807 lines
No EOL
176 KiB
XML
807 lines
No EOL
176 KiB
XML
<?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="NBK1315" /><meta name="ncbi_domain" content="gene" /><meta name="ncbi_report" content="printable" /><meta name="ncbi_type" content="fulltext" /><meta name="ncbi_objectid" content="" /><meta name="ncbi_pcid" content="/NBK1315/?report=printable" /><meta name="ncbi_app" content="bookshelf" />
|
|
<!-- Logger end -->
|
|
|
|
<title>X-Linked Adrenoleukodystrophy - 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="X-Linked Adrenoleukodystrophy" /><meta name="citation_publisher" content="University of Washington, Seattle" /><meta name="citation_date" content="2023/04/06" /><meta name="citation_author" content="Gerald V Raymond" /><meta name="citation_author" content="Ann B Moser" /><meta name="citation_author" content="Ali Fatemi" /><meta name="citation_pmid" content="20301491" /><meta name="citation_fulltext_html_url" content="https://www.ncbi.nlm.nih.gov/books/NBK1315/" /><meta name="citation_keywords" content="X-ALD" /><meta name="citation_keywords" content="X-ALD" /><meta name="citation_keywords" content="Adrenomyeloneuropathy (AMN)" /><meta name="citation_keywords" content="Childhood Cerebral Adrenoleukodystrophy (cCALD)" /><meta name="citation_keywords" content="Primary Adrenocortical Insufficiency (Addison Disease)" /><meta name="citation_keywords" content="ATP-binding cassette sub-family D member 1" /><meta name="citation_keywords" content="ABCD1" /><meta name="citation_keywords" content="X-Linked Adrenoleukodystrophy" /><link rel="schema.DC" href="http://purl.org/DC/elements/1.0/" /><meta name="DC.Title" content="X-Linked Adrenoleukodystrophy" /><meta name="DC.Type" content="Text" /><meta name="DC.Publisher" content="University of Washington, Seattle" /><meta name="DC.Contributor" content="Gerald V Raymond" /><meta name="DC.Contributor" content="Ann B Moser" /><meta name="DC.Contributor" content="Ali Fatemi" /><meta name="DC.Date" content="2023/04/06" /><meta name="DC.Identifier" content="https://www.ncbi.nlm.nih.gov/books/NBK1315/" /><meta name="description" content="X-linked adrenoleukodystrophy (X-ALD) involves the central or peripheral nervous system and the adrenal cortex. The nervous system and adrenal glands are involved independently; thus, an affected male may be diagnosed with cerebral adrenoleukodystrophy (CALD), adrenomyeloneuropathy (AMN), and/or primary adrenocortical insufficiency. CALD is characterized by progressive behavioral, cognitive, and neurologic deficits; onset of symptoms ranges from childhood (typically ages 4 to 8 years) to adolescence (ages 11 to 21 years) and adulthood. AMN is characterized by leg weakness, spasticity, clumsy gait, pain, and bladder and bowel dysfunction; onset is typically in the 20s and 30s. Onset of primary adrenocortical insufficiency ranges from age two years to adulthood (most commonly by age 7.5 years). Heterozygous females are not at increased risk to develop CALD, but are at increased risk to develop AMN and primary adrenocortical insufficiency with increasing age." /><meta name="og:title" content="X-Linked Adrenoleukodystrophy" /><meta name="og:type" content="book" /><meta name="og:description" content="X-linked adrenoleukodystrophy (X-ALD) involves the central or peripheral nervous system and the adrenal cortex. The nervous system and adrenal glands are involved independently; thus, an affected male may be diagnosed with cerebral adrenoleukodystrophy (CALD), adrenomyeloneuropathy (AMN), and/or primary adrenocortical insufficiency. CALD is characterized by progressive behavioral, cognitive, and neurologic deficits; onset of symptoms ranges from childhood (typically ages 4 to 8 years) to adolescence (ages 11 to 21 years) and adulthood. AMN is characterized by leg weakness, spasticity, clumsy gait, pain, and bladder and bowel dysfunction; onset is typically in the 20s and 30s. Onset of primary adrenocortical insufficiency ranges from age two years to adulthood (most commonly by age 7.5 years). Heterozygous females are not at increased risk to develop CALD, but are at increased risk to develop AMN and primary adrenocortical insufficiency with increasing age." /><meta name="og:url" content="https://www.ncbi.nlm.nih.gov/books/NBK1315/" /><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/x-ald/" /><link rel="canonical" href="https://www.ncbi.nlm.nih.gov/books/NBK1315/" /><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" /><style type="text/css">p a.figpopup{display:inline !important} .bk_tt {font-family: monospace} .first-line-outdent .bk_ref {display: inline} </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">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>
|
|
|
|
<!-- Page meta end -->
|
|
<link rel="shortcut icon" href="//www.ncbi.nlm.nih.gov/favicon.ico" /><meta name="ncbi_phid" content="CE8E6EEF7C8B13110000000000E900C7.m_5" />
|
|
<meta name='referrer' content='origin-when-cross-origin'/><link type="text/css" rel="stylesheet" href="//static.pubmed.gov/portal/portal3rc.fcgi/4216699/css/3852956/3985586/3808861/4121862/3974050/3917732/251717/4216701/14534/45193/4113719/3849091/3984811/3751656/4033350/3840896/3577051/3852958/3984801/12930/3964959.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 no_max_width">
|
|
<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 class="header">
|
|
|
|
|
|
</div>
|
|
|
|
|
|
|
|
<!--<component id="Page" label="headcontent"/>-->
|
|
|
|
</div>
|
|
<div class="content">
|
|
<!-- site messages -->
|
|
<div class="container content">
|
|
<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></div>
|
|
<div class="main-content lit-style" itemscope="itemscope" itemtype="http://schema.org/CreativeWork"><div class="meta-content fm-sec"><h1 id="_NBK1315_"><span class="title" itemprop="name">X-Linked Adrenoleukodystrophy</span></h1><div itemprop="alternativeHeadline" class="subtitle whole_rhythm">Synonym: X-ALD</div><div class="contrib half_rhythm"><span itemprop="author">Gerald V Raymond</span>, MD<div class="affiliation small">Department of Genetic Medicine<br />Johns Hopkins Hospital<br />Baltimore, Maryland<div><span class="email-label">Email: </span><a href="mailto:dev@null" data-email="ude.imhj@4nomyarg" class="oemail">ude.imhj@4nomyarg</a></div></div></div><div class="contrib half_rhythm"><span itemprop="author">Ann B Moser</span>, BA<div class="affiliation small">Department of Neurogenetics<br />Kennedy Krieger Institute<br />Baltimore, Maryland<div><span class="email-label">Email: </span><a href="mailto:dev@null" data-email="gro.regeirkydennek@aresom" class="oemail">gro.regeirkydennek@aresom</a></div></div></div><div class="contrib half_rhythm"><span itemprop="author">Ali Fatemi</span>, MD<div class="affiliation small">Department of Neurogenetics<br />Kennedy Krieger Institute<br />Baltimore, Maryland<div><span class="email-label">Email: </span><a href="mailto:dev@null" data-email="gro.regeirkydennek@imetaf" class="oemail">gro.regeirkydennek@imetaf</a></div></div></div><p class="small">Initial Posting: <span itemprop="datePublished">March 26, 1999</span>; Last Update: <span itemprop="dateModified">April 6, 2023</span>.</p><p><em>Estimated reading time: 37 minutes</em></p></div><div class="body-content whole_rhythm" itemprop="text"><div id="x-ald.Summary" itemprop="description"><h2 id="_x-ald_Summary_">Summary</h2><div><h4 class="inline">Clinical characteristics.</h4><p>X-linked adrenoleukodystrophy (X-ALD) involves the central or peripheral nervous system and the adrenal cortex. The nervous system and adrenal glands are involved independently; thus, an affected male may be diagnosed with cerebral adrenoleukodystrophy (CALD), adrenomyeloneuropathy (AMN), and/or primary adrenocortical insufficiency. CALD is characterized by progressive behavioral, cognitive, and neurologic deficits; onset of symptoms ranges from childhood (typically ages 4 to 8 years) to adolescence (ages 11 to 21 years) and adulthood. AMN is characterized by leg weakness, spasticity, clumsy gait, pain, and bladder and bowel dysfunction; onset is typically in the 20s and 30s. Onset of primary adrenocortical insufficiency ranges from age two years to adulthood (most commonly by age 7.5 years). Heterozygous females are not at increased risk to develop CALD, but are at increased risk to develop AMN and primary adrenocortical insufficiency with increasing age.</p></div><div><h4 class="inline">Diagnosis/testing.</h4><p>Three scenarios for suspecting the diagnosis are: (1) positive newborn screening result, which to date is performed in more than half of the United States; (2) a male or female proband with suggestive clinical and laboratory findings; (3) a male not known to have X-ALD ascertained and diagnosed via family screening. The diagnosis is established by identification of a hemizygous <i>ABCD1</i> pathogenic variant in a male or a heterozygous <i>ABCD1</i> pathogenic variant in a female on molecular genetic testing.</p></div><div><h4 class="inline">Management.</h4><p><i>Targeted therapy:</i> Newborns and asymptomatic infant boys (most commonly diagnosed following a positive newborn screening result or family screening) require immediate referral to a neurologist or biochemical geneticist who will develop a plan for scheduled neurologic examinations and brain MRIs to identify promptly those boys at risk to develop childhood CALD (cCALD) who will benefit from targeted therapy (either hematopoietic stem cell transplantation or, in some, an ex vivo gene therapy recently approved in the US).</p><p><i>Supportive care:</i> Older males with CALD and males and females with AMN require supportive treatment by multidisciplinary specialists in relevant fields to improve quality of life, maximize function, and reduce complications. For primary adrenocortical insufficiency, newborn males and asymptomatic infant boys with confirmed X-ALD require immediate referral to a pediatric endocrinologist to screen for adrenocortical insufficiency in order to either promptly treat those with confirmed adrenal insufficiency according to published steroid replacement guidelines or institute a plan for scheduled screening throughout childhood for boys who do not yet have adrenal insufficiency. Older males require scheduled screening to detect later-onset adrenal insufficiency.</p><p><i>Surveillance:</i> For boys receiving targeted therapy for neurologic disease, the treating neurologist / biochemical geneticist monitors existing manifestations, the individual's response to targeted therapy, and need for supportive care. Older males with CALD and males and females with AMN receiving supportive care require scheduled examinations by their multidisciplinary care providers to identify and address emerging issues. Boys at risk for cCALD who are possible candidates for targeted therapy require frequent assessments starting at age 12 months. For primary adrenocortical insufficiency, boys who do not yet have adrenal involvement require scheduled assessments by their treating pediatric endocrinologist throughout childhood. Males with AMN require scheduled assessment (at least yearly) by their treating endocrinologist.</p><p><i>Agents/circumstances to avoid:</i> Triggers known or suspected to be associated with activation of cerebral disease, including significant head injury, coma associated with adrenal crisis, and neurosurgical procedures.</p><p><i>Evaluation of relatives at risk:</i> It is appropriate to evaluate at-risk male relatives of an affected individual through measurement of plasma concentration of very long-chain fatty acids – or molecular genetic testing if the familial <i>ABCD1</i> pathogenic variant is known – in order to identify as early as possible those who would benefit from screening for primary adrenocortical insufficiency and to facilitate timely identification of young males who might benefit from targeted treatment for cCALD.</p></div><div><h4 class="inline">Genetic counseling.</h4><p>X-ALD is inherited in an X-linked manner. Approximately 95% of probands inherit an <i>ABCD1</i> pathogenic variant from one parent; at least 4% of individuals with X-ALD have a <i>de novo</i> pathogenic variant. If the mother of the proband has an <i>ABCD1</i> pathogenic variant, the chance of the mother transmitting it in each pregnancy is 50%; if the father of the proband is affected (i.e., hemizygous for an <i>ABCD1</i> pathogenic variant), he will transmit the pathogenic variant to all of his daughters and none of his sons. Males who inherit the pathogenic variant will be affected; females who inherit the pathogenic variant will typically be symptom-free in childhood but may manifest findings in adulthood. A positive newborn screening result in a female infant should prompt identification and evaluation of at-risk male relatives, as identification of males with X-ALD before symptoms occur or early in the course of the disease can allow for diagnosis and management of adrenal insufficiency before life-threatening complications occur; such testing can also allow for correct diagnosis of early (and often nonspecific) neurologic, behavioral, and/or cognitive signs and symptoms. Once the <i>ABCD1</i> pathogenic variant has been identified in an affected family member, heterozygote testing for at-risk female relatives and prenatal and preimplantation genetic testing are possible.</p></div></div><div id="x-ald.GeneReview_Scope"><h2 id="_x-ald_GeneReview_Scope_"><i>GeneReview</i> Scope</h2><div id="x-ald.T.xlinked_adrenoleukodystrophy_inc" class="table"><div class="caption"><p>X-Linked Adrenoleukodystrophy: Included Clinical Scenarios and Key Management Issues</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK1315/table/x-ald.T.xlinked_adrenoleukodystrophy_inc/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__x-ald.T.xlinked_adrenoleukodystrophy_inc_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_x-ald.T.xlinked_adrenoleukodystrophy_inc_1_1_1_1" colspan="2" scope="colgroup" rowspan="1" style="text-align:left;vertical-align:middle;">Clinical Scenario</th><th id="hd_h_x-ald.T.xlinked_adrenoleukodystrophy_inc_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Key Management Issues</th></tr></thead><tbody><tr><td headers="hd_h_x-ald.T.xlinked_adrenoleukodystrophy_inc_1_1_1_1" rowspan="2" scope="row" colspan="1" style="text-align:left;vertical-align:middle;">Scenario 1: Positive newborn screening (NBS) result</td><td headers="hd_h_x-ald.T.xlinked_adrenoleukodystrophy_inc_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Male infants w/positive NBS for X-ALD & confirmed <i>ABCD1</i> pathogenic variant</td><td headers="hd_h_x-ald.T.xlinked_adrenoleukodystrophy_inc_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Refer all male infants to:
|
|
<ul><li class="half_rhythm"><div>A pediatric endocrinologist for screening for primary adrenocortical insufficiency to prevent life-threatening complications of adrenal insufficiency;</div></li><li class="half_rhythm"><div>A neurologist or biochemical geneticist to develop a plan to monitor neurologic & brain MRI findings to identify promptly those at risk for cCALD &, thus, candidates for targeted therapy to prevent progression of CNS disease.</div></li></ul>
|
|
</td></tr><tr><td headers="hd_h_x-ald.T.xlinked_adrenoleukodystrophy_inc_1_1_1_1" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">Female infants w/positive NBS for X-ALD</td><td headers="hd_h_x-ald.T.xlinked_adrenoleukodystrophy_inc_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Refer parents for genetic counseling to identify male relatives at risk for X-ALD & primary adrenocortical insufficiency who might warrant diagnostic evaluation & management as recommended for male infants w/positive NBS. <sup>1</sup></td></tr><tr><td headers="hd_h_x-ald.T.xlinked_adrenoleukodystrophy_inc_1_1_1_1" rowspan="3" scope="row" colspan="1" style="text-align:left;vertical-align:middle;">Scenario 2: Symptomatic individual</td><td headers="hd_h_x-ald.T.xlinked_adrenoleukodystrophy_inc_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Childhood CALD <sup>2, 3</sup></td><td headers="hd_h_x-ald.T.xlinked_adrenoleukodystrophy_inc_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Adrenal assessment;</div></li><li class="half_rhythm"><div>Consultation w/center w/expertise in evaluating males for possible HSCT</div></li></ul>
|
|
</td></tr><tr><td headers="hd_h_x-ald.T.xlinked_adrenoleukodystrophy_inc_1_1_1_1" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">Adrenomyeloneuropathy</td><td headers="hd_h_x-ald.T.xlinked_adrenoleukodystrophy_inc_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Measure cortisol & ACTH levels to evaluate for concomitant adrenal insufficiency.</div></li><li class="half_rhythm"><div>Brain MRI to evaluate for cerebral disease <sup>1</sup></div></li></ul>
|
|
</td></tr><tr><td headers="hd_h_x-ald.T.xlinked_adrenoleukodystrophy_inc_1_1_1_1" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">Primary adrenocortical insufficiency (Addison disease)</td><td headers="hd_h_x-ald.T.xlinked_adrenoleukodystrophy_inc_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Provide appropriate steroid replacement & consult w/endocrinologist.</td></tr><tr><td headers="hd_h_x-ald.T.xlinked_adrenoleukodystrophy_inc_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Scenario 3:<br />Male identified by family screening</td><td headers="hd_h_x-ald.T.xlinked_adrenoleukodystrophy_inc_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">May be asymptomatic or symptomatic</td><td headers="hd_h_x-ald.T.xlinked_adrenoleukodystrophy_inc_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Assess clinically w/appropriate endocrine studies & brain MRI.</td></tr></tbody></table></div><div><div><dl class="temp-labeled-list small"><dt></dt><dd><div><p class="no_margin">ACTH = adrenocorticotropic hormone; CALD = cerebral adrenoleukodystrophy; CNS = central nervous system; HSCT = hematopoietic stem cell transplantation; X-ALD = X-linked adrenoleukodystrophy</p></div></dd><dt></dt><dd><div><p class="no_margin">For synonyms and outdated names see <a href="#x-ald.Nomenclature">Nomenclature</a>.</p></div></dd><dt>1. </dt><dd><div id="x-ald.TF.d.1"><p class="no_margin">
|
|
<a class="bk_pop" href="#x-ald.REF.engelen.2022.940">Engelen et al [2022]</a>
|
|
