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Entry
- #300100 - ADRENOLEUKODYSTROPHY; ALD
- OMIM
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<span class="h4">#300100</span>
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<strong>Table of Contents</strong>
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<a href="#title"><strong>Title</strong></a>
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<a href="#phenotypeMap"><strong>Phenotype-Gene Relationships</strong></a>
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<a href="/clinicalSynopsis/300100"><strong>Clinical Synopsis</strong></a>
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<a href="#text"><strong>Text</strong></a>
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<a href="#description">Description</a>
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<a href="#clinicalFeatures">Clinical Features</a>
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<li role="presentation" style="margin-left: 1em">
<a href="#biochemicalFeatures">Biochemical Features</a>
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<li role="presentation" style="margin-left: 1em">
<a href="#inheritance">Inheritance</a>
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<li role="presentation" style="margin-left: 1em">
<a href="#mapping">Mapping</a>
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<li role="presentation" style="margin-left: 1em">
<a href="#pathogenesis">Pathogenesis</a>
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<li role="presentation" style="margin-left: 1em">
<a href="#diagnosis">Diagnosis</a>
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<a href="#clinicalManagement">Clinical Management</a>
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<a href="#molecularGenetics">Molecular Genetics</a>
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<a href="#populationGenetics">Population Genetics</a>
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<a href="#history">History</a>
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<a href="#seeAlso"><strong>See Also</strong></a>
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<a href="#references"><strong>References</strong></a>
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<a href="#contributors"><strong>Contributors</strong></a>
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<a href="#creationDate"><strong>Creation Date</strong></a>
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<div><a href="https://clinicaltrials.gov/search?cond=ADRENOLEUKODYSTROPHY" class="mim-tip-hint" title="A registry of federally and privately supported clinical trials conducted in the United States and around the world." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Clinical Trials', 'domain': 'clinicaltrials.gov'})">Clinical Trials</a></div>
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<div style="margin-left: 0.5em;"><a href="https://www.orpha.net/consor/cgi-bin/ClinicalLabs_Search_Simple.php?lng=EN&LnkId=16884&Typ=Pat" title="X-linked cerebral adrenoleukodystrophy" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'EuroGentest', 'domain': 'orpha.net'})">X-linked cerebral adrenole…&nbsp;</a></div><div style="margin-left: 0.5em;"><a href="https://www.orpha.net/consor/cgi-bin/ClinicalLabs_Search_Simple.php?lng=EN&LnkId=16885&Typ=Pat" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'EuroGentest', 'domain': 'orpha.net'})">Adrenomyeloneuropathy&nbsp;</a></div><div style="margin-left: 0.5em;"><a href="https://www.orpha.net/consor/cgi-bin/ClinicalLabs_Search_Simple.php?lng=EN&LnkId=761&Typ=Pat" title="X-linked adrenoleukodystrophy" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'EuroGentest', 'domain': 'orpha.net'})">X-linked adrenoleukodystro…&nbsp;</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/books/NBK1315/" class="mim-tip-hint" title="Expert-authored, peer-reviewed descriptions of inherited disorders including the uses of genetic testing in diagnosis, management, and genetic counseling." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Gene Reviews', 'domain': 'ncbi.nlm.nih.gov'})">Gene Reviews</a></div>
<div><a href="https://www.diseaseinfosearch.org/x/242" class="mim-tip-hint" title="Network of disease-specific advocacy organizations, universities, private companies, government agencies, and public policy organizations." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Genetic Alliance', 'domain': 'diseaseinfosearch.org'})">Genetic Alliance</a></div>
<div><a href="https://medlineplus.gov/genetics/condition/x-linked-adrenoleukodystrophy" class="mim-tip-hint" title="Consumer-friendly information about the effects of genetic variation on human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MedlinePlus Genetics', 'domain': 'medlineplus.gov'})">MedlinePlus Genetics</a></div>
<div><a href="https://www.ncbi.nlm.nih.gov/gtr/all/tests/?term=300100[mim]" class="mim-tip-hint" title="Genetic Testing Registry." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'GTR', 'domain': 'ncbi.nlm.nih.gov'})">GTR</a></div>
<div><a href="https://www.acmg.net/PDFLibrary/X-ALD-ACT-Sheet.pdf" class="mim-tip-hint" title="Information and resources for newborn screening and genetics." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Newborn Screening', 'domain': 'www.acmg.net'})">Newborn Screening</a></div>
<div><a href="#mimOrphanetFold" id="mimOrphanetToggle" data-toggle="collapse" class="mim-tip-hint mimTriangleToggle" title="European reference portal for information on rare diseases and orphan drugs."><span id="mimOrphanetToggleTriangle" class="small" style="margin-left: -0.8em;">&#9658;</span>Orphanet</div>
<div id="mimOrphanetFold" class="collapse">
<div style="margin-left: 0.5em;"><a href="https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=139396" title="X-linked cerebral adrenoleukodystrophy" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'OrphaNet', 'domain': 'orpha.net'})">X-linked cerebral adrenole…</a></div><div style="margin-left: 0.5em;"><a href="https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=139399" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'OrphaNet', 'domain': 'orpha.net'})">Adrenomyeloneuropathy</a></div><div style="margin-left: 0.5em;"><a href="https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=43" title="X-linked adrenoleukodystrophy" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'OrphaNet', 'domain': 'orpha.net'})">X-linked adrenoleukodystro…</a></div>
</div>
</div>
</div>
</div>
<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
<div class="panel-heading mim-panel-heading" role="tab" id="mimAnimalModels">
<span class="panel-title">
<span class="small">
<a href="#mimAnimalModelsLinksFold" id="mimAnimalModelsLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
<div style="display: table-row">
<div id="mimAnimalModelsLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">&#9658;</div>
&nbsp;
<div style="display: table-cell;">Animal Models</div>
</div>
</a>
</span>
</span>
</div>
<div id="mimAnimalModelsLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
<div class="panel-body small mim-panel-body">
<div><a href="https://www.alliancegenome.org/disease/DOID:10588" class="mim-tip-hint" title="Search Across Species; explore model organism and human comparative genomics." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Alliance Genome', 'domain': 'alliancegenome.org'})">Alliance Genome</a></div>
<div><a href="http://www.informatics.jax.org/disease/300100" class="mim-tip-hint" title="Phenotypes, alleles, and disease models from Mouse Genome Informatics." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MGI Mouse Phenotype', 'domain': 'informatics.jax.org'})">MGI Mouse Phenotype</a></div>
<div><a href="https://wormbase.org/resources/disease/DOID:10588" class="mim-tip-hint" title="Database of the biology and genome of Caenorhabditis elegans and related nematodes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Wormbase Disease Ontology', 'domain': 'wormbase.org'})">Wormbase Disease Ontology</a></div>
</div>
</div>
</div>
<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
<div class="panel-heading mim-panel-heading" role="tab" id="mimCellLines">
<span class="panel-title">
<span class="small">
<a href="#mimCellLinesLinksFold" id="mimCellLinesLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
<div style="display: table-row">
<div id="mimCellLinesLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">&#9658;</div>
&nbsp;
<div style="display: table-cell;">Cell Lines</div>
</div>
</a>
</span>
</span>
</div>
<div id="mimCellLinesLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
<div class="panel-body small mim-panel-body">
<div><a href="https://catalog.coriell.org/Search?q=OmimNum:300100" class="definition" title="Coriell Cell Repositories; cell cultures and DNA derived from cell cultures." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'CCR', 'domain': 'ccr.coriell.org'})">Coriell</a></div>
</div>
</div>
</div>
</div>
</div>
</div>
<span>
<span class="mim-tip-bottom" qtip_title="<strong>Looking for this gene or this phenotype in other resources?</strong>" qtip_text="Select a related resource from the dropdown menu and click for a targeted link to information directly relevant.">
&nbsp;
</span>
</span>
</div>
<div class="col-lg-8 col-lg-pull-2 col-md-8 col-md-pull-2 col-sm-8 col-sm-pull-2 col-xs-12">
<div>
<a id="title" class="mim-anchor"></a>
<div>
<a id="number" class="mim-anchor"></a>
<div class="text-right">
<a href="#" class="mim-tip-icd" qtip_title="<strong>ICD+</strong>" qtip_text="
<strong>SNOMEDCT:</strong> 1269423000, 65389002<br />
<strong>ICD10CM:</strong> E71.52, E71.522, E71.529<br />
<strong>ORPHA:</strong> 139396, 139399, 43<br />
<strong>DO:</strong> 10588<br />
">ICD+</a>
</div>
<div>
<span class="h3">
<span class="mim-font mim-tip-hint" title="Phenotype description, molecular basis known">
<span class="text-danger"><strong>#</strong></span>
300100
</span>
</span>
</div>
</div>
<div>
<a id="preferredTitle" class="mim-anchor"></a>
<h3>
<span class="mim-font">
ADRENOLEUKODYSTROPHY; ALD
</span>
</h3>
</div>
<div>
<br />
</div>
<div>
<a id="alternativeTitles" class="mim-anchor"></a>
<div>
<p>
<span class="mim-font">
<em>Alternative titles; symbols</em>
</span>
</p>
</div>
<div>
<h4>
<span class="mim-font">
X-ALD<br />
ADDISON DISEASE AND CEREBRAL SCLEROSIS<br />
SIEMERLING-CREUTZFELDT DISEASE<br />
BRONZE SCHILDER DISEASE<br />
MELANODERMIC LEUKODYSTROPHY
</span>
</h4>
</div>
</div>
<div>
<br />
</div>
<div>
<a id="includedTitles" class="mim-anchor"></a>
<div>
<p>
<span class="mim-font">
Other entities represented in this entry:
</span>
</p>
</div>
<div>
<span class="h3 mim-font">
ADRENOMYELONEUROPATHY, INCLUDED; AMN, INCLUDED
</span>
</div>
</div>
<div>
<br />
</div>
</div>
<div>
<a id="phenotypeMap" class="mim-anchor"></a>
<h4>
<span class="mim-font">
<strong>Phenotype-Gene Relationships</strong>
</span>
</h4>
<div>
<table class="table table-bordered table-condensed table-hover small mim-table-padding">
<thead>
<tr class="active">
<th>
Location
</th>
<th>
Phenotype
</th>
<th>
Phenotype <br /> MIM number
</th>
<th>
Inheritance
</th>
<th>
Phenotype <br /> mapping key
</th>
<th>
Gene/Locus
</th>
<th>
Gene/Locus <br /> MIM number
</th>
</tr>
</thead>
<tbody>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/X/836?start=-3&limit=10&highlight=836">
Xq28
</a>
</span>
</td>
<td>
<span class="mim-font">
Adrenomyeloneuropathy, adult
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/300100"> 300100 </a>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="X-linked recessive">XLR</abbr>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
</span>
</td>
<td>
<span class="mim-font">
ABCD1
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/300371"> 300371 </a>
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/X/836?start=-3&limit=10&highlight=836">
Xq28
</a>
</span>
</td>
<td>
<span class="mim-font">
Adrenoleukodystrophy
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/300100"> 300100 </a>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="X-linked recessive">XLR</abbr>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
</span>
</td>
<td>
<span class="mim-font">
ABCD1
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/300371"> 300371 </a>
</span>
</td>
</tr>
</tbody>
</table>
</div>
</div>
<div>
<div class="btn-group ">
<a href="/clinicalSynopsis/300100" class="btn btn-warning" role="button"> Clinical Synopsis </a>
<button type="button" id="mimPhenotypicSeriesToggle" class="btn btn-warning dropdown-toggle mimSingletonFoldToggle" data-toggle="collapse" href="#mimClinicalSynopsisFold" onclick="ga('send', 'event', 'Unfurl', 'ClinicalSynopsis', 'omim.org')">
<span class="caret"></span>
<span class="sr-only">Toggle Dropdown</span>
</button>
</div>
&nbsp;
<div class="btn-group">
<button type="button" class="btn btn-success dropdown-toggle" data-toggle="dropdown" aria-haspopup="true" aria-expanded="false">
PheneGene Graphics <span class="caret"></span>
</button>
<ul class="dropdown-menu" style="width: 17em;">
<li><a href="/graph/linear/300100" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Linear'})"> Linear </a></li>
<li><a href="/graph/radial/300100" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Radial'})"> Radial </a></li>
</ul>
</div>
