000 births [<a class="bk_pop" href="#tyrosinemia.REF.mitchell.2001">Mitchell et al 2001</a>]. Because of the inconsistent and confusing nature of its clinical presentation, it is estimated that fewer than 50% of affected individuals are diagnosed while alive.</p><p>In the general US population, the <a class="def" href="/books/n/gene/glossary/def-item/carrier/">carrier</a> frequency is estimated at 1:150 to 1:100.</p><p>Two regions of the world have a higher than expected frequency of tyrosinemia type I due to the increased frequency of certain pathogenic variants resulting from a <a class="def" href="/books/n/gene/glossary/def-item/founder-effect/">founder effect</a>:</p><ul><li class="half_rhythm"><div>In the Scandanavian countries (<a href="/books/NBK1515/table/tyrosinemia.T.fah_variants_discussed_in/?report=objectonly" target="object" rid-ob="figobtyrosinemiaTfahvariantsdiscussedin">c.1062+5G>A (IVS 12+5 G>A)</a>, <a href="/books/NBK1515/table/tyrosinemia.T.fah_variants_discussed_in/?report=objectonly" target="object" rid-ob="figobtyrosinemiaTfahvariantsdiscussedin">p.Gly337Ser</a>, and/or p.249HisfsTer5.5) and in Finland (<a href="/books/NBK1515/table/tyrosinemia.T.fah_variants_discussed_in/?report=objectonly" target="object" rid-ob="figobtyrosinemiaTfahvariantsdiscussedin">p.Trp262Ter</a>), the birth prevalence is estimated at 1:74,000 and 1:60,000 live births, respectively [<a class="bk_pop" href="#tyrosinemia.REF.bliksrud.2012.369">Bliksrud et al 2012</a>].</div></li><li class="half_rhythm"><div>A <a class="def" href="/books/n/gene/glossary/def-item/founder-effect/">founder effect</a> from colonization by French settlers is present in the province of Quebec, Canada. The c.1062+5G>A (IVS12+5 G>A) <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a> accounts for 87% of allelic variants in this population. The birth prevalence in the province of Quebec is 1:16,000. In the Saguenay-Lac Saint-Jean region of Quebec, it is 1:1,846 live births. The overall <a class="def" href="/books/n/gene/glossary/def-item/carrier/">carrier</a> frequency in Quebec is 1:66 based on newborn screening data. The carrier frequency in the Saguenay-Lac St-Jean region is 1:16-1:20.</div></li></ul></div></div><div id="tyrosinemia.Genetically_Related_Allelic"><h2 id="_tyrosinemia_Genetically_Related_Allelic_">Genetically Related (Allelic) Disorders</h2><p>No phenotypes other than those discussed in this <i>GeneReview</i> are known to be associated with pathogenic variants in <i>FAH</i>.</p></div><div id="tyrosinemia.Differential_Diagnosis"><h2 id="_tyrosinemia_Differential_Diagnosis_">Differential Diagnosis</h2><p>Children with any of the following presenting findings (see <a href="/books/NBK1515/table/tyrosinemia.T.differential_diagnosis_of/?report=objectonly" target="object" rid-ob="figobtyrosinemiaTdifferentialdiagnosisof">Table 2</a>) should be evaluated for tyrosinemia type I.</p><div id="tyrosinemia.T.differential_diagnosis_of" class="table"><h3><span class="label">Table 2. </span></h3><div class="caption"><p>Differential Diagnosis of Tyrosinemia Type I in Infants by Presenting Finding</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK1515/table/tyrosinemia.T.differential_diagnosis_of/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__tyrosinemia.T.differential_diagnosis_of_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_tyrosinemia.T.differential_diagnosis_of_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Presenting Finding</th><th id="hd_h_tyrosinemia.T.differential_diagnosis_of_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Differential Diagnosis</th></tr></thead><tbody><tr><td headers="hd_h_tyrosinemia.T.differential_diagnosis_of_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Hypertyrosinemia</b>
|
||
</td><td headers="hd_h_tyrosinemia.T.differential_diagnosis_of_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Immature liver</div></li><li class="half_rhythm"><div>High-protein diet <sup>1, 2</sup></div></li><li class="half_rhythm"><div><a href="/books/n/gene/tyrosinemia-2/">Tyrosinemia type II</a></div></li><li class="half_rhythm"><div>Tyrosinemia type III (OMIM <a href="https://omim.org/entry/276710" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">276710</a>)</div></li><li class="half_rhythm"><div>Other liver disease</div></li></ul>
|
||
</td></tr><tr><td headers="hd_h_tyrosinemia.T.differential_diagnosis_of_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Hypermethioninemia</b>
|
||
</td><td headers="hd_h_tyrosinemia.T.differential_diagnosis_of_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div><a href="/books/n/gene/homocystinuria/">Homocystinuria</a></div></li><li class="half_rhythm"><div>Disorders of methionine metabolism</div></li><li class="half_rhythm"><div>Other liver disease</div></li></ul>
|
||
</td></tr><tr><td headers="hd_h_tyrosinemia.T.differential_diagnosis_of_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Liver disease</b>
|
||
</td><td headers="hd_h_tyrosinemia.T.differential_diagnosis_of_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div><a href="/books/n/gene/galactosemia/">Galactosemia</a></div></li><li class="half_rhythm"><div><a href="/books/n/gene/hfi/">Hereditary fructose intolerance</a></div></li><li class="half_rhythm"><div>Fructose 1, 6 biphosphatase deficiency (OMIM <a href="https://omim.org/entry/229700" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">229700</a>)</div></li><li class="half_rhythm"><div><a href="/books/n/gene/npc/">Niemann-Pick disease type C</a></div></li><li class="half_rhythm"><div><a href="/books/n/gene/wilson/">Wilson disease</a></div></li><li class="half_rhythm"><div>Neonatal hemochromatosis (OMIM <a href="https://omim.org/entry/231100" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">231100</a>)</div></li><li class="half_rhythm"><div><a href="/books/n/gene/hlh/">Hemophagocytic lymphohistiocytosis</a></div></li><li class="half_rhythm"><div><a href="/books/n/gene/mt-overview/">Mitochondrial cytopathies</a></div></li><li class="half_rhythm"><div><a href="/books/n/gene/cdg/">Congenital disorders of glycosylation</a></div></li><li class="half_rhythm"><div>Transaldolase deficiency (OMIM <a href="https://omim.org/entry/606003" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">606003</a>)</div></li><li class="half_rhythm"><div>Acetaminophen toxicity</div></li><li class="half_rhythm"><div>Bacterial infections (sepsis, salmonella, TB)</div></li><li class="half_rhythm"><div>Viral infections (e.g., CMV, hepatitis A/B, herpes)</div></li><li class="half_rhythm"><div>Mushroom poisoning <sup>3</sup></div></li><li class="half_rhythm"><div>Herbal medicines <sup>3</sup></div></li><li class="half_rhythm"><div>Idiosyncratic drug reaction, toxin, vascular/ischemic or infiltrative process <sup>3</sup></div></li></ul>
|
||
</td></tr><tr><td headers="hd_h_tyrosinemia.T.differential_diagnosis_of_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Renal syndrome</b>
|
||
</td><td headers="hd_h_tyrosinemia.T.differential_diagnosis_of_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div><a href="/books/n/gene/lowe/">Lowe syndrome</a></div></li><li class="half_rhythm"><div><a href="/books/n/gene/ctns/">Cystinosis</a></div></li><li class="half_rhythm"><div>Renal tubular acidosis</div></li><li class="half_rhythm"><div>Fanconi syndrome</div></li></ul>
|
||
</td></tr><tr><td headers="hd_h_tyrosinemia.T.differential_diagnosis_of_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Rickets</b>
|
||
</td><td headers="hd_h_tyrosinemia.T.differential_diagnosis_of_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div><a href="/books/n/gene/hops/">Hypophosphatasia</a></div></li><li class="half_rhythm"><div>Vitamin D deficiency (nutritional/genetic)</div></li><li class="half_rhythm"><div><a href="/books/n/gene/rickets-xlh/">Hypophosphatemic rickets</a></div></li><li class="half_rhythm"><div>Vitamin D-dependent rickets</div></li><li class="half_rhythm"><div>Fanconi syndrome</div></li></ul>
|
||
</td></tr><tr><td headers="hd_h_tyrosinemia.T.differential_diagnosis_of_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Neurologic crisis</b>
|
||
</td><td headers="hd_h_tyrosinemia.T.differential_diagnosis_of_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Cerebral hemorrhage/edema</div></li><li class="half_rhythm"><div>Bacterial/viral meningitis</div></li><li class="half_rhythm"><div>Hypernatremic dehydration</div></li><li class="half_rhythm"><div><a href="/books/n/gene/aip/">Acute intermittent porphyria</a></div></li></ul>
|
||
</td></tr></tbody></table></div><div><div><dl class="temp-labeled-list small"><dt>1. </dt><dd><div id="tyrosinemia.TF.2.1"><p class="no_margin">
|
||
<a class="bk_pop" href="#tyrosinemia.REF.techakittiroj.2005.281">Techakittiroj et al [2005]</a>
|
||
</p></div></dd><dt>2. </dt><dd><div id="tyrosinemia.TF.2.2"><p class="no_margin">Undiluted goat's milk [<a class="bk_pop" href="#tyrosinemia.REF.hendriksz.2004.552">Hendriksz & Walter 2004</a>]</p></div></dd><dt>3. </dt><dd><div id="tyrosinemia.TF.2.3"><p class="no_margin">
|
||
<a class="bk_pop" href="#tyrosinemia.REF.bansal.2004">Bansal & Dhawan [2004]</a>
|
||
</p></div></dd></dl></div></div></div><p><a href="/books/n/gene/tyrosinemia-2/"><b>Tyrosinemia type II</b></a> is caused by a defect in tyrosine aminotransferase (TAT) (<a href="https://enzyme.expasy.org/EC/2.6.1.5" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">EC 2.6.1.5</a>). Establishing the diagnosis of tyrosinemia type II relies on the following:</p><ul><li class="half_rhythm"><div>Plasma tyrosine concentration typically greater than 500 µmol/L that may exceed 1,000 µmol/L (The concentration of other amino acids is normal.)</div></li><li class="half_rhythm"><div>Increased excretion of <i>p</i>-hydroxyphenylpyruvate, <i>p</i>-hydroxyphenyllactate, and <i>p</i>-hydroxyphenylacetate and presence of small quantities of <i>N</i>-acetyltyrosine and 4-tyramine on urine organic acid analysis</div></li></ul><p>Affected individuals have painful, nonpruritic, and hyperkeratotic plaques on the soles and palms. The plantar surface of the digits may show marked yellowish thickening associated with the hyperkeratosis. Ophthalmologic involvement is recalcitrant pseudodendritic keratitis [<a class="bk_pop" href="#tyrosinemia.REF.macsai.2001.522">Macsai et al 2001</a>]. Although developmental delay appears to be common, it is unclear if ascertainment bias accounts for this and the reports of neurologic symptoms.</p><p>Findings improve on a diet restricted in tyrosine and phenylalanine [<a class="bk_pop" href="#tyrosinemia.REF.ellaway.2001.824">Ellaway et al 2001</a>].</p><p><b>Tyrosinemia type III,</b> the rarest of the tyrosine disorders, is caused by a deficiency of <i>p</i>-hydroxyphenylpyruvic acid dioxygenase (<a href="https://enzyme.expasy.org/EC/1.13.11.27" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">EC.1.13.11.27</a>). Plasma concentration of tyrosine ranges from 350 to 650 µmol/L. Excretion of 4-hydroxyphenylpyruvic acid, 4-hydroxyphenyllactate, and 4-hydroxyphenylacetate is increased. The precise quantities vary with protein intake.</p><p>Few individuals with the disorder have been identified, and the clinical <a class="def" href="/books/n/gene/glossary/def-item/phenotype/">phenotype</a> remains ill defined. The first affected individuals came to medical attention because of intellectual disability or ataxia; another was detected on routine screening [<a class="bk_pop" href="#tyrosinemia.REF.mitchell.2001">Mitchell et al 2001</a>]. These individuals, like those with tyrosinemia type II, have no liver involvement but have skin or ocular changes. It remains unclear if tyrosinemia type III is truly associated with cognitive delays or if the association has resulted from ascertainment bias [<a class="bk_pop" href="#tyrosinemia.REF.ellaway.2001.824">Ellaway et al 2001</a>].</p><p>A diet low in phenylalanine and tyrosine can lower plasma tyrosine concentration.</p></div><div id="tyrosinemia.Management"><h2 id="_tyrosinemia_Management_">Management</h2><div id="tyrosinemia.Evaluations_Following_Initia"><h3>Evaluations Following Initial Diagnosis</h3><p>To establish the extent of disease and needs of a child diagnosed with tyrosinemia type I <b>on the basis of newborn screening</b>, the following evaluations are recommended (see <a href="/books/NBK1515/table/tyrosinemia.T.suggested_guidelines_for_m/?report=objectonly" target="object" rid-ob="figobtyrosinemiaTsuggestedguidelinesform">Table 3</a>):</p><ul><li class="half_rhythm"><div>CBC with platelet count</div></li><li class="half_rhythm"><div>Serum concentration of electrolytes</div></li><li class="half_rhythm"><div>Assessment of liver function (PT, PTT, AST, ALT, GGT, serum bilirubin concentration, alkaline phosphatase, and serum AFP).</div></li></ul><p>For children ascertained <b>on the basis of clinical symptoms</b> (see <a href="/books/NBK1515/bin/tyrosinemia-Table4.pdf">Table 4</a>; pdf), testing should include the evaluations listed above in addition to:</p><ul><li class="half_rhythm"><div>Baseline abdominal imagining by CT or MRI (with contrast) to evaluate for liver adenomas or nodules (see <a class="bk_pop" href="#tyrosinemia.REF.dubois.1996.845">Dubois et al [1996]</a>) and renal size;</div></li><li class="half_rhythm"><div>X-ray of wrist to document presence or absence of rickets.</div></li></ul><p>Clinical genetics consultation is indicated for all affected individuals.</p></div><div id="tyrosinemia.Treatment_of_Manifestations"><h3>Treatment of Manifestations</h3><p>Management guidelines have been published. US recommendations include <a class="bk_pop" href="#tyrosinemia.REF.chinsky.2017">Chinsky et al [2017]</a>; European recommendations include <a class="bk_pop" href="#tyrosinemia.REF.de_laet.2013">de Laet et al [2013]</a>.</p><p><b>Acute management of liver failure.</b> Children may require respiratory support, appropriate fluid management, and blood products for correction of bleeding diathesis.</p><p><b>Nitisinone (Orfadin<sup>®</sup>).</b> 2-(2-nitro-4-trifluoro-methylbenzyol) 1,3 cyclohexanedione (NTBC) blocks parahydroxyphenylpyruvic acid dioxygenase <i>(p</i>-HPPD), the second step in the tyrosine degradation pathway, and prevents the accumulation of FAA and its conversion to succinylacetone (<a class="figpopup" href="/books/NBK1515/figure/tyrosinemia.F1/?report=objectonly" target="object" rid-figpopup="figtyrosinemiaF1" rid-ob="figobtyrosinemiaF1">Figure 1</a>).</p><ul><li class="half_rhythm"><div>Nitisinone should be prescribed as soon as the diagnosis of tyrosinemia type I is confirmed.</div></li><li class="half_rhythm"><div>Nitisinone is generally prescribed at 1.0 mg/kg/day; individual requirements may vary. Dosage should be adjusted to maintain blood nitisinone levels between 40 and 60 µmol/L, which theoretically blocks more than 99% of <i>p</i>-HPPD activity. Rarely, an individual may require higher blood levels of nitisinone (70 µmol/L) to suppress succinylacetone excretion. As long as blood concentration of nitisinone is within the therapeutic range, urine succinylacetone does not need to be measured.</div></li><li class="half_rhythm"><div>Nitisinone is typically given in two divided doses; however, because of the long half-life (50-60 hours), affected individuals who are older than one year and stable may maintain adequate therapy with 1x/day dosing [<a class="bk_pop" href="#tyrosinemia.REF.schlune.2012.831">Schlune et al 2012</a>].</div></li><li class="half_rhythm"><div>Rare side effects of nitisinone have included: transient low platelet count and transient low neutrophil count that resolved without intervention; and photophobia that resolved with stricter dietary control and subsequent lowering of blood tyrosine concentrations.</div></li></ul><p><b>Low-tyrosine diet.</b> Nitisinone increases blood concentration of tyrosine, necessitating a low-tyrosine diet to prevent tyrosine crystals from forming in the cornea.