</p></div></dd><dt>2. </dt><dd><div id="x-ald.TF.d.2"><p class="no_margin">Childhood CALD (cCALD) is also referred to as cerebral adrenoleukodystrophy (CALD), but cerebral disease is not exclusive to children.</p></div></dd><dt>3. </dt><dd><div id="x-ald.TF.d.3"><p class="no_margin">Confirmed in males with elevated very long-chain fatty acids (VLCFAs) and identification of a hemizygous pathogenic variant in <i>ABCD1</i>, and in females by elevated VLCFAs or C26:0-lysophosphatidylcholine and identification of a heterozygous <i>ABCD1</i> pathogenic variant in <i>ABCD1</i>.</p></div></dd></dl></div></div></div></div><div id="x-ald.Diagnosis"><h2 id="_x-ald_Diagnosis_">Diagnosis</h2><p>Note: For the purposes of this <i>GeneReview</i>, the terms "male" and "female" are narrowly defined as the individual's biological sex at birth as it determines clinical care [<a class="bk_pop" href="#x-ald.REF.caughey.2021.1953">Caughey et al 2021</a>].</p><div id="x-ald.Suggestive_Findings"><h3>Suggestive Findings</h3><p>The three scenarios in which X-linked adrenoleukodystrophy (X-ALD) may be considered are a <a href="#x-ald.Scenario_1_Positive_Newborn_Screen">positive newborn screening result</a>, a <a href="#x-ald.Scenario_2_Symptomatic_Individual">symptomatic individual</a>, and a male who is asymptomatic but <a href="#x-ald.Scenario_3_Male_Identified_by_Fami">identified by family screening</a>.</p><div id="x-ald.Scenario_1_Positive_Newborn_Screen"><h4>Scenario 1: Positive Newborn Screening Result</h4><p>Newborn screening (NBS) for X-ALD has been added to the recommended uniform screening panel in the United States and, to date, more than half the states have begun screening. While the specific methodologies vary, testing is presently performed measuring the concentration of C26:0-lysophosphatidylcholine (C26:0-LPC) [<a class="bk_pop" href="#x-ald.REF.vogel.2015.599">Vogel et al 2015</a>]. Some states have incorporated molecular genetic testing to assist in confirmatory testing for the proband as well as family screening (see <a href="#x-ald.Molecular_Genetic_Testing">Molecular Genetic Testing</a>).</p><p><b>All male infants</b> with a positive NBS for X-ALD and a confirmed <i>ABCD1</i> pathogenic variant (see <a href="#x-ald.Establishing_the_Diagnosis">Establishing the Diagnosis</a>) need immediate referral to:</p><ul><li class="half_rhythm"><div>A pediatric endocrinologist for screening for primary adrenocortical insufficiency and prompt treatment to prevent life-threatening complications of primary adrenal insufficiency (see <a href="/books/NBK1315/table/x-ald.T.recommended_evaluations_and_next/?report=objectonly" target="object" rid-ob="figobxaldTrecommendedevaluationsandnext">Table 4</a>);</div></li><li class="half_rhythm"><div>A biochemical geneticist or neurologist familiar with targeted treatment for childhood cerebral adrenoleukodystrophy (cCALD) to develop a plan for routine brain MRI monitoring and neurologic evaluations to identify those with early cerebral disease who may be candidates for targeted therapy to prevent progression of central nervous system disease (see Management, <a href="#x-ald.Targeted_Therapy">Targeted Therapy</a>).</div></li></ul><p><b>Female infants</b> with a positive NBS do not require immediate medical follow up, as females do not have X-ALD-related medical issues in childhood. However, it is critical that their parents be referred promptly for <a href="#x-ald.Genetic_Counseling">genetic counseling</a> to identify all male relatives at risk for X-ALD and to facilitate diagnostic workup (see <a href="#x-ald.Evaluation_of_Relatives_at_Risk">Evaluation of Relatives at Risk</a>).</p></div><div id="x-ald.Scenario_2_Symptomatic_Individual"><h4>Scenario 2: Symptomatic Individual</h4><p>X-ALD <b>should be suspected</b> in symptomatic male and female probands with the supportive clinical and neuroimaging findings outlined in <a href="/books/NBK1315/table/x-ald.T.suggestive_findings_in_males_and/?report=objectonly" target="object" rid-ob="figobxaldTsuggestivefindingsinmalesand">Table 1</a> and a family history consistent with X-linked inheritance (e.g., no male-to-male transmission). Note: Absence of a known family history does not preclude the diagnosis.</p><div id="x-ald.T.suggestive_findings_in_males_and" class="table"><h3><span class="label">Table 1. </span></h3><div class="caption"><p>Suggestive Findings in Males and Females with Symptomatic X-Linked Adrenoleukodystrophy</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK1315/table/x-ald.T.suggestive_findings_in_males_and/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__x-ald.T.suggestive_findings_in_males_and_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_x-ald.T.suggestive_findings_in_males_and_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Sex</th><th id="hd_h_x-ald.T.suggestive_findings_in_males_and_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Age<br />(years)</th><th id="hd_h_x-ald.T.suggestive_findings_in_males_and_1_1_1_3" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Presenting Phenotype (Frequency of Persons Presenting w/Phenotype)</th><th id="hd_h_x-ald.T.suggestive_findings_in_males_and_1_1_1_4" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Clinical</th><th id="hd_h_x-ald.T.suggestive_findings_in_males_and_1_1_1_5" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Brain MRI</th></tr></thead><tbody><tr><td headers="hd_h_x-ald.T.suggestive_findings_in_males_and_1_1_1_1" rowspan="5" scope="row" colspan="1" style="text-align:left;vertical-align:middle;">
|
|
<b>Male</b>
|
|
</td><td headers="hd_h_x-ald.T.suggestive_findings_in_males_and_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Typically 4-8 yrs (peak 7 yrs); rarely before 3 yrs</td><td headers="hd_h_x-ald.T.suggestive_findings_in_males_and_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Childhood CALD (30%-35% of males)</td><td headers="hd_h_x-ald.T.suggestive_findings_in_males_and_1_1_1_4" rowspan="2" colspan="1" style="text-align:left;vertical-align:middle;">Progressive behavioral, cognitive, & neurologic deficits</td><td headers="hd_h_x-ald.T.suggestive_findings_in_males_and_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Symmetric T<sub>2</sub>-weighted hyperintensity, typically involving splenium of corpus callosum; active disease will have contrast enhancement.</td></tr><tr><td headers="hd_h_x-ald.T.suggestive_findings_in_males_and_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">11-21 yrs</td><td headers="hd_h_x-ald.T.suggestive_findings_in_males_and_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Adolescent CALD (~5% of males)</td><td headers="hd_h_x-ald.T.suggestive_findings_in_males_and_1_1_1_5" colspan="1" rowspan="1" style="text-align:left;vertical-align:middle;">Similar to cCALD</td></tr><tr><td headers="hd_h_x-ald.T.suggestive_findings_in_males_and_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">>21 yrs</td><td headers="hd_h_x-ald.T.suggestive_findings_in_males_and_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Adult CALD (~20% of males)</td><td headers="hd_h_x-ald.T.suggestive_findings_in_males_and_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Dementia, behavioral disturbances, & focal neurologic deficits</td><td headers="hd_h_x-ald.T.suggestive_findings_in_males_and_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Similar to cCALD</td></tr><tr><td headers="hd_h_x-ald.T.suggestive_findings_in_males_and_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">20s & 30s</td><td headers="hd_h_x-ald.T.suggestive_findings_in_males_and_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">AMN (40%-45% of males)<br />Note: ~70% have impaired adrenocortical function at onset of neurologic findings.</td><td headers="hd_h_x-ald.T.suggestive_findings_in_males_and_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Leg weakness, spasticity, clumsy gait, pain, bladder & bowel dysfunction</td><td headers="hd_h_x-ald.T.suggestive_findings_in_males_and_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Brain & spinal cord neuroimaging are normal.</td></tr><tr><td headers="hd_h_x-ald.T.suggestive_findings_in_males_and_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">2 yrs to adulthood (most commonly by 7.5 yrs)</td><td headers="hd_h_x-ald.T.suggestive_findings_in_males_and_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Primary adrenocortical insufficiency only (~10% of males)</td><td headers="hd_h_x-ald.T.suggestive_findings_in_males_and_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Primary adrenocortical insufficiency w/o apparent neurologic involvement</td><td headers="hd_h_x-ald.T.suggestive_findings_in_males_and_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr><tr><td headers="hd_h_x-ald.T.suggestive_findings_in_males_and_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
|
<b>Female</b>
|
|
</td><td headers="hd_h_x-ald.T.suggestive_findings_in_males_and_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Adulthood</td><td headers="hd_h_x-ald.T.suggestive_findings_in_males_and_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">AMN (~50% age >40 yrs; ~ 65% by age 65 yrs)</td><td headers="hd_h_x-ald.T.suggestive_findings_in_males_and_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Primary adrenocortical insufficiency is rare & does not precede AMN (as is seen in males).</td><td headers="hd_h_x-ald.T.suggestive_findings_in_males_and_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Normal except in rare exceptions</td></tr></tbody></table></div><div><div><dl class="temp-labeled-list small"><dt></dt><dd><div><p class="no_margin">Based on <a class="bk_pop" href="#x-ald.REF.turk.2020.52">Turk et al [2020]</a>, <a class="bk_pop" href="#x-ald.REF.engelen.2022.940">Engelen et al [2022]</a></p></div></dd><dt></dt><dd><div><p class="no_margin">AMN = adrenomyeloneuropathy; CALD = cerebral adrenoleukodystrophy; cCALD = childhood cerebral adrenoleukodystrophy</p></div></dd></dl></div></div></div></div><div id="x-ald.Scenario_3_Male_Identified_by_Fami"><h4>Scenario 3: Male Identified by Family Screening</h4><p>Males identified by family screening may be any age, and the urgency of evaluation will depend on age at diagnosis. Boys who are at risk for cCALD should be promptly diagnosed and receive appropriate evaluations (see <a href="/books/NBK1315/table/x-ald.T.recommended_evaluations_and_next_1/?report=objectonly" target="object" rid-ob="figobxaldTrecommendedevaluationsandnext1">Table 7</a>).</p><p>Note: Male children and adults ascertained and diagnosed with X-ALD via family screening may be asymptomatic or have features consistent with X-ALD but erroneously attributed to other causes (e.g., young males diagnosed as having worsening learning issues or autism spectrum disorder) [G Raymond, personal observation].</p></div></div><div id="x-ald.Establishing_the_Diagnosis"><h3>Establishing the Diagnosis</h3><p>The diagnosis of X-ALD is established in a proband by identification of abnormally elevated very long-chain fatty acids (VLCFAs) on <a href="#x-ald.Biochemical_Testing">biochemical testing</a>
|
|
<b>and</b> identification of a hemizygous <i>ABCD1</i> pathogenic (or likely pathogenic) variant in a male or a heterozygous <i>ABCD1</i> pathogenic (or likely pathogenic) variant in a female on <a href="#x-ald.Molecular_Genetic_Testing">molecular genetic testing</a>.</p><p>Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic 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="#x-ald.REF.richards.2015.405">Richards et al 2015</a>]. Reference to "pathogenic variants" in this <i>GeneReview</i> is understood to include any likely pathogenic variants. (2) Identification of a hemizygous or heterozygous <i>ABCD1</i> variant of uncertain significance does not establish or rule out the diagnosis.</p><div id="x-ald.Biochemical_Testing"><h4>Biochemical Testing</h4><p>VLCFAs may be determined in serum or plasma. The characteristic elevation is in the saturated VLCFAs (especially hexacosanoic acid, abbreviated as C26:0). The derivative species of C26:0-lysophosphatidylcholine (C26:0-LPC) is also elevated and is used in newborn screening and in some centers for all diagnostic testing [<a class="bk_pop" href="#x-ald.REF.jaspers.2020.690">Jaspers et al 2020</a>].</p><p>Since elevated VLCFAs are not specific to X-ALD and may be seen in other peroxisomal disorders of beta-oxidation, determination of VLCFAs should be paired with <i>ABCD1</i> molecular genetic testing.</p></div><div id="x-ald.Molecular_Genetic_Testing"><h4>Molecular Genetic Testing</h4><p><b>Male proband.</b> The diagnosis of X-ALD <b>is established</b> in a male proband with suggestive findings (see <a href="/books/NBK1315/table/x-ald.T.suggestive_findings_in_males_and/?report=objectonly" target="object" rid-ob="figobxaldTsuggestivefindingsinmalesand">Table 1</a>), elevated VLCFAs, and a hemizygous pathogenic variant in <i>ABCD1</i> identified by molecular genetic testing (see <a href="/books/NBK1315/table/x-ald.T.molecular_genetic_testing_used_i/?report=objectonly" target="object" rid-ob="figobxaldTmoleculargenetictestingusedi">Table 2</a>).</p><p>Note: Many <i>ABCD1</i> variants are private missense variants (i.e., usually found only in a single family or a small population) and, therefore, are likely novel. Thus, many such variants are interpreted by clinical diagnostic laboratories as variants of uncertain significance (VUS). For these reasons, assessment of VLCFA levels and correlation with clinical findings are critical for interpreting <i>ABCD1</i> variants referred to as VUS. See <a href="#x-ald.Molecular_Genetics">Molecular Genetics</a>, <b><i>ABCD1</i>-specific laboratory technical considerations</b>.</p><p><b>Female proband.</b> The diagnosis of X-ALD <b>is established</b> in a female proband with suggestive findings (see <a href="/books/NBK1315/table/x-ald.T.suggestive_findings_in_males_and/?report=objectonly" target="object" rid-ob="figobxaldTsuggestivefindingsinmalesand">Table 1</a>), elevated VLCFAs or C26:0-LPC, and a heterozygous pathogenic variant in <i>ABCD1</i> identified by molecular genetic testing (see <a href="/books/NBK1315/table/x-ald.T.molecular_genetic_testing_used_i/?report=objectonly" target="object" rid-ob="figobxaldTmoleculargenetictestingusedi">Table 2</a>).</p><p>Molecular genetic testing approaches can include a combination of <b>gene-targeted testing</b> (single-gene testing, multigene panel) and <b>comprehensive</b>
|
|
<b>genomic testing</b> (exome sequencing, genome sequencing). Gene-targeted testing requires that the clinician determine which gene(s) are likely involved (see <a href="#x-ald.Option_1">Option 1</a>), whereas genomic testing does not (see <a href="#x-ald.Option_2">Option 2</a>).</p><div id="x-ald.Option_1"><h5>
|
|
<b>Option 1</b>
|
|
</h5><p>When the phenotypic, laboratory, and brain MRI findings strongly suggest the diagnosis of X-ALD, molecular genetic testing approaches can include <b>single-gene testing</b> or use of a <b>multigene panel.</b></p><ul><li class="half_rhythm"><div class="half_rhythm"><b>Single-gene testing.</b> Sequence analysis of <i>ABCD1</i> is performed first to detect missense, nonsense, and splice site variants and small intragenic deletions/insertions. Note: Depending on the sequencing method used, single-exon, multiexon, or whole-gene deletions/duplications may not be detected. If no variant is detected by the sequencing method used, the next step is to perform gene-targeted deletion/duplication analysis to detect exon and whole-gene deletions or duplications.</div></li><li class="half_rhythm"><div class="half_rhythm"><b>A leukodystrophy multigene panel</b> that includes <i>ABCD1</i> and other genes of interest (see <a href="#x-ald.Differential_Diagnosis">Differential Diagnosis</a>) is most likely to identify the genetic cause of the condition. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this <i>GeneReview</i>. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests. (5) Given the specificity of the combination of clinical and biochemical abnormalities for X-ALD, and to minimize the likelihood of identifying variants of uncertain significance on a multigene panel, single-gene testing is generally recommended when X-ALD is strongly suspected.</div><div class="half_rhythm">For an introduction to multigene panels click <a href="/books/n/gene/app5/#app5.Multigene_Panels">here</a>. More detailed information for clinicians ordering genetic tests can be found <a href="/books/n/gene/app5/#app5.Multigene_Panels_FAQs">here</a>.</div></li></ul></div><div id="x-ald.Option_2"><h5>
|
|
<b>Option 2</b>
|
|
</h5><p><b>Comprehensive</b>
|
|
<b>genomic testing</b> does not require the clinician to determine which gene is likely involved. <b>Exome sequencing</b> is most commonly used; <b>genome sequencing</b> is also possible.</p><p>For an introduction to comprehensive genomic testing click <a href="/books/n/gene/app5/#app5.Comprehensive_Genomic_Testing">here</a>. More detailed information for clinicians ordering genomic testing can be found <a href="/books/n/gene/app5/#app5.Comprehensive_Genomic_Testing_1">here</a>.</p><div id="x-ald.T.molecular_genetic_testing_used_i" class="table"><h3><span class="label">Table 2. </span></h3><div class="caption"><p>Molecular Genetic Testing Used in X-Linked Adrenoleukodystrophy</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK1315/table/x-ald.T.molecular_genetic_testing_used_i/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__x-ald.T.molecular_genetic_testing_used_i_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_x-ald.T.molecular_genetic_testing_used_i_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_x-ald.T.molecular_genetic_testing_used_i_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Method</th><th id="hd_h_x-ald.T.molecular_genetic_testing_used_i_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_x-ald.T.molecular_genetic_testing_used_i_1_1_1_1" rowspan="2" scope="row" colspan="1" style="text-align:left;vertical-align:middle;">
|
|
<i>ABCD1</i>
|
|
</td><td headers="hd_h_x-ald.T.molecular_genetic_testing_used_i_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_x-ald.T.molecular_genetic_testing_used_i_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">97.5% <sup>4</sup></td></tr><tr><td headers="hd_h_x-ald.T.molecular_genetic_testing_used_i_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">Gene-targeted deletion/duplication analysis <sup>5</sup></td><td headers="hd_h_x-ald.T.molecular_genetic_testing_used_i_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">2.5% <sup>4</sup></td></tr></tbody></table></div><div><div><dl class="temp-labeled-list small"><dt>1. </dt><dd><div id="x-ald.TF.2.1"><p class="no_margin">See <a href="/books/NBK1315/#x-ald.molgen.TA">Table A. Genes and Databases</a> for chromosome locus and protein.</p></div></dd><dt>2. </dt><dd><div id="x-ald.TF.2.2"><p class="no_margin">See <a href="#x-ald.Molecular_Genetics">Molecular Genetics</a> for information on variants detected in this gene.</p></div></dd><dt>3. </dt><dd><div id="x-ald.TF.2.3"><p class="no_margin">Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click <a href="/books/n/gene/app2/">here</a>.</p></div></dd><dt>4. </dt><dd><div id="x-ald.TF.2.4"><p class="no_margin">Data derived from the <a href="https://adrenoleukodystrophy.info/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri"><i>ABCD1</i> variant database</a> [<a class="bk_pop" href="#x-ald.REF.mallack.2022a.283">Mallack et al 2022a</a>]</p></div></dd><dt>5. </dt><dd><div id="x-ald.TF.2.5"><p class="no_margin">Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.</p></div></dd></dl></div></div></div></div></div></div></div><div id="x-ald.Clinical_Characteristics"><h2 id="_x-ald_Clinical_Characteristics_">Clinical Characteristics</h2><div id="x-ald.Clinical_Description"><h3>Clinical Description</h3><p>X-linked adrenoleukodystrophy (X-ALD) affects the nervous system and the adrenal cortex. The involvement of nervous system and adrenal gland is independent and determines whether the affected male is diagnosed with cerebral disease, adrenomyeloneuropathy, or primary adrenocortical insufficiency.</p><p>The range of phenotypic expression in X-ALD is wide and cannot be predicted by very long-chain fatty acid (VLCFA) levels, the <i>ABCD1</i> pathogenic variant, or family history. Varying phenotypes often co-occur in a single kindred or sibship. Some individuals with X-ALD remain asymptomatic until their adult years.</p><div id="x-ald.Affected_Males"><h4>Affected Males</h4><div id="x-ald.Childhood_Cerebral_Adrenoleukodyst"><h5>
|
|
<b>Childhood Cerebral Adrenoleukodystrophy (cCALD)</b>
|
|