<span class="glyphicon glyphicon-question-sign mim-tip-hint" title="OMIM PheneGene graphics depict relationships between phenotypes, groups of related phenotypes (Phenotypic Series), and genes.<br /><a href='/static/omim/pdf/OMIM_Graphics.pdf' target='_blank'>A quick reference overview and guide (PDF)</a>"></span>
<div>
<p />
</div>
<div id="mimClinicalSynopsisFold" class="well well-sm collapse mimSingletonToggleFold">
<div class="small" style="margin: 5px">
<div>
<div>
<span class="h5 mim-font">
<strong> INHERITANCE </strong>
</span>
</div>
<div style="margin-left: 2em;">
<div>
<span class="mim-font">
- X-linked recessive <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1845977&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1845977</a>, <a href="https://bioportal.bioontology.org/search?q=C1279481&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1279481</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001419" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001419</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001419" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001419</a>]</span><br />
</span>
</div>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<strong> HEAD & NECK </strong>
</span>
</div>
<div style="margin-left: 2em;">
<div>
<div>
<span class="h5 mim-font">
<em> Ears </em>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
- Hearing loss <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/103276001" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">103276001</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/343087000" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">343087000</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/15188001" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">15188001</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/H91.9" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">H91.9</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/389.9" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">389.9</a>, <a href="https://purl.bioontology.org/ontology/ICD9CM/389" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">389</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0011053&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0011053</a>, <a href="https://bioportal.bioontology.org/search?q=C0018772&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0018772</a>, <a href="https://bioportal.bioontology.org/search?q=C1384666&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1384666</a>, <a href="https://bioportal.bioontology.org/search?q=C3887873&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C3887873</a>, <a href="https://bioportal.bioontology.org/search?q=C2029884&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C2029884</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000365" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000365</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000365" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000365</a>]</span><br />
</span>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<em> Eyes </em>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
- Loss of vision <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/246635007" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">246635007</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/7973008" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">7973008</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/H54.7" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">H54.7</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/369.9" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">369.9</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C3665346&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C3665346</a>, <a href="https://bioportal.bioontology.org/search?q=C3665386&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C3665386</a>, <a href="https://bioportal.bioontology.org/search?q=C0042798&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0042798</a>, <a href="https://bioportal.bioontology.org/search?q=C0456909&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0456909</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000618" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000618</a>, <a href="https://hpo.jax.org/app/browse/term/HP:0000572" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000572</a>, <a href="https://hpo.jax.org/app/browse/term/HP:0000505" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000505</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000572" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000572</a>]</span><br />
</span>
</div>
</div>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<strong> ABDOMEN </strong>
</span>
</div>
<div style="margin-left: 2em;">
<div>
<div>
<span class="h5 mim-font">
<em> Gastrointestinal </em>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
- Fecal incontinence <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/72042002" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">72042002</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/R15.9" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">R15.9</a>, <a href="https://purl.bioontology.org/ontology/ICD10CM/R15" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">R15</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/787.6" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">787.6</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0015732&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0015732</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002607" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002607</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002607" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002607</a>]</span><br />
</span>
</div>
</div>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<strong> GENITOURINARY </strong>
</span>
</div>
<div style="margin-left: 2em;">
<div>
<div>
<span class="h5 mim-font">
<em> External Genitalia (Male) </em>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
- Impotence <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/860914002" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">860914002</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/N52.9" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">N52.9</a>, <a href="https://purl.bioontology.org/ontology/ICD10CM/N52" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">N52</a>, <a href="https://purl.bioontology.org/ontology/ICD10CM/F52.21" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">F52.21</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C2187990&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C2187990</a>, <a href="https://bioportal.bioontology.org/search?q=C0242350&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0242350</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0100639" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0100639</a>, <a href="https://hpo.jax.org/app/browse/term/HP:0000802" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000802</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000802" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000802</a>]</span><br />
</span>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<em> Bladder </em>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
- Urinary incontinence <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/165232002" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">165232002</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/R32" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">R32</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/788.30" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">788.30</a>, <a href="https://purl.bioontology.org/ontology/ICD9CM/788.3" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">788.3</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0042024&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0042024</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000020" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000020</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000020" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000020</a>]</span><br />
</span>
</div>
</div>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<strong> NEUROLOGIC </strong>
</span>
</div>
<div style="margin-left: 2em;">
<div>
<div>
<span class="h5 mim-font">
<em> Central Nervous System </em>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
- Neurodegeneration, progressive <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1854838&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1854838</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002344" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002344</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002180" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002180</a>]</span><br /> -
Cognitive decline <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/386806002" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">386806002</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0338656&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0338656</a>, <a href="https://bioportal.bioontology.org/search?q=C0234985&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0234985</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0100543" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0100543</a>, <a href="https://hpo.jax.org/app/browse/term/HP:0001268" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001268</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001268" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001268</a>]</span><br /> -
Loss of speech <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0542223&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0542223</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002371" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002371</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002371" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002371</a>]</span><br /> -
Dementia <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/52448006" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">52448006</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/12348006" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">12348006</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/F03.90" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">F03.90</a>, <a href="https://purl.bioontology.org/ontology/ICD10CM/F03" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">F03</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/290.1" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">290.1</a>, <a href="https://purl.bioontology.org/ontology/ICD9CM/294.2" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">294.2</a>, <a href="https://purl.bioontology.org/ontology/ICD9CM/290" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">290</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0011265&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0011265</a>, <a href="https://bioportal.bioontology.org/search?q=C0497327&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0497327</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000726" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000726</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000726" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000726</a>]</span><br /> -
Bulbar palsy <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/54304004" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">54304004</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/G12.22" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">G12.22</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/335.22" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">335.22</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C4082299&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C4082299</a>, <a href="https://bioportal.bioontology.org/search?q=C0030442&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0030442</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001283" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001283</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001283" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001283</a>]</span><br /> -
Seizures <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/91175000" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">91175000</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0036572&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0036572</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001250" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001250</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001250" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001250</a>]</span><br /> -
Paraparesis <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/1845001" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">1845001</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/G82.2" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">G82.2</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0221166&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0221166</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002385" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002385</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002385" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002385</a>]</span><br /> -