</p><ul><li class="half_rhythm"><div>Dietary management should be started immediately upon diagnosis and should provide a nutritionally complete diet with controlled intakes of phenylalanine and tyrosine using a vegetarian diet with low-protein foods and a medical formula such as Tyrex<sup>®</sup> (Ross) or Tyros-1<sup>®</sup> (Mead Johnson).</div></li><li class="half_rhythm"><div>Phenylalanine and tyrosine requirements are interdependent and vary from individual to individual and within the same individual depending on growth rate, adequacy of energy and protein intakes, and state of health. With appropriate dietary management, plasma tyrosine concentration should be 300-600 µmol/L, regardless of age; plasma phenylalanine concentration should be 20-80 µmol/L (0.3-1.3 mg/dL). If the blood concentration of phenylalanine is too low (<20 µmol/L), additional protein should be added to the diet from milk or foods.</div></li></ul><p><b>Liver transplantation.</b> Prior to the availability of nitisinone for the treatment of tyrosinemia type I, the only definitive therapy was liver transplantation.</p><ul><li class="half_rhythm"><div>Liver transplantation should be reserved for those children who (1) have severe liver failure at clinical presentation and fail to respond to nitisinone therapy or (2) have documented evidence of malignant changes in hepatic tissue [<a class="bk_pop" href="#tyrosinemia.REF.bartlett.2014.745">Bartlett et al 2014</a>].</div></li><li class="half_rhythm"><div>Transplant recipients require long-term immunosuppression. Mortality associated with liver transplantation in young children is approximately 10%.</div></li><li class="half_rhythm"><div>Transplant recipients may also benefit from low-dose (0.1mg/kg/day) nitisinone therapy to prevent continued renal tubular and glomerular dysfunction resulting from persistence of succinylacetone in the plasma and urine [<a class="bk_pop" href="#tyrosinemia.REF.bartlett.2013.15">Bartlett et al 2013</a>].</div></li></ul></div><div id="tyrosinemia.Prevention_of_Primary_Manife"><h3>Prevention of Primary Manifestations</h3><p>Treatment with nitisinone (Orfadin<sup>®</sup>) should begin as soon as the diagnosis is confirmed.</p></div><div id="tyrosinemia.Prevention_of_Secondary_Comp"><h3>Prevention of Secondary Complications</h3><p>Because carnitine deficiency secondary to the renal tubular Fanconi syndrome can cause skeletal muscle weakness, serum concentration of carnitine should be measured so that carnitine deficiency, if identified, can be treated [<a class="bk_pop" href="#tyrosinemia.REF.nissenkorn.2001.642">Nissenkorn et al 2001</a>].</p><p>Osteoporosis and rickets resulting from renal tubular damage are treated by correction of acidosis, restoring of calcium and phosphate balance, and administration of 25-hydroxy-vitamin D.</p></div><div id="tyrosinemia.Surveillance"><h3>Surveillance</h3><p>Frequent evaluation of the following parameters is typical in the management of individuals with tyrosinemia type I (<a href="/books/NBK1515/table/tyrosinemia.T.suggested_guidelines_for_m/?report=objectonly" target="object" rid-ob="figobtyrosinemiaTsuggestedguidelinesform">Table 3</a>) [CR Scott, personal recommendations].</p><div id="tyrosinemia.T.suggested_guidelines_for_m" class="table"><h3><span class="label">Table 3. </span></h3><div class="caption"><p>Suggested Guidelines for Monitoring in Individuals with Tyrosinemia Type I Diagnosed by Newborn Screening</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK1515/table/tyrosinemia.T.suggested_guidelines_for_m/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__tyrosinemia.T.suggested_guidelines_for_m_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_tyrosinemia.T.suggested_guidelines_for_m_1_1_1_1" rowspan="2" colspan="2" scope="colgroup" headers="hd_h_tyrosinemia.T.suggested_guidelines_for_m_1_1_1_1" style="text-align:left;vertical-align:middle;">Evaluation</th><th id="hd_h_tyrosinemia.T.suggested_guidelines_for_m_1_1_1_2" rowspan="2" scope="col" colspan="1" headers="hd_h_tyrosinemia.T.suggested_guidelines_for_m_1_1_1_2" style="text-align:left;vertical-align:middle;">Initiation of Therapy (Baseline)</th><th id="hd_h_tyrosinemia.T.suggested_guidelines_for_m_1_1_1_3" colspan="2" scope="colgroup" rowspan="1" style="text-align:left;vertical-align:middle;">First 6 Mos:</th><th id="hd_h_tyrosinemia.T.suggested_guidelines_for_m_1_1_1_4" rowspan="2" scope="col" colspan="1" headers="hd_h_tyrosinemia.T.suggested_guidelines_for_m_1_1_1_4" style="text-align:left;vertical-align:middle;">After 6 Mos of Rx: Every 6-12 Mos</th><th id="hd_h_tyrosinemia.T.suggested_guidelines_for_m_1_1_1_5" rowspan="2" scope="col" colspan="1" headers="hd_h_tyrosinemia.T.suggested_guidelines_for_m_1_1_1_5" style="text-align:left;vertical-align:middle;">After 2 Yrs of Rx: Every 6-12 Mos</th><th id="hd_h_tyrosinemia.T.suggested_guidelines_for_m_1_1_1_6" rowspan="2" scope="col" colspan="1" headers="hd_h_tyrosinemia.T.suggested_guidelines_for_m_1_1_1_6" style="text-align:left;vertical-align:middle;">As Clinically Indicated</th></tr><tr><th headers="hd_h_tyrosinemia.T.suggested_guidelines_for_m_1_1_1_3" id="hd_h_tyrosinemia.T.suggested_guidelines_for_m_1_1_2_1" colspan="1" scope="colgroup" rowspan="1" style="text-align:left;vertical-align:middle;">1x/Mo</th><th headers="hd_h_tyrosinemia.T.suggested_guidelines_for_m_1_1_1_3" id="hd_h_tyrosinemia.T.suggested_guidelines_for_m_1_1_2_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Every 3 Mos</th></tr></thead><tbody><tr><td headers="hd_h_tyrosinemia.T.suggested_guidelines_for_m_1_1_1_1" rowspan="3" scope="row" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Tyrosinemia type I markers</b>
|
||
</td><td headers="hd_h_tyrosinemia.T.suggested_guidelines_for_m_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Plasma concentration of methionine, phenylalanine, tyrosine</td><td headers="hd_h_tyrosinemia.T.suggested_guidelines_for_m_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">X</td><td headers="hd_h_tyrosinemia.T.suggested_guidelines_for_m_1_1_1_3 hd_h_tyrosinemia.T.suggested_guidelines_for_m_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">x</td><td headers="hd_h_tyrosinemia.T.suggested_guidelines_for_m_1_1_1_3 hd_h_tyrosinemia.T.suggested_guidelines_for_m_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td><td headers="hd_h_tyrosinemia.T.suggested_guidelines_for_m_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">X</td><td headers="hd_h_tyrosinemia.T.suggested_guidelines_for_m_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">X</td><td headers="hd_h_tyrosinemia.T.suggested_guidelines_for_m_1_1_1_6" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">or X</td></tr><tr><td headers="hd_h_tyrosinemia.T.suggested_guidelines_for_m_1_1_1_1" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">Blood / urine succinylacetone</td><td headers="hd_h_tyrosinemia.T.suggested_guidelines_for_m_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">X</td><td headers="hd_h_tyrosinemia.T.suggested_guidelines_for_m_1_1_1_3 hd_h_tyrosinemia.T.suggested_guidelines_for_m_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">X<br />(urine)</td><td headers="hd_h_tyrosinemia.T.suggested_guidelines_for_m_1_1_1_3 hd_h_tyrosinemia.T.suggested_guidelines_for_m_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td><td headers="hd_h_tyrosinemia.T.suggested_guidelines_for_m_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td><td headers="hd_h_tyrosinemia.T.suggested_guidelines_for_m_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">X</td><td headers="hd_h_tyrosinemia.T.suggested_guidelines_for_m_1_1_1_6" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">or X</td></tr><tr><td headers="hd_h_tyrosinemia.T.suggested_guidelines_for_m_1_1_1_1" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">Blood nitisinone concentration</td><td headers="hd_h_tyrosinemia.T.suggested_guidelines_for_m_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td><td headers="hd_h_tyrosinemia.T.suggested_guidelines_for_m_1_1_1_3 hd_h_tyrosinemia.T.suggested_guidelines_for_m_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">X</td><td headers="hd_h_tyrosinemia.T.suggested_guidelines_for_m_1_1_1_3 hd_h_tyrosinemia.T.suggested_guidelines_for_m_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td><td headers="hd_h_tyrosinemia.T.suggested_guidelines_for_m_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">X</td><td headers="hd_h_tyrosinemia.T.suggested_guidelines_for_m_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">X</td><td headers="hd_h_tyrosinemia.T.suggested_guidelines_for_m_1_1_1_6" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">or X</td></tr><tr><td headers="hd_h_tyrosinemia.T.suggested_guidelines_for_m_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>CBC</b>
|
||
</td><td headers="hd_h_tyrosinemia.T.suggested_guidelines_for_m_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Hemoglobin, hematocrit, WBC, platelet count</td><td headers="hd_h_tyrosinemia.T.suggested_guidelines_for_m_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">X</td><td headers="hd_h_tyrosinemia.T.suggested_guidelines_for_m_1_1_1_3 hd_h_tyrosinemia.T.suggested_guidelines_for_m_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">X</td><td headers="hd_h_tyrosinemia.T.suggested_guidelines_for_m_1_1_1_3 hd_h_tyrosinemia.T.suggested_guidelines_for_m_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td><td headers="hd_h_tyrosinemia.T.suggested_guidelines_for_m_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">X</td><td headers="hd_h_tyrosinemia.T.suggested_guidelines_for_m_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">X</td><td headers="hd_h_tyrosinemia.T.suggested_guidelines_for_m_1_1_1_6" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">or X</td></tr><tr><td headers="hd_h_tyrosinemia.T.suggested_guidelines_for_m_1_1_1_1" rowspan="6" scope="row" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Liver</b>
|
||
<br />
|
||
<b>evaluation</b>
|
||
</td><td headers="hd_h_tyrosinemia.T.suggested_guidelines_for_m_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Serum AFP concentration</td><td headers="hd_h_tyrosinemia.T.suggested_guidelines_for_m_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">X</td><td headers="hd_h_tyrosinemia.T.suggested_guidelines_for_m_1_1_1_3 hd_h_tyrosinemia.T.suggested_guidelines_for_m_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">X</td><td headers="hd_h_tyrosinemia.T.suggested_guidelines_for_m_1_1_1_3 hd_h_tyrosinemia.T.suggested_guidelines_for_m_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td><td headers="hd_h_tyrosinemia.T.suggested_guidelines_for_m_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">X</td><td headers="hd_h_tyrosinemia.T.suggested_guidelines_for_m_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">X</td><td headers="hd_h_tyrosinemia.T.suggested_guidelines_for_m_1_1_1_6" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">X</td></tr><tr><td headers="hd_h_tyrosinemia.T.suggested_guidelines_for_m_1_1_1_1" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">PT/PTT</td><td headers="hd_h_tyrosinemia.T.suggested_guidelines_for_m_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">X</td><td headers="hd_h_tyrosinemia.T.suggested_guidelines_for_m_1_1_1_3 hd_h_tyrosinemia.T.suggested_guidelines_for_m_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">X<br />(until nl)</td><td headers="hd_h_tyrosinemia.T.suggested_guidelines_for_m_1_1_1_3 hd_h_tyrosinemia.T.suggested_guidelines_for_m_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td><td headers="hd_h_tyrosinemia.T.suggested_guidelines_for_m_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td><td headers="hd_h_tyrosinemia.T.suggested_guidelines_for_m_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td><td headers="hd_h_tyrosinemia.T.suggested_guidelines_for_m_1_1_1_6" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr><tr><td headers="hd_h_tyrosinemia.T.suggested_guidelines_for_m_1_1_1_1" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">Bilirubin</td><td headers="hd_h_tyrosinemia.T.suggested_guidelines_for_m_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">X</td><td headers="hd_h_tyrosinemia.T.suggested_guidelines_for_m_1_1_1_3 hd_h_tyrosinemia.T.suggested_guidelines_for_m_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td><td headers="hd_h_tyrosinemia.T.suggested_guidelines_for_m_1_1_1_3 hd_h_tyrosinemia.T.suggested_guidelines_for_m_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td><td headers="hd_h_tyrosinemia.T.suggested_guidelines_for_m_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td><td headers="hd_h_tyrosinemia.T.suggested_guidelines_for_m_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td><td headers="hd_h_tyrosinemia.T.suggested_guidelines_for_m_1_1_1_6" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr><tr><td headers="hd_h_tyrosinemia.T.suggested_guidelines_for_m_1_1_1_1" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">ALT/AST/GGT</td><td headers="hd_h_tyrosinemia.T.suggested_guidelines_for_m_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">X</td><td headers="hd_h_tyrosinemia.T.suggested_guidelines_for_m_1_1_1_3 hd_h_tyrosinemia.T.suggested_guidelines_for_m_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td><td headers="hd_h_tyrosinemia.T.suggested_guidelines_for_m_1_1_1_3 hd_h_tyrosinemia.T.suggested_guidelines_for_m_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">X<br />(until nl)</td><td headers="hd_h_tyrosinemia.T.suggested_guidelines_for_m_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">X</td><td headers="hd_h_tyrosinemia.T.suggested_guidelines_for_m_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td><td headers="hd_h_tyrosinemia.T.suggested_guidelines_for_m_1_1_1_6" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr><tr><td headers="hd_h_tyrosinemia.T.suggested_guidelines_for_m_1_1_1_1" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">Alkaline phosphatase</td><td headers="hd_h_tyrosinemia.T.suggested_guidelines_for_m_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">X</td><td headers="hd_h_tyrosinemia.T.suggested_guidelines_for_m_1_1_1_3 hd_h_tyrosinemia.T.suggested_guidelines_for_m_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td><td headers="hd_h_tyrosinemia.T.suggested_guidelines_for_m_1_1_1_3 hd_h_tyrosinemia.T.suggested_guidelines_for_m_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">X<br />(until nl)</td><td headers="hd_h_tyrosinemia.T.suggested_guidelines_for_m_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">X</td><td headers="hd_h_tyrosinemia.T.suggested_guidelines_for_m_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td><td headers="hd_h_tyrosinemia.T.suggested_guidelines_for_m_1_1_1_6" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">X</td></tr><tr><td headers="hd_h_tyrosinemia.T.suggested_guidelines_for_m_1_1_1_1" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">CT or MRI <sup>1</sup></td><td headers="hd_h_tyrosinemia.T.suggested_guidelines_for_m_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td><td headers="hd_h_tyrosinemia.T.suggested_guidelines_for_m_1_1_1_3 hd_h_tyrosinemia.T.suggested_guidelines_for_m_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td><td headers="hd_h_tyrosinemia.T.suggested_guidelines_for_m_1_1_1_3 hd_h_tyrosinemia.T.suggested_guidelines_for_m_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td><td headers="hd_h_tyrosinemia.T.suggested_guidelines_for_m_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td><td headers="hd_h_tyrosinemia.T.suggested_guidelines_for_m_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td><td headers="hd_h_tyrosinemia.T.suggested_guidelines_for_m_1_1_1_6" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">X</td></tr><tr><td headers="hd_h_tyrosinemia.T.suggested_guidelines_for_m_1_1_1_1" rowspan="2" scope="row" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Renal studies</b>
|
||