</h5><p>Inflammatory cerebral demyelination may occur at almost any age in X-ALD, but it is characteristically seen as a childhood presentation. It most commonly occurs between ages four and eight years, with a peak at age seven years. It rarely occurs before age three years.</p><p>It is important to identify as early as possible males with neuroimaging findings of cCALD in order to refer them promptly to determine if they are candidates for targeted therapy that can slow the disease course (see Management, <a href="#x-ald.Targeted_Therapy">Targeted Therapy</a>).</p><p>Affected males present with behavioral or learning deficits, often diagnosed as attention-deficit/hyperactivity disorder, which may respond to stimulant medication. These behaviors may persist for months or longer, and are followed by symptoms suggestive of a more serious underlying disorder, including "spacing out" in school (inattention, deterioration in handwriting skills, and diminishing school performance); difficulty in understanding speech (though sound perception is normal); difficulty in reading, spatial orientation, and comprehension of written material; clumsiness; visual disturbances and occasionally diplopia; and aggressive or disinhibited behavior.</p><p>Brain MRI examination performed at this time can be strikingly abnormal even when symptoms are relatively mild. The presence of advanced disease on MRI even with seemingly mild neurologic findings may preclude an attempt at targeted therapy.</p><p>In some males, seizures may be the first manifestation.</p><p>While variable, the rate of disease progression may be rapid, with total disability occurring within six months to two years, followed by death at varying ages.</p><p>Most individuals have impaired adrenocortical function at the time that neurologic disturbances are first noted.</p></div><div id="x-ald.Adrenomyeloneuropathy_AMN"><h5>
|
|
<b>Adrenomyeloneuropathy (AMN)</b>
|
|
</h5><p>The typical presentation is a man in his adult years who develops progressive stiffness and weakness in the legs (due to spastic paraparesis), abnormalities of bladder and bowel control, abnormal sensory perception (especially of vibratory sense), and sexual dysfunction. All manifestations progress over decades.</p><p>Approximately 40%-45% of individuals with AMN show some degree of involvement on brain MRI or clinical examination. In 20%-63% of individuals with AMN, progressive brain involvement leads to serious cognitive and behavioral disturbances that may progress to total disability and death [<a class="bk_pop" href="#x-ald.REF.de_beer.2014.2227">de Beer et al 2014</a>].</p><p>Approximately 70% of men with AMN have impaired adrenocortical function at the time that neurologic manifestations are first noted.</p></div><div id="x-ald.Primary_Adrenocortical_Insufficien"><h5>
|
|
<b>Primary Adrenocortical Insufficiency</b>
|
|
</h5><p>Males can present with signs of adrenal insufficiency at any age, although commonly by age 7.5 years. Presenting signs include unexplained vomiting and weakness or coma, leading to the diagnosis of primary adrenocortical insufficiency. A variable finding is increased skin pigmentation resulting from excessive adrenocorticotropic hormone secretion.</p><p>Overall, adrenocortical function is abnormal in 90% of neurologically symptomatic boys and 70% of men with AMN. Most males who are initially diagnosed as having only primary adrenocortical insufficiency will develop some neurologic manifestations; however, it may be decades later.</p></div></div><div id="x-ald.Heterozygous_Females"><h4>Heterozygous Females</h4><p>Heterozygous females are symptom-free in childhood. In adulthood, an AMN-like phenotype in females is reported as mild-to-moderate spastic paraparesis with bladder and bowel issues. The onset of these issues is often subtle and – if not specifically examined for – easily overlooked. The findings do correlate with age, and may not become evident until later in life. Progression is also slower than that seen in males with AMN [<a class="bk_pop" href="#x-ald.REF.huffnagel.2019.30">Huffnagel et al 2019</a>]. For these reasons, the reported incidence of an AMN-like phenotype in heterozygous females varies between 65% and 80% [<a class="bk_pop" href="#x-ald.REF.huffnagel.2019.30">Huffnagel et al 2019</a>, <a class="bk_pop" href="#x-ald.REF.schirinzi.2019.326">Schirinzi et al 2019</a>].</p><p>It may be stated that adrenal insufficiency in heterozygous females is rare, and the present recommendation is not to routinely screen females for this feature. There are also rare reports of cerebral myelin involvement caused, in some females, by genetic mechanisms such as chromosomal rearrangement or skewed X-inactivation [<a class="bk_pop" href="#x-ald.REF.hershkovitz.2002.234">Hershkovitz et al 2002</a>].</p></div></div><div id="x-ald.GenotypePhenotype_Correlations"><h3>Genotype-Phenotype Correlations</h3><p>The X-ALD phenotype cannot be predicted by VLCFA plasma concentration or by the nature of the <i>ABCD1</i> pathogenic variant, as the same pathogenic variant can be associated with each of the known phenotypes.</p><p>Likewise, the same phenotype can be observed both with large deletions that result in absence of the gene product and with missense pathogenic variants associated with abundant immunoreactive protein product [<a class="bk_pop" href="#x-ald.REF.mallack.2022a.283">Mallack et al 2022a</a>].</p></div><div id="x-ald.Penetrance"><h3>Penetrance</h3><p>Although the variation in X-ALD clinical phenotypes is great, neurologic manifestations are present in nearly all males by adulthood [<a class="bk_pop" href="#x-ald.REF.huffnagel.2019.30">Huffnagel et al 2019</a>].</p><p>The X-ALD biochemical phenotype of elevated plasma concentration of VLCFAs has 100% penetrance in males regardless of age [<a class="bk_pop" href="#x-ald.REF.engelen.2022.940">Engelen et al 2022</a>].</p></div><div id="x-ald.Nomenclature"><h3>Nomenclature</h3><p>Siemerling-Creuzfeldt disease is the eponym for X-ALD.</p><p>Historically, the eponym Schilder's disease referred to several clinical entities including X-ALD; on occasion, families may have been given this diagnosis. Schilder's disease is still sometimes (incorrectly) used to refer to sudanophilic cerebral sclerosis and certain forms of multiple sclerosis, which may lead to diagnostic confusion.</p><p>Childhood cerebral adrenoleukodystrophy (cCALD) may also be referred to as cerebral adrenoleukodystrophy (CALD), but it should be emphasized that cerebral involvement may occur at any age.</p><p>Primary adrenocortical insufficiency may also be referred to as Addison disease.</p></div><div id="x-ald.Prevalence"><h3>Prevalence</h3><p>The prevalence of X-ALD is estimated at between one in 14,000 and one in 17,000 male births [<a class="bk_pop" href="#x-ald.REF.gupta.2022.1151">Gupta et al 2022</a>].</p></div></div><div id="x-ald.Genetically_Related_Allelic_Disord"><h2 id="_x-ald_Genetically_Related_Allelic_Disord_">Genetically Related (Allelic) Disorders</h2><p>No phenotypes other than those discussed in this <i>GeneReview</i> are known to be associated with germline pathogenic variants in <i>ABCD1</i>.</p><p>A <b>contiguous deletion syndrome</b> involving <i>BCAP31</i> and the 5' end of <i>ABCD1</i> (termed CADDS [<b>c</b>ontiguous <b><i>A</i></b><i>BCD1/</i><b><i>D</i></b><i>XS1357E</i>
|
|
<b>d</b>eletion <b>s</b>yndrome]; OMIM <a href="https://omim.org/entry/300475" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">300475</a>) has been described in males with a phenotype that is earlier in onset and distinct from the phenotypes resulting from pathogenic variants in <i>ABCD1</i> alone. Neonatal cholestasis, hypotonia, and developmental delay have been reported in males with CADDS, and all affected males died before age one year [<a class="bk_pop" href="#x-ald.REF.calhoun.2014.2613">Calhoun & Raymond 2014</a>, <a class="bk_pop" href="#x-ald.REF.van_de_kamp.2015.141">van de Kamp et al 2015</a>]. Plasma very long-chain fatty acid concentrations were elevated in males with CADDS, but the remainder of the clinical features appear to be due to the loss of <i>BCAP31</i> [<a class="bk_pop" href="#x-ald.REF.cacciagli.2013.579">Cacciagli et al 2013</a>].</p></div><div id="x-ald.Differential_Diagnosis"><h2 id="_x-ald_Differential_Diagnosis_">Differential Diagnosis</h2><p>Peroxisomal biogenesis disorders with elevated plasma very long-chain fatty acids are summarized in <a href="/books/NBK1315/table/x-ald.T.peroxisomal_biogenesis_disorders/?report=objectonly" target="object" rid-ob="figobxaldTperoxisomalbiogenesisdisorders">Table 3</a>.</p><div id="x-ald.T.peroxisomal_biogenesis_disorders" class="table"><h3><span class="label">Table 3. </span></h3><div class="caption"><p>Peroxisomal Biogenesis Disorders with Elevated Plasma Very Long-Chain Fatty Acids</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK1315/table/x-ald.T.peroxisomal_biogenesis_disorders/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__x-ald.T.peroxisomal_biogenesis_disorders_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_x-ald.T.peroxisomal_biogenesis_disorders_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Gene</th><th id="hd_h_x-ald.T.peroxisomal_biogenesis_disorders_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Disorder</th><th id="hd_h_x-ald.T.peroxisomal_biogenesis_disorders_1_1_1_3" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">MOI</th></tr></thead><tbody><tr><td headers="hd_h_x-ald.T.peroxisomal_biogenesis_disorders_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
|
<i>ABCD1</i>
|
|
</td><td headers="hd_h_x-ald.T.peroxisomal_biogenesis_disorders_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">X-linked adrenoleukodystrophy (topic of this <i>GeneReview</i>)</td><td headers="hd_h_x-ald.T.peroxisomal_biogenesis_disorders_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">XL</td></tr><tr><td headers="hd_h_x-ald.T.peroxisomal_biogenesis_disorders_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
|
<i>ACBD5</i>
|
|
</td><td headers="hd_h_x-ald.T.peroxisomal_biogenesis_disorders_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Retinal dystrophy w/leukodystrophy (OMIM <a href="https://omim.org/entry/618863" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">618863</a>)</td><td headers="hd_h_x-ald.T.peroxisomal_biogenesis_disorders_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">AR</td></tr><tr><td headers="hd_h_x-ald.T.peroxisomal_biogenesis_disorders_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
|
<i>ACOX1</i>
|
|
</td><td headers="hd_h_x-ald.T.peroxisomal_biogenesis_disorders_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Acyl-coenzyme A oxidase deficiency (OMIM <a href="https://omim.org/entry/264470" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">264470</a>)</td><td headers="hd_h_x-ald.T.peroxisomal_biogenesis_disorders_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">AR</td></tr><tr><td headers="hd_h_x-ald.T.peroxisomal_biogenesis_disorders_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
|
<i>DNM1L</i>
|
|
</td><td headers="hd_h_x-ald.T.peroxisomal_biogenesis_disorders_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Lethal encephalopathy due to defective mitochondrial peroxisomal fission 1 (OMIM <a href="https://omim.org/entry/614388" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">614388</a>)</td><td headers="hd_h_x-ald.T.peroxisomal_biogenesis_disorders_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">AD<br />AR</td></tr><tr><td headers="hd_h_x-ald.T.peroxisomal_biogenesis_disorders_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
|
<i>HSD17B4</i>
|
|
</td><td headers="hd_h_x-ald.T.peroxisomal_biogenesis_disorders_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">D-bifunctional enzyme deficiency (OMIM <a href="https://omim.org/entry/261515" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">261515</a>)</td><td headers="hd_h_x-ald.T.peroxisomal_biogenesis_disorders_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">AR</td></tr><tr><td headers="hd_h_x-ald.T.peroxisomal_biogenesis_disorders_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><i>PEX</i> genes</td><td headers="hd_h_x-ald.T.peroxisomal_biogenesis_disorders_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
|
<a href="/books/n/gene/pbd/">Zellweger spectrum disorder</a>
|
|
</td><td headers="hd_h_x-ald.T.peroxisomal_biogenesis_disorders_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">AR <sup>1</sup></td></tr><tr><td headers="hd_h_x-ald.T.peroxisomal_biogenesis_disorders_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
|
<i>SCP2</i>
|
|
</td><td headers="hd_h_x-ald.T.peroxisomal_biogenesis_disorders_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Leukoencephalopathy w/dystonia & motor neuropathy (OMIM <a href="https://omim.org/entry/613724" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">613724</a>)</td><td headers="hd_h_x-ald.T.peroxisomal_biogenesis_disorders_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">AR</td></tr></tbody></table></div><div><div><dl class="temp-labeled-list small"><dt></dt><dd><div><p class="no_margin">AD = autosomal dominant; AR = autosomal recessive; MOI = mode of inheritance; XL = X-linked</p></div></dd><dt>1. </dt><dd><div id="x-ald.TF.3.1"><p class="no_margin">Zellweger spectrum disorder (ZSD) is typically inherited in an autosomal recessive manner; however, one <i>PEX6</i> pathogenic variant, p.Arg860Trp, has been associated with ZSD in the heterozygous state.</p></div></dd></dl></div></div></div><p><b>Females.</b> See <a href="/books/n/gene/hsp/">Hereditary Spastic Paraplegia Overview</a> for other genetic causes of spastic paraparesis and a review of genetic and acquired conditions in the differential diagnosis of hereditary spastic paraplegia.</p></div><div id="x-ald.Management"><h2 id="_x-ald_Management_">Management</h2><p>With the institution of newborn screening and increasing numbers of individuals being diagnosed with X-linked adrenoleukodystrophy (X-ALD), clinical practice guidelines have been developed for diagnosis and treatment; see <a class="bk_pop" href="#x-ald.REF.regelmann.2018.4324">Regelmann et al [2018]</a> (<a href="https://academic.oup.com/jcem/article/103/11/4324/5114467?login=false" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">full text</a>), <a class="bk_pop" href="#x-ald.REF.engelen.2022.940">Engelen et al [2022]</a> (<a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9687408/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">full text</a>), and <a class="bk_pop" href="#x-ald.REF.mallack.2022b.e512">Mallack et al [2022b]</a> (<a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9421600/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">full text</a>).</p><div id="x-ald.Evaluations_Following_Initial_Diag"><h3>Evaluations Following Initial Diagnosis</h3><div id="x-ald.Confirmed_Positive_Newborn_Screeni"><h4>Confirmed Positive Newborn Screening Result: Initial Evaluations</h4><p>For male infants with a positive newborn screening (NBS) result for X-ALD, the initial evaluations summarized in <a href="/books/NBK1315/table/x-ald.T.recommended_evaluations_and_next/?report=objectonly" target="object" rid-ob="figobxaldTrecommendedevaluationsandnext">Table 4</a> are recommended in order to prevent life-threatening complications of primary adrenal insufficiency and to develop a plan for neurologic and brain MRI monitoring to identify promptly those at risk for childhood cerebral adrenoleukodystrophy (cCALD). Boys identified with early changes on brain MRI consistent with cCALD are candidates for targeted therapy to prevent progression of central nervous system disease.</p><div id="x-ald.T.recommended_evaluations_and_next" class="table"><h3><span class="label">Table 4. </span></h3><div class="caption"><p>Recommended Evaluations and Next Steps for Infants with a Confirmed Positive Newborn Screening Result for X-Linked Adrenoleukodystrophy</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK1315/table/x-ald.T.recommended_evaluations_and_next/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__x-ald.T.recommended_evaluations_and_next_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_x-ald.T.recommended_evaluations_and_next_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">System/Concern</th><th id="hd_h_x-ald.T.recommended_evaluations_and_next_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Issue</th><th id="hd_h_x-ald.T.recommended_evaluations_and_next_1_1_1_3" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Comment</th></tr></thead><tbody><tr><td headers="hd_h_x-ald.T.recommended_evaluations_and_next_1_1_1_1" rowspan="3" scope="row" colspan="1" style="text-align:left;vertical-align:middle;">
|
|
<b>Males at risk for primary adrenocortical insufficiency <sup>1</sup></b>
|
|
</td><td headers="hd_h_x-ald.T.recommended_evaluations_and_next_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Immediate referral to pediatric endocrinologist</td><td headers="hd_h_x-ald.T.recommended_evaluations_and_next_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Screening for ACTH & cortisol levels</div></li><li class="half_rhythm"><div>Follow up per Pediatric Endocrine Society published guidance recommendations <sup>1</sup></div></li></ul>
|
|
</td></tr><tr><td headers="hd_h_x-ald.T.recommended_evaluations_and_next_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">Treatment of documented primary adrenocortical insufficiency</td><td headers="hd_h_x-ald.T.recommended_evaluations_and_next_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">By pediatric endocrinologist per published guidance recommendations <sup>1</sup></td></tr><tr><td headers="hd_h_x-ald.T.recommended_evaluations_and_next_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">Institute plan for scheduled screening throughout childhood & adulthood</td><td headers="hd_h_x-ald.T.recommended_evaluations_and_next_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Recommended screening every 3-6 mos until age 10 yrs, then yearly thereafter <sup>2</sup></td></tr><tr><td headers="hd_h_x-ald.T.recommended_evaluations_and_next_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
|
<b>Males at risk for cCALD</b>
|
|
</td><td headers="hd_h_x-ald.T.recommended_evaluations_and_next_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Referral to neurologist or biochemical geneticist to develop plan for neurologic & brain MRI monitoring to identify promptly those at risk for cCALD <sup>3</sup></td><td headers="hd_h_x-ald.T.recommended_evaluations_and_next_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">See <a href="/books/NBK1315/table/x-ald.T.recommended_brain_mri_schedule_f/?report=objectonly" target="object" rid-ob="figobxaldTrecommendedbrainmrischedulef">Table 8</a> for age-related recommended intervals for repeat brain MRI.</td></tr><tr><td headers="hd_h_x-ald.T.recommended_evaluations_and_next_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
|
<b>Genetic counseling</b>
|
|
</td><td headers="hd_h_x-ald.T.recommended_evaluations_and_next_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">By genetics professionals <sup>4</sup></td><td headers="hd_h_x-ald.T.recommended_evaluations_and_next_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>To inform affected persons & their families re nature, MOI, & implications of X-ALD to facilitate medical & personal decision making</div></li><li class="half_rhythm"><div>To identify male relatives at risk for X-ALD (At-risk males may be identified by use of plasma or serum VLCFA levels or <i>ABCD1</i> testing. Affected males should be evaluated as recommended in this table.)</div></li></ul>
|
|
</td></tr></tbody></table></div><div><div><dl class="temp-labeled-list small"><dt></dt><dd><div><p class="no_margin">ACTH = adrenocorticotropic hormone; CALD = cerebral adrenoleukodystrophy; cCALD = childhood cerebral adrenoleukodystrophy; VLCFA = very long-chain fatty acid; X-ALD = X-linked adrenoleukodystrophy</p></div></dd><dt>1. </dt><dd><div id="x-ald.TF.4.1"><p class="no_margin">
|
|
<a class="bk_pop" href="#x-ald.REF.regelmann.2018.4324">Regelmann et al [2018]</a>
|
|
</p></div></dd><dt>2. </dt><dd><div id="x-ald.TF.4.2"><p class="no_margin">
|
|
<a class="bk_pop" href="#x-ald.REF.engelen.2022.940">Engelen et al [2022]</a>
|
|