Spasticity <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/221360009" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">221360009</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/397790002" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">397790002</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0026838&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0026838</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001257" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001257</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001257" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001257</a>]</span><br /> -
Incoordination <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/281016006" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">281016006</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/302289002" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">302289002</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/R27.9" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">R27.9</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/781.3" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">781.3</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0520966&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0520966</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002311" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002311</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002311" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002311</a>]</span><br /> -
Ataxia <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/20262006" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">20262006</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/39384006" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">39384006</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/85102008" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">85102008</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/R27.0" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">R27.0</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/438.84" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">438.84</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0004134&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0004134</a>, <a href="https://bioportal.bioontology.org/search?q=C1135207&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1135207</a>, <a href="https://bioportal.bioontology.org/search?q=C0007758&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0007758</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001251" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001251</a>, <a href="https://hpo.jax.org/app/browse/term/HP:0010867" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0010867</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001251" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001251</a>]</span><br /> -
White matter abnormalities <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0948163&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0948163</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002500" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002500</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002500" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002500</a>]</span><br /> -
Cerebral demyelination and inflammation <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C3806584&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C3806584</a>]</span><br />
</span>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<em> Peripheral Nervous System </em>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
- Sensory loss <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/33653009" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">33653009</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0278134&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0278134</a>]</span><br /> -
Distal axonopathy (adrenomyeloneuropathy) <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C3806585&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C3806585</a>]</span><br />
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<em> Behavioral Psychiatric Manifestations </em>
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<div style="margin-left: 2em;">
<span class="mim-font">
- Behavioral changes <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/315244000" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">315244000</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0542299&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0542299</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000708" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000708</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000708" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000708</a>]</span><br /> -
Attention deficit-hyperactivity disorder <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/7461003" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">7461003</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/406506008" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">406506008</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/F90" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">F90</a>, <a href="https://purl.bioontology.org/ontology/ICD10CM/F90.9" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">F90.9</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/314.01" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">314.01</a>, <a href="https://purl.bioontology.org/ontology/ICD9CM/314" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">314</a>, <a href="https://purl.bioontology.org/ontology/ICD9CM/314.9" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">314.9</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1263846&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1263846</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000752" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000752</a>, <a href="https://hpo.jax.org/app/browse/term/HP:0007018" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0007018</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0007018" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0007018</a>]</span><br /> -
Autistic features <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1846135&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1846135</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000729" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000729</a>]</span><br /> -
Psychosis <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/191525009" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">191525009</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/69322001" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">69322001</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/F29" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">F29</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/298.9" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">298.9</a>, <a href="https://purl.bioontology.org/ontology/ICD9CM/290-299.99" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">290-299.99</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0349204&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0349204</a>, <a href="https://bioportal.bioontology.org/search?q=C0033975&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0033975</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000709" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000709</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000709" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000709</a>]</span><br />
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<strong> ENDOCRINE FEATURES </strong>
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- Adrenal insufficiency (Addison disease) <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/363732003" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">363732003</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/E27.1" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">E27.1</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0001403&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0001403</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0008207" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0008207</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/255.4" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">255.4</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000846" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000846</a>]</span><br />
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<strong> LABORATORY ABNORMALITIES </strong>
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- Systemic accumulation of very long chain fatty acids (VLCFA) <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C3806586&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C3806586</a>]</span><br />
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<strong> MISCELLANEOUS </strong>
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- Highly variable phenotype, ranging from asymptomatic to death by age 3 years<br /> -
Onset ranges from childhood (severe phenotype) to adulthood (limited phenotype)<br /> -
Progressive disorder <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1864985&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1864985</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003676" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003676</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003676" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003676</a>]</span><br /> -
Heterozygous female carriers may manifest symptoms<br /> -
Estimated incidence of 1 in 17,000<br />
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<strong> MOLECULAR BASIS </strong>
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- Caused by mutation in the ATP-binding cassette, subfamily D, member 1 gene (ABCD1, <a href="/entry/300371#0001">300371.0001</a>)<br />
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<p>A number sign (#) is used with this entry because of evidence that adrenoleukodystrophy (ALD) and adrenomyeloneuropathy (AMN) are caused by mutation in the ABCD1 gene (<a href="/entry/300371">300371</a>) on chromosome Xq28.</p>
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<strong>Description</strong>
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<p>Adrenoleukodystrophy (ALD) is an X-linked disorder which is secondary to a mutation in the ABCD1 gene and results in the apparent defect in peroxisomal beta oxidation and the accumulation of the saturated very long chain fatty acids (VLCFA) in all tissues of the body. The manifestations of the disorder occur primarily in the adrenal cortex, the myelin of the central nervous system, and the Leydig cells of the testes.</p><p>ABCD1 is an ATPase binding cassette protein in the same category of transporter proteins such as the CFTR and MDR proteins.</p><p>Identification of X-ALD as a lipid-storage disease, as a defect in the capacity to degrade VLCFAs, and its characterization as a peroxisomal disorder was reviewed by <a href="#100" class="mim-tip-reference" title="Moser, H. W. &lt;strong&gt;Adrenoleukodystrophy: phenotype, genetics, pathogenesis and therapy.&lt;/strong&gt; Brain 120: 1485-1508, 1997.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/9278636/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;9278636&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1093/brain/120.8.1485&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="9278636">Moser (1997)</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9278636" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#92" class="mim-tip-reference" title="Moser, H. W., Raymond, G. V., Dubey, P. &lt;strong&gt;Adrenoleukodystrophy: new approaches to a neurodegenerative disease.&lt;/strong&gt; JAMA 294: 3131-3134, 2005.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/16380594/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;16380594&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1001/jama.294.24.3131&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="16380594">Moser et al. (2005)</a> provided a clinical review of ALD. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16380594" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>Clinical Features</strong>