</td><td headers="hd_h_tyrosinemia.T.suggested_guidelines_for_m_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">BUN / creatinine</td><td headers="hd_h_tyrosinemia.T.suggested_guidelines_for_m_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td><td headers="hd_h_tyrosinemia.T.suggested_guidelines_for_m_1_1_1_3 hd_h_tyrosinemia.T.suggested_guidelines_for_m_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td><td headers="hd_h_tyrosinemia.T.suggested_guidelines_for_m_1_1_1_3 hd_h_tyrosinemia.T.suggested_guidelines_for_m_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td><td headers="hd_h_tyrosinemia.T.suggested_guidelines_for_m_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td><td headers="hd_h_tyrosinemia.T.suggested_guidelines_for_m_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td><td headers="hd_h_tyrosinemia.T.suggested_guidelines_for_m_1_1_1_6" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">X</td></tr><tr><td headers="hd_h_tyrosinemia.T.suggested_guidelines_for_m_1_1_1_1" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">Urine: PO4, Ca, Prot/Cr ratio</td><td headers="hd_h_tyrosinemia.T.suggested_guidelines_for_m_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td><td headers="hd_h_tyrosinemia.T.suggested_guidelines_for_m_1_1_1_3 hd_h_tyrosinemia.T.suggested_guidelines_for_m_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td><td headers="hd_h_tyrosinemia.T.suggested_guidelines_for_m_1_1_1_3 hd_h_tyrosinemia.T.suggested_guidelines_for_m_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td><td headers="hd_h_tyrosinemia.T.suggested_guidelines_for_m_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td><td headers="hd_h_tyrosinemia.T.suggested_guidelines_for_m_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td><td headers="hd_h_tyrosinemia.T.suggested_guidelines_for_m_1_1_1_6" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">X</td></tr><tr><td headers="hd_h_tyrosinemia.T.suggested_guidelines_for_m_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Skeletal evaluation</b>
|
||
</td><td headers="hd_h_tyrosinemia.T.suggested_guidelines_for_m_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Radiograph of wrist (for rickets)</td><td headers="hd_h_tyrosinemia.T.suggested_guidelines_for_m_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td><td headers="hd_h_tyrosinemia.T.suggested_guidelines_for_m_1_1_1_3 hd_h_tyrosinemia.T.suggested_guidelines_for_m_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td><td headers="hd_h_tyrosinemia.T.suggested_guidelines_for_m_1_1_1_3 hd_h_tyrosinemia.T.suggested_guidelines_for_m_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td><td headers="hd_h_tyrosinemia.T.suggested_guidelines_for_m_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td><td headers="hd_h_tyrosinemia.T.suggested_guidelines_for_m_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td><td headers="hd_h_tyrosinemia.T.suggested_guidelines_for_m_1_1_1_6" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">X</td></tr></tbody></table></div><div><div><dl class="temp-labeled-list small"><dt></dt><dd><div><p class="no_margin">AFP = alpha-fetoprotein; ALT/AST = alanine transaminase/aspartate transaminase; BUN = blood urea nitrogen; CBC = complete blood count; GGT = gamma-glutamyl transferase; nl = normal; PT/PTT = prothrombin time/partial thromboplastin time</p></div></dd><dt>1. </dt><dd><div id="tyrosinemia.TF.3.1"><p class="no_margin">MRI with contrast to evaluate for liver adenomas or nodules and for kidney size</p></div></dd></dl></div></div></div><p>For monitoring children diagnosed based on clinical presention, see <a href="/books/NBK1515/bin/tyrosinemia-Table4.pdf">Table 4</a> (pdf).</p><p>For alternative management recommendations, see <a class="bk_pop" href="#tyrosinemia.REF.de_laet.2013">de Laet et al [2013]</a>.</p></div><div id="tyrosinemia.AgentsCircumstances_to_Avoid"><h3>Agents/Circumstances to Avoid</h3><p>Avoid inappropriate protein intake.</p></div><div id="tyrosinemia.Evaluation_of_Relatives_at_R"><h3>Evaluation of Relatives at Risk</h3><p>It is appropriate to evaluate apparently asymptomatic older and younger sibs of a <a class="def" href="/books/n/gene/glossary/def-item/proband/">proband</a> in order to identify as early as possible those who would benefit from prompt initiation of treatment and preventive measures. Evaluations can include:</p><ul><li class="half_rhythm"><div>Molecular genetic testing if the pathogenic variants in the family are known. Prenatal testing can be used to clarify the genetic status of at-risk sibs before birth.</div></li><li class="half_rhythm"><div>Blood or urine succinylacetone analysis as soon as possible after birth if <a class="def" href="/books/n/gene/glossary/def-item/prenatal-testing/">prenatal testing</a> was not performed. This allows prompt initiation of treatment, as postnatal genetic testing results may not be available in a timely fashion.</div></li><li class="half_rhythm"><div>If the pathogenic variants in the family are not known, consideration of analysis for urine succinylacetone in healthy older sibs</div></li></ul><p>See <a href="#tyrosinemia.Related_Genetic_Counseling_I">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="tyrosinemia.Pregnancy_Management"><h3>Pregnancy Management</h3><p>Little data exist on the use of nitisinone during human pregnancy. Speculation would assume that the pregnant woman remains safe from untoward events; however, the developing fetus may be at risk because of alterations in tyrosine metabolism.</p><p>At least two women have given birth to healthy infants while receiving therapeutic doses of nitisinone [<a class="bk_pop" href="#tyrosinemia.REF.garcia_segarra.2010.s507">Garcia Segarra et al 2010</a>].</p><ul><li class="half_rhythm"><div>In one instance the affected mother gave birth to an unaffected infant who is reported to be healthy and developing normally at age 2.5 years [<a class="bk_pop" href="#tyrosinemia.REF.garcia_segarra.2010.s507">Garcia Segarra et al 2010</a>, <a class="bk_pop" href="#tyrosinemia.REF.vanclooster.2012.27">Vanclooster et al 2012</a>].</div></li><li class="half_rhythm"><div>In another instance, an affected woman gave birth to an affected child. The child is reported to have normal growth and development at age seven months [<a class="bk_pop" href="#tyrosinemia.REF.garcia_segarra.2010.s507">Garcia Segarra et al 2010</a>]. The authors speculate that the affected child was protected from in utero liver damage by maternal treatment with nitisinone during pregnancy.</div></li></ul><p>See <a href="https://www.mothertobaby.org/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">MotherToBaby</a> for more information on medication exposure during pregnancy.</p></div><div id="tyrosinemia.Therapies_Under_Investigatio"><h3>Therapies Under Investigation</h3><p>Search <a href="https://clinicaltrials.gov/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">ClinicalTrials.gov</a> in the US and <a href="https://www.clinicaltrialsregister.eu/ctr-search/search" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">EU Clinical Trials Register</a> in Europe for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.</p></div><div id="tyrosinemia.Other"><h3>Other</h3><p>Prior to the availability of nitisinone, the only available non-transplant therapy was a diet limiting the availability of phenylalorine and tyrosine. Although the diet was modestly helpful, recurrent episodes of neurologic crises and progression of liver disease occurred. Average survival was less than age ten years.</p></div></div><div id="tyrosinemia.Genetic_Counseling"><h2 id="_tyrosinemia_Genetic_Counseling_">Genetic Counseling</h2><p>
|
||
<i>Genetic counseling is the process of providing individuals and families with
|
||
information on the nature, mode(s) of inheritance, and implications of genetic disorders to help them
|
||
make informed medical and personal decisions. The following section deals with genetic
|
||
risk assessment and the use of family history and genetic testing to clarify genetic
|
||
status for family members; it is not meant to address all personal, cultural, or
|
||
ethical issues that may arise or to substitute for consultation with a genetics
|
||
professional</i>. —ED.</p><div id="tyrosinemia.Mode_of_Inheritance"><h3>Mode of Inheritance</h3><p>Tyrosinemia type I is inherited in an <a class="def" href="/books/n/gene/glossary/def-item/autosomal-recessive/">autosomal recessive</a> manner.</p></div><div id="tyrosinemia.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., carriers of one <i>FAH</i> <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</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>At conception, each sib of an affected individual has 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.</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> The offspring of an individual with tyrosinemia type I are obligate heterozygotes (carriers) for a <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a> in <i>FAH</i>.</p><p><b>Other family members.</b> Each sib of the <a class="def" href="/books/n/gene/glossary/def-item/proband/">proband</a>'s parents is at a 50% risk of being a <a class="def" href="/books/n/gene/glossary/def-item/carrier/">carrier</a> of a <i>FAH</i> <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a>.</p></div><div id="tyrosinemia.Carrier_Detection"><h3>Carrier Detection</h3><p>Carrier testing for at-risk relatives requires prior identification of the <i>FAH</i> pathogenic variants in the family.</p></div><div id="tyrosinemia.Related_Genetic_Counseling_I"><h3>Related Genetic Counseling Issues</h3><p>See Management, <a href="#tyrosinemia.Evaluation_of_Relatives_at_R">Evaluation of Relatives at Risk</a> for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.</p><p>
|
||
<b>Family planning</b>
|
||
</p><ul><li class="half_rhythm"><div>The optimal time for determination of genetic risk, clarification of <a class="def" href="/books/n/gene/glossary/def-item/carrier/">carrier</a> status, 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><p><b>DNA banking.</b> Because it is likely that testing methodology and our understanding of genes, pathogenic mechanisms, and diseases will improve in the future, consideration should be given to banking DNA from probands in whom a molecular diagnosis has not been confirmed (i.e., the causative pathogenic mechanism is unknown). For more information, see <a class="bk_pop" href="#tyrosinemia.REF.huang.2022.389">Huang et al [2022]</a>.</p></div><div id="tyrosinemia.Prenatal_Testing_and_Preimpl"><h3>Prenatal Testing and Preimplantation Genetic Testing</h3><p><b>Molecular genetic testing.</b> Once the <i>FAH</i> pathogenic variants have been identified in an affected family member, prenatal and <a class="def" href="/books/n/gene/glossary/def-item/preimplantation-genetic-testing/">preimplantation genetic testing</a> for tyrosinemia type I are possible.</p><p><b>Biochemical testing.</b> Prenatal testing for pregnancies at 25% risk is possible by detection of succinylacetone in amniotic fluid obtained by amniocentesis usually performed at approximately 15 to 18 weeks' gestation. Although detection of succinylacetone in amniotic fluid is diagnostic, false negative results have been reported; thus, this method should only be used by laboratories consistently able to identify succinylacetone at low levels by stable isotope detection. Because of these issues with biochemical testing, <a class="def" href="/books/n/gene/glossary/def-item/molecular-genetic-testing/">molecular genetic testing</a> is the preferred method of <a class="def" href="/books/n/gene/glossary/def-item/prenatal-diagnosis/">prenatal diagnosis</a>.</p></div></div><div id="tyrosinemia.Resources"><h2 id="_tyrosinemia_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>MedlinePlus</b>
|
||
</div><div>
|
||
<a href="https://medlineplus.gov/genetics/condition/tyrosinemia/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">Tyrosinemia</a>
|
||
</div></li><li class="half_rhythm"><div>
|
||
<b>American Liver Foundation</b>
|
||
</div><div><b>Phone:</b> 800-465-4837 (HelpLine)</div><div>
|
||
<a href="http://www.liverfoundation.org" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">liverfoundation.org</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&targetsite=external&targetcat=link&targettype=uri">metabolicsupportuk.org</a>
|
||
</div></li><li class="half_rhythm"><div>
|
||
<b>Newborn Screening in Your State</b>
|
||
</div><div>Health Resources & Services Administration</div><div>
|
||
<a href="https://newbornscreening.hrsa.gov/your-state" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">newbornscreening.hrsa.gov/your-state</a>
|
||
</div></li></ul>
|
||
</div><div id="tyrosinemia.Molecular_Genetics"><h2 id="_tyrosinemia_Molecular_Genetics_">Molecular Genetics</h2><p><i>Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —</i>ED.</p><div id="tyrosinemia.molgen.TA" class="table"><h3><span class="label">Table A.</span></h3><div class="caption"><p>Tyrosinemia Type I: Genes and Databases</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK1515/table/tyrosinemia.molgen.TA/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__tyrosinemia.molgen.TA_lrgtbl__"><table class="no_bottom_margin"><tbody><tr><th id="hd_b_tyrosinemia.molgen.TA_1_1_1_1" rowspan="1" colspan="1" style="vertical-align:top;">Gene</th><th id="hd_b_tyrosinemia.molgen.TA_1_1_1_2" rowspan="1" colspan="1" style="vertical-align:top;">Chromosome Locus</th><th id="hd_b_tyrosinemia.molgen.TA_1_1_1_3" rowspan="1" colspan="1" style="vertical-align:top;">Protein</th><th id="hd_b_tyrosinemia.molgen.TA_1_1_1_4" rowspan="1" colspan="1" style="vertical-align:top;">Locus-Specific Databases</th><th id="hd_b_tyrosinemia.molgen.TA_1_1_1_5" rowspan="1" colspan="1" style="vertical-align:top;">HGMD</th><th id="hd_b_tyrosinemia.molgen.TA_1_1_1_6" rowspan="1" colspan="1" style="vertical-align:top;">ClinVar</th></tr><tr><td headers="hd_b_tyrosinemia.molgen.TA_1_1_1_1" rowspan="1" colspan="1" style="vertical-align:top;">
|
||
<a href="/gene/2184" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=gene">
|
||
<i>FAH</i>
|
||
</a>
|
||
</td><td headers="hd_b_tyrosinemia.molgen.TA_1_1_1_2" rowspan="1" colspan="1" style="vertical-align:top;">
|
||
<a href="https://www.ncbi.nlm.nih.gov/genome/gdv/?context=gene&acc=2184" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">15q25<wbr style="display:inline-block"></wbr>.1</a>
|
||
</td><td headers="hd_b_tyrosinemia.molgen.TA_1_1_1_3" rowspan="1" colspan="1" style="vertical-align:top;">
|
||
<a href="http://www.uniprot.org/uniprot/P16930" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">Fumarylacetoacetase</a>
|
||
</td><td headers="hd_b_tyrosinemia.molgen.TA_1_1_1_4" rowspan="1" colspan="1" style="vertical-align:top;">
|
||
<a href="http://databases.lovd.nl/shared/genes/FAH" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">FAH database</a>
|
||
</td><td headers="hd_b_tyrosinemia.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=FAH" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">FAH</a>
|
||
</td><td headers="hd_b_tyrosinemia.molgen.TA_1_1_1_6" rowspan="1" colspan="1" style="vertical-align:top;">
|
||
<a href="https://www.ncbi.nlm.nih.gov/clinvar/?term=FAH[gene]" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">FAH</a>
|
||
</td></tr></tbody></table></div><div><div><dl class="temp-labeled-list small"><dt></dt><dd><div id="tyrosinemia.TFA.1"><p class="no_margin">Data are compiled from the following standard references: <a class="def" href="/books/n/gene/glossary/def-item/gene/">gene</a> from
|
||
<a href="http://www.genenames.org/index.html" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">HGNC</a>;
|
||
<a class="def" href="/books/n/gene/glossary/def-item/chromosome/">chromosome</a> <a class="def" href="/books/n/gene/glossary/def-item/locus/">locus</a> from
|
||
<a href="http://www.omim.org/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">OMIM</a>;
|
||
protein from <a href="http://www.uniprot.org/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">UniProt</a>.