</p></div></dd><dt>3. </dt><dd><div id="x-ald.TF.4.3"><p class="no_margin"><a class="bk_pop" href="#x-ald.REF.mallack.2021b.728">Mallack et al [2021b]</a>, <a class="bk_pop" href="#x-ald.REF.mallack.2022b.e512">Mallack et al [2022b]</a></p></div></dd><dt>4. </dt><dd><div id="x-ald.TF.4.4"><p class="no_margin">Medical geneticist, certified genetic counselor, certified advanced genetic nurse</p></div></dd></dl></div></div></div></div><div id="x-ald.Males_with_Symptomatic_cCALD_Initi"><h4>Males with Symptomatic cCALD: Initial Evaluations</h4><p>Recommended initial evaluations for symptomatic males with cCALD are summarized in <a href="/books/NBK1315/table/x-ald.T.recommended_evaluations_followin/?report=objectonly" target="object" rid-ob="figobxaldTrecommendedevaluationsfollowin">Table 5</a>.</p><div id="x-ald.T.recommended_evaluations_followin" class="table"><h3><span class="label">Table 5. </span></h3><div class="caption"><p>Recommended Evaluations Following Initial Diagnosis in Symptomatic Males with Childhood Cerebral Adrenoleukodystrophy (cCALD)</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK1315/table/x-ald.T.recommended_evaluations_followin/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__x-ald.T.recommended_evaluations_followin_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_x-ald.T.recommended_evaluations_followin_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">System/Concern</th><th id="hd_h_x-ald.T.recommended_evaluations_followin_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Evaluation</th><th id="hd_h_x-ald.T.recommended_evaluations_followin_1_1_1_3" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Comment</th></tr></thead><tbody><tr><td headers="hd_h_x-ald.T.recommended_evaluations_followin_1_1_1_1" rowspan="2" scope="row" colspan="1" style="text-align:left;vertical-align:middle;">
|
|
<b>Neurologic impairment</b>
|
|
</td><td headers="hd_h_x-ald.T.recommended_evaluations_followin_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">By pediatric neurologist</td><td headers="hd_h_x-ald.T.recommended_evaluations_followin_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Assess for:
|
|
<ul><li class="half_rhythm"><div>Specific neurologic deficits (e.g., hemiparesis, visual field defect);</div></li><li class="half_rhythm"><div>Seizures if history is suggestive.</div></li></ul>
|
|
In presence of above, perform brain MRI if not performed at time of initial eval.</td></tr><tr><td headers="hd_h_x-ald.T.recommended_evaluations_followin_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">Consultation w/X-ALD comprehensive center w/experience in transplantation or ex vivo gene therapy</td><td headers="hd_h_x-ald.T.recommended_evaluations_followin_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Assess for eligibility for <a href="#x-ald.Targeted_Therapy">targeted therapy</a>.</td></tr><tr><td headers="hd_h_x-ald.T.recommended_evaluations_followin_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
|
<b>Behavioral issues</b>
|
|
</td><td headers="hd_h_x-ald.T.recommended_evaluations_followin_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Behavioral assessment by developmental pediatrician, primary care physician</td><td headers="hd_h_x-ald.T.recommended_evaluations_followin_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Assess for:
|
|
<ul><li class="half_rhythm"><div>Behaviors that may respond to medication;</div></li><li class="half_rhythm"><div>Aggressive or disinhibited behavior.</div></li></ul>
|
|
</td></tr><tr><td headers="hd_h_x-ald.T.recommended_evaluations_followin_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
|
<b>Developmental delay/regression</b>
|
|
</td><td headers="hd_h_x-ald.T.recommended_evaluations_followin_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Developmental assessment</td><td headers="hd_h_x-ald.T.recommended_evaluations_followin_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Assess:
|
|
<ul><li class="half_rhythm"><div>Educational needs;</div></li><li class="half_rhythm"><div>Need for OT service;</div></li><li class="half_rhythm"><div>Need for PT services incl durable medical equipment.</div></li></ul>
|
|
</td></tr><tr><td headers="hd_h_x-ald.T.recommended_evaluations_followin_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
|
<b>Speech impairment</b>
|
|
</td><td headers="hd_h_x-ald.T.recommended_evaluations_followin_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">By speech-language pathologist</td><td headers="hd_h_x-ald.T.recommended_evaluations_followin_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Assess for aphasia & need for alternative means of communication.</td></tr><tr><td headers="hd_h_x-ald.T.recommended_evaluations_followin_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
|
<b>Adrenocortical insufficiency</b>
|
|
</td><td headers="hd_h_x-ald.T.recommended_evaluations_followin_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">By pediatric endocrinologist</td><td headers="hd_h_x-ald.T.recommended_evaluations_followin_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Screening tests per Pediatric Endocrine Society published guidance recommendations <sup>1</sup></td></tr><tr><td headers="hd_h_x-ald.T.recommended_evaluations_followin_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
|
<b>Genetic counseling</b>
|
|
</td><td headers="hd_h_x-ald.T.recommended_evaluations_followin_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">By genetics professionals <sup>2</sup></td><td headers="hd_h_x-ald.T.recommended_evaluations_followin_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>To inform affected persons & their families re nature, MOI, & implications of cCALD to facilitate medical & personal decision making</div></li><li class="half_rhythm"><div>To identify male relatives at risk for X-ALD (At-risk males may be identified by use of plasma or serum VLCFA levels or <i>ABCD1</i> testing. Affected males should be evaluated as recommended in <a href="/books/NBK1315/table/x-ald.T.recommended_evaluations_and_next/?report=objectonly" target="object" rid-ob="figobxaldTrecommendedevaluationsandnext">Table 4</a>.)</div></li></ul>
|
|
</td></tr><tr><td headers="hd_h_x-ald.T.recommended_evaluations_followin_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
|
<b>Family support</b>
|
|
<br />
|
|
<b>& resources</b>
|
|
</td><td headers="hd_h_x-ald.T.recommended_evaluations_followin_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Assess need for:
|
|
<ul><li class="half_rhythm"><div>Community or <a href="#x-ald.Resources">online resources</a> such as <a href="https://www.p2pusa.org/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">Parent to Parent</a>;</div></li><li class="half_rhythm"><div>Social work involvement for parental/family support;</div></li><li class="half_rhythm"><div>Home nursing referral.</div></li></ul>
|
|
</td><td headers="hd_h_x-ald.T.recommended_evaluations_followin_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr></tbody></table></div><div><div><dl class="temp-labeled-list small"><dt></dt><dd><div><p class="no_margin">cCALD = childhood cerebral adrenoleukodystrophy; VLCFA = very long-chain fatty acid; X-ALD = X-linked adrenoleukodystrophy</p></div></dd><dt>1. </dt><dd><div id="x-ald.TF.5.1"><p class="no_margin">
|
|
<a class="bk_pop" href="#x-ald.REF.regelmann.2018.4324">Regelmann et al [2018]</a>
|
|
</p></div></dd><dt>2. </dt><dd><div id="x-ald.TF.5.2"><p class="no_margin">Medical geneticist, certified genetic counselor, certified advanced genetic nurse</p></div></dd></dl></div></div></div></div><div id="x-ald.Males_and_Females_with_Adrenomyelo"><h4>Males and Females with Adrenomyeloneuropathy (AMN): Initial Evaluations</h4><p>For recommended initial evaluations for males and females who have adrenomyeloneuropathy (AMN), see <a href="/books/NBK1315/table/x-ald.T.recommended_evaluations_followin_1/?report=objectonly" target="object" rid-ob="figobxaldTrecommendedevaluationsfollowin1">Table 6</a>.</p><div id="x-ald.T.recommended_evaluations_followin_1" class="table"><h3><span class="label">Table 6. </span></h3><div class="caption"><p>Recommended Evaluations Following Initial Diagnosis in Males and Females with Adrenomyeloneuropathy (AMN)</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK1315/table/x-ald.T.recommended_evaluations_followin_1/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__x-ald.T.recommended_evaluations_followin_1_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_x-ald.T.recommended_evaluations_followin_1_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">System/Concern</th><th id="hd_h_x-ald.T.recommended_evaluations_followin_1_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Evaluation</th><th id="hd_h_x-ald.T.recommended_evaluations_followin_1_1_1_1_3" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Comment</th></tr></thead><tbody><tr><td headers="hd_h_x-ald.T.recommended_evaluations_followin_1_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
|
<b>Neurologic impairment</b>
|
|
</td><td headers="hd_h_x-ald.T.recommended_evaluations_followin_1_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">By neurologist</td><td headers="hd_h_x-ald.T.recommended_evaluations_followin_1_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Assess for cognitive impairment, progressive spastic gait disturbance, paralysis, ataxia, weakness, & restless legs syndrome.</div></li><li class="half_rhythm"><div>Brain MRI to assess for cerebral disease (Spine MRIs are generally not helpful.)</div></li><li class="half_rhythm"><div>Further services such as mental health, speech, & behavior if appropriate</div></li></ul>
|
|
</td></tr><tr><td headers="hd_h_x-ald.T.recommended_evaluations_followin_1_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
|
<b>Sleep disturbance</b>
|
|
</td><td headers="hd_h_x-ald.T.recommended_evaluations_followin_1_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">By neurologist or sleep specialist</td><td headers="hd_h_x-ald.T.recommended_evaluations_followin_1_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Assess for clonus &/or pain</td></tr><tr><td headers="hd_h_x-ald.T.recommended_evaluations_followin_1_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
|
<b>Neurogenic bladder</b>
|
|
</td><td headers="hd_h_x-ald.T.recommended_evaluations_followin_1_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">By urologist</td><td headers="hd_h_x-ald.T.recommended_evaluations_followin_1_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Eval & treatment per standard practice</td></tr><tr><td headers="hd_h_x-ald.T.recommended_evaluations_followin_1_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
|
<b>Bowel incontinence</b>
|
|
</td><td headers="hd_h_x-ald.T.recommended_evaluations_followin_1_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">By gastroenterologist</td><td headers="hd_h_x-ald.T.recommended_evaluations_followin_1_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Eval & treatment of constipation or incontinence per standard practice</td></tr><tr><td headers="hd_h_x-ald.T.recommended_evaluations_followin_1_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
|
<b>Sexual dysfunction</b>
|
|
</td><td headers="hd_h_x-ald.T.recommended_evaluations_followin_1_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">By urologist</td><td headers="hd_h_x-ald.T.recommended_evaluations_followin_1_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Eval & treatment of sexual dysfunction per standard practice</td></tr><tr><td headers="hd_h_x-ald.T.recommended_evaluations_followin_1_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
|
<b>Adrenocortical insufficiency</b>
|
|
</td><td headers="hd_h_x-ald.T.recommended_evaluations_followin_1_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">By endocrinologist</td><td headers="hd_h_x-ald.T.recommended_evaluations_followin_1_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Males: yearly ACTH & cortisol levels</td></tr><tr><td headers="hd_h_x-ald.T.recommended_evaluations_followin_1_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
|
<b>Genetic counseling</b>
|
|
</td><td headers="hd_h_x-ald.T.recommended_evaluations_followin_1_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">By genetics professionals <sup>1</sup></td><td headers="hd_h_x-ald.T.recommended_evaluations_followin_1_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>To inform affected persons & their families re nature, MOI, & implications of X-ALD to facilitate medical & personal decision making</div></li><li class="half_rhythm"><div>To identify male relatives at risk for X-ALD (At-risk males may be identified by use of plasma or serum VLCFA levels or <i>ABCD1</i> testing. Affected males should be evaluated as recommended in <a href="/books/NBK1315/table/x-ald.T.recommended_evaluations_and_next/?report=objectonly" target="object" rid-ob="figobxaldTrecommendedevaluationsandnext">Table 4</a>.)</div></li></ul>
|
|
</td></tr><tr><td headers="hd_h_x-ald.T.recommended_evaluations_followin_1_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
|
<b>Family support</b>
|
|
<br />
|
|
<b>& resources</b>
|
|
</td><td headers="hd_h_x-ald.T.recommended_evaluations_followin_1_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Assess need for:
|
|
<ul><li class="half_rhythm"><div>Community or <a href="#x-ald.Resources">online resources</a>;</div></li><li class="half_rhythm"><div>Social work involvement for parental/family support.</div></li></ul>
|
|
</td><td headers="hd_h_x-ald.T.recommended_evaluations_followin_1_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr></tbody></table></div><div><div><dl class="temp-labeled-list small"><dt></dt><dd><div><p class="no_margin">ACTH = adrenocorticotropic hormone; VLCFA = very long-chain fatty acid; X-ALD = X-linked adrenoleukodystrophy</p></div></dd><dt>1. </dt><dd><div id="x-ald.TF.6.1"><p class="no_margin">Medical geneticist, certified genetic counselor, certified advanced genetic nurse</p></div></dd></dl></div></div></div></div><div id="x-ald.Males_Identified_by_Family_Screeni"><h4>Males Identified by Family Screening: Initial Evaluations and Next Steps</h4><p>Males identified by family screening may be any age (infancy through adulthood), and the urgency of evaluation will depend on age at diagnosis. See <a href="/books/NBK1315/table/x-ald.T.recommended_evaluations_and_next_1/?report=objectonly" target="object" rid-ob="figobxaldTrecommendedevaluationsandnext1">Table 7</a> for recommended initial evaluations and next steps.</p><div id="x-ald.T.recommended_evaluations_and_next_1" class="table"><h3><span class="label">Table 7. </span></h3><div class="caption"><p>Recommended Evaluations and Next Steps for Males Identified by Family Screening</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK1315/table/x-ald.T.recommended_evaluations_and_next_1/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__x-ald.T.recommended_evaluations_and_next_1_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_x-ald.T.recommended_evaluations_and_next_1_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">System/Concern</th><th id="hd_h_x-ald.T.recommended_evaluations_and_next_1_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Evaluation</th><th id="hd_h_x-ald.T.recommended_evaluations_and_next_1_1_1_1_3" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Comment</th></tr></thead><tbody><tr><td headers="hd_h_x-ald.T.recommended_evaluations_and_next_1_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
|
<b>Neurologic assessment</b>
|
|
</td><td headers="hd_h_x-ald.T.recommended_evaluations_and_next_1_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Brain MRI</td><td headers="hd_h_x-ald.T.recommended_evaluations_and_next_1_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"><ul><li class="half_rhythm"><div>Assess for presence of cerebral disease.</div></li><li class="half_rhythm"><div>Urgency will depend on age of affected person. Males age <2-10 yrs need expedited imaging (see <a href="/books/NBK1315/table/x-ald.T.recommended_brain_mri_schedule_f/?report=objectonly" target="object" rid-ob="figobxaldTrecommendedbrainmrischedulef">Table 8</a>).</div></li></ul>
|
|
</td></tr><tr><td headers="hd_h_x-ald.T.recommended_evaluations_and_next_1_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
|
<b>Endocrine</b>
|
|
</td><td headers="hd_h_x-ald.T.recommended_evaluations_and_next_1_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"><ul><li class="half_rhythm"><div>ACTH & cortisol levels</div></li><li class="half_rhythm"><div>Referral to pediatric endocrinology</div></li></ul>
|
|
</td><td headers="hd_h_x-ald.T.recommended_evaluations_and_next_1_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Replacement glucocorticoid therapy</td></tr><tr><td headers="hd_h_x-ald.T.recommended_evaluations_and_next_1_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
|
<b>Genetic counseling</b>
|
|
</td><td headers="hd_h_x-ald.T.recommended_evaluations_and_next_1_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">By genetics professionals <sup>1</sup></td><td headers="hd_h_x-ald.T.recommended_evaluations_and_next_1_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"><ul><li class="half_rhythm"><div>To inform affected persons & their families re nature, MOI, & implications of X-ALD to facilitate medical & personal decision making</div></li><li class="half_rhythm"><div>To identify male relatives at risk for X-ALD & primary adrenocortical insufficiency who might warrant diagnostic eval & treatment/screening as recommended in <a href="/books/NBK1315/table/x-ald.T.recommended_evaluations_and_next/?report=objectonly" target="object" rid-ob="figobxaldTrecommendedevaluationsandnext">Table 4</a>.</div></li></ul>
|
|
</td></tr><tr><td headers="hd_h_x-ald.T.recommended_evaluations_and_next_1_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
|
<b>Family support</b>
|
|
<br />
|
|
<b>& resources</b>
|
|
</td><td headers="hd_h_x-ald.T.recommended_evaluations_and_next_1_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Assess need for:
|
|
<ul><li class="half_rhythm"><div>Community or <a href="#x-ald.Resources">online resources</a>;</div></li><li class="half_rhythm"><div>Social work involvement for parental/family support.</div></li></ul>
|
|
</td><td headers="hd_h_x-ald.T.recommended_evaluations_and_next_1_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td></tr></tbody></table></div><div><div><dl class="temp-labeled-list small"><dt></dt><dd><div><p class="no_margin">ACTH = adrenocorticotropic hormone; X-ALD = X-linked adrenoleukodystrophy</p></div></dd><dt>1. </dt><dd><div id="x-ald.TF.7.1"><p class="no_margin">Medical geneticist, certified genetic counselor, certified advanced genetic nurse</p></div></dd></dl></div></div></div></div></div><div id="x-ald.Treatment_of_Manifestations"><h3>Treatment of Manifestations</h3><p>There is no cure for X-linked adrenoleukodystrophy (X-ALD).</p><div id="x-ald.Targeted_Therapy"><h4>Targeted Therapy</h4><p>
|
|
<i>In GeneReviews, a targeted therapy is one that addresses the specific underlying mechanism of disease causation (regardless of whether the therapy is significantly efficacious for one or more manifestation of the genetic condition); would otherwise not be considered without knowledge of the underlying genetic cause of the condition; or could lead to a cure</i>. —ED</p><div id="x-ald.Childhood_Cerebral_Adrenoleukodyst_1"><h5>
|
|
<b>Childhood Cerebral Adrenoleukodystrophy (cCALD)</b>
|
|