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<p>Adrenoleukodystrophy can present at a variety of ages and with different manifestations depending on the presence and type of neurologic findings. <a href="#87" class="mim-tip-reference" title="Moser, H. W., Loes, D. J., Melhem, E. R., Raymond, G. V., Bezman, L., Cox, C. S., Lu, S. E. &lt;strong&gt;X-linked adrenoleukodystrophy: overview and prognosis as a function of age and brain magnetic resonance imaging abnormality: a study involving 372 patients.&lt;/strong&gt; Neuropediatrics 31: 227-239, 2000.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/11204280/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;11204280&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1055/s-2000-9236&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="11204280">Moser et al. (2000)</a> stated that there are 7 phenotypes, which include the childhood cerebral form, adrenomyeloneuropathy (AMN), adult cerebral, adolescent, adrenal insufficiency without neurologic disease, asymptomatic, and heterozygotes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11204280" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>The clinical presentation can vary within the same family. One male may have the childhood form of the disorder and his brother may have the adult form. It is apparent that neither the genetic mutation nor the level of biochemical abnormality predicts the phenotypic presentation.</p><p><a href="#29" class="mim-tip-reference" title="Davis, L. E., Snyder, R. D., Orth, D. N., Nicholson, W. E., Kornfeld, M., Seelinger, D. F. &lt;strong&gt;Adrenoleukodystrophy and adrenomyeloneuropathy associated with partial adrenal insufficiency in three generations of a kindred.&lt;/strong&gt; Am. J. Med. 66: 342-347, 1979.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/218453/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;218453&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/0002-9343(79)90562-x&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="218453">Davis et al. (1979)</a> observed a family with 4 cases of adrenoleukodystrophy and 1 of adrenomyeloneuropathy, suggesting the fundamental identity of the 2 disorders. The patient with adrenomyeloneuropathy was well until age 21 years when he developed spastic paraparesis. He subsequently fathered 2 daughters and a stillborn child. He was 41 years old at the time of study and showed no clinical manifestations of adrenal insufficiency. A brother of his developed paraparesis at age 13 and progressed to death at age 19. A nephew became ill at age 4 and died at age 7. Autopsy showed atrophic adrenals although no clinical signs of adrenal insufficiency were observed. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=218453" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#106" class="mim-tip-reference" title="O&#x27;Neill, B. P., Moser, H. W., Marmion, L. C. &lt;strong&gt;Adrenoleukodystrophy: elevated C26 fatty acid in cultured skin fibroblasts and correlation with disease expression in three generations of a kindred.&lt;/strong&gt; Neurology 32: 540-542, 1982.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/6280106/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;6280106&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1212/wnl.32.5.540&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="6280106">O'Neill et al. (1982)</a> studied a kindred in which 14 members were affected with a variable combination of neurologic and adrenal manifestations. Abnormality was identified by increased content of C(26:0) fatty acid (hexacosanoic acid) in cultured skin fibroblasts and abnormal C26/C22 fatty acid ratios. The latter ratios were not proportional to severity of disease, duration, or character of the neurologic syndrome. In the family reported by O'Neill et al. (<a href="#105" class="mim-tip-reference" title="O&#x27;Neill, B. P., Moser, H. W., Marmion, L. C. &lt;strong&gt;The adrenoleukomyeloneuropathy (ALMN) complex: elevated C26 fatty acid in cultured skin fibroblasts and correlation with disease expression in three generations of a kindred. (Abstract)&lt;/strong&gt; Neurology 30: 352 only, 1980."None>1980</a>, <a href="#106" class="mim-tip-reference" title="O&#x27;Neill, B. P., Moser, H. W., Marmion, L. C. &lt;strong&gt;Adrenoleukodystrophy: elevated C26 fatty acid in cultured skin fibroblasts and correlation with disease expression in three generations of a kindred.&lt;/strong&gt; Neurology 32: 540-542, 1982.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/6280106/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;6280106&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1212/wnl.32.5.540&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="6280106">1982</a>), clinically apparent Addison disease without neurologic involvement was the expression of adrenoleukodystrophy in males, and spastic paraplegia and sphincter disturbances occurred in female carriers. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=6280106" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#13" class="mim-tip-reference" title="Berg, K. A., Beaty, T. H., Raven, M. B., Moser, A. B., Moser, H. W. &lt;strong&gt;X-linked adrenoleukodystrophy in a 362 member kindred. (Abstract)&lt;/strong&gt; Am. J. Hum. Genet. 45 (suppl.): A39, 1989."None>Berg et al. (1989)</a> described phenotypic features of a 362-member kindred spanning 6 generations. They observed clustering of phenotypes within individual sibships of the pedigree.</p><p><a href="#159" class="mim-tip-reference" title="Willems, P. J., Vits, L., Wanders, R. J. A., Coucke, P. J., Van der Auwera, B. J., Van Elsen, A. F., Raeymaekers, P., Van Broeckhoven, C., Schutgens, R. B. H., Dacremont, G., Leroy, J. G., Martin, J.-J., Dumon, J. E. &lt;strong&gt;Linkage of DNA markers at Xq28 to adrenoleukodystrophy and adrenomyeloneuropathy present within the same family.&lt;/strong&gt; Arch. Neurol. 47: 665-669, 1990.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/2161209/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;2161209&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1001/archneur.1990.00530060077022&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="2161209">Willems et al. (1990)</a> showed that patients with ALD and AMN in the same pedigree had identical haplotypes, demonstrating that they are not caused by different allelic mutations. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2161209" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#59" class="mim-tip-reference" title="Holmberg, B. H., Hagg, E., Hagenfeldt, L. &lt;strong&gt;Adrenomyeloneuropathy--report on a family.&lt;/strong&gt; J. Intern. Med. 230: 535-538, 1991.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/1660916/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;1660916&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1111/j.1365-2796.1991.tb00485.x&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="1660916">Holmberg et al. (1991)</a> described a remarkable family in Sweden in which there was Addison disease in a 13-year-old boy, adrenomyeloneuropathy in a 58-year-old man, and spastic paraparesis and peripheral neuropathy in at least 3 heterozygous females, including the 85-year-old mother of the man with AMN. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1660916" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#142" class="mim-tip-reference" title="Sobue, G., Ueno-Natsukari, I., Okamoto, H., Connell, T. A., Aizawa, I., Mizoguchi, K., Honma, M., Ishikawa, G., Mitsuma, T., Natsukari, N. &lt;strong&gt;Phenotypic heterogeneity of an adult form of adrenoleukodystrophy in monozygotic twins.&lt;/strong&gt; Ann. Neurol. 36: 912-915, 1994.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/7998779/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;7998779&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ana.410360617&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="7998779">Sobue et al. (1994)</a> described considerable phenotypic heterogeneity between 2 proven monozygotic twins, both of whom had myeloneuropathy. Extensive demyelination in the brain was only prominent in the older twin, while adrenal insufficiency was prominent in the younger twin. They suggested that nongenetic factors were important determinants of the phenotypic variation of the adrenoleukodystrophy gene. <a href="#68" class="mim-tip-reference" title="Korenke, G. C., Fuchs, S., Krasemann, E., Doerr, H. G., Wilichowski, E., Hunneman, D. H., Hanefeld, F. &lt;strong&gt;Cerebral adrenoleukodystrophy (ALD) in only one of monozygotic twins with an identical ALD genotype.&lt;/strong&gt; Ann. Neurol. 40: 254-257, 1996.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/8773611/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;8773611&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ana.410400221&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="8773611">Korenke et al. (1996)</a> and <a href="#31" class="mim-tip-reference" title="Di Rocco, M., Doria-Lamba, L., Caruso, U. &lt;strong&gt;Monozygotic twins with X-linked adrenoleukodystrophy and different phenotypes.&lt;/strong&gt; Ann. Neurol. 50: 424 only, 2001.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/11558805/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;11558805&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ana.1220&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="11558805">Di Rocco et al. (2001)</a> also reported pairs of identical male twins with different clinical expressions of ALD. <a href="#158" class="mim-tip-reference" title="Wilichowski, E., Ohlenbusch, A., Korenke, G. C., Hunneman, D. H., Hanefeld, F. &lt;strong&gt;Identical mitochondrial DNA in monozygotic twins with discordant adrenoleukodystrophy phenotype. (Letter)&lt;/strong&gt; Ann. Neurol. 43: 835-836, 1998.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/9629856/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;9629856&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ana.410430621&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="9629856">Wilichowski et al. (1998)</a> found no difference in mitochondrial DNA in the twins reported by <a href="#68" class="mim-tip-reference" title="Korenke, G. C., Fuchs, S., Krasemann, E., Doerr, H. G., Wilichowski, E., Hunneman, D. H., Hanefeld, F. &lt;strong&gt;Cerebral adrenoleukodystrophy (ALD) in only one of monozygotic twins with an identical ALD genotype.&lt;/strong&gt; Ann. Neurol. 40: 254-257, 1996.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/8773611/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;8773611&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ana.410400221&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="8773611">Korenke et al. (1996)</a>. <a href="#31" class="mim-tip-reference" title="Di Rocco, M., Doria-Lamba, L., Caruso, U. &lt;strong&gt;Monozygotic twins with X-linked adrenoleukodystrophy and different phenotypes.&lt;/strong&gt; Ann. Neurol. 50: 424 only, 2001.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/11558805/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;11558805&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ana.1220&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="11558805">Di Rocco et al. (2001)</a> stated that the discordant adrenoleukodystrophy phenotypes in 3 pairs of monozygotic twins indicated that modifier genes were not involved in determining the occurrence of CNS degeneration. They suggested that identifying environmental factors could be important for effectively preventing CNS degeneration in this disorder. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=8773611+11558805+9629856+7998779" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>By neuropsychologic testing, <a href="#28" class="mim-tip-reference" title="Cox, C. S., Dubey, P., Raymond, G. V., Mahmood, A., Moser, A. B., Moser, H. W. &lt;strong&gt;Cognitive evaluation of neurologically asymptomatic boys with X-linked adrenoleukodystrophy.&lt;/strong&gt; Arch. Neurol. 63: 69-73, 2006.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/16401737/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;16401737&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1001/archneur.63.1.69&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="16401737">Cox et al. (2006)</a> found normal cognitive function in 48 of 52 neurologically asymptomatic boys with ALD (mean age, 6.7 years). All of the patients had normal brain MRI studies. However, there was a negative correlation between age and visual perception as well as age and visuomotor skills. <a href="#28" class="mim-tip-reference" title="Cox, C. S., Dubey, P., Raymond, G. V., Mahmood, A., Moser, A. B., Moser, H. W. &lt;strong&gt;Cognitive evaluation of neurologically asymptomatic boys with X-linked adrenoleukodystrophy.&lt;/strong&gt; Arch. Neurol. 63: 69-73, 2006.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/16401737/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;16401737&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1001/archneur.63.1.69&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="16401737">Cox et al. (2006)</a> concluded that a subset of patients with the childhood form of ALD have normal neurodevelopment despite an inherent defect in the ABCD1 gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16401737" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Childhood Cerebral Adrenoleukodystrophy</em></strong></p><p>