|
||
For a description of databases (Locus Specific, HGMD, ClinVar) to which links are provided, click
|
||
<a href="/books/n/gene/app1/">here</a>.</p></div></dd></dl></div></div></div><div id="tyrosinemia.molgen.TB" class="table"><h3><span class="label">Table B.</span></h3><div class="caption"><p>OMIM Entries for Tyrosinemia Type I (<a href="/omim/276700,613871" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=omim">View All in OMIM</a>) </p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK1515/table/tyrosinemia.molgen.TB/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__tyrosinemia.molgen.TB_lrgtbl__"><table><tbody><tr><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
||
<a href="/omim/276700" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=omim">276700</a></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">TYROSINEMIA, TYPE I; TYRSN1</td></tr><tr><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
||
<a href="/omim/613871" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=omim">613871</a></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">FUMARYLACETOACETATE HYDROLASE; FAH</td></tr></tbody></table></div></div><p><b>Gene structure.</b>
|
||
<i>FAH</i> is approximately 35 kbp in size and comprises 14 exons. For a detailed summary of <a class="def" href="/books/n/gene/glossary/def-item/gene/">gene</a> and protein information, see <a href="/books/NBK1515/#tyrosinemia.molgen.TA">Table A</a>, <b>Gene</b>.</p><p><b>Benign variants.</b> A single pseudodeficiency <a class="def" href="/books/n/gene/glossary/def-item/allele/">allele</a>, c.1021C>T (p.Arg341Trp), leads to decreased FAH enzyme activity and very little immunoreactive protein, but adequate amounts of FAH <a class="def" href="/books/n/gene/glossary/def-item/mrna/">mRNA</a> [<a class="bk_pop" href="#tyrosinemia.REF.rootwelt.1994.1122">Rootwelt et al 1994</a>].</p><p><b>Pathogenic variants.</b> See <a href="/books/NBK1515/table/tyrosinemia.T.fah_variants_discussed_in/?report=objectonly" target="object" rid-ob="figobtyrosinemiaTfahvariantsdiscussedin">Table 5</a>. Pathogenic <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, as well as small deletions and indels of <i>FAH</i>, have been reported. <a class="bk_pop" href="#tyrosinemia.REF.park.2009.930">Park et al [2009]</a> reported a large <a class="def" href="/books/n/gene/glossary/def-item/deletion/">deletion</a> involving <i>FAH.</i></p><p>The following population-specific pathogenic variants result from founder effects or genetic drift [<a class="bk_pop" href="#tyrosinemia.REF.angileri.2015.43">Angileri et al 2015</a>] (see <a href="/books/NBK1515/table/tyrosinemia.T.fah_variants_discussed_in/?report=objectonly" target="object" rid-ob="figobtyrosinemiaTfahvariantsdiscussedin">Table 5</a>):</p><ul><li class="half_rhythm"><div><a class="def" href="/books/n/gene/glossary/def-item/ashkenazi-jewish/">Ashkenazi Jewish</a>: p.Pro261Leu</div></li><li class="half_rhythm"><div>Finnish: p.Trp262Ter</div></li><li class="half_rhythm"><div>French Canadian: c.1062+5G>A</div></li><li class="half_rhythm"><div>Pakistani: p.Gln64His</div></li><li class="half_rhythm"><div>Scandinavian: p.Gly337Ser</div></li><li class="half_rhythm"><div>Turkish: p.Asp233Val</div></li><li class="half_rhythm"><div>Northern European: c.1062+5G>A</div></li><li class="half_rhythm"><div>Southern European: c.554-1G>T</div></li></ul><div id="tyrosinemia.T.fah_variants_discussed_in" class="table"><h3><span class="label">Table 5. </span></h3><div class="caption"><p><i>FAH</i> Variants Discussed in This <i>GeneReview</i></p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK1515/table/tyrosinemia.T.fah_variants_discussed_in/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__tyrosinemia.T.fah_variants_discussed_in_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_tyrosinemia.T.fah_variants_discussed_in_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Variant<br />Classification</th><th id="hd_h_tyrosinemia.T.fah_variants_discussed_in_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">DNA Nucleotide Change<br />(Alias <sup>1</sup>)</th><th id="hd_h_tyrosinemia.T.fah_variants_discussed_in_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_tyrosinemia.T.fah_variants_discussed_in_1_1_1_4" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Reference Sequences</th></tr></thead><tbody><tr><td headers="hd_h_tyrosinemia.T.fah_variants_discussed_in_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Pseudodeficiency</b>
|
||
</td><td headers="hd_h_tyrosinemia.T.fah_variants_discussed_in_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">c.1021C>T</td><td headers="hd_h_tyrosinemia.T.fah_variants_discussed_in_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">p.Arg341Trp</td><td headers="hd_h_tyrosinemia.T.fah_variants_discussed_in_1_1_1_4" rowspan="4" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<a href="https://www.ncbi.nlm.nih.gov/entrez/viewer.fcgi?val=NM_000137.1" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">NM_000137<wbr style="display:inline-block"></wbr>.1</a>
|
||
<br />
|
||
<a href="https://www.ncbi.nlm.nih.gov/entrez/viewer.fcgi?val=NP_000128.1" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">NP_000128<wbr style="display:inline-block"></wbr>.1</a>
|
||
</td></tr><tr><td headers="hd_h_tyrosinemia.T.fah_variants_discussed_in_1_1_1_1" rowspan="10" scope="row" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Pathogenic</b>
|
||
</td><td headers="hd_h_tyrosinemia.T.fah_variants_discussed_in_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">c.103G>A</td><td headers="hd_h_tyrosinemia.T.fah_variants_discussed_in_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">p.Ala35Thr</td></tr><tr><td headers="hd_h_tyrosinemia.T.fah_variants_discussed_in_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">c.192G>T</td><td headers="hd_h_tyrosinemia.T.fah_variants_discussed_in_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">p.Gln64His</td></tr><tr><td headers="hd_h_tyrosinemia.T.fah_variants_discussed_in_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">c.424A>G</td><td headers="hd_h_tyrosinemia.T.fah_variants_discussed_in_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">p.Arg142Gly</td></tr><tr><td headers="hd_h_tyrosinemia.T.fah_variants_discussed_in_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">c.554-1G>T<br />(IVS6-1G>T)</td><td headers="hd_h_tyrosinemia.T.fah_variants_discussed_in_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">--</td><td headers="hd_h_tyrosinemia.T.fah_variants_discussed_in_1_1_1_4" rowspan="2" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<a href="https://www.ncbi.nlm.nih.gov/entrez/viewer.fcgi?val=NM_000137.1" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">NM_000137<wbr style="display:inline-block"></wbr>.1</a>
|
||
</td></tr><tr><td headers="hd_h_tyrosinemia.T.fah_variants_discussed_in_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">c.607-6T>G<br />(IVS7-6T>G)</td><td headers="hd_h_tyrosinemia.T.fah_variants_discussed_in_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">--</td></tr><tr><td headers="hd_h_tyrosinemia.T.fah_variants_discussed_in_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">c.698A>T</td><td headers="hd_h_tyrosinemia.T.fah_variants_discussed_in_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">p.Asp233Val</td><td headers="hd_h_tyrosinemia.T.fah_variants_discussed_in_1_1_1_4" rowspan="4" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<a href="https://www.ncbi.nlm.nih.gov/entrez/viewer.fcgi?val=NM_000137.1" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">NM_000137<wbr style="display:inline-block"></wbr>.1</a>
|
||
<br />
|
||
<a href="https://www.ncbi.nlm.nih.gov/entrez/viewer.fcgi?val=NP_000128.1" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">NP_000128<wbr style="display:inline-block"></wbr>.1</a>
|
||
</td></tr><tr><td headers="hd_h_tyrosinemia.T.fah_variants_discussed_in_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">c.782C>T</td><td headers="hd_h_tyrosinemia.T.fah_variants_discussed_in_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">p.Pro261Leu</td></tr><tr><td headers="hd_h_tyrosinemia.T.fah_variants_discussed_in_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">c.786G>A</td><td headers="hd_h_tyrosinemia.T.fah_variants_discussed_in_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">p.Trp262Ter</td></tr><tr><td headers="hd_h_tyrosinemia.T.fah_variants_discussed_in_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">c.1009G>A</td><td headers="hd_h_tyrosinemia.T.fah_variants_discussed_in_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">p.Gly337Ser</td></tr><tr><td headers="hd_h_tyrosinemia.T.fah_variants_discussed_in_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">c.1062+5G>A<br />(IVS12+5 G>A)</td><td headers="hd_h_tyrosinemia.T.fah_variants_discussed_in_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">--</td><td headers="hd_h_tyrosinemia.T.fah_variants_discussed_in_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<a href="https://www.ncbi.nlm.nih.gov/entrez/viewer.fcgi?val=NM_000137.1" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">NM_000137<wbr style="display:inline-block"></wbr>.1</a>
|
||
</td></tr></tbody></table></div><div><div><dl class="temp-labeled-list small"><dt></dt><dd><div><p class="no_margin">Variants listed in the table have been provided by the authors. <i>GeneReviews</i> staff have not independently verified the classification of variants.</p></div></dd><dt></dt><dd><div><p class="no_margin"><i>GeneReviews</i> follows the standard naming conventions of the Human Genome Variation Society (<a href="https://varnomen.hgvs.org/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">varnomen<wbr style="display:inline-block"></wbr>.hgvs.org</a>). See <a href="/books/n/gene/app3/">Quick Reference</a> for an explanation of nomenclature.</p></div></dd><dt>1. </dt><dd><div id="tyrosinemia.TF.5.1"><p class="no_margin">Variant designation that does not conform to current naming conventions</p></div></dd></dl></div></div></div><p>For additional pathogenic variants identified in North American patients, see <a href="/books/NBK1515/bin/tyrosinemia-Table6.pdf">Table 6</a> (pdf).</p><p><b>Normal <a class="def" href="/books/n/gene/glossary/def-item/gene-product/">gene product</a>.</b> FAH is a cytosolic protein that acts as a homodimer and has a molecular weight of approximately 80 kd. The <a class="def" href="/books/n/gene/glossary/def-item/wild_type/">wild type</a> FAH has a Km for FAA of about 3.5 μmol/L. FAH catalyzes the conversion of FAA to fumarate and acetoacetate and the conversion of succinylacetoacetate to succinate and acetoacetate.</p><p><b>Abnormal <a class="def" href="/books/n/gene/glossary/def-item/gene-product/">gene product</a>.</b> Pathogenic <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 result in loss of FAH enzyme activity, leading to an intracellular accumulation of FAA resulting in cellular damage and apoptosis.</p></div><div id="tyrosinemia.Chapter_Notes"><h2 id="_tyrosinemia_Chapter_Notes_">Chapter Notes</h2><div id="tyrosinemia.Author_Notes"><h3>Author Notes</h3><p>
|
||
<a href="https://depts.washington.edu/tyros/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">University of Washington Biochemical Genetics Clinic Tyrosinemia Home Page</a>
|
||
</p></div><div id="tyrosinemia.Acknowledgments"><h3>Acknowledgments</h3><p>Supported by grants from the Food and Drug Administration (FD-4-001445) and Rare Disease Therapeutics. The authors are appreciative of the collaboration and discussions with Dr Grant Mitchell of Montreal, Canada, and Dr Sven Lindstedt and Dr Elisabeth Holme of Gothenburg, Sweden.</p></div><div id="tyrosinemia.Revision_History"><h3>Revision History</h3><ul><li class="half_rhythm"><div>25 May 2017 (ma) Comprehensive update posted live</div></li><li class="half_rhythm"><div>17 July 2014 (me) Comprehensive update posted live</div></li><li class="half_rhythm"><div>25 August 2011 (me) Comprehensive update posted live</div></li><li class="half_rhythm"><div>21 October 2008 (cg) Comprehensive update posted live</div></li><li class="half_rhythm"><div>24 July 2006 (me) Review posted live</div></li><li class="half_rhythm"><div>29 June 2005 (crs) Original submission</div></li></ul></div></div><div id="tyrosinemia.References"><h2 id="_tyrosinemia_References_">References</h2><div id="tyrosinemia.Literature_Cited"><h3>Literature Cited</h3><ul class="simple-list"><li class="half_rhythm"><div class="bk_ref" id="tyrosinemia.REF.ahmad.2002.266">Ahmad
|
||
S, Teckman
|
||
JH, Lueder
|
||
GT. Corneal opacities associated with NTBC treatment.