</h5><p>Evidence clearly shows that hematopoietic stem cell transplantation (HSCT) has the best outcome when performed on an asymptomatic individual with minimal but characteristic imaging findings of cCALD [<a class="bk_pop" href="#x-ald.REF.gupta.2022.1151">Gupta et al 2022</a>].</p><p>Early-stage cCALD brain MRI findings are characterized by small T<sub>2</sub> hyperintensities centered most often within the splenium or genu of the corpus callosum; less often they may appear in the corticospinal tracts or cerebellar white matter. Since normal imaging findings may occasionally be mistaken for early disease, it is strongly recommended that all findings be confirmed by a neuroradiologist with experience in this condition [<a class="bk_pop" href="#x-ald.REF.gupta.2022.1151">Gupta et al 2022</a>].</p><p>See <a href="/books/NBK1315/table/x-ald.T.recommended_brain_mri_schedule_f/?report=objectonly" target="object" rid-ob="figobxaldTrecommendedbrainmrischedulef">Table 8</a> for a recommended schedule of brain MRI monitoring of at-risk males for early identification of cCALD to detect brain abnormalities that occur well in advance of clinical disease [<a class="bk_pop" href="#x-ald.REF.loes.2003.369">Loes et al 2003</a>, <a class="bk_pop" href="#x-ald.REF.mallack.2021a.1904">Mallack et al 2021a</a>, <a class="bk_pop" href="#x-ald.REF.mallack.2022b.e512">Mallack et al 2022b</a>].</p><div id="x-ald.T.recommended_brain_mri_schedule_f" class="table"><h3><span class="label">Table 8. </span></h3><div class="caption"><p>Recommended Brain MRI Schedule for Early Detection of Childhood Cerebral Adrenoleukodystrophy (cCALD) Abnormalities in At-Risk Males</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK1315/table/x-ald.T.recommended_brain_mri_schedule_f/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__x-ald.T.recommended_brain_mri_schedule_f_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_x-ald.T.recommended_brain_mri_schedule_f_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Age</th><th id="hd_h_x-ald.T.recommended_brain_mri_schedule_f_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Interval</th><th id="hd_h_x-ald.T.recommended_brain_mri_schedule_f_1_1_1_3" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Type of Brain MRI</th><th id="hd_h_x-ald.T.recommended_brain_mri_schedule_f_1_1_1_4" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Comment</th></tr></thead><tbody><tr><td headers="hd_h_x-ald.T.recommended_brain_mri_schedule_f_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">12 mos - 3 yrs</td><td headers="hd_h_x-ald.T.recommended_brain_mri_schedule_f_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Yearly</td><td headers="hd_h_x-ald.T.recommended_brain_mri_schedule_f_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Standard T<sub>1</sub>/T<sub>2</sub>-weighted sequences</td><td headers="hd_h_x-ald.T.recommended_brain_mri_schedule_f_1_1_1_4" rowspan="2" colspan="1" style="text-align:left;vertical-align:middle;">Use of general anesthesia is advisable until the boy can lie still.</td></tr><tr><td headers="hd_h_x-ald.T.recommended_brain_mri_schedule_f_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">3-12 yrs</td><td headers="hd_h_x-ald.T.recommended_brain_mri_schedule_f_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Every 6 mos</td><td headers="hd_h_x-ald.T.recommended_brain_mri_schedule_f_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Standard T<sub>1</sub>/T<sub>2</sub>-weighted sequences w/contrast</td></tr><tr><td headers="hd_h_x-ald.T.recommended_brain_mri_schedule_f_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">>12 yrs</td><td headers="hd_h_x-ald.T.recommended_brain_mri_schedule_f_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Yearly</td><td headers="hd_h_x-ald.T.recommended_brain_mri_schedule_f_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Standard T<sub>1</sub>/T<sub>2</sub>-weighted sequences</td><td headers="hd_h_x-ald.T.recommended_brain_mri_schedule_f_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Repeat yearly; some males develop cerebral changes in adulthood.</td></tr></tbody></table></div><div><div><dl class="temp-labeled-list small"><dt></dt><dd><div><p class="no_margin">Based on <a class="bk_pop" href="#x-ald.REF.loes.2003.369">Loes et al [2003]</a>, <a class="bk_pop" href="#x-ald.REF.mallack.2021a.1904">Mallack et al [2021a]</a>, <a class="bk_pop" href="#x-ald.REF.mallack.2022b.e512">Mallack et al [2022b]</a></p></div></dd><dt></dt><dd><div><p class="no_margin">cCALD = childhood cerebral adrenoleukodystrophy</p></div></dd></dl></div></div></div><p>If early-stage cCALD is diagnosed, the boy should be referred to a center with expertise in monitoring and treating cCALD.</p><p>The following are NOT presently recommended for screening males at risk for cCALD:</p><ul><li class="half_rhythm"><div>The routine use of advanced imaging techniques such as spectroscopy or diffusion tensor imaging outside of a research protocol with IRB approval</div></li><li class="half_rhythm"><div>The routine use of neuropsychological testing [<a class="bk_pop" href="#x-ald.REF.engelen.2022.940">Engelen et al 2022</a>]</div></li></ul><p>
|
|
<b>Hematopoietic stem cell transplantation (HSCT)</b>
|
|
</p><ul><li class="half_rhythm"><div class="half_rhythm"><b>Indications and potential benefits.</b> HSCT is only recommended for males with evidence of early cCALD on MRI, which is associated with inflammatory demyelination.</div><div class="half_rhythm">Note: HSCT is not recommended for individuals with severe neurologic and neuropsychological dysfunction (i.e., performance IQ <80) [<a class="bk_pop" href="#x-ald.REF.gupta.2022.1151">Gupta et al 2022</a>].</div></li><li class="half_rhythm"><div class="half_rhythm"><b>Methods used for HSCT.</b> Allogeneic stem cell transplant is performed. Although a matched-sib donor provides the lowest risk, other donor sources include unrelated matched donors and umbilical cord blood. Individuals undergoing an allogeneic stem cell transplant receive a preparatory regimen and appropriate post-procedure support and monitoring. Individuals continue to require monitoring following the procedure, and this may be done either at the center doing the procedure or at a site closer to home.</div></li><li class="half_rhythm"><div class="half_rhythm"><b>Potential risks of HSCT.</b> In X-ALD, HSCT has an overall survival of 82% two years following the transplant and 74% five years following the transplant. Risks involved include the preparatory regimen, transplantation itself, infections, and graft failure. These risks should be considered in the context that untreated cCALD has only an overall 55% survival rate at age five years [<a class="bk_pop" href="#x-ald.REF.raymond.2019.538">Raymond et al 2019</a>]. Factors that improve survival and absence of major functional disabilities following HSCT include matched-sib donors, early detection of disease on neuroimaging, and absence of any neurologic signs at the time of transplant [<a class="bk_pop" href="#x-ald.REF.raymond.2019.538">Raymond et al 2019</a>].</div></li></ul><p><b>Elivaldogene autotemcel (Skysona<sup>®</sup>) therapy.</b> An ex vivo gene therapy has been recently approved in the United States. The manufactured product is elivaldogene autotemcel, marketed under the brand name Skysona<sup>®</sup> [<a class="bk_pop" href="#x-ald.REF.eichler.2017.1630">Eichler et al 2017</a>, <a class="bk_pop" href="#x-ald.REF.gupta.2022.1151">Gupta et al 2022</a>]. Using a lentiviral approach, a working copy of <i>ABCD1</i> is transfected into the patient's precursor hematopoietic cells.</p><ul><li class="half_rhythm"><div class="half_rhythm"><b>Indications and potential benefits.</b> The indications are similar to those presently used in standard-risk HSCT.</div><ul><li class="half_rhythm"><div>Individuals should have early cCALD as seen on contrast-enhanced MRI.</div></li><li class="half_rhythm"><div>They should not have neurologic signs.</div></li><li class="half_rhythm"><div>Neuropsychological testing should indicate a performance IQ greater than 80.</div></li></ul><div class="half_rhythm">An added criterion is absence of a matched-sib donor.</div><div class="half_rhythm">The potential benefit is that risk of graft versus host disease is less than that associated with HSCT.</div></li><li class="half_rhythm"><div class="half_rhythm"><b>Method of administration and dosage.</b> Patients must undergo hematopoietic stem cell mobilization to obtain CD34+ cells for manufacturing of cells. The minimum recommended dose is 5 x 10<sup>6</sup> CD34+ cells per kg. Following conditioning, manufactured cells are given intravenously.</div></li><li class="half_rhythm"><div class="half_rhythm"><b>Potential risks.</b> Hematologic malignancy including instances of myelodysplastic syndrome have occurred in individuals treated with elivaldogene. These cancers appear to be the result of the integration of the elivaldogene lentiviral vector, Lenti-D<sup>®</sup>, into proto-oncogenes. Because of the increased risk of this adverse event in some individuals, subsequent required monitoring is a complete blood count every six months in the first year and then yearly thereafter.</div></li></ul></div></div><div id="x-ald.Supportive_Care"><h4>Supportive Care</h4><div id="x-ald.Childhood_Cerebral_Adrenoleukodyst_2"><h5>
|
|
<b>Childhood Cerebral Adrenoleukodystrophy (cCALD)</b>
|
|
</h5><p>Boys whose neurologic disease is too advanced at the time of diagnosis are not candidates for targeted therapy. Thus, supportive care to improve quality of life, maximize function, and reduce complications is recommended. This ideally involves multidisciplinary care by specialists in relevant fields (see <a href="/books/NBK1315/table/x-ald.T.supportive_treatment_of_manifest/?report=objectonly" target="object" rid-ob="figobxaldTsupportivetreatmentofmanifest">Table 9</a>).</p><div id="x-ald.T.supportive_treatment_of_manifest" class="table"><h3><span class="label">Table 9. </span></h3><div class="caption"><p>Supportive Treatment of Manifestations in Males with Childhood Cerebral Adrenoleukodystrophy (cCALD)</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK1315/table/x-ald.T.supportive_treatment_of_manifest/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__x-ald.T.supportive_treatment_of_manifest_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_x-ald.T.supportive_treatment_of_manifest_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Manifestation/Concern</th><th id="hd_h_x-ald.T.supportive_treatment_of_manifest_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Treatment</th><th id="hd_h_x-ald.T.supportive_treatment_of_manifest_1_1_1_3" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Considerations/Other</th></tr></thead><tbody><tr><td headers="hd_h_x-ald.T.supportive_treatment_of_manifest_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
|
<b>Cognitive decline</b>
|
|
</td><td headers="hd_h_x-ald.T.supportive_treatment_of_manifest_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td><td headers="hd_h_x-ald.T.supportive_treatment_of_manifest_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Need for a 504 plan or IEP services</td></tr><tr><td headers="hd_h_x-ald.T.supportive_treatment_of_manifest_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
|
<b>Seizures</b>
|
|
</td><td headers="hd_h_x-ald.T.supportive_treatment_of_manifest_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">With ASMs by experienced neurologist</td><td headers="hd_h_x-ald.T.supportive_treatment_of_manifest_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">No contraindications for type of anticonvulsant</td></tr><tr><td headers="hd_h_x-ald.T.supportive_treatment_of_manifest_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
|
<b>Behavioral issues</b>
|
|
</td><td headers="hd_h_x-ald.T.supportive_treatment_of_manifest_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">By mental health professional</td><td headers="hd_h_x-ald.T.supportive_treatment_of_manifest_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr><tr><td headers="hd_h_x-ald.T.supportive_treatment_of_manifest_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
|
<b>Communication</b>
|
|
</td><td headers="hd_h_x-ald.T.supportive_treatment_of_manifest_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">By speech-language pathologist</td><td headers="hd_h_x-ald.T.supportive_treatment_of_manifest_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Consider alternative means of communication.</td></tr><tr><td headers="hd_h_x-ald.T.supportive_treatment_of_manifest_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
|
<b>Motor impairment / ADL</b>
|
|
</td><td headers="hd_h_x-ald.T.supportive_treatment_of_manifest_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Orthopedics / physical medicine & rehab / PT & OT incl stretching to help avoid contractures & falls</td><td headers="hd_h_x-ald.T.supportive_treatment_of_manifest_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Consider need for positioning & mobility devices, disability parking placard.</td></tr><tr><td headers="hd_h_x-ald.T.supportive_treatment_of_manifest_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
|
<b>Feeding issues</b>
|
|
</td><td headers="hd_h_x-ald.T.supportive_treatment_of_manifest_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Speech-language therapy or OT</div></li><li class="half_rhythm"><div>Discuss gastrostomy tube placement.</div></li></ul>
|
|
</td><td headers="hd_h_x-ald.T.supportive_treatment_of_manifest_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr><tr><td headers="hd_h_x-ald.T.supportive_treatment_of_manifest_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
|
<b>Adrenocortical insufficiency <sup>1</sup></b>
|
|
</td><td headers="hd_h_x-ald.T.supportive_treatment_of_manifest_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Corticosteroid replacement therapy <sup>2</sup></td><td headers="hd_h_x-ald.T.supportive_treatment_of_manifest_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Children: per treating pediatric endocrinologist</div></li><li class="half_rhythm"><div>Adults: per treating endocrinologist</div></li></ul>
|
|
</td></tr><tr><td headers="hd_h_x-ald.T.supportive_treatment_of_manifest_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
|
<b>Family/Community</b>
|
|
</td><td headers="hd_h_x-ald.T.supportive_treatment_of_manifest_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Ensure appropriate social work involvement to connect families w/local resources, respite, & support.</div></li><li class="half_rhythm"><div>Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies.</div></li></ul>
|
|
</td><td headers="hd_h_x-ald.T.supportive_treatment_of_manifest_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Ongoing assessment of need for palliative care involvement w/home nursing</div></li><li class="half_rhythm"><div>Discussion of hospice</div></li></ul>
|
|
</td></tr></tbody></table></div><div><div><dl class="temp-labeled-list small"><dt></dt><dd><div><p class="no_margin">ADL = activities of daily living; ASM = anti-seizure medication; IEP = individualized education plan; OT = occupational therapy; PT = physical therapy</p></div></dd><dt>1. </dt><dd><div id="x-ald.TF.9.1"><p class="no_margin">
|
|
<a class="bk_pop" href="#x-ald.REF.regelmann.2018.4324">Regelmann et al [2018]</a>
|
|
</p></div></dd><dt>2. </dt><dd><div id="x-ald.TF.9.2"><p class="no_margin">Corticosteroid replacement therapy has no effect on nervous system involvement.</p></div></dd></dl></div></div></div></div><div id="x-ald.Adrenomyeloneuropathy_AMN_1"><h5>
|
|
<b>Adrenomyeloneuropathy (AMN)</b>
|
|
</h5><p>Supportive care for males and females with adrenomyeloneuropathy (AMN) to improve quality of life, maximize function, and reduce complications is recommended. This ideally involves multidisciplinary care by specialists in relevant fields (see <a href="/books/NBK1315/table/x-ald.T.supportive_treatment_of_manifest_1/?report=objectonly" target="object" rid-ob="figobxaldTsupportivetreatmentofmanifest1">Table 10</a>).</p><div id="x-ald.T.supportive_treatment_of_manifest_1" class="table"><h3><span class="label">Table 10. </span></h3><div class="caption"><p>Supportive Treatment of Manifestations in Males and Females with Adrenomyeloneuropathy (AMN)</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK1315/table/x-ald.T.supportive_treatment_of_manifest_1/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__x-ald.T.supportive_treatment_of_manifest_1_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_x-ald.T.supportive_treatment_of_manifest_1_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Manifestation/Concern</th><th id="hd_h_x-ald.T.supportive_treatment_of_manifest_1_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Treatment</th><th id="hd_h_x-ald.T.supportive_treatment_of_manifest_1_1_1_1_3" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Considerations/Other</th></tr></thead><tbody><tr><td headers="hd_h_x-ald.T.supportive_treatment_of_manifest_1_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
|
<b>Cognitive decline</b>
|
|
</td><td headers="hd_h_x-ald.T.supportive_treatment_of_manifest_1_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">By neuropsychologist</td><td headers="hd_h_x-ald.T.supportive_treatment_of_manifest_1_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr><tr><td headers="hd_h_x-ald.T.supportive_treatment_of_manifest_1_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
|
<b>Behavioral issues</b>
|
|
</td><td headers="hd_h_x-ald.T.supportive_treatment_of_manifest_1_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">By mental health providers</td><td headers="hd_h_x-ald.T.supportive_treatment_of_manifest_1_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr><tr><td headers="hd_h_x-ald.T.supportive_treatment_of_manifest_1_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
|
<b>Communication</b>
|
|
</td><td headers="hd_h_x-ald.T.supportive_treatment_of_manifest_1_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">By speech-language pathologist</td><td headers="hd_h_x-ald.T.supportive_treatment_of_manifest_1_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Consider alternative means of communication.</td></tr><tr><td headers="hd_h_x-ald.T.supportive_treatment_of_manifest_1_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
|
<b>Seizures</b>
|
|
</td><td headers="hd_h_x-ald.T.supportive_treatment_of_manifest_1_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">By neurologist</td><td headers="hd_h_x-ald.T.supportive_treatment_of_manifest_1_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Appropriate ASMs</td></tr><tr><td headers="hd_h_x-ald.T.supportive_treatment_of_manifest_1_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
|
<b>Motor impairment / ADL</b>
|
|
</td><td headers="hd_h_x-ald.T.supportive_treatment_of_manifest_1_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Orthopedics / physical medicine & rehab / PT & OT incl stretching to help avoid contractures & falls</td><td headers="hd_h_x-ald.T.supportive_treatment_of_manifest_1_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Consider need for positioning & mobility devices, disability parking placard.</td></tr><tr><td headers="hd_h_x-ald.T.supportive_treatment_of_manifest_1_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
|
<b>Neurogenic bladder</b>
|
|
</td><td headers="hd_h_x-ald.T.supportive_treatment_of_manifest_1_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">By urologist</td><td headers="hd_h_x-ald.T.supportive_treatment_of_manifest_1_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr><tr><td headers="hd_h_x-ald.T.supportive_treatment_of_manifest_1_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
|
<b>Bowel control</b>
|
|