The classic presentation of childhood cerebral ALD has been analyzed in several large series (<a href="#134" class="mim-tip-reference" title="Schaumburg, H. H., Powers, J. M., Raine, C. S., Suzuki, K., Richardson, E. P., Jr. &lt;strong&gt;Adrenoleukodystrophy: a clinical and pathological study of 17 cases.&lt;/strong&gt; Arch. Neurol. 32: 577-591, 1975.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/169765/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;169765&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1001/archneur.1975.00490510033001&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="169765">Schaumburg et al., 1975</a>; <a href="#6" class="mim-tip-reference" title="Aubourg, P., Chaussain, J. L., Dulac, O., Arthuis, M. &lt;strong&gt;Adrenoleukodystrophy in children: apropos of 20 cases.&lt;/strong&gt; Arch. Franc. Pediat. 39: 663-669, 1982.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/6299222/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;6299222&lt;/a&gt;]" pmid="6299222">Aubourg et al., 1982</a>). This is the form of the illness that was originally described by <a href="#140" class="mim-tip-reference" title="Siemerling, E., Creutzfeldt, H. G. &lt;strong&gt;Bronzekrankheit und sklerosierende Encephalomyelitis.&lt;/strong&gt; Arch. Psychiat. Nervkrankh. 68: 217-244, 1923."None>Siemerling and Creutzfeldt (1923)</a> and, until it was possible to make the biochemical diagnosis, it was the only form of the disease recognized as adrenoleukodystrophy. It is a rapidly progressive demyelinating condition affecting the cerebral white matter. It is by definition confined to boys who develop cerebral involvement before the age of 10 years. The boys are normal at birth and have unremarkable development. The mean age of onset is approximately 7 years. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=6299222+169765" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>The disease usually manifests itself early with behavioral manifestations including inattention, hyperactivity, and emotional lability. It often becomes apparent through school difficulties. It progresses into visual symptoms, auditory processing difficulties, and motor incoordination. Once the neurologic manifestations appear, progression of the illness is tragically rapid and the child is often in a vegetative state within 1 to 2 years.</p><p>Magnetic resonance imaging is often the first diagnostic study and shows a characteristic pattern of symmetric involvement of the posterior parietooccipital white matter in 85% of patients, frontal involvement in 10%, and an asymmetric pattern in the rest.</p><p><strong><em>Adult/Adrenomyeloneuropathy</em></strong></p><p>
<a href="#23" class="mim-tip-reference" title="Budka, H., Sluga, E., Heiss, W.-D. &lt;strong&gt;Spastic paraplegia associated with Addison&#x27;s disease: adult variant of adreno-leukodystrophy.&lt;/strong&gt; J. Neurol. 213: 237-250, 1976.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/61263/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;61263&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1007/BF00312873&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="61263">Budka et al. (1976)</a> reported a case they interpreted as an adult variant of adrenoleukodystrophy. At the time, a geneticist could raise the possibility of this form being the consequence of an allelic mutation, but phenotypic variability within families has subsequently been demonstrated. The neurologic picture was dominated by spastic paraplegia. Both clinically and pathologically, absence of diffuse cerebral involvement was noteworthy. The endocrinologic disorder was the particularly striking feature. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=61263" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#47" class="mim-tip-reference" title="Griffin, J. W., Goren, E., Schaumburg, H. H., Engel, W. K., Loriaux, L. &lt;strong&gt;Adrenomyeloneuropathy: a probable variant of adrenoleukodystrophy. I. Clinical and endocrinologic aspects.&lt;/strong&gt; Neurology 27: 1107-1113, 1977.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/200861/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;200861&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1212/wnl.27.12.1107&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="200861">Griffin et al. (1977)</a> and <a href="#133" class="mim-tip-reference" title="Schaumburg, H. H., Powers, J. M., Raine, C. S., Spencer, P. S., Griffin, J. W., Prineas, J. W., Boehme, D. M. &lt;strong&gt;Adrenomyeloneuropathy: a probable variant of adrenoleukodystrophy. II. General pathologic, neuropathologic, and biochemical aspects.&lt;/strong&gt; Neurology 27: 1114-1119, 1977.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/200862/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;200862&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1212/wnl.27.12.1114&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="200862">Schaumburg et al. (1977)</a> described a variant that they called adrenomyeloneuropathy. Hypogonadism was present in all cases appropriately studied. Adrenal insufficiency began in childhood and progressive spastic paraparesis in the third decade. Neurologic features included peripheral neuropathy, impotence, and sphincter disturbances. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=200861+200862" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#108" class="mim-tip-reference" title="O&#x27;Neill, B. P., Swanson, J. W., Brown, F. R., III, Griffin, J. W., Moser, H. W. &lt;strong&gt;Familial spastic paraparesis: an adrenoleukodystrophy phenotype?&lt;/strong&gt; Neurology 35: 1233-1235, 1985.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/4022363/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;4022363&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1212/wnl.35.8.1233&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="4022363">O'Neill et al. (1985)</a> found biochemical characteristics of ALD in 2 brothers with spastic paraplegia of onset at age 40 and 50 years. Further study in the family revealed 2 nephews who were also affected as well as asymptomatic carriers in a typical X-linked pedigree pattern. None had symptoms of adrenal insufficiency. <a href="#27" class="mim-tip-reference" title="Cotrufo, R., Melone, M. A. B., Monsurro, M. R., Di Iorio, G., Carella, C., Moser, H. W. &lt;strong&gt;Phenotype heterogeneity among hemizygotes in a family biochemically screened for adrenoleukodystrophy.&lt;/strong&gt; Am. J. Med. Genet. 26: 833-838, 1987.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/3591825/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;3591825&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ajmg.1320260410&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="3591825">Cotrufo et al. (1987)</a> reported the remarkable cases of an uncle and nephew who were completely asymptomatic at ages 25 and 10, respectively, but who showed levels of very long chain fatty acids in plasma consistent with the ALD hemizygote state. Both were found to have adrenocortical insufficiency as evidenced by compensatory high ACTH release. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=3591825+4022363" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#148" class="mim-tip-reference" title="Uyama, E., Iwagoe, H., Maeda, J., Nakamura, M., Terasaki, T., Ando, M. &lt;strong&gt;Presenile-onset cerebral adrenoleukodystrophy presenting as Balint&#x27;s syndrome and dementia.&lt;/strong&gt; Neurology 43: 1249-1251, 1993.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/8170577/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;8170577&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1212/wnl.43.6.1249&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="8170577">Uyama et al. (1993)</a> described a man who had presenile onset (at age 51 years) of the cerebral form of ALD. The first manifestation was difficulty in recalling where he had placed things. Shortly thereafter, he had problems operating farm machinery and gradually developed difficulty seeing clearly and writing at normal speeds. He could dress himself but often put garments on backward or inside out. He later developed Balint syndrome and dementia. (Balint syndrome is an acquired visuospatial disorder characterized by psychic paralysis of visual fixation, optic ataxia, and disturbance of visual attention with relatively intact vision (<a href="#52" class="mim-tip-reference" title="Hecaen, H., De Ajuriaguerra, J. &lt;strong&gt;Balint&#x27;s syndrome (psychic paralysis of visual fixation) and its minor forms.&lt;/strong&gt; Brain 77: 373-400, 1954.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/13208876/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;13208876&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1093/brain/77.3.373&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="13208876">Hecaen and De Ajuriaguerra, 1954</a>).) MRI demonstrated demyelinating lesions in the bilateral posterior parietooccipital white matter involving the splenium of the corpus callosum. The patient could not move his eyes on command or follow a moving object. He had difficulty in maintaining central fixation. Optic ataxia was also shown by frequent errors when he attempted to grasp an object at which he was looking. The patient was bedridden by age 54 and died at age 55. Tests of adrenal function yielded normal results. Ratios of C26:0 to C22:0 in plasma and in erythrocyte membranes established the diagnosis of ALD in the proband and demonstrated that his mother was a heterozygote. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=13208876+8170577" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#150" class="mim-tip-reference" title="van Geel, B. M., Bezman, L., Loes, D. J., Moser, H. W., Raymond, G. V. &lt;strong&gt;Evolution of phenotypes in adult male patients with X-linked adrenoleukodystrophy.&lt;/strong&gt; Ann. Neurol. 49: 186-194, 2001.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/11220738/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;11220738&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/1531-8249(20010201)49:2&lt;186::aid-ana38&gt;3.0.co;2-r&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="11220738">Van Geel et al. (2001)</a> studied the evolution of the disease in adults. They studied 129 men retrospectively, with a mean follow-up period of 10.1 +/- 5.0 years. Among 32 neurologically asymptomatic patients, 16 (50%) developed some neurologic involvement. Among 68 men with AMN without cerebral involvement, 13 (19%) developed clinically apparent cerebral demyelination. There was a high risk for adult neurologically asymptomatic patients to develop neurologic deficits and for AMN patients to develop cerebral demyelination. This had implications for the phenotype classification, search for modifying factors, and the development and evaluation of new therapies. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11220738" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#36" class="mim-tip-reference" title="Eichler, F., Mahmood, A., Loes, D., Bezman, L., Lin, D., Moser, H. W., Raymond, G. V. &lt;strong&gt;Magnetic resonance imaging detection of lesion progression in adult patients with X-linked adrenoleukodystrophy.&lt;/strong&gt; Arch. Neurol. 64: 659-664, 2007.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/17502464/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;17502464&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1001/archneur.64.5.659&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="17502464">Eichler et al. (2007)</a> reviewed serial brain MRI scans of 56 adult patients with ALD and white matter abnormalities. Forty-two (75%) of these patients had corticospinal tract involvement, and 21 (50%) of the 42 showed lesion progression over a 3 to 5-year period. Disease progression was slower in adults compared to that previously observed in affected children. Only 3 adult patients showed isolated lesions in the genu or the splenium, all of which developed in childhood or adolescence. The findings suggested that progressive inflammatory demyelination can occur along with the known axonopathy of adulthood. <a href="#36" class="mim-tip-reference" title="Eichler, F., Mahmood, A., Loes, D., Bezman, L., Lin, D., Moser, H. W., Raymond, G. V. &lt;strong&gt;Magnetic resonance imaging detection of lesion progression in adult patients with X-linked adrenoleukodystrophy.&lt;/strong&gt; Arch. Neurol. 64: 659-664, 2007.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/17502464/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;17502464&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1001/archneur.64.5.659&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="17502464">Eichler et al. (2007)</a> suggested that the vulnerability of specific fiber tracts in ALD changes with age. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17502464" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Adrenal Insufficiency</em></strong></p><p>