|
||
Am J Ophthalmol.
|
||
2002;134:266–8.
|
||
[<a href="https://pubmed.ncbi.nlm.nih.gov/12140036" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 12140036</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="tyrosinemia.REF.angileri.2015.43">Angileri
|
||
F, Bergeron
|
||
A, Morrow
|
||
G, Lettre
|
||
F, Gray
|
||
G, Hutchin
|
||
T, Ball
|
||
S, Tanguay
|
||
RM. Geographical and ethnic distribution of mutations of the fumarylacetoacetate hydrolase gene in hereditary tyrosinemia type 1.
|
||
JIMD Rep.
|
||
2015;19:43–58.
|
||
[<a href="/pmc/articles/PMC4501228/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC4501228</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/25681080" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 25681080</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="tyrosinemia.REF.bansal.2004">Bansal S, Dhawan A. Acute liver failure. In: Walker WA, Kleinman RE, Sherman PM, Shneider BL, Sanderson IR, eds. Pediatric Gastrointestinal Disease - Pathophysiology, Diagnosis, Management. 4 ed. Ch 58. Hamilton, Ontario: BC Decker, Inc; 2004:1491-507.</div></li><li class="half_rhythm"><div class="bk_ref" id="tyrosinemia.REF.bartlett.2014.745">Bartlett
|
||
DC, Lloyd
|
||
C, McKiernan
|
||
PJ, Newsome
|
||
PN. Early nitisinone treatment reduces the need for liver transplantation in children with tyrosinaemia type 1 and improves post-transplant renal function.
|
||
J Inherit Metab Dis.
|
||
2014;37:745–52.
|
||
[<a href="https://pubmed.ncbi.nlm.nih.gov/24515874" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 24515874</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="tyrosinemia.REF.bartlett.2013.15">Bartlett
|
||
DC, Preece
|
||
MA, Holme
|
||
E, Lloyd
|
||
C, Newsome
|
||
PN, McKiernan
|
||
PJ. Plasma succinylacetone is persistently raised after liver transplantation in tyrosinaemia type 1.
|
||
J Inherit Metab Dis.
|
||
2013;36:15–20.
|
||
[<a href="https://pubmed.ncbi.nlm.nih.gov/22456946" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 22456946</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="tyrosinemia.REF.baumann.2005.131">Baumann
|
||
U, Preece
|
||
MA, Green
|
||
A, Kelly
|
||
DA, McKiernan
|
||
PJ. Hyperinsulinism in tyrosinaemia type I.
|
||
J Inherit Metab Dis.
|
||
2005;28:131–5.
|
||
[<a href="https://pubmed.ncbi.nlm.nih.gov/15877201" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 15877201</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="tyrosinemia.REF.bergeron.2004.1381">Bergeron
|
||
A, Lettre
|
||
F, Russo
|
||
P, Morissette
|
||
J, Tanguay
|
||
RM. No evidence of maternal cell colonization in reverted liver nodules of tyrosinemia type I patients.
|
||
Gastroenterology.
|
||
2004;127:1381–5.
|
||
[<a href="https://pubmed.ncbi.nlm.nih.gov/15521007" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 15521007</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="tyrosinemia.REF.blackburn.2016.1097">Blackburn
|
||
PR, Hickey
|
||
RD, Nace
|
||
RA, Giama
|
||
NH, Kraft
|
||
DL, Bordner
|
||
AJ, Chaiteerakij
|
||
R, McCormick
|
||
JB, Radulovic
|
||
M, Graham
|
||
RP, Torbenson
|
||
MS, Tortorelli
|
||
S, Scott
|
||
CR, Lindor
|
||
NM, Milliner
|
||
DS, Oglesbee
|
||
D, Al-Qabandi
|
||
W, Grompe
|
||
M, Gavrilov
|
||
DK, El-Youssef
|
||
M, Clark
|
||
KJ, Atwal
|
||
PS, Roberts
|
||
LR, Klee
|
||
EW, Ekker
|
||
SC. Silent tyrosinemia type I without elevated tyrosine or succinylacetone associated with liver cirrhosis and hepatocellular carcinoma.
|
||
Hum Mutat.
|
||
2016;37:1097–105.
|
||
[<a href="/pmc/articles/PMC5108417/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC5108417</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/27397503" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 27397503</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="tyrosinemia.REF.bliksrud.2012.369">Bliksrud
|
||
YT, Brodtkorb
|
||
E, Backe
|
||
PH, Woldseth
|
||
B, Rootwelt
|
||
H. Hereditary tyrosinaemia type I in Norway: incidence and three novel small deletions in the fumarylacetoacetase gene.
|
||
Scand J Clin Lab Invest.
|
||
2012; 72:369–73.
|
||
[<a href="https://pubmed.ncbi.nlm.nih.gov/22554029" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 22554029</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="tyrosinemia.REF.bliksrud.2005.406">Bliksrud
|
||
YT, Brodtkorb
|
||
E, Andresen
|
||
PA, van den Berg
|
||
IE, Kvittingen
|
||
EA. Tyrosinaemia type I--de novo mutation in liver tissue suppressing an inborn splicing defect.
|
||
J Mol Med.
|
||
2005;83:406–10.
|
||
[<a href="https://pubmed.ncbi.nlm.nih.gov/15759101" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 15759101</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="tyrosinemia.REF.cassiman.2009.28">Cassiman
|
||
D, Zeevaert
|
||
R, Holme
|
||
E, Kvittingen
|
||
EA, Jaeken
|
||
J. A novel mutation causing mild, atypical fumarylacetoacetase deficiency (Tyrosinemia type I): a case report.
|
||
Orphanet J Rare Dis.
|
||
2009;4:28.
|
||
[<a href="/pmc/articles/PMC2802351/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC2802351</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/20003495" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 20003495</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="tyrosinemia.REF.chinsky.2017">Chinsky
|
||
JM, Singh
|
||
R, Ficicioglu
|
||
C, van Karnebeek
|
||
CDM, Grompe
|
||
M, Mitchell
|
||
G, Waisbren
|
||
SE, Gucsavas-Calikoglu
|
||
M, Wasserstein
|
||
MP, Coakley
|
||
K, Scott
|
||
CR. Diagnosis and treatment of tyrosinemia type I: a US and Canadian consensus group review and recommendations.
|
||
Genet Med.
|
||
2017;19(12).
|
||
[<a href="/pmc/articles/PMC5729346/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC5729346</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/28771246" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 28771246</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="tyrosinemia.REF.demers.2003.1313">Demers
|
||
SI, Russo
|
||
P, Lettre
|
||
F, Tanguay
|
||
RM. Frequent mutation reversion inversely correlates with clinical severity in a genetic liver disease, hereditary tyrosinemia.
|
||
Hum Pathol.
|
||
2003;34:1313–20.
|
||
[<a href="https://pubmed.ncbi.nlm.nih.gov/14691918" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 14691918</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="tyrosinemia.REF.dubois.1996.845">Dubois
|
||
J, Garel
|
||
L, Patriquin
|
||
H, Paradis
|
||
K, Forget
|
||
S, Filiatrault
|
||
D, Grignon
|
||
A, Russo
|
||
P, St-Vil
|
||
D.
|
||
Imaging features of type 1 hereditary tyrosinemia: a review of 30 patients.
|
||
Pediatr Radiol.
|
||
1996;26:845–51.
|
||
[<a href="https://pubmed.ncbi.nlm.nih.gov/8929295" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 8929295</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="tyrosinemia.REF.ellaway.2001.824">Ellaway
|
||
CJ, Holme
|
||
E, Standing
|
||
S, Preece
|
||
MA, Green
|
||
A, Ploechl
|
||
E, Ugarte
|
||
M, Trefz
|
||
FK, Leonard
|
||
JV. Outcome of tyrosinaemia type III.
|
||
J Inherit Metab Dis.
|
||
2001;24:824–32.
|
||
[<a href="https://pubmed.ncbi.nlm.nih.gov/11916315" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 11916315</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="tyrosinemia.REF.elpeleg.2002.80">Elpeleg
|
||
ON, Shaag
|
||
A, Holme
|
||
E, Zughayar
|
||
G, Ronen
|
||
S, Fisher
|
||
D, Hurvitz
|
||
H. Mutation analysis of the FAH gene in Israeli patients with tyrosinemia type I.
|
||
Hum Mutat.
|
||
2002;19:80–1.
|
||
[<a href="https://pubmed.ncbi.nlm.nih.gov/11754109" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 11754109</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="tyrosinemia.REF.endo.2002.227">Endo
|
||
F, Sun
|
||
MS. Tyrosinaemia type I and apoptosis of hepatocytes and renal tubular cells.
|
||
J Inherit Metab Dis.
|
||
2002;25:227–34.
|
||
[<a href="https://pubmed.ncbi.nlm.nih.gov/12137232" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 12137232</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="tyrosinemia.REF.garcia_segarra.2010.s507">Garcia Segarra
|
||
N, Roche
|
||
S, Imbard
|
||
A, Benoist
|
||
JF, Grenèche
|
||
MO, Davit-Spraul
|
||
A, Ogier de Baulny
|
||
H. Maternal and fetal tyrosinemia type I.
|
||
J Inherit Metab Dis.
|
||
2010;33
|
||
Suppl 3:S507–10.
|
||
[<a href="https://pubmed.ncbi.nlm.nih.gov/23250512" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 23250512</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="tyrosinemia.REF.gigu_re.2005">Giguère Y, Ruel J, Belanger N, Grenier A, Laberge C, Quebec Neonatal Blood Screening Programme, CHUL du CHUQ, Quebec, Canada. Neonatal mass screening for hereditary tyrosinemia type 1 in Quebec: a historical perspective (1970-2005). Portland, OR: Newborn Screening and Genetic Testing Symposium. 2005.</div></li><li class="half_rhythm"><div class="bk_ref" id="tyrosinemia.REF.grompe.2001.563">Grompe
|
||
M.
|
||
The pathophysiology and treatment of hereditary tyrosinemia type 1.
|
||
Semin Liver Dis.
|
||
2001;21:563–71.
|
||
[<a href="https://pubmed.ncbi.nlm.nih.gov/11745044" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 11745044</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="tyrosinemia.REF.hegarty.2015.1387">Hegarty
|
||
R, Hadzic
|
||
N, Gissen
|
||
P, Dhawan
|
||
A. Inherited metabolic disorders presenting as acute liver failure in newborns and young children: King's College Hospital experience.
|
||
Eur J Pediatr.
|
||
2015;174:1387–92.
|
||
[<a href="https://pubmed.ncbi.nlm.nih.gov/25902754" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 25902754</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="tyrosinemia.REF.hendriksz.2004.552">Hendriksz
|
||
CJ, Walter
|
||
JH. Feeding infants with undiluted goat's milk can mimic tyrosinaemia type 1.
|
||
Acta Paediatr.
|
||
2004;93:552–3.
|
||
[<a href="https://pubmed.ncbi.nlm.nih.gov/15188986" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 15188986</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="tyrosinemia.REF.holme.2000.805">Holme
|
||
E, Lindstedt
|
||
S. Nontransplant treatment of tyrosinemia.
|
||
Clin Liver Dis.
|
||
2000;4:805–14.
|
||
[<a href="https://pubmed.ncbi.nlm.nih.gov/11232358" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 11232358</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="tyrosinemia.REF.huang.2022.389">Huang
|
||
SJ, Amendola
|
||
LM, Sternen
|
||
DL. Variation among DNA banking consent forms: points for clinicians to bank on.
|
||
J Community Genet.
|
||
2022;13:389-97.
|
||
[<a href="/pmc/articles/PMC9314484/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC9314484</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/35834113" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 35834113</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="tyrosinemia.REF.kim.2000.791">Kim
|
||
SZ, Kupke
|
||
KG, Ierardi-Curto
|
||
L, Holme
|
||
E, Greter
|
||
J, Tanguay
|
||
RM, Poudrier
|
||
J, D'Astous
|
||
M, Lettre
|
||
F, Hahn
|
||
SH, Levy
|
||
HL. Hepatocellular carcinoma despite long-term survival in chronic tyrosinaemia I.
|
||
J Inherit Metab Dis.
|
||
2000;23:791–804.
|
||
[<a href="https://pubmed.ncbi.nlm.nih.gov/11196105" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 11196105</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="tyrosinemia.REF.kvittingen.1994.1657">Kvittingen
|
||
EA, Rootwelt
|
||
H, Berger
|
||
R, Brandtzaeg
|
||
P. Self-induced correction of the genetic defect in tyrosinemia type I.
|
||
J Clin Invest.
|
||
1994;94:1657–61.