</td><td headers="hd_h_x-ald.T.supportive_treatment_of_manifest_1_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">By gastroenterologist</td><td headers="hd_h_x-ald.T.supportive_treatment_of_manifest_1_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr><tr><td headers="hd_h_x-ald.T.supportive_treatment_of_manifest_1_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
|
<b>Sexual dysfunction</b>
|
|
</td><td headers="hd_h_x-ald.T.supportive_treatment_of_manifest_1_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">By urologist</td><td headers="hd_h_x-ald.T.supportive_treatment_of_manifest_1_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">In males only</td></tr><tr><td headers="hd_h_x-ald.T.supportive_treatment_of_manifest_1_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
|
<b>Emotional & vocational counseling</b>
|
|
</td><td headers="hd_h_x-ald.T.supportive_treatment_of_manifest_1_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">By mental health providers</td><td headers="hd_h_x-ald.T.supportive_treatment_of_manifest_1_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">If necessary</td></tr><tr><td headers="hd_h_x-ald.T.supportive_treatment_of_manifest_1_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
|
<b>Adrenocortical insufficiency <sup>1</sup></b>
|
|
</td><td headers="hd_h_x-ald.T.supportive_treatment_of_manifest_1_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Corticosteroid replacement therapy <sup>2</sup> (which can be lifesaving in males, & is rarely needed in females)</td><td headers="hd_h_x-ald.T.supportive_treatment_of_manifest_1_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Per treating endocrinologist</td></tr><tr><td headers="hd_h_x-ald.T.supportive_treatment_of_manifest_1_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
|
<b>Family/Community</b>
|
|
</td><td headers="hd_h_x-ald.T.supportive_treatment_of_manifest_1_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Ensure appropriate social work involvement to connect families w/local resources, respite, & support.</div></li><li class="half_rhythm"><div>Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies.</div></li></ul>
|
|
</td><td headers="hd_h_x-ald.T.supportive_treatment_of_manifest_1_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Ongoing assessment of need for palliative care involvement &/or home nursing</td></tr></tbody></table></div><div><div><dl class="temp-labeled-list small"><dt></dt><dd><div><p class="no_margin">ADL = activities of daily living; ASM = anti-seizure medication; OT = occupational therapy; PT = physical therapy</p></div></dd><dt>1. </dt><dd><div id="x-ald.TF.10.1"><p class="no_margin">
|
|
<a class="bk_pop" href="#x-ald.REF.regelmann.2018.4324">Regelmann et al [2018]</a>
|
|
</p></div></dd><dt>2. </dt><dd><div id="x-ald.TF.10.2"><p class="no_margin">Corticosteroid replacement therapy has no effect on nervous system involvement.</p></div></dd></dl></div></div></div></div></div></div><div id="x-ald.Surveillance"><h3>Surveillance</h3><div id="x-ald.Childhood_Cerebral_Adrenoleukodyst_3"><h4>Childhood Cerebral Adrenoleukodystrophy (cCALD)</h4><p>To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in <a href="/books/NBK1315/table/x-ald.T.recommended_surveillance_for_mal/?report=objectonly" target="object" rid-ob="figobxaldTrecommendedsurveillanceformal">Table 11</a> are recommended for males with cCALD.</p><div id="x-ald.T.recommended_surveillance_for_mal" class="table"><h3><span class="label">Table 11. </span></h3><div class="caption"><p>Recommended Surveillance for Males with Childhood Cerebral Adrenoleukodystrophy (cCALD)</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK1315/table/x-ald.T.recommended_surveillance_for_mal/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__x-ald.T.recommended_surveillance_for_mal_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_x-ald.T.recommended_surveillance_for_mal_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">System/Concern</th><th id="hd_h_x-ald.T.recommended_surveillance_for_mal_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Evaluation</th><th id="hd_h_x-ald.T.recommended_surveillance_for_mal_1_1_1_3" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Frequency</th></tr></thead><tbody><tr><td headers="hd_h_x-ald.T.recommended_surveillance_for_mal_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
|
<b>Feeding</b>
|
|
</td><td headers="hd_h_x-ald.T.recommended_surveillance_for_mal_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Measurement of growth parameters</div></li><li class="half_rhythm"><div>Eval of nutritional status & safety of oral intake</div></li></ul>
|
|
</td><td headers="hd_h_x-ald.T.recommended_surveillance_for_mal_1_1_1_3" rowspan="5" colspan="1" style="text-align:left;vertical-align:middle;">At each visit</td></tr><tr><td headers="hd_h_x-ald.T.recommended_surveillance_for_mal_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
|
<b>Neurologic</b>
|
|
</td><td headers="hd_h_x-ald.T.recommended_surveillance_for_mal_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Monitor those w/seizures as clinically indicated.</div></li><li class="half_rhythm"><div>Assess for new manifestations such as onset of seizures, changes in tone, & movement disorders.</div></li></ul>
|
|
</td></tr><tr><td headers="hd_h_x-ald.T.recommended_surveillance_for_mal_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
|
<b>Educational</b>
|
|
</td><td headers="hd_h_x-ald.T.recommended_surveillance_for_mal_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Monitor developmental needs & educational progress.</td></tr><tr><td headers="hd_h_x-ald.T.recommended_surveillance_for_mal_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
|
<b>Psychiatric/</b>
|
|
<br />
|
|
<b>Behavioral</b>
|
|
</td><td headers="hd_h_x-ald.T.recommended_surveillance_for_mal_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Behavioral assessment for anxiety, attention, & aggressive or self-injurious behavior</td></tr><tr><td headers="hd_h_x-ald.T.recommended_surveillance_for_mal_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
|
<b>Musculoskeletal</b>
|
|
</td><td headers="hd_h_x-ald.T.recommended_surveillance_for_mal_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Physical medicine, OT/PT assessment of mobility, self-help skills</td></tr><tr><td headers="hd_h_x-ald.T.recommended_surveillance_for_mal_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
|
<b>Adrenocortical insufficiency</b>
|
|
</td><td headers="hd_h_x-ald.T.recommended_surveillance_for_mal_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Endocrine assessment</td><td headers="hd_h_x-ald.T.recommended_surveillance_for_mal_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>For those not yet known to have adrenocortical insufficiency: ACTH & cortisol levels every 6 mos</div></li><li class="half_rhythm"><div>For those w/known adrenocortical insufficiency: per treating endocrinologist, but at least yearly</div></li></ul>
|
|
</td></tr><tr><td headers="hd_h_x-ald.T.recommended_surveillance_for_mal_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
|
<b>Family/Community</b>
|
|
</td><td headers="hd_h_x-ald.T.recommended_surveillance_for_mal_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Assess family need for social work support (e.g., palliative/respite care, home nursing, other local resources), care coordination, or follow-up genetic counseling if new questions arise (e.g., family planning).</td><td headers="hd_h_x-ald.T.recommended_surveillance_for_mal_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">At each visit</td></tr></tbody></table></div><div><div><dl class="temp-labeled-list small"><dt></dt><dd><div><p class="no_margin">ACTH = adrenocorticotropic hormone; OT = occupational therapy; PT = physical therapy</p></div></dd></dl></div></div></div></div><div id="x-ald.Adrenomyeloneuropathy_AMN_2"><h4>Adrenomyeloneuropathy (AMN)</h4><p>To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in <a href="/books/NBK1315/table/x-ald.T.recommended_surveillance_for_mal_1/?report=objectonly" target="object" rid-ob="figobxaldTrecommendedsurveillanceformal1">Table 12</a> are recommended for males and females with AMN.</p><div id="x-ald.T.recommended_surveillance_for_mal_1" class="table"><h3><span class="label">Table 12. </span></h3><div class="caption"><p>Recommended Surveillance for Males and Females with Adrenomyeloneuropathy (AMN)</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK1315/table/x-ald.T.recommended_surveillance_for_mal_1/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__x-ald.T.recommended_surveillance_for_mal_1_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_x-ald.T.recommended_surveillance_for_mal_1_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">System/Concern</th><th id="hd_h_x-ald.T.recommended_surveillance_for_mal_1_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Evaluation</th><th id="hd_h_x-ald.T.recommended_surveillance_for_mal_1_1_1_1_3" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Frequency</th></tr></thead><tbody><tr><td headers="hd_h_x-ald.T.recommended_surveillance_for_mal_1_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
|
<b>Neurologic</b>
|
|
</td><td headers="hd_h_x-ald.T.recommended_surveillance_for_mal_1_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Assess for new manifestations such as changes in tone, symptoms of neurogenic bladder, bowel incontinence, &/or sexual dysfunction.</td><td headers="hd_h_x-ald.T.recommended_surveillance_for_mal_1_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Yearly</td></tr><tr><td headers="hd_h_x-ald.T.recommended_surveillance_for_mal_1_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
|
<b>Educational/</b>
|
|
<br />
|
|
<b>Vocational</b>
|
|
</td><td headers="hd_h_x-ald.T.recommended_surveillance_for_mal_1_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Monitor educational & vocational training needs.</td><td headers="hd_h_x-ald.T.recommended_surveillance_for_mal_1_1_1_1_3" rowspan="3" colspan="1" style="text-align:left;vertical-align:middle;">At each visit</td></tr><tr><td headers="hd_h_x-ald.T.recommended_surveillance_for_mal_1_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
|
<b>Psychiatric/</b>
|
|
<br />
|
|
<b>Behavioral</b>
|
|
</td><td headers="hd_h_x-ald.T.recommended_surveillance_for_mal_1_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Behavioral assessment for anxiety, attention, & aggressive or self-injurious behavior</td></tr><tr><td headers="hd_h_x-ald.T.recommended_surveillance_for_mal_1_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
|
<b>Musculoskeletal</b>
|
|
</td><td headers="hd_h_x-ald.T.recommended_surveillance_for_mal_1_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Physical medicine, OT/PT assessment of mobility, self-help skills</td></tr><tr><td headers="hd_h_x-ald.T.recommended_surveillance_for_mal_1_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
|
<b>Adrenocortical insufficiency</b>
|
|
</td><td headers="hd_h_x-ald.T.recommended_surveillance_for_mal_1_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Endocrine assessment</td><td headers="hd_h_x-ald.T.recommended_surveillance_for_mal_1_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Males not yet known to have adrenocortical insufficiency: yearly ACTH & cortisol levels</div></li><li class="half_rhythm"><div>Males w/known adrenocortical insufficiency: per treating endocrinologist, but at least yearly</div></li><li class="half_rhythm"><div>Females: not warranted given rarity of adrenocortical insufficiency</div></li></ul>
|
|
</td></tr><tr><td headers="hd_h_x-ald.T.recommended_surveillance_for_mal_1_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
|
<b>Family/Community</b>
|
|
</td><td headers="hd_h_x-ald.T.recommended_surveillance_for_mal_1_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Assess family need for social work support (e.g., palliative/respite care, home nursing, other local resources), care coordination, or follow-up genetic counseling if new questions arise (e.g., family planning).</td><td headers="hd_h_x-ald.T.recommended_surveillance_for_mal_1_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">At each visit</td></tr></tbody></table></div><div><div><dl class="temp-labeled-list small"><dt></dt><dd><div><p class="no_margin">ACTH = adrenocorticotropic hormone; OT = occupational therapy; PT = physical therapy</p></div></dd></dl></div></div></div></div><div id="x-ald.Primary_Adrenocortical_Insufficien_1"><h4>Primary Adrenocortical Insufficiency</h4><p>Recommended surveillance for primary adrenocortical insufficiency in males is summarized in <a href="/books/NBK1315/table/x-ald.T.recommended_agesintervals_of_sur/?report=objectonly" target="object" rid-ob="figobxaldTrecommendedagesintervalsofsur">Table 13</a>.</p><div id="x-ald.T.recommended_agesintervals_of_sur" class="table"><h3><span class="label">Table 13. </span></h3><div class="caption"><p>Recommended Ages/Intervals of Surveillance for Primary Adrenocortical Insufficiency for At-Risk but Not Yet Symptomatic Males</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK1315/table/x-ald.T.recommended_agesintervals_of_sur/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__x-ald.T.recommended_agesintervals_of_sur_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_x-ald.T.recommended_agesintervals_of_sur_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Age</th><th id="hd_h_x-ald.T.recommended_agesintervals_of_sur_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Interval</th><th id="hd_h_x-ald.T.recommended_agesintervals_of_sur_1_1_1_3" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Evaluation</th></tr></thead><tbody><tr><td headers="hd_h_x-ald.T.recommended_agesintervals_of_sur_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"><2 yrs</td><td headers="hd_h_x-ald.T.recommended_agesintervals_of_sur_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Every 3-4 mos</td><td headers="hd_h_x-ald.T.recommended_agesintervals_of_sur_1_1_1_3" rowspan="3" colspan="1" style="text-align:left;vertical-align:middle;">Measurement of cortisol & ACTH levels</td></tr><tr><td headers="hd_h_x-ald.T.recommended_agesintervals_of_sur_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">2-13 yrs</td><td headers="hd_h_x-ald.T.recommended_agesintervals_of_sur_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Every 4-6 mos</td></tr><tr><td headers="hd_h_x-ald.T.recommended_agesintervals_of_sur_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">>13 yrs</td><td headers="hd_h_x-ald.T.recommended_agesintervals_of_sur_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Every 6-12 mos</td></tr></tbody></table></div><div><div><dl class="temp-labeled-list small"><dt></dt><dd><div><p class="no_margin">Based on <a class="bk_pop" href="#x-ald.REF.regelmann.2018.4324">Regelmann et al [2018]</a>, <a class="bk_pop" href="#x-ald.REF.engelen.2022.940">Engelen et al [2022]</a></p></div></dd><dt></dt><dd><div><p class="no_margin">ACTH = adrenocorticotropic hormone</p></div></dd></dl></div></div></div></div></div><div id="x-ald.AgentsCircumstances_to_Avoid"><h3>Agents/Circumstances to Avoid</h3><p>Significant head injury has been associated with activation of cerebral disease [<a class="bk_pop" href="#x-ald.REF.bouquet.2015.1991">Bouquet et al 2015</a>]. Other triggers anecdotally reported have included coma associated with adrenal crisis and neurosurgical procedures.</p></div><div id="x-ald.Evaluation_of_Relatives_at_Risk"><h3>Evaluation of Relatives at Risk</h3><p>It is appropriate to evaluate at-risk male relatives (i.e., male relatives not known to have X-ALD) of an affected individual in order to identify as early as possible those who would benefit from screening for primary adrenocortical insufficiency and to facilitate timely identification of young males who might benefit from targeted treatment for cCALD. Such testing can also allow for correct diagnosis of early (and often nonspecific) neurologic, behavioral, and/or cognitive signs and symptoms. Because these issues are not limited by age, all at-risk males should be offered diagnostic testing.</p><p>If born in the United States, males affected with X-ALD may be diagnosed by universal newborn screening soon after birth. If newborn screening data are not available for at-risk sibs, several evaluations can be considered:</p><ul><li class="half_rhythm"><div>If the <i>ABCD1</i> pathogenic variant in the family is known, molecular genetic testing can be used to clarify the genetic status of at-risk relatives.</div></li><li class="half_rhythm"><div>If the <i>ABCD1</i> pathogenic variant in the family has not been confirmed, very long-chain fatty acid analysis may be used to clarify the disease status of at-risk male relatives.</div></li></ul><p>See <a href="#x-ald.Related_Genetic_Counseling_Issues">Genetic Counseling</a> for issues related to testing of at-risk relatives for genetic counseling purposes.</p></div><div id="x-ald.Therapies_Under_Investigation"><h3>Therapies Under Investigation</h3><p><b>PPAR activators</b> have been under investigation for many years. A recent study showed the effect of leriglitazone in individuals with AMN; the primary outcome did not demonstrate efficacy. There were improvements in sway amplitude, a measure of balance [<a class="bk_pop" href="#x-ald.REF.k_hler.2023.127">Köhler et al 2023</a>].</p><p><b>AAV9-based targeted gene therapy</b> has been explored in preclinical models of ALD, and the first human trials are being conducted. The safety and efficacy of this approach remains under investigation [<a class="bk_pop" href="#x-ald.REF.gong.2015.824">Gong et al 2015</a>, <a class="bk_pop" href="#x-ald.REF._zg_rg_nes.2022.936">Özgür-Günes et al 2022</a>].</p><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 information on clinical studies for a wide range of diseases and conditions.</p></div></div><div id="x-ald.Genetic_Counseling"><h2 id="_x-ald_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="x-ald.Mode_of_Inheritance"><h3>Mode of Inheritance</h3><p>By definition, X-linked adrenoleukodystrophy (X-ALD) is inherited in an X-linked manner.</p></div><div id="x-ald.Risk_to_Family_Members"><h3>Risk to Family Members</h3><p>
|
|
<b>Parents of a male proband</b>
|
|
</p><ul><li class="half_rhythm"><div>The father of an affected male will not have the disorder nor will he be hemizygous for the <i>ABCD1</i> pathogenic variant; therefore, he does not require further evaluation/testing.</div></li><li class="half_rhythm"><div>In a family with more than one affected individual, the mother of an affected male is an obligate heterozygote. Note: If a female has more than one affected child and no other affected relatives and if the <i>ABCD1</i> pathogenic variant cannot be detected in her leukocyte DNA, she most likely has germline mosaicism.</div></li><li class="half_rhythm"><div>If a male is the only affected family member (i.e., a simplex case), the mother:</div><ul><li class="half_rhythm"><div>May be a heterozygote. Approximately 95% of probands inherit an <i>ABCD1</i> pathogenic variant from one parent.</div></li><li class="half_rhythm"><div>May not be heterozygous, and the affected male has a <i>de novo</i>
|
|
<i>ABCD1</i> pathogenic variant. At least 4.1% of individuals with X-ALD have a <i>de novo</i> pathogenic variant [<a class="bk_pop" href="#x-ald.REF.wang.2011.160">Wang et al 2011</a>].</div></li><li class="half_rhythm"><div>May have somatic/germline mosaicism. Evidence of germline or somatic/germline mosaicism is present in <1% of parents.</div></li></ul></li><li class="half_rhythm"><div>If an <i>ABCD1</i> pathogenic variant has been identified in an affected family member, molecular genetic testing of the mother is recommended to confirm her genetic status and allow reliable recurrence risk assessment. <i>ABCD1</i> molecular genetic testing is the preferred method for the evaluation of mothers of affected males.</div></li></ul><p>