Addison disease in young males should prompt consideration of ALD as the underlying abnormality. See also <a href="#130" class="mim-tip-reference" title="Sadeghi-Nejad, A., Senior, B. &lt;strong&gt;Adrenomyeloneuropathy presenting as Addison&#x27;s disease in childhood.&lt;/strong&gt; New Eng. J. Med. 322: 13-16, 1990.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/2294415/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;2294415&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1056/NEJM199001043220103&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="2294415">Sadeghi-Nejad and Senior (1990)</a>. <a href="#72" class="mim-tip-reference" title="Laureti, S., Casucci, G., Santeusanio, F., Angeletti, G., Aubourg, P., Brunetti, P. &lt;strong&gt;X-linked adrenoleukodystrophy is a frequent cause of idiopathic Addison&#x27;s disease in young adult male patients.&lt;/strong&gt; J. Clin. Endocr. Metab. 81: 470-474, 1996.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/8636252/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;8636252&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1210/jcem.81.2.8636252&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="8636252">Laureti et al. (1996)</a> performed biochemical analysis of very long chain fatty acids in 14 male patients (age ranging from 12-45 years at diagnosis) previously diagnosed as having primary idiopathic adrenocortical insufficiency. In 5 of the 14 patients, elevated levels of very long chain fatty acids (VLCFA) were found in plasma; none had adrenocortical antibodies. By electrophysiologic tests and magnetic resonance imaging, it was determined that 2 had cerebral ALD, 1 had adrenomyeloneuropathy with cerebral involvement, and 2 had preclinical AMN. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=2294415+8636252" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Since the adrenal insufficiency may long precede neurologic manifestations and perhaps may occur alone, caution must be exercised in the interpretation of isolated X-linked Addison disease as a separate entity. Of course, autopsy-confirmed adrenal hypoplasia (<a href="/entry/300200">300200</a>) is a well-established entity.</p><p>The achalasia-Addisonian syndrome (<a href="/entry/231550">231550</a>), which appears to be autosomal recessive, is another example of combined adrenal and neurologic (autonomic) involvement.</p><p>The postperfusion syndrome is an uncommon event following open-heart surgery with extracorporeal circulation. It is associated with a young age at surgery (less than 1 year) and bypass lasting longer than 60 minutes. <a href="#75" class="mim-tip-reference" title="Luciani, G. B., Pessotto, R., Mazzucco, A. &lt;strong&gt;Adrenoleukodystrophy presenting as postperfusion syndrome. (Letter)&lt;/strong&gt; New Eng. J. Med. 336: 731-732, 1997.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/9045051/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;9045051&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1056/NEJM199703063361015&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="9045051">Luciani et al. (1997)</a> observed the syndrome in an 18-year-old man who underwent transpulmonary patch repair of a ventricular septal defect with cardiopulmonary bypass for 50 minutes. Preoperatively, the patient exhibited a slight gait disorder and unremarkable EEG and laboratory findings. Twelve hours after surgery he developed hypotension and circulatory collapse. This was treated successfully, but 10 days after discharge the patient was admitted with findings suggesting Addison disease. He showed a worsening disturbance of gait, with ataxia and EEG abnormalities. The diagnosis of adrenoleukodystrophy was supported by MRI of the head and confirmed by increased plasma levels of very long chain saturated fatty acids. Thus, <a href="#75" class="mim-tip-reference" title="Luciani, G. B., Pessotto, R., Mazzucco, A. &lt;strong&gt;Adrenoleukodystrophy presenting as postperfusion syndrome. (Letter)&lt;/strong&gt; New Eng. J. Med. 336: 731-732, 1997.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/9045051/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;9045051&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1056/NEJM199703063361015&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="9045051">Luciani et al. (1997)</a> concluded that this was a case of Addisonian crisis precipitated by surgery in a patient with previously unrecognized ALD. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9045051" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Heterozygote</em></strong></p><p>
Women who are carriers for the condition may develop spastic paraparesis with bowel and bladder difficulties. This appears to be partially a function of age.</p><p><a href="#53" class="mim-tip-reference" title="Heffungs, W., Hameister, H., Ropers, H. H. &lt;strong&gt;Addison disease and cerebral sclerosis in an apparently heterozygous girl: evidence for inactivation of the adrenoleukodystrophy locus.&lt;/strong&gt; Clin. Genet. 18: 184-188, 1980.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/7438498/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;7438498&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1111/j.1399-0004.1980.tb00868.x&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="7438498">Heffungs et al. (1980)</a> observed cerebral sclerosis and Addison disease in a previously healthy 14-year-old sister of an affected boy. They suggested that this was the first documented example of adrenoleukodystrophy in a heterozygote. Several other unusual examples have been published. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7438498" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Also see <a href="#106" class="mim-tip-reference" title="O&#x27;Neill, B. P., Moser, H. W., Marmion, L. C. &lt;strong&gt;Adrenoleukodystrophy: elevated C26 fatty acid in cultured skin fibroblasts and correlation with disease expression in three generations of a kindred.&lt;/strong&gt; Neurology 32: 540-542, 1982.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/6280106/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;6280106&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1212/wnl.32.5.540&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="6280106">O'Neill et al. (1982)</a>. The patient reported by <a href="#103" class="mim-tip-reference" title="Noetzel, M. J., Landau, W. M., Moser, H. W. &lt;strong&gt;Adrenoleukodystrophy carrier state presenting as a chronic nonprogressive spinal cord disorder.&lt;/strong&gt; Arch. Neurol. 44: 566-567, 1987.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/3579671/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;3579671&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1001/archneur.1987.00520170092031&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="3579671">Noetzel et al. (1987)</a> illustrates further the occurrence of a chronic nonprogressive spinal cord syndrome in women heterozygous for ALD. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=6280106+3579671" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#55" class="mim-tip-reference" title="Hershkovitz, E., Narkis, G., Shorer, Z., Moser, A. B., Watkins, P. A., Moser, H. W., Manor, E. &lt;strong&gt;Cerebral X-linked adrenoleukodystrophy in a girl with Xq27-ter deletion.&lt;/strong&gt; Ann. Neurol. 52: 234-237, 2002.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/12210797/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;12210797&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ana.10248&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="12210797">Hershkovitz et al. (2002)</a> reported an 8.5-year-old girl who presented with declining school performance and diffuse frontal white matter demyelination. She was known to be at risk for heterozygosity because 2 maternal uncles had ALD. Levels of very long chain fatty acids were elevated. DNA analysis of the patient and her mother showed a cytosine insertion in codon 515 (515insC) of the ABCD1 gene, resulting in a frameshift after amino acid 171 (tyrosine). Immunocytochemical studies showed that ALDP reactivity was lacking in 99% of the fibroblasts analyzed. Cytogenetic analysis showed a deletion at Xq27.2-qter. Both parents were normal. She underwent bone marrow transplantation from a normal sister and at 18 months was stable. <a href="#55" class="mim-tip-reference" title="Hershkovitz, E., Narkis, G., Shorer, Z., Moser, A. B., Watkins, P. A., Moser, H. W., Manor, E. &lt;strong&gt;Cerebral X-linked adrenoleukodystrophy in a girl with Xq27-ter deletion.&lt;/strong&gt; Ann. Neurol. 52: 234-237, 2002.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/12210797/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;12210797&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ana.10248&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="12210797">Hershkovitz et al. (2002)</a> recommended that cytogenetic studies be performed in the 1% of heterozygotes who show evidence of cerebral involvement. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12210797" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#62" class="mim-tip-reference" title="Jung, H. H., Wimplinger, I., Jung, S., Landau, K., Gal, A., Heppner, F. L. &lt;strong&gt;Phenotypes of female adrenoleukodystrophy.&lt;/strong&gt; Neurology 68: 960-961, 2007.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/17372139/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;17372139&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1212/01.wnl.0000257129.51273.73&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="17372139">Jung et al. (2007)</a> reported 2 unrelated women with heterozygous mutations in the ABCD1 gene. The first patient was diagnosed at age 8 years with manic-hebephrenic disorder and subsequent psychotic episodes. She had spastic paraparesis at age 25 and developed cognitive deficits, cerebellar signs, and more severe spastic paraparesis at age 45. She died of pneumonia at age 52. Her brother had Addison disease at age 47, and later developed spastic paraparesis and polyneuropathy. The second patient developed inability to run at age 35 years, 1 year after her son died of ALD. She was wheelchair-bound by age 48. Later features included bilateral visual loss and mild polyneuropathy. She was cognitively intact. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17372139" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Other--Spinocerebellar</em></strong></p><p>
<a href="#65" class="mim-tip-reference" title="Kobayashi, T., Noda, S., Umezaki, H., Goto, I., Suzuki, S., Kitaguchi, T., Kuroiwa, Y. &lt;strong&gt;Familial spinocerebellar degeneration as an expression of adrenoleukodystrophy.&lt;/strong&gt; J. Neurol. Neurosurg. Psychiat. 49: 1438-1440, 1986.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/3468205/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;3468205&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1136/jnnp.49.12.1438&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="3468205">Kobayashi et al. (1986)</a> described 2 adult male first cousins with spinocerebellar degeneration manifested by progressive limb and truncal ataxia, slurred speech, and spasticity of the limbs. Brain CT scans showed atrophy of the pons and cerebellum. Very long chain fatty acids were elevated in the plasma and red cell membranes of the affected patients and were increased to intermediate levels in the female carriers. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=3468205" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>An important observation was that of <a href="#60" class="mim-tip-reference" title="Igarashi, M., Schaumburg, H. H., Powers, J., Kishimoto, Y., Kolodny, E. H., Suzuki, K. &lt;strong&gt;Fatty acid abnormality in adrenoleukodystrophy.&lt;/strong&gt; J. Neurochem. 26: 851-860, 1976.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/965973/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;965973&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1111/j.1471-4159.1976.tb04462.x&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="965973">Igarashi et al. (1976)</a>. They found that cholesterol esters in the brain and adrenals of these patients had an unusually high proportion of fatty acids with a chain length of 24-30 carbon atoms, rather than the usual length of less than 20. This might interfere with myelin formation in the CNS and steroidogenesis in the adrenal. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=965973" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Biochemical studies of cerebral white matter showed increased amounts of long chain saturated fatty acids in cholesterol esters.</p><p>ALD is characterized by the accumulation of unbranched saturated fatty acids with a chain length of 24 to 30 carbons, particularly hexacosanoate (C26), in the cholesterol esters of brain white matter and in adrenal cortex and in certain sphingolipids of brain. Accumulation also occurs in plasma-cultured skin fibroblasts and this fact can be used for diagnosis (including prenatal diagnosis) and for the study of the disease's basic mechanisms (<a href="#89" class="mim-tip-reference" title="Moser, H. W., Moser, A. B., Kawamura, N., Murphy, J., Suzuki, K., Schaumburg, H., Kishimoto, Y. &lt;strong&gt;Adrenoleukodystrophy: elevated C26 fatty acid in cultured skin fibroblasts.&lt;/strong&gt; Ann. Neurol. 7: 542-549, 1980.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/7436359/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;7436359&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ana.410070607&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="7436359">Moser et al., 1980</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7436359" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>It appears that the defect is in the catabolism of the very long chain fatty acids (see <a href="/entry/603314">603314</a>) themselves. A parallel to Refsum disease (<a href="/entry/266500">266500</a>) in which a fatty acid of dietary origin accumulates because of deficiency of an enzyme for its catabolism is suggested by the finding that the accumulating long chain fatty acids are, at least in part, of exogenous origin (<a href="#96" class="mim-tip-reference" title="Moser, H. W. &lt;strong&gt;Personal Communication.&lt;/strong&gt; Baltimore, Md. 1980."None>Moser, 1980</a>). This finding and analogy suggest that dietary modification may be beneficial in ALD.</p><p><a href="#88" class="mim-tip-reference" title="Moser, H. W., Moser, A. B., Frayer, K. K., Chen, W., Schulman, J. D., O&#x27;Neill, B. P., Kishimoto, Y. &lt;strong&gt;Adrenoleukodystrophy: increased plasma content of saturated very long chain fatty acids.&lt;/strong&gt; Neurology 31: 1241-1249, 1981.