|
||
[<a href="/pmc/articles/PMC295327/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC295327</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/7929843" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 7929843</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="tyrosinemia.REF.de_laet.2013">de Laet C, Dionisi-Vici C, Leonard JV, McKiernan P, Mitchell G, Monti L, de Baulny HO, Pintos-Morell G, Spiekerkötter U. Recommendations for the management of tyrosinaemia type 1. Orphanet J Rare Dis. 2013;2013;8:8. [<a href="/pmc/articles/PMC3558375/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC3558375</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/23311542" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 23311542</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="tyrosinemia.REF.larochelle.2012.49">Larochelle
|
||
J, Alvarez
|
||
F, Bussières
|
||
JF, Chevalier
|
||
I, Dallaire
|
||
L, Dubois
|
||
J, Faucher
|
||
F, Fenyves
|
||
D, Goodyer
|
||
P, Grenier
|
||
A, Holme
|
||
E, Laframboise
|
||
R, Lambert
|
||
M, Lindstedt
|
||
S, Maranda
|
||
B, Melançon
|
||
S, Merouani
|
||
A, Mitchell
|
||
J, Parizeault
|
||
G, Pelletier
|
||
L, Phan
|
||
V, Rinaldo
|
||
P, Scott
|
||
CR, Scriver
|
||
C, Mitchell
|
||
GA. Effect of nitisinone (NTBC) treatment on the clinical course of hepatorenal tyrosinemia in Québec.
|
||
Mol Genet Metab.
|
||
2012;107:49–54.
|
||
[<a href="https://pubmed.ncbi.nlm.nih.gov/22885033" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 22885033</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="tyrosinemia.REF.macsai.2001.522">Macsai
|
||
MS, Schwartz
|
||
TL, Hinkle
|
||
D, Hummel
|
||
MB, Mulhern
|
||
MG, Rootman
|
||
D. Tyrosinemia type II: nine cases of ocular signs and symptoms.
|
||
Am J Ophthalmol.
|
||
2001;132:522–7.
|
||
[<a href="https://pubmed.ncbi.nlm.nih.gov/11589874" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 11589874</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="tyrosinemia.REF.masurelpaulet.2008.81">Masurel-Paulet
|
||
A, Poggi-Bach
|
||
J, Rolland
|
||
MO, Bernard
|
||
O, Guffon
|
||
N, Dobbelaere
|
||
D, Sarles
|
||
J, de Baulny
|
||
HO, Touati
|
||
G. NTBC treatment in tyrosinaemia type 1: long-term outcome in French patients.
|
||
J Inherit Metab Dis.
|
||
2008;31:81–7.
|
||
[<a href="https://pubmed.ncbi.nlm.nih.gov/18214711" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 18214711</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="tyrosinemia.REF.mckiernan.2006.743">McKiernan
|
||
PJ. Nitisinone in the treatment of hereditary tyrosinaemia type 1.
|
||
Drugs.
|
||
2006;66:743–50.
|
||
[<a href="https://pubmed.ncbi.nlm.nih.gov/16706549" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 16706549</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="tyrosinemia.REF.mitchell.1990.432">Mitchell
|
||
G, Larochelle
|
||
J, Lambert
|
||
M, Michaud
|
||
J, Grenier
|
||
A, Ogier
|
||
H, Gauthier
|
||
M, Lacroix
|
||
J, Vanasse
|
||
M, Larbrisseau
|
||
A, et al.
|
||
Neurologic crises in hereditary tyrosinemia.
|
||
N Engl J Med.
|
||
1990;322:432–7.
|
||
[<a href="https://pubmed.ncbi.nlm.nih.gov/2153931" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 2153931</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="tyrosinemia.REF.mitchell.2001">Mitchell GA, Grompe M, Lambert M, Tanguay RM. Hypertyrosinemia. In: Scriver CR, Beaudet AL, Sly WS, Valle D, eds. The Metabolic and Molecular Bases of Inherited Disease. New York, NY: McGraw Hill; 2001:1777-806.</div></li><li class="half_rhythm"><div class="bk_ref" id="tyrosinemia.REF.nissenkorn.2001.642">Nissenkorn
|
||
A, Korman
|
||
SH, Vardi
|
||
O, Levine
|
||
A, Katzir
|
||
Z, Ballin
|
||
A, Lerman-Sagie
|
||
T. Carnitine-deficient myopathy as a presentation of tyrosinemia type I.
|
||
J Child Neurol.
|
||
2001;16:642–4.
|
||
[<a href="https://pubmed.ncbi.nlm.nih.gov/11575602" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 11575602</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="tyrosinemia.REF.park.2009.930">Park
|
||
HD, Lee
|
||
DH, Choi
|
||
TY, Lee
|
||
YK, Kim
|
||
JW, Ki
|
||
CS, Lee
|
||
YW. Clinical, biochemical, and genetic analysis of a Korean neonate with hereditary tyrosinemia type 1.
|
||
Clin Chem Lab Med.
|
||
2009;47:930–3.
|
||
[<a href="https://pubmed.ncbi.nlm.nih.gov/19569981" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 19569981</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="tyrosinemia.REF.poudrier.1998.119">Poudrier
|
||
J, Lettre
|
||
F, Scriver
|
||
CR, Larochelle
|
||
J, Tanguay
|
||
RM. Different clinical forms of hereditary tyrosinemia (type I) in patients with identical genotypes.
|
||
Mol Genet Metab.
|
||
1998;64:119–25.
|
||
[<a href="https://pubmed.ncbi.nlm.nih.gov/9705236" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 9705236</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="tyrosinemia.REF.poudrier.1996.59">Poudrier
|
||
J, St-Louis
|
||
M, Lettre
|
||
F, Gibson
|
||
K, Prevost
|
||
C, Larochelle
|
||
J, Tanguay
|
||
RM. Frequency of the IVS12 + 5G-->A splice mutation of the fumarylacetoacetate hydrolase gene in carriers of hereditary tyrosinaemia in the French Canadian population of Saguenay-Lac-St-Jean.
|
||
Prenat Diagn.
|
||
1996;16:59–64.
|
||
[<a href="https://pubmed.ncbi.nlm.nih.gov/8821854" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 8821854</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="tyrosinemia.REF.richards.2015.405">Richards
|
||
S, Aziz
|
||
N, Bale
|
||
S, Bick
|
||
D, Das
|
||
S, Gastier-Foster
|
||
J, Grody
|
||
WW, Hegde
|
||
M, Lyon
|
||
E, Spector
|
||
E, Voelkerding
|
||
K, Rehm
|
||
HL; ACMG Laboratory Quality Assurance Committee. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.
|
||
Genet Med.
|
||
2015;17:405-24.
|
||
[<a href="/pmc/articles/PMC4544753/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC4544753</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/25741868" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 25741868</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="tyrosinemia.REF.rootwelt.1994.1122">Rootwelt
|
||
H, Brodtkorb
|
||
E, Kvittingen
|
||
EA. Identification of a frequent pseudodeficiency mutation in the fumarylacetoacetase gene, with implications for diagnosis of tyrosinemia type I.
|
||
Am J Hum Genet.
|
||
1994;55:1122-7.
|
||
[<a href="/pmc/articles/PMC1918441/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC1918441</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/7977370" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 7977370</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="tyrosinemia.REF.sassa.1983.625">Sassa
|
||
S, Kappas
|
||
A. Hereditary tyrosinemia and the heme biosynthetic pathway. Profound inhibition of delta-aminolevulinic acid dehydratase activity by succinylacetone.
|
||
J Clin Invest.
|
||
1983;71:625–34.
|
||
[<a href="/pmc/articles/PMC436912/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC436912</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/6826727" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 6826727</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="tyrosinemia.REF.schlune.2012.831">Schlune
|
||
A, Thimm
|
||
E, Herebian
|
||
D, Spiekerkoetter
|
||
U.
|
||
Single dose NTBC-treatment of hereditary tyrosinemia type I.
|
||
J Inherit Metab Dis.
|
||
2012; 35:831–6.
|
||
[<a href="https://pubmed.ncbi.nlm.nih.gov/22307209" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 22307209</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="tyrosinemia.REF.schulze.2001.1424">Schulze
|
||
A, Frommhold
|
||
D, Hoffmann
|
||
GF, Mayatepek
|
||
E. Spectrophotometric microassay for delta-aminolevulinate dehydratase in dried-blood spots as confirmation for hereditary tyrosinemia type I.
|
||
Clin Chem.
|
||
2001;47:1424–9.
|
||
[<a href="https://pubmed.ncbi.nlm.nih.gov/11468232" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 11468232</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="tyrosinemia.REF.techakittiroj.2005.281">Techakittiroj
|
||
C, Cunningham
|
||
A, Hooper
|
||
PF, Andersson
|
||
HC, Thoene
|
||
J. High protein diet mimics hypertyrosinemia in newborn infants.
|
||
J Pediatr.
|
||
2005;146:281–2.
|
||
[<a href="https://pubmed.ncbi.nlm.nih.gov/15689925" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 15689925</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="tyrosinemia.REF.vanclooster.2012.27">Vanclooster
|
||
A, Devlieger
|
||
R, Meersseman
|
||
W, Spraul
|
||
A, Kerckhove
|
||
KV, Vermeersch
|
||
P, Meulemans
|
||
A, Allegaert
|
||
K, Cassiman
|
||
D. Pregnancy during nitisinone treatment for tyrosinaemia type I: first human experience.
|
||
JIMD Rep.
|
||
2012;5:27–33.
|
||
[<a href="/pmc/articles/PMC3509920/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC3509920</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/23430914" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 23430914</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="tyrosinemia.REF.van_spronsen.2005.90">van Spronsen
|
||
FJ, Bijleveld
|
||
CM, van Maldegem
|
||
BT, Wijburg
|
||
FA. Hepatocellular carcinoma in hereditary tyrosinemia type I despite 2-(2 nitro-4-3 trifl).
|
||
J Pediatr Gastroenterol Nutr.
|
||
2005;40:90–3.
|
||
[<a href="https://pubmed.ncbi.nlm.nih.gov/15625434" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 15625434</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="tyrosinemia.REF.van_spronsen.1994.1187">van Spronsen
|
||
FJ, Thomasse
|
||
Y, Smit
|
||
GP, Leonard
|
||
JV, Clayton
|
||
PT, Fidler
|
||
V, Berger
|
||
R, Heymans
|
||
HS. Hereditary tyrosinemia type I: a new clinical classification with difference in prognosis on dietary treatment.
|
||
Hepatology.
|
||
1994;20:1187–91.
|
||
[<a href="https://pubmed.ncbi.nlm.nih.gov/7927251" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 7927251</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="tyrosinemia.REF.vogel.2004.433">Vogel
|
||
A, van Den Berg
|
||
IE, Al-Dhalimy
|
||
M, Groopman
|
||
J, Ou
|
||
CN, Ryabinina
|
||
O, Iordanov
|
||
MS, Finegold
|
||
M, Grompe
|
||
M. Chronic liver disease in murine hereditary tyrosinemia type 1 induces resistance to cell death.
|
||
Hepatology.
|
||
2004;39:433–43.