|
|
<b>Parents of a female proband</b>
|
|
</p><ul><li class="half_rhythm"><div>A female proband may have inherited the <i>ABCD1</i> pathogenic variant from either her mother or her father, or the pathogenic variant may be <i>de novo</i>.</div></li><li class="half_rhythm"><div>Detailed evaluation of the parents and review of the extended family history may help distinguish probands with a <i>de novo</i> pathogenic variant from those with an inherited pathogenic variant.</div></li><li class="half_rhythm"><div>Recommendations for the evaluation of the parents of a female proband:</div><ul><li class="half_rhythm"><div>If an <i>ABCD1</i> pathogenic variant has been identified in an affected family member, molecular genetic testing can be used for the evaluation of the parents.</div></li><li class="half_rhythm"><div>Fathers of newly identified heterozygous females may be evaluated by very long-chain fatty acid (VLCFA) testing (see <a href="#x-ald.Related_Genetic_Counseling_Issues">Related Genetic Counseling Issues</a>).</div></li></ul></li></ul><p><b>Sibs of a male proband.</b> The risk to sibs depends on the genetic status of the mother:</p><ul><li class="half_rhythm"><div>If the mother of the proband has an <i>ABCD1</i> pathogenic variant, the chance of the mother transmitting it in each pregnancy is 50%.</div><ul><li class="half_rhythm"><div class="half_rhythm">Males who inherit the pathogenic variant will be affected.</div><div class="half_rhythm">Note: The phenotype in a male sib who inherits an <i>ABCD1</i> pathogenic variant cannot be predicted by family history, VLCFA plasma concentration, or the nature of the pathogenic variant; the same <i>ABCD1</i> pathogenic variant can be associated with each of the known X-ALD phenotypes.</div></li><li class="half_rhythm"><div class="half_rhythm">Females who inherit the pathogenic variant will be heterozygous. Heterozygous females are symptom-free in childhood but may manifest findings in adulthood (see Clinical Characteristics, <a href="#x-ald.Heterozygous_Females">Heterozygous Females</a>).</div></li></ul></li><li class="half_rhythm"><div>If the proband represents a simplex case and if the <i>ABCD1</i> pathogenic variant cannot be detected in the leukocyte DNA of the mother, the recurrence risk to sibs is slightly greater than that of the general population because of the possibility of maternal germline mosaicism [<a class="bk_pop" href="#x-ald.REF.wang.2011.160">Wang et al 2011</a>].</div></li></ul><p><b>Sibs of a female proband.</b> The risk to sibs depends on the genetic status of the parents:</p><ul><li class="half_rhythm"><div>If the mother of the proband has an <i>ABCD1</i> pathogenic variant, the chance of the mother transmitting it in each pregnancy is 50% (see <b>Sibs of male proband</b>).</div></li><li class="half_rhythm"><div>If the father of the proband is affected (i.e., hemizygous for an <i>ABCD1</i> pathogenic variant), he will transmit the pathogenic variant to all of his daughters and none of his sons.</div></li></ul><p>
|
|
<b>Offspring of a proband</b>
|
|
</p><ul><li class="half_rhythm"><div>Affected males transmit the <i>ABCD1</i> pathogenic variant to all of their daughters and none of their sons (see <b>Sibs of male proband</b>).</div></li><li class="half_rhythm"><div>Heterozygous females have a 50% chance of transmitting the <i>ABCD1</i> pathogenic variant in each pregnancy (see <b>Sibs of male proband</b>).</div></li><li class="half_rhythm"><div>Note: Varying phenotypes often coexist in the same family.</div></li></ul><p><b>Other family members.</b> Depending on their sex, family relationship, and the genetic status of the proband's parents, the proband's aunts and uncles and their offspring may be at risk of having the <i>ABCD1</i> pathogenic variant (see <a href="#x-ald.Related_Genetic_Counseling_Issues">Related Genetic Counseling Issues</a>).</p></div><div id="x-ald.Heterozygote_Detection"><h3>Heterozygote Detection</h3><p>Molecular genetic testing of at-risk female relatives to determine their genetic status is most informative if the <i>ABCD1</i> pathogenic variant has been identified in the proband.</p><ul><li class="half_rhythm"><div>Females who are heterozygous for this X-linked disorder are symptom-free in childhood but may manifest findings in adulthood (see Clinical Characteristics, <a href="#x-ald.Heterozygous_Females">Heterozygous Females</a>).</div></li><li class="half_rhythm"><div>Identification of female heterozygotes requires either prior identification of the <i>ABCD1</i> pathogenic variant in the family or, if an affected male is not available for testing, molecular genetic testing first by sequence analysis, and if no pathogenic variant is identified, then by gene-targeted deletion/duplication analysis.</div></li></ul><p>Note: VLCFA analysis is not recommended as a screening method for females known to be at risk (see <a href="#x-ald.Establishing_the_Diagnosis">Establishing the Diagnosis</a>).</p></div><div id="x-ald.Related_Genetic_Counseling_Issues"><h3>Related Genetic Counseling Issues</h3><p><b>At-risk, asymptomatic, or symptomatic but undiagnosed family members.</b> It is appropriate for at-risk males in a family to be identified and to be informed of their risk for X-ALD, while respecting principles of patient confidentiality. Identification of males with X-ALD through measurement of plasma concentration of VLCFA – or molecular genetic testing if the familial <i>ABCD1</i> pathogenic variant is known – before symptoms occur or early in the course of the disease can allow for diagnosis and management of adrenal insufficiency before life-threatening complications occur. Such testing can also allow for correct diagnosis of early (and often nonspecific) neurologic, behavioral, and/or cognitive signs and symptoms.</p><p><b>Considerations for female infants with positive X-ALD newborn screening (NBS) results.</b> Females identified by NBS do not require monitoring in childhood. When older, it may be appropriate for them to meet with a genetics professional to discuss reproductive options (see <b>Family planning</b>) and broadly discuss potential issues. A positive NBS in a female infant should prompt identification and evaluation of at-risk male relatives.</p><p>See Management, <a href="#x-ald.Evaluation_of_Relatives_at_Risk">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 and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.</div></li><li class="half_rhythm"><div>It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are heterozygous, or are at risk of being heterozygous.</div></li></ul></div><div id="x-ald.Prenatal_Testing_and_Preimplantati"><h3>Prenatal Testing and Preimplantation Genetic Testing</h3><p><b>Molecular genetic testing.</b> Once the <i>ABCD1</i> pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing are possible.</p><p>Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.</p></div></div><div id="x-ald.Resources"><h2 id="_x-ald_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>ALD Alliance (formerly Aidan Jack Seeger Foundation)</b>
|
|
</div><div><b>Phone:</b> 917-750-9390</div><div><b>Email:</b> elisa@aldalliance.org</div><div>
|
|
<a href="https://www.aldalliance.org/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">www.aldalliance.org</a>
|
|
</div></li><li class="half_rhythm"><div>
|
|
<b>ALD Connect</b>
|
|
</div><div>
|
|
<a href="http://www.x-ald.nl/clinical-diagnosis/the-ald-connect-patient-portal/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">ALD Connect Patient Portal</a>
|
|
</div></li><li class="half_rhythm"><div>
|
|
<b>Leukodystrophy Australia</b>
|
|
</div><div>Australia</div><div><b>Phone:</b> 1800 141 400</div><div><b>Email:</b> info@leuko.org.au</div><div>
|
|
<a href="https://www.leuko.org.au/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">leuko.org.au</a>
|
|
</div></li><li class="half_rhythm"><div>
|
|
<b>National Institute of Neurological Disorders and Stroke (NINDS)</b>
|
|
</div><div>PO Box 5801</div><div>Bethesda MD 20824</div><div><b>Phone:</b> 800-352-9424 (toll-free); 301-496-5751; 301-468-5981 (TTY)</div><div>
|
|
<a href="https://www.ninds.nih.gov/Disorders/All-Disorders/Adrenoleukodystrophy-Information-Page" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">Adrenoleukodystrophy Information Page</a>
|
|
</div></li><li class="half_rhythm"><div>
|
|
<b>NCBI Genes and Disease</b>
|
|
</div><div>
|
|
<a href="/books/NBK22230/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">Adrenoleukodystrophy</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><li class="half_rhythm"><div>
|
|
<b>United Leukodystrophy Foundation</b>
|
|
</div><div><b>Phone:</b> 815-748-0844</div><div><b>Email:</b> office@ulf.org</div><div>
|
|
<a href="https://ulf.org/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">ulf.org</a>
|
|
</div></li><li class="half_rhythm"><div>
|
|
<b>Myelin Disorders Bioregistry Project</b>
|
|
</div><div><b>Phone:</b> 215-590-1719</div><div><b>Email:</b> sherbinio@chop.edu</div><div>
|
|
<a href="https://www.chop.edu/research/myelin-disorders-biorepository-project" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">Myelin Disorders Bioregistry Project</a>
|
|
</div></li></ul>
|
|
</div><div id="x-ald.Molecular_Genetics"><h2 id="_x-ald_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="x-ald.molgen.TA" class="table"><h3><span class="label">Table A.</span></h3><div class="caption"><p>X-Linked Adrenoleukodystrophy: Genes and Databases</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK1315/table/x-ald.molgen.TA/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__x-ald.molgen.TA_lrgtbl__"><table class="no_bottom_margin"><tbody><tr><th id="hd_b_x-ald.molgen.TA_1_1_1_1" rowspan="1" colspan="1" style="vertical-align:top;">Gene</th><th id="hd_b_x-ald.molgen.TA_1_1_1_2" rowspan="1" colspan="1" style="vertical-align:top;">Chromosome Locus</th><th id="hd_b_x-ald.molgen.TA_1_1_1_3" rowspan="1" colspan="1" style="vertical-align:top;">Protein</th><th id="hd_b_x-ald.molgen.TA_1_1_1_4" rowspan="1" colspan="1" style="vertical-align:top;">Locus-Specific Databases</th><th id="hd_b_x-ald.molgen.TA_1_1_1_5" rowspan="1" colspan="1" style="vertical-align:top;">HGMD</th><th id="hd_b_x-ald.molgen.TA_1_1_1_6" rowspan="1" colspan="1" style="vertical-align:top;">ClinVar</th></tr><tr><td headers="hd_b_x-ald.molgen.TA_1_1_1_1" rowspan="1" colspan="1" style="vertical-align:top;">
|
|
<a href="/gene/215" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=gene">
|
|
<i>ABCD1</i>
|
|
</a>
|
|
</td><td headers="hd_b_x-ald.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=215" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">Xq28</a>
|
|
</td><td headers="hd_b_x-ald.molgen.TA_1_1_1_3" rowspan="1" colspan="1" style="vertical-align:top;">
|
|
<a href="http://www.uniprot.org/uniprot/P33897" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">ATP-binding cassette sub-family D member 1</a>
|
|
</td><td headers="hd_b_x-ald.molgen.TA_1_1_1_4" rowspan="1" colspan="1" style="vertical-align:top;">
|
|
<a href="http://www.LOVD.nl/ABCD1" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">ABCD1 @ LOVD</a>
|
|
<br />
|
|
<a href="http://www.x-ald.nl" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">X-linked Adrenoleukodystrophy Database (ABCD1)</a>
|
|
</td><td headers="hd_b_x-ald.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=ABCD1" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">ABCD1</a>
|
|
</td><td headers="hd_b_x-ald.molgen.TA_1_1_1_6" rowspan="1" colspan="1" style="vertical-align:top;">
|
|
<a href="https://www.ncbi.nlm.nih.gov/clinvar/?term=ABCD1[gene]" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">ABCD1</a>
|
|
</td></tr></tbody></table></div><div><div><dl class="temp-labeled-list small"><dt></dt><dd><div id="x-ald.TFA.1"><p class="no_margin">Data are compiled from the following standard references: gene from
|
|
<a href="http://www.genenames.org/index.html" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">HGNC</a>;
|
|
chromosome locus 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="x-ald.molgen.TB" class="table"><h3><span class="label">Table B.</span></h3><div class="caption"><p>OMIM Entries for X-Linked Adrenoleukodystrophy (<a href="/omim/300100,300371" 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/NBK1315/table/x-ald.molgen.TB/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__x-ald.molgen.TB_lrgtbl__"><table><tbody><tr><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
|
<a href="/omim/300100" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=omim">300100</a></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">ADRENOLEUKODYSTROPHY; ALD</td></tr><tr><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
|
<a href="/omim/300371" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=omim">300371</a></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">ATP-BINDING CASSETTE, SUBFAMILY D, MEMBER 1; ABCD1</td></tr></tbody></table></div></div><div id="x-ald.Molecular_Pathogenesis"><h3>Molecular Pathogenesis</h3><p><i>ABCD1</i> encodes adrenoleukodystrophy protein (ALDP), a member of the ATP-binding cassette (ABC) protein transporter family. This protein serves as a transporter of certain fatty acids into the peroxisome. Failure to transport these fatty acids into the peroxisome prevents beta-oxidation and allows continued elongation of fatty acids, resulting in accumulation of very long-chain fatty acids (VLCFAs) [<a class="bk_pop" href="#x-ald.REF.turk.2020.52">Turk et al 2020</a>]. As a result, these lipids accumulate abnormally in all tissues, but predominantly affect the nervous system, adrenal cortex, and Leydig cells of the testes. The mechanisms by which accumulation of VLCFAs causes neurology or adrenal dysfunction is not very well understood [<a class="bk_pop" href="#x-ald.REF.turk.2020.52">Turk et al 2020</a>].</p><p><b>Mechanism of disease causation.</b> Loss of function</p><p><b><i>ABCD1</i>-specific laboratory technical considerations.</b>
|
|
<i>ABCD1</i> contains ten exons and spans 21 kb. Sequence analysis is complicated by the presence of five known autosomal paralogs or pseudogenes. These pseudogenes, <i>ABCD1P1</i> (2p11.1), <i>ABCD1P2</i> (10p11), <i>ABCD1P3</i> (16p11), <i>ABCD1P4</i> (22q11), and <i>ABCD51P</i> (2p11.2), are 9.7 kb in length and encompass exons 7 through 10 of <i>ABCD1</i>. These duplicated fragments share 92%-96% sequence homology with <i>ABCD1</i>. Therefore, variants in these pseudogenes may be misidentified as variants in <i>ABCD1</i>, resulting in misdiagnosis of the disease. A specific set of primers have been developed for accurate variant analysis without interference of the pseudogenes [<a class="bk_pop" href="#x-ald.REF.boehm.1999.128">Boehm et al 1999</a>]. Current molecular diagnostic testing approaches may utilize next-generation sequencing with specific capture probes to sequence <i>ABCD1</i>.</p></div></div><div id="x-ald.Chapter_Notes"><h2 id="_x-ald_Chapter_Notes_">Chapter Notes</h2><div id="x-ald.Author_Notes"><h3>Author Notes</h3><p>Gerald Raymond (<a href="mailto:dev@null" data-email="ude.imhj@4nomyarg" class="oemail">ude.imhj@4nomyarg</a>) and Ali Fatemi (<a href="mailto:dev@null" data-email="gro.regeirkydennek@imetaf" class="oemail">gro.regeirkydennek@imetaf</a>) are actively involved in clinical research regarding individuals with X-linked adrenoleukodystrophy (X-ALD). They would be happy to communicate with persons who have any questions regarding diagnosis of X-ALD or other considerations. A special area of focus for Dr Raymond is the confirmatory diagnostics and surveillance following identification by newborn screening.</p><p>Drs Raymond and Fatemi are also interested in hearing from clinicians treating families affected by X-ALD in whom no causative variant has been identified through molecular genetic testing.</p><p>Contact Dr Raymond to inquire about review of <i>ABCD1</i> variants of uncertain significance.</p><p>Contact Ms Ann Moser (<a href="mailto:dev@null" data-email="gro.regeirkydennek@aresom" class="oemail">gro.regeirkydennek@aresom</a>) to discuss technical issues with very long-chain fatty acid or C26:0-lysophosphatidylcholine determinations.</p></div><div id="x-ald.Acknowledgments"><h3>Acknowledgments</h3><p>The authors' work has been supported in the past by the National Institutes of Health and the Food and Drug Administration.</p></div><div id="x-ald.Author_History"><h3>Author History</h3><p>Corinne D Boehm, MS; Johns Hopkins Hospital (1999-2002)<br />Ali Fatemi, MD (2018-present)<br />Ann B Moser, BA (1999-present)<br />Hugo W Moser, MD; Johns Hopkins University School of Medicine (1999-2007)*<br />Gerald V Raymond, MD (2006-present)<br />Steven J Steinberg, PhD; Johns Hopkins University School of Medicine (2002-2018)</p><p>* Hugo W Moser, MD, was Professor of Neurology and Pediatrics at Johns Hopkins University School of Medicine and former Director of the Kennedy Krieger Institute in Baltimore. He was a world-renowned expert in the field of neurogenetics. He was best known for his leadership role in understanding, diagnosing, and treating adrenoleukodystrophy. Dr Moser died of cancer on January 20, 2007, at age 82. He is greatly missed by his family, friends, colleagues, and patients.</p></div><div id="x-ald.Revision_History"><h3>Revision History</h3><ul><li class="half_rhythm"><div>6 April 2023 (bp) Comprehensive update posted live</div></li><li class="half_rhythm"><div>15 February 2018 (ha) Comprehensive update posted live</div></li><li class="half_rhythm"><div>9 April 2015 (me) Comprehensive update posted live</div></li><li class="half_rhythm"><div>19 April 2012 (me) Comprehensive update posted live</div></li><li class="half_rhythm"><div>2 June 2009 (me) Comprehensive update posted live</div></li><li class="half_rhythm"><div>27 July 2006 (me) Comprehensive update posted live</div></li><li class="half_rhythm"><div>15 April 2004 (me) Comprehensive update posted live</div></li><li class="half_rhythm"><div>26 August 2002 (ss) Author revisions</div></li><li class="half_rhythm"><div>26 February 2002 (me) Comprehensive update posted live</div></li><li class="half_rhythm"><div>26 March 1999 (pb) Review posted live</div></li><li class="half_rhythm"><div>2 February 1999 (hm) Original submission</div></li></ul></div></div><div id="x-ald.References"><h2 id="_x-ald_References_">References</h2><div id="x-ald.Literature_Cited"><h3>Literature Cited</h3><ul class="simple-list"><li class="half_rhythm"><div class="bk_ref" id="x-ald.REF.boehm.1999.128">Boehm
|
|
CD, Cutting
|
|
GR, Lachtermacher
|
|
MB, Moser
|
|
HW, Chong
|
|
SS. Accurate DNA-based diagnostic and carrier testing for X-linked adrenoleukodystrophy.
|
|
Mol Genet Metab.
|
|
1999;66:128-36.
|
|
[<a href="https://pubmed.ncbi.nlm.nih.gov/10068516" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 10068516</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="x-ald.REF.bouquet.2015.1991">Bouquet
|
|
F, Dehais
|
|
C, Sanson
|
|
M, Lubetzki
|
|
C, Louapre
|
|
C. Dramatic worsening of adult-onset X-linked adrenoleukodystrophy after head trauma.
|
|
Neurology.
|
|
2015;85:1991-3.
|
|
[<a href="https://pubmed.ncbi.nlm.nih.gov/26537054" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 26537054</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="x-ald.REF.cacciagli.2013.579">Cacciagli
|
|
P, Sutera-Sardo
|
|
J, Borges-Correia
|
|
A, Roux
|
|
JC, Dorboz
|
|
I, Desvignes
|
|
JP, Badens
|
|
C, Delepine
|
|
M, Lathrop
|
|
M, Cau
|
|
P, Lévy
|
|
N, Girard
|
|
N, Sarda
|
|
P, Boespflug-Tanguy
|
|
O, Villard
|
|
L. Mutations in BCAP31 cause a severe X-linked phenotype with deafness, dystonia, and central hypomyelination and disorganize the Golgi apparatus
|
|
Am J Hum Genet.