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/7202134/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;7202134&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1212/wnl.31.10.1241&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="7202134">Moser et al. (1981)</a> investigated a possible defect in a peroxisomal beta-oxidation system. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7202134" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>The work of <a href="#51" class="mim-tip-reference" title="Hashmi, M., Stanley, W., Singh, I. &lt;strong&gt;Lignoceroyl-CoASH ligase: enzyme defect in fatty acid beta-oxidation system in X-linked childhood adrenoleukodystrophy.&lt;/strong&gt; FEBS Lett. 196: 247-250, 1986.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/3948997/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;3948997&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/0014-5793(86)80256-3&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="3948997">Hashmi et al. (1986)</a> and of <a href="#141" class="mim-tip-reference" title="Singh, I., Lazo, O., Contreras, M., Hashmi, M., Stanley, W. S. &lt;strong&gt;Peroxisomal lignoceroyl-CoA ligase deficiency in X-linked adrenoleukodystrophy. (Abstract)&lt;/strong&gt; Am. J. Hum. Genet. 43: A16, 1988."None>Singh et al. (1988)</a> suggested that the basic defect in X-linked ALD is deficient activity of lignoceroyl-CoA ligase. <a href="#141" class="mim-tip-reference" title="Singh, I., Lazo, O., Contreras, M., Hashmi, M., Stanley, W. S. &lt;strong&gt;Peroxisomal lignoceroyl-CoA ligase deficiency in X-linked adrenoleukodystrophy. (Abstract)&lt;/strong&gt; Am. J. Hum. Genet. 43: A16, 1988."None>Singh et al. (1988)</a> and <a href="#73" class="mim-tip-reference" title="Lazo, O., Contreras, M., Hashmi, M., Stanley, W., Irazu, C., Singh, I. &lt;strong&gt;Peroxisomal lignoceroyl-CoA ligase deficiency in childhood adrenoleukodystrophy and adrenomyeloneuropathy.&lt;/strong&gt; Proc. Nat. Acad. Sci. 85: 7647-7651, 1988.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/3174658/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;3174658&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1073/pnas.85.20.7647&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="3174658">Lazo et al. (1988)</a> presented data demonstrating that the accumulation of very long chain fatty acids in ALD is the result of deficient peroxisomal lignoceroyl-CoA ligase activity. It had previously been thought that the same ligase was responsible for the activation of C16:0 (palmitic acid) and C24:0 (lignoceric acid). Later data indicated that they are separate enzymes. Wanders et al. (<a href="#154" class="mim-tip-reference" title="Wanders, R. J. A., van Roermund, C. W. T., van Wijland, M. J. A., Nijenhuis, A. A., Tromp, A., Schutgens, R. B. H., Brouwer-Kelder, E. M., Schram, A. W., Tager, J. M., van den Bosch, H., Schalkwijk, C. &lt;strong&gt;X-linked adrenoleukodystrophy: defective peroxisomal oxidation of very long chain fatty acids but not of very long chain fatty acyl-CoA esters.&lt;/strong&gt; Clin. Chim. Acta 165: 321-329, 1987.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/3652454/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;3652454&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/0009-8981(87)90177-x&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="3652454">1987</a>, <a href="#156" class="mim-tip-reference" title="Wanders, R. J. A., van Roermund, C. W. T., van Wijland, M. J. A., Schutgens, R. B. H., van den Bosch, H., Schram, A. W., Tager, J. M. &lt;strong&gt;Direct demonstration that the deficient oxidation of very long chain fatty acids in X-linked adrenoleukodystrophy is due to an impaired ability of peroxisomes to activate very long chain fatty acids.&lt;/strong&gt; Biochem. Biophys. Res. Commun. 153: 618-624, 1988.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/3382393/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;3382393&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/s0006-291x(88)81140-9&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="3382393">1988</a>) had interpreted their results as indicating that the basic defect in X-linked ALD resides in peroxisomal very long chain fatty acyl-CoA synthetase. This enzyme is present not only in peroxisomes but also in microsomes. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=3382393+3652454+3948997+3174658" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>The identification of the genetic defect and protein abnormality in ALD has resulted, however, in different conclusions. The defect is not in an enzyme, but in a protein, ABCD1, that has a role in peroxisomal beta-oxidation. It has been suggested that the protein has a role in transport.</p><p>Beta-oxidation of fatty acids occurs through a carnitine-dependent pathway in the mitochondria and a carnitine-independent pathway in the peroxisomes. In cell cultures and mouse tissue, <a href="#80" class="mim-tip-reference" title="McGuinness, M. C., Lu, J.-F., Zhang, H.-P., Dong, G.-X., Heinzer, A. K., Watkins, P. A., Powers, J., Smith, K. D. &lt;strong&gt;Role of ALDP (ABCD1) and mitochondria in X-linked adrenoleukodystrophy.&lt;/strong&gt; Molec. Cell. Biol. 23: 744-753, 2003.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/12509471/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;12509471&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=12509471[PMID]&amp;report=imagesdocsum&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed Image&#x27;, &#x27;domain&#x27;: &#x27;ncbi.nlm.nih.gov&#x27;})&quot;&gt;images&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1128/MCB.23.2.744-753.2003&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="12509471">McGuinness et al. (2003)</a> showed that the ALDP protein transporter may facilitate an interaction between peroxisomes and mitochondria, which is disturbed in X-linked ALD. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12509471" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#144" class="mim-tip-reference" title="Stradomska, T. J., Tylki-Szymanska, A. &lt;strong&gt;Decreasing serum VLCFA levels in ageing X-ALD female carriers.&lt;/strong&gt; J. Inherit. Metab. Dis. 24: 851-857, 2001.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/11916318/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;11916318&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1023/a:1013992224811&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="11916318">Stradomska and Tylki-Szymanska (2001)</a> described the results of measuring serum very long chain fatty acid concentrations in 59 females of various ages with heightened risk of carrier status for ALD. In female carriers aged 22 to 50 years, they found serum VLCFA concentrations in a range characteristic of heterozygotes; VLCFA levels were normal in female carriers aged 55 to 64 years. In women aged 37 to 50 years in whom repeat studies of VLCFA concentrations were performed after 5 years, a reduction in VLCFA was observed. <a href="#144" class="mim-tip-reference" title="Stradomska, T. J., Tylki-Szymanska, A. &lt;strong&gt;Decreasing serum VLCFA levels in ageing X-ALD female carriers.&lt;/strong&gt; J. Inherit. Metab. Dis. 24: 851-857, 2001.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/11916318/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;11916318&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1023/a:1013992224811&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="11916318">Stradomska and Tylki-Szymanska (2001)</a> suggested that the results point to a reduction of serum VLCFA concentrations as X-ALD heterozygotes age. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11916318" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="inheritance" class="mim-anchor"></a>
<h4 href="#mimInheritanceFold" id="mimInheritanceToggle" class="mimTriangleToggle" style="cursor: pointer;" data-toggle="collapse">
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<strong>Inheritance</strong>
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<p><a href="#40" class="mim-tip-reference" title="Fanconi, A., Prader, A., Isler, W., Luthy, F., Siebenmann, R. E. &lt;strong&gt;Morbus Addison mit Hirnsklerose im Kindesalter. Ein hereditaeres Syndrom mit X-chromosomaler Vererbung?&lt;/strong&gt; Helv. Paediat. Acta 18: 480-501, 1963.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/14110277/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;14110277&lt;/a&gt;]" pmid="14110277">Fanconi et al. (1963)</a> suggested X-linked recessive inheritance of a syndrome of Addison disease and cerebral sclerosis. All cases had been male, and in many instances a brother and/or a maternal uncle of the proband has been similarly affected. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14110277" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Using content of C26 fatty acids in cultured fibroblasts, <a href="#82" class="mim-tip-reference" title="Migeon, B. R., Moser, H. W., Moser, A. B., Axelman, J., Sillence, D., Norum, R. A. &lt;strong&gt;Adrenoleukodystrophy: evidence for X linkage inactivation, and selection favoring the mutant allele in heterozygous cells.&lt;/strong&gt; Proc. Nat. Acad. Sci. 78: 5066-5070, 1981.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/6795626/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;6795626&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1073/pnas.78.8.5066&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="6795626">Migeon et al. (1981)</a> demonstrated two types of clones in heterozygotes, thus corroborating X-linkage and demonstrating lyonization of the ALD locus. The presence of more mutant than wildtype clones in cultures from most heterozygotes suggested a proliferative advantage of the mutant cells. This advantage appears to exist in vivo also because most heterozygotes showed increased levels of fatty acids in plasma and, in 1 family, women heterozygous for both ALD and G6PD showed an excess of G6PD blood cells of the A (rather than B) type, which was in coupling with the mutant gene. (In Lesch-Nyhan syndrome (<a href="/entry/308000">308000</a>), it is the wildtype red cell precursors that enjoy a selective advantage so that in heterozygotes the levels of HPRT in red cells are normal.) <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=6795626" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Using the probe M27-beta, <a href="#157" class="mim-tip-reference" title="Watkiss, E., Webb, T., Bundey, S. &lt;strong&gt;Is skewed X inactivation responsible for symptoms in female carriers for adrenoleucodystrophy?&lt;/strong&gt; J. Med. Genet. 30: 651-654, 1993.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/8411051/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;8411051&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1136/jmg.30.8.651&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="8411051">Watkiss et al. (1993)</a> found no evidence for skewed X-inactivation in 12 female carriers of ALD. The probe M27-beta detects locus DXS225, which contains a highly polymorphic VNTR sequence. In addition, the locus contains MspI sites that are methylated on the active X chromosome but unmethylated on the inactive X chromosome. Because such sites are vulnerable to digestion by the isoschizomer HpaII only when they are unmethylated, i.e., when they lie on the inactive X chromosome, M27-beta can be used to differentiate between the active and inactive X chromosomes. In the 5 families, they observed 3 manifesting heterozygotes who had presented to a neurologist independently of the illness in affected males in the family. Only 1 of the 3 manifesting carriers showed skewing, but 2 of 9 nonmanifesting carriers did also. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8411051" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#76" class="mim-tip-reference" title="Maestri, N. E., Beaty, T. H. &lt;strong&gt;Predictions of a 2-locus model for disease heterogeneity: application to adrenoleukodystrophy.&lt;/strong&gt; Am. J. Med. Genet. 44: 576-582, 1992.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/1481812/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;1481812&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ajmg.1320440509&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="1481812">Maestri and Beaty (1992)</a> examined the implications of a 2-locus model to explain heterogeneity in ALD, i.e., the occurrence of severe childhood form (ALD) and the milder adult-onset form (AMN) in the same family, or even the same sibship. They considered 2 models. Under a dominant epistatic model, a single M allele at an autosomal modifier locus ameliorates the most severe effects of the disease allele, thus leading to the milder AMN phenotype; only males with genotype mm would have ALD. Under a recessive epistatic model, 2 copies of the M allele would be necessary to have the milder AMN phenotype. <a href="#76" class="mim-tip-reference" title="Maestri, N. E., Beaty, T. H. &lt;strong&gt;Predictions of a 2-locus model for disease heterogeneity: application to adrenoleukodystrophy.&lt;/strong&gt; Am. J. Med. Genet. 44: 576-582, 1992.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/1481812/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;1481812&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ajmg.1320440509&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="1481812">Maestri and Beaty (1992)</a> showed that the recurrence risk for a second affected male depended on the frequency of the protective allele at this modifier locus. They suggested sampling discordant affected sib pairs as a strategy for detecting linkage between a polymorphic DNA marker and a possible modifier gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1481812" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="mapping" class="mim-anchor"></a>