|
||
[<a href="https://pubmed.ncbi.nlm.nih.gov/14767996" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 14767996</span></a>]</div></li></ul></div></div><div id="bk_toc_contnr"></div></div></div>
|
||
<div class="post-content"><div><div class="half_rhythm"><a href="/books/about/copyright/">Copyright</a> © 1993-2025, University of Washington, Seattle. GeneReviews is
|
||
a registered trademark of the University of Washington, Seattle. All rights
|
||
reserved.<p class="small">GeneReviews® chapters are owned by the University of Washington. Permission is
|
||
hereby granted to reproduce, distribute, and translate copies of content materials for
|
||
noncommercial research purposes only, provided that (i) credit for source (<a href="http://www.genereviews.org/" ref="pagearea=meta&targetsite=external&targetcat=link&targettype=uri">http://www.genereviews.org/</a>) and copyright (© 1993-2025 University of
|
||
Washington) are included with each copy; (ii) a link to the original material is provided
|
||
whenever the material is published elsewhere on the Web; and (iii) reproducers,
|
||
distributors, and/or translators comply with the <a href="https://www.ncbi.nlm.nih.gov/books/n/gene/GRcopyright_permiss/" ref="pagearea=meta&targetsite=external&targetcat=link&targettype=uri">GeneReviews® Copyright Notice and Usage
|
||
Disclaimer</a>. No further modifications are allowed. For clarity, excerpts
|
||
of GeneReviews chapters for use in lab reports and clinic notes are a permitted
|
||
use.</p><p class="small">For more information, see the <a href="https://www.ncbi.nlm.nih.gov/books/n/gene/GRcopyright_permiss/" ref="pagearea=meta&targetsite=external&targetcat=link&targettype=uri">GeneReviews® Copyright Notice and Usage
|
||
Disclaimer</a>.</p><p class="small">For questions regarding permissions or whether a specified use is allowed,
|
||
contact: <a href="mailto:dev@null" data-email="ude.wu@tssamda" class="oemail">ude.wu@tssamda</a>.</p></div><div class="small"><span class="label">Bookshelf ID: NBK1515</span><span class="label">PMID: <a href="https://pubmed.ncbi.nlm.nih.gov/20301688" title="PubMed record of this page" ref="pagearea=meta&targetsite=entrez&targetcat=link&targettype=pubmed">20301688</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/thdrd/" title="Previous page in this title">< Prev</a><a class="active page_link next" href="/books/n/gene/tyrosinemia-2/" title="Next page in this title">Next ></a></div></div></div></div>
|
||
|
||
</div>
|
||
|
||
<!-- Custom content below content -->
|
||
<div class="col4">
|
||
|
||
</div>
|
||
|
||
|
||
<!-- Book content -->
|
||
|
||
<!-- Custom contetnt below bottom nav -->
|
||
<div class="col5">
|
||
|
||
</div>
|
||
</div>
|
||
|
||
<div id="rightcolumn" class="four_col col last">
|
||
<!-- Custom content above discovery portlets -->
|
||
<div class="col6">
|
||
<div id="ncbi_share_book"><a href="#" class="ncbi_share" data-ncbi_share_config="popup:false,shorten:true" ref="id=NBK1515&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/NBK1515/?report=reader">PubReader</a></li><li><a href="/books/NBK1515/?report=printable">Print View</a></li><li><a data-jig="ncbidialog" href="#_ncbi_dlg_citbx_NBK1515" data-jigconfig="width:400,modal:true">Cite this Page</a><div id="_ncbi_dlg_citbx_NBK1515" style="display:none" title="Cite this Page"><div class="bk_tt">Sniderman King L, Trahms C, Scott CR. Tyrosinemia Type I. 2006 Jul 24 [Updated 2017 May 25]. 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/NBK1515/pdf/Bookshelf_NBK1515.pdf">PDF version of this page</a> (555K)</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="#tyrosinemia.Summary" ref="log$=inpage&link_id=inpage">Summary</a></li><li><a href="#tyrosinemia.Diagnosis" ref="log$=inpage&link_id=inpage">Diagnosis</a></li><li><a href="#tyrosinemia.Clinical_Characteristics" ref="log$=inpage&link_id=inpage">Clinical Characteristics</a></li><li><a href="#tyrosinemia.Genetically_Related_Allelic" ref="log$=inpage&link_id=inpage">Genetically Related (Allelic) Disorders</a></li><li><a href="#tyrosinemia.Differential_Diagnosis" ref="log$=inpage&link_id=inpage">Differential Diagnosis</a></li><li><a href="#tyrosinemia.Management" ref="log$=inpage&link_id=inpage">Management</a></li><li><a href="#tyrosinemia.Genetic_Counseling" ref="log$=inpage&link_id=inpage">Genetic Counseling</a></li><li><a href="#tyrosinemia.Resources" ref="log$=inpage&link_id=inpage">Resources</a></li><li><a href="#tyrosinemia.Molecular_Genetics" ref="log$=inpage&link_id=inpage">Molecular Genetics</a></li><li><a href="#tyrosinemia.Chapter_Notes" ref="log$=inpage&link_id=inpage">Chapter Notes</a></li><li><a href="#tyrosinemia.References" ref="log$=inpage&link_id=inpage">References</a></li></ul></div></div><div class="portlet"><div class="portlet_head"><div class="portlet_title"><h3><span>Bulk Download</span></h3></div><a name="Shutter" sid="1" href="#" class="portlet_shutter" title="Show/hide content" remembercollapsed="true" pgsec_name="source-links" id="Shutter"></a></div><div class="portlet_content"><ul xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="simple-list"><li><a href="https://ftp.ncbi.nlm.nih.gov/pub/litarch/ca/84/" ref="pagearea=source-links&targetsite=external&targetcat=link&targettype=uri">Bulk download GeneReviews data from FTP</a></li></ul></div></div><div class="portlet"><div class="portlet_head"><div class="portlet_title"><h3><span>GeneReviews Links</span></h3></div><a name="Shutter" sid="1" href="#" class="portlet_shutter" title="Show/hide content" remembercollapsed="true" pgsec_name="source-links" id="Shutter"></a></div><div class="portlet_content"><ul xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="simple-list"><li><a href="/books/n/gene/advanced/"><i>GeneReviews</i> Advanced Search</a></li><li><a href="/books/n/gene/glossary/"><i>GeneReviews</i> Glossary</a></li><li><a href="/books/n/gene/resource_mats/">Resource Materials</a> <span class="bk_hlight1">NEW FEATURE</span></li><li><a href="/books/n/gene/updates/">New in <i>GeneReviews</i></a></li><li><a href="/books/n/gene/authors/">Author List</a></li><li><a href="/books/n/gene/prospective_authors/">For Current/Prospective Authors</a></li><li><a href="/books/n/gene/GRpersonnel/"><i>GeneReviews</i> Personnel</a></li><li><a href="/books/n/gene/howto_linkin/">Download/Link to <i>GeneReviews</i></a></li><li><a href="/books/n/gene/contact_us/">Contact Us</a></li></ul></div></div><div class="portlet"><div class="portlet_head"><div class="portlet_title"><h3><span>Tests in GTR by Gene</span></h3></div><a name="Shutter" sid="1" href="#" class="portlet_shutter" title="Show/hide content" remembercollapsed="true" pgsec_name="document-links" id="Shutter"></a></div><div class="portlet_content"><ul xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="simple-list"><li>
|
||
<a href="https://www.ncbi.nlm.nih.gov/gtr/tests/?term=2184[geneid]" ref="pagearea=document-links&targetsite=external&targetcat=link&targettype=uri&link_id=tests_in_gtr_by_gene">FAH</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=NBK1515+AND+genereviews[submitter]" ref="pagearea=document-links&targetsite=external&targetcat=link&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=omim&DbFrom=books&Cmd=Link&LinkName=books_omim&IdsFromResult=1499788" ref="log$=recordlinks">OMIM</a><div class="brieflinkpop offscreen_noflow">Related OMIM records</div></li><li class="brieflinkpopper"><a class="brieflinkpopperctrl" href="/books/?Db=pmc&DbFrom=books&Cmd=Link&LinkName=books_pmc_refs&IdsFromResult=1499788" ref="log$=recordlinks">PMC</a><div class="brieflinkpop offscreen_noflow">PubMed Central citations</div></li><li class="brieflinkpopper"><a class="brieflinkpopperctrl" href="/books/?Db=pubmed&DbFrom=books&Cmd=Link&LinkName=books_pubmed_refs&IdsFromResult=1499788" ref="log$=recordlinks">PubMed</a><div class="brieflinkpop offscreen_noflow">Links to PubMed</div></li><li class="brieflinkpopper"><a class="brieflinkpopperctrl" href="/books/?Db=gene&DbFrom=books&Cmd=Link&LinkName=books_gene&IdsFromResult=1499788" ref="log$=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/20301631" ref="ordinalpos=1&linkpos=1&log$=relatedreviews&logdbfrom=pubmed"><span xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="invert">Review</span> Citrullinemia Type I.</a><span class="source">[GeneReviews(®). 1993]</span><div class="brieflinkpop offscreen_noflow"><span xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="invert">Review</span> Citrullinemia Type I.<div class="brieflinkpopdesc"><em xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="author">Quinonez SC, Lee KN. </em><em xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="cit">GeneReviews(®). 1993</em></div></div></li><li class="brieflinkpopper two_line"><a class="brieflinkpopperctrl" href="/pubmed/20301656" ref="ordinalpos=1&linkpos=2&log$=relatedreviews&logdbfrom=pubmed"><span xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="invert">Review</span> 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/20301495" ref="ordinalpos=1&linkpos=3&log$=relatedreviews&logdbfrom=pubmed"><span xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="invert">Review</span> Maple Syrup Urine Disease.</a><span class="source">[GeneReviews(®). 1993]</span><div class="brieflinkpop offscreen_noflow"><span xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="invert">Review</span> Maple Syrup Urine Disease.<div class="brieflinkpopdesc"><em xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="author">Strauss KA, Puffenberger EG, Carson VJ. </em><em xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="cit">GeneReviews(®). 1993</em></div></div></li><li class="brieflinkpopper two_line"><a class="brieflinkpopperctrl" href="/pubmed/20301574" ref="ordinalpos=1&linkpos=4&log$=relatedreviews&logdbfrom=pubmed"><span xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="invert">Review</span> Cystinosis.</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> Cystinosis.<div class="brieflinkpopdesc"><em xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="author">Nesterova G, Gahl WA. </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&linkpos=5&log$=relatedreviews&logdbfrom=pubmed"><span xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="invert">Review</span> Biotinidase Deficiency.</a><span class="source">[GeneReviews(®). 1993]</span><div class="brieflinkpop offscreen_noflow"><span xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="invert">Review</span> Biotinidase Deficiency.<div class="brieflinkpopdesc"><em xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="author">Wolf B. </em><em xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="cit">GeneReviews(®). 1993</em></div></div></li></ul><a class="seemore" href="/sites/entrez?db=pubmed&cmd=link&linkname=pubmed_pubmed_reviews&uid=20301688" ref="ordinalpos=1&log$=relatedreviews_seeall&logdbfrom=pubmed">See reviews...</a><a class="seemore" href="/sites/entrez?db=pubmed&cmd=link&linkname=pubmed_pubmed&uid=20301688" ref="ordinalpos=1&log$=relatedarticles_seeall&logdbfrom=pubmed">See all...</a></div></div><div class="portlet"><div class="portlet_head"><div class="portlet_title"><h3><span>Recent Activity</span></h3></div><a name="Shutter" sid="1" href="#" class="portlet_shutter" title="Show/hide content" remembercollapsed="true" pgsec_name="recent_activity" id="Shutter"></a></div><div class="portlet_content"><div xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" id="HTDisplay" class=""><div class="action"><a href="javascript:historyDisplayState('ClearHT')">Clear</a><a href="javascript:historyDisplayState('HTOff')" class="HTOn">Turn Off</a><a href="javascript:historyDisplayState('HTOn')" class="HTOff">Turn On</a></div><ul id="activity"><li class="ra_rcd ralinkpopper two_line"><a class="htb ralinkpopperctrl" ref="log$=activity&linkpos=1" href="/portal/utils/pageresolver.fcgi?recordid=67d2b12bf4a390645e595d9e">Tyrosinemia Type I - GeneReviews®</a><div class="ralinkpop offscreen_noflow">Tyrosinemia Type I - GeneReviews®<div class="brieflinkpopdesc"></div></div><div class="tertiary"></div></li><li class="ra_rcd ralinkpopper two_line"><a class="htb ralinkpopperctrl" ref="log$=activity&linkpos=2" href="/portal/utils/pageresolver.fcgi?recordid=67d2b12984f3725e5957d402">Tyrosine Hydroxylase Deficiency - GeneReviews®</a><div class="ralinkpop offscreen_noflow">Tyrosine Hydroxylase Deficiency - GeneReviews®<div class="brieflinkpopdesc"></div></div><div class="tertiary"></div></li><li class="ra_rcd ralinkpopper two_line"><a class="htb ralinkpopperctrl" ref="log$=activity&linkpos=3" href="/portal/utils/pageresolver.fcgi?recordid=67d2b124f4a390645e592fac">Tuberous Sclerosis Complex - GeneReviews®</a><div class="ralinkpop offscreen_noflow">Tuberous Sclerosis Complex - GeneReviews®<div class="brieflinkpopdesc"></div></div><div class="tertiary"></div></li><li class="ra_rcd ralinkpopper two_line"><a class="htb ralinkpopperctrl" ref="log$=activity&linkpos=4" href="/portal/utils/pageresolver.fcgi?recordid=67d2b121a68b6b5afca1d3ed">Troyer Syndrome - GeneReviews®</a><div class="ralinkpop offscreen_noflow">Troyer Syndrome - GeneReviews®<div class="brieflinkpopdesc"></div></div><div class="tertiary"></div></li><li class="ra_rcd ralinkpopper two_line"><a class="htb ralinkpopperctrl" ref="log$=activity&linkpos=5" href="/portal/utils/pageresolver.fcgi?recordid=67d2b11eb15b832ebc3a7953">Trichorhinophalangeal Syndrome - GeneReviews®</a><div class="ralinkpop offscreen_noflow">Trichorhinophalangeal Syndrome - GeneReviews®<div class="brieflinkpopdesc"></div></div><div class="tertiary"></div></li></ul><p class="HTOn">Your browsing activity is empty.</p><p class="HTOff">Activity recording is turned off.</p><p id="turnOn" class="HTOff"><a href="javascript:historyDisplayState('HTOn')">Turn recording back on</a></p><a class="seemore" href="/sites/myncbi/recentactivity">See more...</a></div></div></div>