|
|
2013;93:579-86.
|
|
[<a href="/pmc/articles/PMC3769969/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC3769969</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/24011989" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 24011989</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="x-ald.REF.calhoun.2014.2613">Calhoun
|
|
AR, Raymond
|
|
GV. Distal Xq28 microdeletions: clarification of the spectrum of contiguous gene deletions involving ABCD1, BCAP31, and SLC6A8 with a new case and review of the literature.
|
|
Am J Med Genet A.
|
|
2014;164A:2613-7.
|
|
[<a href="https://pubmed.ncbi.nlm.nih.gov/25044748" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 25044748</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="x-ald.REF.caughey.2021.1953">Caughey
|
|
AB, Krist
|
|
AH, Wolff
|
|
TA, Barry
|
|
MJ, Henderson
|
|
JT, Owens
|
|
DK, Davidson
|
|
KW, Simon
|
|
MA, Mangione
|
|
CM. USPSTF approach to addressing sex and gender when making recommendations for clinical preventive services.
|
|
JAMA. 2021;326:1953-61.
|
|
[<a href="https://pubmed.ncbi.nlm.nih.gov/34694343" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 34694343</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="x-ald.REF.de_beer.2014.2227">de Beer
|
|
M, Engelen
|
|
M, van Geel
|
|
BM. Frequent occurrence of cerebral demyelination in adrenomyeloneuropathy.
|
|
Neurology.
|
|
2014;83:2227-31.
|
|
[<a href="https://pubmed.ncbi.nlm.nih.gov/25378668" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 25378668</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="x-ald.REF.eichler.2017.1630">Eichler
|
|
F, Duncan
|
|
C, Musolino
|
|
PL, Orchard
|
|
PJ, De Oliveira
|
|
S, Thrasher
|
|
AJ, Armant
|
|
M, Dansereau
|
|
C, Lund
|
|
TC, Miller
|
|
WP, Raymond
|
|
GV, Sankar
|
|
R, Shah
|
|
AJ, Sevin
|
|
C, Gaspar
|
|
HB, Gissen
|
|
P, Amartino
|
|
H, Bratkovic
|
|
D, Smith
|
|
NJC, Paker
|
|
AM, Shamir
|
|
E, O'Meara
|
|
T, Davidson
|
|
D, Aubourg
|
|
P, Williams
|
|
DA. Hematopoietic stem-cell gene therapy for cerebral adrenoleukodystrophy.
|
|
N Engl J Med.
|
|
2017;377:1630-8.
|
|
[<a href="/pmc/articles/PMC5708849/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC5708849</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/28976817" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 28976817</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="x-ald.REF.engelen.2022.940">Engelen
|
|
M, van Ballegoij
|
|
WJC, Mallack
|
|
EJ, Van Haren
|
|
KP, Köhler
|
|
W, Salsano
|
|
E, van Trotsenburg
|
|
ASP, Mochel
|
|
F, Sevin
|
|
C, Regelmann
|
|
MO, Tritos
|
|
NA, Halper
|
|
A, Lachmann
|
|
RH, Davison
|
|
J, Raymond
|
|
GV, Lund
|
|
TC, Orchard
|
|
PJ, Kuehl
|
|
JS, Lindemans
|
|
CA, Caruso
|
|
P, Turk
|
|
BR, Moser
|
|
AB, Vaz
|
|
FM, Ferdinandusse
|
|
S, Kemp
|
|
S, Fatemi
|
|
A, Eichler
|
|
FS, Huffnagel
|
|
IC. International recommendations for the diagnosis and management of patients with adrenoleukodystrophy: a consensus-based approach.
|
|
Neurology.
|
|
2022;99:940-51.
|
|
[<a href="/pmc/articles/PMC9687408/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC9687408</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/36175155" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 36175155</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="x-ald.REF.gong.2015.824">Gong
|
|
Y, Mu
|
|
D, Prabhakar
|
|
S, Moser
|
|
A, Musolino
|
|
P, Ren
|
|
J, Breakefield
|
|
XO, Maguire
|
|
CA, Eichler
|
|
FS. Adenoassociated virus serotype 9-mediated gene therapy for X-linked adrenoleukodystrophy.
|
|
Mol Ther.
|
|
2015;23:824-34.
|
|
[<a href="/pmc/articles/PMC4427888/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC4427888</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/25592337" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 25592337</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="x-ald.REF.gupta.2022.1151">Gupta
|
|
AO, Raymond
|
|
G, Pierpont
|
|
EI, Kemp
|
|
S, McIvor
|
|
RS, Rayannavar
|
|
A, Miller
|
|
B, Lund
|
|
TC, Orchard
|
|
PJ. Treatment of cerebral adrenoleukodystrophy: allogeneic transplantation and lentiviral gene therapy.
|
|
Expert Opin Biol Ther.
|
|
2022;22:1151-62.
|
|
[<a href="https://pubmed.ncbi.nlm.nih.gov/36107226" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 36107226</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="x-ald.REF.hershkovitz.2002.234">Hershkovitz
|
|
E, Narkis
|
|
G, Shorer
|
|
Z, Moser
|
|
AB, Watkins
|
|
PA, Moser
|
|
HW, Manor
|
|
E. Cerebral X-linked adrenoleukodystrophy in a girl with Xq27-Ter deletion.
|
|
Ann Neurol.
|
|
2002;52:234-7.
|
|
[<a href="https://pubmed.ncbi.nlm.nih.gov/12210797" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 12210797</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="x-ald.REF.huffnagel.2019.30">Huffnagel
|
|
IC, Dijkgraaf
|
|
MGW, Janssens
|
|
GE, van Weeghel
|
|
M, van Geel
|
|
BM, Poll-The
|
|
BT, Kemp
|
|
S, Engelen
|
|
M. Disease progression in women with X-linked adrenoleukodystrophy is slow.
|
|
Orphanet J Rare Dis.
|
|
2019;14:30.
|
|
[<a href="/pmc/articles/PMC6367840/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC6367840</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/30732635" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 30732635</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="x-ald.REF.jaspers.2020.690">Jaspers
|
|
YRJ, Ferdinandusse
|
|
S, Dijkstra
|
|
IME, Barendsen
|
|
RW, van Lenthe
|
|
H, Kulik
|
|
W, Engelen
|
|
M, Goorden
|
|
SMI, Vaz
|
|
FM, Kemp
|
|
S. Comparison of the diagnostic performance of C26:0-lysophosphatidylcholine and very long-chain fatty acids analysis for peroxisomal disorders
|
|
Front Cell Dev Biol.
|
|
2020;8:690
|
|
[<a href="/pmc/articles/PMC7438929/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC7438929</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/32903870" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 32903870</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="x-ald.REF.k_hler.2023.127">Köhler
|
|
W, Engelen
|
|
M, Eichler
|
|
F, Lachmann
|
|
R, Fatemi
|
|
A, Sampson
|
|
J, Salsano
|
|
E, Gamez
|
|
J, Molnar
|
|
MJ, Pascual
|
|
S, Rovira
|
|
M, Vilà
|
|
A, Pina
|
|
G, Martín-Ugarte
|
|
I, Mantilla
|
|
A, Pizcueta
|
|
P, Rodríguez-Pascau
|
|
L, Traver
|
|
E, Vilalta
|
|
A, Pascual
|
|
M, Martinell
|
|
M, Meya
|
|
U, Mochel
|
|
F, et al.
|
|
Safety and efficacy of leriglitazone for preventing disease progression in men with adrenomyeloneuropathy (ADVANCE): a randomized, double blind, multi-centre, placebo-controlled phase 2-3 trial.
|
|
Lancet Neurol
|
|
2023;22:127-36.
|
|
[<a href="/pmc/articles/PMC11847323/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC11847323</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/36681445" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 36681445</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="x-ald.REF.loes.2003.369">Loes
|
|
DJ, Fatemi
|
|
A, Melhem
|
|
ER, Gupte
|
|
N, Bezman
|
|
L, Moser
|
|
HW, Raymond
|
|
GV (2003) Analysis of MRI patterns aids prediction of progression in X-linked adrenoleukodystrophy.
|
|
Neurology
|
|
61:369-74
|
|
[<a href="https://pubmed.ncbi.nlm.nih.gov/12913200" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 12913200</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="x-ald.REF.mallack.2021a.1904">Mallack
|
|
EJ, Askin
|
|
G, van de Stadt
|
|
S, Caruso
|
|
PA, Musolino
|
|
PL, Engelen
|
|
M, Niogi
|
|
SN, Eichler
|
|
FS. A longitudinal analysis of early lesion growth in presymptomatic patients with cerebral adrenoleukodystrophy.
|
|
AJNR Am J Neuroradiol.
|
|
2021a;42:1904-11.
|
|
[<a href="/pmc/articles/PMC8562733/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC8562733</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/34503945" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 34503945</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="x-ald.REF.mallack.2021b.728">Mallack
|
|
EJ, Turk
|
|
BR, Yan
|
|
H, Price
|
|
C, Demetres
|
|
M, Moser
|
|
AB, Becker
|
|
C, Hollandsworth
|
|
K, Adang
|
|
L, Vanderver
|
|
A, Van Haren
|
|
K, Ruzhnikov
|
|
M, Kurtzberg
|
|
J, Maegawa
|
|
G, Orchard
|
|
PJ, Lund
|
|
TC, Raymond
|
|
GV, Regelmann
|
|
M, Orsini
|
|
JJ, Seeger
|
|
E, Kemp
|
|
S, Eichler
|
|
F, Fatemi
|
|
A. MRI surveillance of boys with X-linked adrenoleukodystrophy identified by newborn screening: meta-analysis and consensus guidelines.
|
|
J Inherit Metab Dis.
|
|
2021b;44:728-39.
|
|
[<a href="/pmc/articles/PMC8113077/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC8113077</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/33373467" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 33373467</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="x-ald.REF.mallack.2022a.283">Mallack
|
|
EJ, Gao
|
|
K, Engelen
|
|
M, Kemp
|
|
S. Structure and function of the ABCD1 variant database: 20 years, 940 pathogenic variants, and 3400 cases of adrenoleukodystrophy.
|
|
Cells.
|
|
2022a;11:283.
|
|
[<a href="/pmc/articles/PMC8773697/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC8773697</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/35053399" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 35053399</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="x-ald.REF.mallack.2022b.e512">Mallack
|
|
EJ, Van Haren
|
|
KP, Torrey
|
|
A, van de Stadt
|
|
S, Engelen
|
|
M, Raymond
|
|
GV, Fatemi
|
|
A, Eichler
|
|
FS. Presymptomatic lesion in childhood cerebral adrenoleukodystrophy: timing and treatment.
|
|
Neurology.
|
|
2022b;99:e512-20
|
|
[<a href="/pmc/articles/PMC9421600/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC9421600</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/35609989" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 35609989</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="x-ald.REF._zg_rg_nes.2022.936">Özgür-Günes
|
|
Y, Chedik
|
|
M, Stunff
|
|
CL, Fovet
|
|
CM, Bougneres
|
|
P. Long-term disease prevention with gene therapy targeting oligodendrocytes in a mouse model of adrenomyeloneuropathy.
|
|
Hum Gene Ther.
|
|
2022;33:936-49.
|
|
[<a href="https://pubmed.ncbi.nlm.nih.gov/35166123" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 35166123</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="x-ald.REF.raymond.2019.538">Raymond
|
|
GV, Aubourg
|
|
P, Paker
|
|
A, Escolar
|
|
M, Fischer
|
|
A, Blanche
|
|
S, Baruchel
|
|
A, Dalle
|
|
JH, Michel
|
|
G, Prasad
|
|
V, Miller
|
|
W, Paadre
|
|
S, Balser
|
|
J, Kurtzberg
|
|
J, Nascene
|
|
DR, Orchard
|
|
PJ, Lund
|
|
T. Survival and functional outcomes in boys with cerebral adrenoleukodystrophy with and without hematopoietic stem cell transplantation.
|
|
Biol Blood Marrow Transplant.
|
|
2019;25:538-48.
|
|
[<a href="https://pubmed.ncbi.nlm.nih.gov/30292747" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 30292747</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="x-ald.REF.regelmann.2018.4324">Regelmann
|
|
MO, Kamboj
|
|
MK, Miller
|
|
BS, Nakamoto
|
|
JM, Sarafoglou
|
|
K, Shah
|
|
S, Stanley
|
|
TL, Marino
|
|
R, et al.
|
|
Adrenoleukodystrophy: guidance for adrenal surveillance in males identified by newborn screen.
|
|
J Clin Endocrinol Metab.
|
|
2018;103:4324-31.
|
|
[<a href="https://pubmed.ncbi.nlm.nih.gov/30289543" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 30289543</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="x-ald.REF.richards.2015.405">Richards
|
|
S, Aziz
|
|
N, Bale
|
|
S, Bick
|
|
D, Das
|
|
S, Gastier-Foster
|
|
J, Grody
|
|
WW, Hegde
|
|
M, Lyon
|
|
E, Spector
|
|
E, Voelkerding
|
|
K, Rehm
|
|
HL, et al.
|
|
Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.
|
|
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="x-ald.REF.schirinzi.2019.326">Schirinzi
|
|
T, Vasco
|
|
G, Aiello
|
|
C, Rizzo
|
|
C, Sancesario
|
|
A, Romano
|
|
A, Favetta
|
|
M, Petrarca
|
|
M, Paone
|
|
L, Castelli
|
|
E, Bertini
|
|
ES, Cappa
|
|
M. Natural history of a cohort of ABCD1 variant female carriers.
|
|
Eur J Neurol.
|
|
2019;26:326-32.
|
|
[<a href="https://pubmed.ncbi.nlm.nih.gov/30295399" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 30295399</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="x-ald.REF.turk.2020.52">Turk
|
|
BR, Theda
|
|
C, Fatemi
|
|
A, Moser
|
|
AB. X-linked adrenoleukodystrophy: pathology, pathophysiology, diagnostic testing, newborn screening and therapies.
|
|
Int J Dev Neurosci.
|
|
2020;80:52-72.
|
|
[<a href="/pmc/articles/PMC7041623/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC7041623</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/31909500" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 31909500</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="x-ald.REF.van_de_kamp.2015.141">van de Kamp
|
|
JM, Errami
|
|
A, Howidi
|
|
M, Anselm
|
|
I, Winter
|
|
S, Phalin-Roque
|
|
J, Osaka
|
|
H, van Dooren
|
|
SJ, Mancini
|
|
GM, Steinberg
|
|
SJ, Salomons
|
|
GS. Genotype-phenotype correlation of contiguous gene deletions of SLC6A8, BCAP31 and ABCD1.
|
|
Clin Genet.
|
|
2015;87:141-7.
|
|
[<a href="https://pubmed.ncbi.nlm.nih.gov/24597975" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 24597975</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="x-ald.REF.vogel.2015.599">Vogel
|
|
BH, Bradley
|
|
SE, Adams
|
|
DJ, D'Aco
|
|
K, Erbe
|
|
RW, Fong
|
|
C, Iglesias
|
|
A, Kronn
|
|
D, Levy
|
|
P, Morrissey
|
|
M, Orsini
|
|
J, Parton
|
|
P, Pellegrino
|
|
J, Saavedra-Matiz
|
|
CA, Shur
|
|
N, Wasserstein
|
|
M, Raymond
|
|
GV, Caggana
|
|
M. Newborn screening for X-linked adrenoleukodystrophy in New York State: diagnostic protocol, surveillance protocol and treatment guidelines.
|
|
Mol Genet Metab.
|
|
2015;114:599-603.
|
|
[<a href="https://pubmed.ncbi.nlm.nih.gov/25724074" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 25724074</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="x-ald.REF.wang.2011.160">Wang
|
|
Y, Busin
|
|
R, Reeves
|
|
C, Bezman
|
|
L, Raymond
|
|
G, Toomer
|
|
CJ, Watkins
|
|
PA, Snowden
|
|
A, Moser
|
|
A, Naidu
|
|
S, Bibat
|
|
G, Hewson
|
|
S, Tam
|
|
K, Clarke
|
|
JT, Charnas
|
|
L, Stetten
|
|
G, Karczeski
|
|
B, Cutting
|
|
G, Steinberg
|
|
S (2011) X-linked adrenoleukodystrophy: ABCD1 de novo mutations and mosaicism.
|
|
Mol Genet Metab.
|
|
104:160-6.
|
|
[<a href="https://pubmed.ncbi.nlm.nih.gov/21700483" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 21700483</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: NBK1315</span><span class="label">PMID: <a href="https://pubmed.ncbi.nlm.nih.gov/20301491" title="PubMed record of this page" ref="pagearea=meta&targetsite=entrez&targetcat=link&targettype=pubmed">20301491</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/x-ag/" title="Previous page in this title">< Prev</a><a class="active page_link next" href="/books/n/gene/xla/" title="Next page in this title">Next ></a></div></div></div></div>
|
|
|
|
</div>
|
|
</div>
|
|
</div>
|
|
<div class="bottom">
|
|
|
|
<div id="NCBIFooter_dynamic">
|
|
<!--<component id="Breadcrumbs" label="breadcrumbs"/>
|
|
<component id="Breadcrumbs" label="helpdesk"/>-->
|
|
|
|
</div>
|
|
|
|
<script type="text/javascript" src="/portal/portal3rc.fcgi/rlib/js/InstrumentNCBIBaseJS/InstrumentPageStarterJS.js"> </script>
|
|
</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=NBK1315&ncbi_domain=gene&ncbi_report=printable&ncbi_type=fulltext&ncbi_objectid=&ncbi_pcid=/NBK1315/?report=printable&ncbi_app=bookshelf" /></noscript>
|
|
|
|
|
|
<!-- usually for JS scripts at page bottom -->
|
|
<!--<component id="PageFixtures" label="styles"></component>-->
|
|
|
|
|
|
<!-- CE8B5AF87C7FFCB1_0191SID /projects/books/PBooks@9.11 portal107 v4.1.r689238 Tue, Oct 22 2024 16:10:51 -->
|
|
<span id="portal-csrf-token" style="display:none" data-token="CE8B5AF87C7FFCB1_0191SID"></span>
|
|
|
|
<script type="text/javascript" src="//static.pubmed.gov/portal/portal3rc.fcgi/4216699/js/3879255/4121861/3501987/4008961/3893018/3821238/3400083/3426610.js" snapshot="books"></script></body>
|
|
</html> |