|
||
|
||
<!-- Custom content below discovery portlets -->
|
||
<div class="col7">
|
||
|
||
</div>
|
||
</div>
|
||
</div>
|
||
|
||
<!-- Custom content after all -->
|
||
<div class="col8">
|
||
|
||
</div>
|
||
<div class="col9">
|
||
|
||
</div>
|
||
|
||
<script type="text/javascript" src="/corehtml/pmc/js/jquery.scrollTo-1.4.2.js"></script>
|
||
<script type="text/javascript">
|
||
(function($){
|
||
$('.skiplink').each(function(i, item){
|
||
var href = $($(item).attr('href'));
|
||
href.attr('tabindex', '-1').addClass('skiptarget'); // ensure the target can receive focus
|
||
$(item).on('click', function(event){
|
||
event.preventDefault();
|
||
$.scrollTo(href, 0, {
|
||
onAfter: function(){
|
||
href.focus();
|
||
}
|
||
});
|
||
});
|
||
});
|
||
})(jQuery);
|
||
</script>
|
||
</div>
|
||
<div class="bottom">
|
||
|
||
<div id="NCBIFooter_dynamic">
|
||
<!--<component id="Breadcrumbs" label="breadcrumbs"/>
|
||
<component id="Breadcrumbs" label="helpdesk"/>-->
|
||
|
||
</div>
|
||
|
||
<div class="footer" id="footer">
|
||
<section class="icon-section">
|
||
<div id="icon-section-header" class="icon-section_header">Follow NCBI</div>
|
||
<div class="grid-container container">
|
||
<div class="icon-section_container">
|
||
<a class="footer-icon" id="footer_twitter" href="https://twitter.com/ncbi" aria-label="Twitter"><svg xmlns="http://www.w3.org/2000/svg" data-name="Layer 1" viewBox="0 0 300 300">
|
||
<defs>
|
||
<style>
|
||
.cls-11 {
|
||
fill: #737373;
|
||
}
|
||
</style>
|
||
</defs>
|
||
<title>Twitter</title>
|
||
<path class="cls-11" d="M250.11,105.48c-7,3.14-13,3.25-19.27.14,8.12-4.86,8.49-8.27,11.43-17.46a78.8,78.8,0,0,1-25,9.55,39.35,39.35,0,0,0-67,35.85,111.6,111.6,0,0,1-81-41.08A39.37,39.37,0,0,0,81.47,145a39.08,39.08,0,0,1-17.8-4.92c0,.17,0,.33,0,.5a39.32,39.32,0,0,0,31.53,38.54,39.26,39.26,0,0,1-17.75.68,39.37,39.37,0,0,0,36.72,27.3A79.07,79.07,0,0,1,56,223.34,111.31,111.31,0,0,0,116.22,241c72.3,0,111.83-59.9,111.83-111.84,0-1.71,0-3.4-.1-5.09C235.62,118.54,244.84,113.37,250.11,105.48Z">
|
||
</path>
|
||
</svg></a>
|
||
<a class="footer-icon" id="footer_facebook" href="https://www.facebook.com/ncbi.nlm" aria-label="Facebook"><svg xmlns="http://www.w3.org/2000/svg" data-name="Layer 1" viewBox="0 0 300 300">
|
||
<title>Facebook</title>
|
||
<path class="cls-11" d="M210.5,115.12H171.74V97.82c0-8.14,5.39-10,9.19-10h27.14V52l-39.32-.12c-35.66,0-42.42,26.68-42.42,43.77v19.48H99.09v36.32h27.24v109h45.41v-109h35Z">
|
||
</path>
|
||
</svg></a>
|
||
<a class="footer-icon" id="footer_linkedin" href="https://www.linkedin.com/company/ncbinlm" aria-label="LinkedIn"><svg xmlns="http://www.w3.org/2000/svg" data-name="Layer 1" viewBox="0 0 300 300">
|
||
<title>LinkedIn</title>
|
||
<path class="cls-11" d="M101.64,243.37H57.79v-114h43.85Zm-22-131.54h-.26c-13.25,0-21.82-10.36-21.82-21.76,0-11.65,8.84-21.15,22.33-21.15S101.7,78.72,102,90.38C102,101.77,93.4,111.83,79.63,111.83Zm100.93,52.61A17.54,17.54,0,0,0,163,182v61.39H119.18s.51-105.23,0-114H163v13a54.33,54.33,0,0,1,34.54-12.66c26,0,44.39,18.8,44.39,55.29v58.35H198.1V182A17.54,17.54,0,0,0,180.56,164.44Z">
|
||
</path>
|
||
</svg></a>
|
||
<a class="footer-icon" id="footer_github" href="https://github.com/ncbi" aria-label="GitHub"><svg xmlns="http://www.w3.org/2000/svg" data-name="Layer 1" viewBox="0 0 300 300">
|
||
<defs>
|
||
<style>
|
||
.cls-11,
|
||
.cls-12 {
|
||
fill: #737373;
|
||
}
|
||
|
||
.cls-11 {
|
||
fill-rule: evenodd;
|
||
}
|
||
</style>
|
||
</defs>
|
||
<title>GitHub</title>
|
||
<path class="cls-11" d="M151.36,47.28a105.76,105.76,0,0,0-33.43,206.1c5.28,1,7.22-2.3,7.22-5.09,0-2.52-.09-10.85-.14-19.69-29.42,6.4-35.63-12.48-35.63-12.48-4.81-12.22-11.74-15.47-11.74-15.47-9.59-6.56.73-6.43.73-6.43,10.61.75,16.21,10.9,16.21,10.9,9.43,16.17,24.73,11.49,30.77,8.79,1-6.83,3.69-11.5,6.71-14.14C108.57,197.1,83.88,188,83.88,147.51a40.92,40.92,0,0,1,10.9-28.39c-1.1-2.66-4.72-13.42,1-28,0,0,8.88-2.84,29.09,10.84a100.26,100.26,0,0,1,53,0C198,88.3,206.9,91.14,206.9,91.14c5.76,14.56,2.14,25.32,1,28a40.87,40.87,0,0,1,10.89,28.39c0,40.62-24.74,49.56-48.29,52.18,3.79,3.28,7.17,9.71,7.17,19.58,0,14.15-.12,25.54-.12,29,0,2.82,1.9,6.11,7.26,5.07A105.76,105.76,0,0,0,151.36,47.28Z">
|
||
</path>
|
||
<path class="cls-12" d="M85.66,199.12c-.23.52-1.06.68-1.81.32s-1.2-1.06-.95-1.59,1.06-.69,1.82-.33,1.21,1.07.94,1.6Zm-1.3-1">
|
||
</path>
|
||
<path class="cls-12" d="M90,203.89c-.51.47-1.49.25-2.16-.49a1.61,1.61,0,0,1-.31-2.19c.52-.47,1.47-.25,2.17.49s.82,1.72.3,2.19Zm-1-1.08">
|
||
</path>
|
||
<path class="cls-12" d="M94.12,210c-.65.46-1.71,0-2.37-.91s-.64-2.07,0-2.52,1.7,0,2.36.89.65,2.08,0,2.54Zm0,0"></path>
|
||
<path class="cls-12" d="M99.83,215.87c-.58.64-1.82.47-2.72-.41s-1.18-2.06-.6-2.7,1.83-.46,2.74.41,1.2,2.07.58,2.7Zm0,0">
|
||
</path>
|
||
<path class="cls-12" d="M107.71,219.29c-.26.82-1.45,1.2-2.64.85s-2-1.34-1.74-2.17,1.44-1.23,2.65-.85,2,1.32,1.73,2.17Zm0,0">
|
||
</path>
|
||
<path class="cls-12" d="M116.36,219.92c0,.87-1,1.59-2.24,1.61s-2.29-.68-2.3-1.54,1-1.59,2.26-1.61,2.28.67,2.28,1.54Zm0,0">
|
||
</path>
|
||
<path class="cls-12" d="M124.42,218.55c.15.85-.73,1.72-2,1.95s-2.37-.3-2.52-1.14.73-1.75,2-2,2.37.29,2.53,1.16Zm0,0"></path>
|
||
</svg></a>
|
||
<a class="footer-icon" id="footer_blog" href="https://ncbiinsights.ncbi.nlm.nih.gov/" aria-label="Blog">
|
||
<svg xmlns="http://www.w3.org/2000/svg" id="Layer_1" data-name="Layer 1" viewBox="0 0 40 40">
|
||
<defs><style>.cls-1{fill:#737373;}</style></defs>
|
||
<title>NCBI Insights Blog</title>
|
||
<path class="cls-1" d="M14,30a4,4,0,1,1-4-4,4,4,0,0,1,4,4Zm11,3A19,19,0,0,0,7.05,15a1,1,0,0,0-1,1v3a1,1,0,0,0,.93,1A14,14,0,0,1,20,33.07,1,1,0,0,0,21,34h3a1,1,0,0,0,1-1Zm9,0A28,28,0,0,0,7,6,1,1,0,0,0,6,7v3a1,1,0,0,0,1,1A23,23,0,0,1,29,33a1,1,0,0,0,1,1h3A1,1,0,0,0,34,33Z"></path>
|
||
</svg>
|
||
</a>
|
||
</div>
|
||
</div>
|
||
</section>
|
||
|
||
<section class="container-fluid bg-primary">
|
||
<div class="container pt-5">
|
||
<div class="row mt-3">
|
||
<div class="col-lg-3 col-12">
|
||
<p><a class="text-white" href="https://www.nlm.nih.gov/socialmedia/index.html">Connect with NLM</a></p>
|
||
<ul class="list-inline social_media">
|
||
<li class="list-inline-item"><a href="https://twitter.com/NLM_NIH" aria-label="Twitter" target="_blank" rel="noopener noreferrer"><svg xmlns="http://www.w3.org/2000/svg" xmlns:xlink="http://www.w3.org/1999/xlink" version="1.1" x="0px" y="0px" viewBox="0 0 249 249" style="enable-background:new 0 0 249 249;" xml:space="preserve">
|
||
<style type="text/css">
|
||
.st20 {
|
||
fill: #FFFFFF;
|
||
}
|
||
|
||
.st30 {
|
||
fill: none;
|
||
stroke: #FFFFFF;
|
||
stroke-width: 8;
|
||
stroke-miterlimit: 10;
|
||
}
|
||
</style>
|
||
<title>Twitter</title>
|
||
<g>
|
||
<g>
|
||
<g>
|
||
<path class="st20" d="M192.9,88.1c-5,2.2-9.2,2.3-13.6,0.1c5.7-3.4,6-5.8,8.1-12.3c-5.4,3.2-11.4,5.5-17.6,6.7 c-10.5-11.2-28.1-11.7-39.2-1.2c-7.2,6.8-10.2,16.9-8,26.5c-22.3-1.1-43.1-11.7-57.2-29C58,91.6,61.8,107.9,74,116 c-4.4-0.1-8.7-1.3-12.6-3.4c0,0.1,0,0.2,0,0.4c0,13.2,9.3,24.6,22.3,27.2c-4.1,1.1-8.4,1.3-12.5,0.5c3.6,11.3,14,19,25.9,19.3 c-11.6,9.1-26.4,13.2-41.1,11.5c12.7,8.1,27.4,12.5,42.5,12.5c51,0,78.9-42.2,78.9-78.9c0-1.2,0-2.4-0.1-3.6 C182.7,97.4,189.2,93.7,192.9,88.1z"></path>
|
||
</g>
|
||
</g>
|
||
<circle class="st30" cx="124.4" cy="128.8" r="108.2"></circle>
|
||
</g>
|
||
</svg></a></li>
|
||
<li class="list-inline-item"><a href="https://www.facebook.com/nationallibraryofmedicine" aria-label="Facebook" rel="noopener noreferrer" target="_blank">
|
||
<svg xmlns="http://www.w3.org/2000/svg" xmlns:xlink="http://www.w3.org/1999/xlink" version="1.1" x="0px" y="0px" viewBox="0 0 249 249" style="enable-background:new 0 0 249 249;" xml:space="preserve">
|
||
<style type="text/css">
|
||
.st10 {
|
||
fill: #FFFFFF;
|
||
}
|
||
|
||
.st110 {
|
||
fill: none;
|
||
stroke: #FFFFFF;
|
||
stroke-width: 8;
|
||
stroke-miterlimit: 10;
|
||
}
|
||
</style>
|
||
<title>Facebook</title>
|
||
<g>
|
||
<g>
|
||
<path class="st10" d="M159,99.1h-24V88.4c0-5,3.3-6.2,5.7-6.2h16.8V60l-24.4-0.1c-22.1,0-26.2,16.5-26.2,27.1v12.1H90v22.5h16.9 v67.5H135v-67.5h21.7L159,99.1z"></path>
|
||
</g>
|
||
</g>
|
||
<circle class="st110" cx="123.6" cy="123.2" r="108.2"></circle>
|
||
</svg>
|
||
</a></li>
|
||
<li class="list-inline-item"><a href="https://www.youtube.com/user/NLMNIH" aria-label="Youtube" target="_blank" rel="noopener noreferrer"><svg xmlns="http://www.w3.org/2000/svg" xmlns:xlink="http://www.w3.org/1999/xlink" version="1.1" x="0px" y="0px" viewBox="0 0 249 249" style="enable-background:new 0 0 249 249;" xml:space="preserve">
|
||
<title>Youtube</title>
|
||
<style type="text/css">
|
||
.st4 {
|
||
fill: none;
|
||
stroke: #FFFFFF;
|
||
stroke-width: 8;
|
||
stroke-miterlimit: 10;
|
||
}
|
||
|
||
.st5 {
|
||
fill: #FFFFFF;
|
||
}
|
||
</style>
|
||
<circle class="st4" cx="124.2" cy="123.4" r="108.2"></circle>
|
||
<g transform="translate(0,-952.36218)">
|
||
<path class="st5" d="M88.4,1037.4c-10.4,0-18.7,8.3-18.7,18.7v40.1c0,10.4,8.3,18.7,18.7,18.7h72.1c10.4,0,18.7-8.3,18.7-18.7 v-40.1c0-10.4-8.3-18.7-18.7-18.7H88.4z M115.2,1058.8l29.4,17.4l-29.4,17.4V1058.8z"></path>
|
||
</g>
|
||
</svg></a></li>
|
||
</ul>
|
||
</div>
|
||
<div class="col-lg-3 col-12">
|
||
<p class="address_footer text-white">National Library of Medicine<br />
|
||
<a href="https://www.google.com/maps/place/8600+Rockville+Pike,+Bethesda,+MD+20894/@38.9959508,-77.101021,17z/data=!3m1!4b1!4m5!3m4!1s0x89b7c95e25765ddb:0x19156f88b27635b8!8m2!3d38.9959508!4d-77.0988323" class="text-white" target="_blank" rel="noopener noreferrer">8600 Rockville Pike<br />
|
||
Bethesda, MD 20894</a></p>
|
||
</div>
|
||
<div class="col-lg-3 col-12 centered-lg">
|
||
<p><a href="https://www.nlm.nih.gov/web_policies.html" class="text-white">Web Policies</a><br />
|
||
<a href="https://www.nih.gov/institutes-nih/nih-office-director/office-communications-public-liaison/freedom-information-act-office" class="text-white">FOIA</a><br />
|
||
<a href="https://www.hhs.gov/vulnerability-disclosure-policy/index.html" class="text-white" id="vdp">HHS Vulnerability Disclosure</a></p>
|
||
</div>
|
||
<div class="col-lg-3 col-12 centered-lg">
|
||
<p><a class="supportLink text-white" href="https://support.nlm.nih.gov/">Help</a><br />
|
||
<a href="https://www.nlm.nih.gov/accessibility.html" class="text-white">Accessibility</a><br />
|
||
<a href="https://www.nlm.nih.gov/careers/careers.html" class="text-white">Careers</a></p>
|
||
</div>
|
||
</div>
|
||
<div class="row">
|
||
<div class="col-lg-12 centered-lg">
|
||
<nav class="bottom-links">
|
||
<ul class="mt-3">
|
||
<li>
|
||
<a class="text-white" href="//www.nlm.nih.gov/">NLM</a>
|
||
</li>
|
||
<li>
|
||
<a class="text-white" href="https://www.nih.gov/">NIH</a>
|
||
</li>
|
||
<li>
|
||
<a class="text-white" href="https://www.hhs.gov/">HHS</a>
|
||
</li>
|
||
<li>
|
||
<a class="text-white" href="https://www.usa.gov/">USA.gov</a>
|
||
</li>
|
||
</ul>
|
||
</nav>
|
||
</div>
|
||
</div>
|
||
</div>
|
||
</section>
|
||
<script type="text/javascript" src="/portal/portal3rc.fcgi/rlib/js/InstrumentOmnitureBaseJS/InstrumentNCBIConfigJS/InstrumentNCBIBaseJS/InstrumentPageStarterJS.js?v=1"> </script>
|
||
<script type="text/javascript" src="/portal/portal3rc.fcgi/static/js/hfjs2.js"> </script>
|
||
</div>
|
||
</div>
|
||
</div>
|
||
<!--/.page-->
|
||
</div>
|
||
<!--/.wrap-->
|
||
</div><!-- /.twelve_col -->
|
||
</div>
|
||
<!-- /.grid -->
|
||
|
||
<span class="PAFAppResources"></span>
|
||
|
||
<!-- BESelector tab -->
|
||
|
||
|
||
|
||
<noscript><img alt="statistics" src="/stat?jsdisabled=true&ncbi_db=books&ncbi_pdid=book-part&ncbi_acc=NBK1515&ncbi_domain=gene&ncbi_report=record&ncbi_type=fulltext&ncbi_objectid=&ncbi_pcid=/NBK1515/&ncbi_pagename=Tyrosinemia Type I - GeneReviews® - NCBI Bookshelf&ncbi_bookparttype=chapter&ncbi_app=bookshelf" /></noscript>
|
||
|
||
|
||
<!-- usually for JS scripts at page bottom -->
|
||
<!--<component id="PageFixtures" label="styles"></component>-->
|
||
|
||
|
||
<!-- CE8B5AF87C7FFCB1_0191SID /projects/books/PBooks@9.11 portal104 v4.1.r689238 Tue, Oct 22 2024 16:10:51 -->
|
||
<span id="portal-csrf-token" style="display:none" data-token="CE8B5AF87C7FFCB1_0191SID"></span>
|
||
|
||
<script type="text/javascript" src="//static.pubmed.gov/portal/portal3rc.fcgi/4216699/js/3879255/4121861/3501987/4008961/3893018/3821238/4062932/4209313/4212053/4076480/3921943/3400083/3426610.js" snapshot="books"></script></body>
|
||
</html> |