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<strong>Mapping</strong>
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<p>Close linkage of ALD and G6PD was indicated by the absence of recombination in 18 opportunities. This means that the ALD locus is in the terminal segment of the long arm of the X, i.e., Xq28. That the locus is not closely linked to Xg had been shown by <a href="#143" class="mim-tip-reference" title="Spira, T. J., Adam, A., Goodman, R. M., Berger, A. &lt;strong&gt;Recombination between cerebral sclerosis--Addison&#x27;s disease and the Xg blood-groups. (Letter)&lt;/strong&gt; Lancet 298: 820-821, 1971. Note: Originally Volume II.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/4106638/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;4106638&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/s0140-6736(71)92776-0&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="4106638">Spira et al. (1971)</a>. Close linkage to DXS52 (maximum lod score = 4.17 at theta = 0.0) was found by <a href="#151" class="mim-tip-reference" title="van Oost, B. A., van Zandvoort, P., Hoogeboom, A., Bakkeren, J., Hamel, B., Brunner, H., Knoers, N., Ropers, H. H. &lt;strong&gt;Tight linkage between adrenoleukodystrophy and DXS 52. (Abstract)&lt;/strong&gt; Cytogenet. Cell Genet. 46: 708 only, 1987."None>van Oost et al. (1987)</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=4106638" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Close linkage of ALD to the cluster of colorblindness genes is indicated by the increased frequency of colorblindness in affected males and by the demonstration of deletion of cone pigment genes with the use of DNA probes (<a href="#10" class="mim-tip-reference" title="Aubourg, P. R., Sack, G. H., Jr., Moser, H. &lt;strong&gt;Frequent alterations of visual pigment genes in adrenoleukodystrophy.&lt;/strong&gt; Am. J. Hum. Genet. 42: 408-413, 1988.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/2894755/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;2894755&lt;/a&gt;]" pmid="2894755">Aubourg et al., 1988</a>). <a href="#10" class="mim-tip-reference" title="Aubourg, P. R., Sack, G. H., Jr., Moser, H. &lt;strong&gt;Frequent alterations of visual pigment genes in adrenoleukodystrophy.&lt;/strong&gt; Am. J. Hum. Genet. 42: 408-413, 1988.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/2894755/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;2894755&lt;/a&gt;]" pmid="2894755">Aubourg et al. (1988)</a> studied the red and green visual pigment genes in 8 kindreds with ALD and demonstrated frequent structural changes, including deletions and intragenic recombinations. <a href="#129" class="mim-tip-reference" title="Sack, G. H., Jr., Raven, M. B., Moser, H. W. &lt;strong&gt;Color vision defects in adrenomyeloneuropathy.&lt;/strong&gt; Am. J. Hum. Genet. 44: 794-798, 1989.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/2729274/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;2729274&lt;/a&gt;]" pmid="2729274">Sack et al. (1989)</a> found increased frequency of abnormal color vision in men with adrenomyeloneuropathy and pointed to these findings as supporting very close linkage of the ALD and the colorblindness loci, thus giving the opportunity for contiguous gene defects. <a href="#5" class="mim-tip-reference" title="Aubourg, P., Blanche, S., Jambaque, I., Rocchiccioli, F., Kalifa, G., Naud-Saudreau, C., Rolland, M.-O., Debre, M., Chaussain, J.-L., Griscelli, C., Fischer, A., Bougneres, P.-F. &lt;strong&gt;Reversal of early neurologic and neuroradiologic manifestations of X-linked adrenoleukodystrophy by bone marrow transplantation.&lt;/strong&gt; New Eng. J. Med. 322: 1860-1866, 1990.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/2348839/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;2348839&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1056/NEJM199006283222607&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="2348839">Aubourg et al. (1990)</a> reported studies on a large number of patients with ALD. No deletions were found with probes that lie 3-prime of the green pigment genes. One of the 8 previously reported ALD patients had a long deletion 5-prime of the red pigment gene, a deletion causing blue cone monochromacy. This finding and the previous finding of a 45% frequency of phenotypic color vision defects in patients with AMN suggested to <a href="#5" class="mim-tip-reference" title="Aubourg, P., Blanche, S., Jambaque, I., Rocchiccioli, F., Kalifa, G., Naud-Saudreau, C., Rolland, M.-O., Debre, M., Chaussain, J.-L., Griscelli, C., Fischer, A., Bougneres, P.-F. &lt;strong&gt;Reversal of early neurologic and neuroradiologic manifestations of X-linked adrenoleukodystrophy by bone marrow transplantation.&lt;/strong&gt; New Eng. J. Med. 322: 1860-1866, 1990.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/2348839/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;2348839&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1056/NEJM199006283222607&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="2348839">Aubourg et al. (1990)</a> that the ALD/AMN gene may lie 5-prime to the red pigment gene and that the frequent phenotypic color vision anomalies owe their origin to deleted DNA that includes regulatory genes for color vision. In studies of an ALD patient who also had blue cone monochromacy, <a href="#42" class="mim-tip-reference" title="Feil, R., Aubourg, P., Mosser, J., Douar, A.-M., Le Paslier, D., Philippe, C., Mandel, J.-L. &lt;strong&gt;Adrenoleukodystrophy: a complex chromosomal rearrangement in the Xq28 red/green-color-pigment gene region indicates two possible gene locations.&lt;/strong&gt; Am. J. Hum. Genet. 49: 1361-1371, 1991.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/1746561/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;1746561&lt;/a&gt;]" pmid="1746561">Feil et al. (1991)</a> characterized a complex chromosomal rearrangement in band Xq28. Two CpG islands were mapped, at 46 and 115 kb upstream from the visual pigment genes, one or the other of which might mark the location of the ALD gene. <a href="#127" class="mim-tip-reference" title="Sack, G. H., Jr., Alpern, M., Webster, T., Feil, R. P., Morrell, J. C., Chen, G., Chen, W., Caskey, C. T., Moser, H. W. &lt;strong&gt;Chromosomal rearrangement segregating with adrenoleukodystrophy: a molecular analysis.&lt;/strong&gt; Proc. Nat. Acad. Sci. 90: 9489-9493, 1993.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/8415728/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;8415728&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1073/pnas.90.20.9489&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="8415728">Sack et al. (1993)</a> gave a molecular analysis of the chromosomal rearrangement in kindred 'O' reported by <a href="#10" class="mim-tip-reference" title="Aubourg, P. R., Sack, G. H., Jr., Moser, H. &lt;strong&gt;Frequent alterations of visual pigment genes in adrenoleukodystrophy.&lt;/strong&gt; Am. J. Hum. Genet. 42: 408-413, 1988.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/2894755/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;2894755&lt;/a&gt;]" pmid="2894755">Aubourg et al. (1988)</a>. <a href="#2" class="mim-tip-reference" title="Alpern, M., Sack, G. H., Jr., Krantz, D. H., Jenness, J., Zhang, H., Moser, H. W. &lt;strong&gt;Chromosomal rearrangement segregating with adrenoleukodystrophy: associated changes in color vision.&lt;/strong&gt; Proc. Nat. Acad. Sci. 90: 9494-9498, 1993.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/8415729/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;8415729&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1073/pnas.90.20.9494&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="8415729">Alpern et al. (1993)</a> characterized the physiologic defect in color vision. The DNA in a hemizygous male showed altered restriction fragment sizes compatible with a deletion extending from the 5-prime end of the color pigment gene cluster. The DNA change had removed the red pigment gene and juxtaposed a 15-kb DNA sequence to the remaining pigment gene. <a href="#127" class="mim-tip-reference" title="Sack, G. H., Jr., Alpern, M., Webster, T., Feil, R. P., Morrell, J. C., Chen, G., Chen, W., Caskey, C. T., Moser, H. W. &lt;strong&gt;Chromosomal rearrangement segregating with adrenoleukodystrophy: a molecular analysis.&lt;/strong&gt; Proc. Nat. Acad. Sci. 90: 9489-9493, 1993.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/8415728/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;8415728&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1073/pnas.90.20.9489&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="8415728">Sack et al. (1993)</a> demonstrated linkage with the ALD gene, located centromeric to the color pigment gene cluster; maximum lod = 3.19 at theta = 0.0. On physiologic testing, <a href="#2" class="mim-tip-reference" title="Alpern, M., Sack, G. H., Jr., Krantz, D. H., Jenness, J., Zhang, H., Moser, H. W. &lt;strong&gt;Chromosomal rearrangement segregating with adrenoleukodystrophy: associated changes in color vision.&lt;/strong&gt; Proc. Nat. Acad. Sci. 90: 9494-9498, 1993.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/8415729/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;8415729&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1073/pnas.90.20.9494&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="8415729">Alpern et al. (1993)</a> found color matching they interpreted as indicating the presence of an abnormal rudimentary visual pigment. They suggested that this may reflect the presence of a recombinant visual pigment protein or altered regulation of residual pigment genes due to the DNA change: deletion of the long-wave pigment gene and reorganized sequences 5-prime to the pigment gene cluster. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=8415729+2894755+8415728+2729274+2348839+1746561" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In several large families with ALD, <a href="#152" class="mim-tip-reference" title="van Oost, B. A., van Zandvoort, P. M., Tunte, W., Brunner, H. G., Hoogeboom, A. J. M., Maaswinkel-Mooy, P. D., Bakkeren, J., Hamel, B., Ropers, H. H. &lt;strong&gt;Linkage analysis in X-linked adrenoleukodystrophy and application in post- and prenatal diagnosis.&lt;/strong&gt; Hum. Genet. 86: 404-407, 1991.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/1671851/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;1671851&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1007/BF00201845&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="1671851">van Oost et al. (1991)</a> extended the linkage of ALD to DXS52 and arrived at a maximal lod score of 22.5 at 1 cM. They also found tight linkage of ALD to F8C and showed that both ALD and F8C are distal to DXS52. No major structural rearrangement in Xqter was observed; in particular, there were no abnormalities in the color vision genes. The occurrence of several cases in which both ALD and Emery-Dreifuss muscular dystrophy (<a href="/entry/310300">310300</a>) were thought to be present suggested that these loci are closely situated (<a href="#97" class="mim-tip-reference" title="Moser, H. W. &lt;strong&gt;Personal Communication.&lt;/strong&gt; Baltimore, Md. 10/13/1987."None>Moser, 1987</a>); however, the diagnosis of ALD was not confirmed in these patients, and in testing of additional patients with EMD, none was found to have ALD (<a href="#98" class="mim-tip-reference" title="Moser, H. W. &lt;strong&gt;Personal Communication.&lt;/strong&gt; Baltimore, Md. 6/29/1989."None>Moser, 1989</a>). Using probe St14 (DXS52), <a href="#20" class="mim-tip-reference" title="Boue, J., Oberle, I., Heilig, R., Mandel, J. L., Moser, A., Moser, H., Larsen, J. W., Jr., Dumez, Y., Boue, A. &lt;strong&gt;First trimester prenatal diagnosis of adrenoleukodystrophy by determination of very long chain fatty acid levels and by linkage analysis to a DNA probe.&lt;/strong&gt; Hum. Genet. 69: 272-274, 1985.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/3856557/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;3856557&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1007/BF00293039&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="3856557">Boue et al. (1985)</a> and <a href="#9" class="mim-tip-reference" title="Aubourg, P. R., Sack, G. H., Jr., Meyers, D. A., Lease, J. J., Moser, H. W. &lt;strong&gt;Linkage of adrenoleukodystrophy to a polymorphic DNA probe.&lt;/strong&gt; Ann. Neurol. 21: 349-352, 1987.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/2883927/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;2883927&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ana.410210406&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="2883927">Aubourg et al. (1987)</a> found a total lod score in their combined families of 13.766 at theta = 0. In an analysis of 59 ALD kindreds, <a href="#128" class="mim-tip-reference" title="Sack, G. H., Jr., Morrell, J. C. &lt;strong&gt;Adrenoleukodystrophy: overlapping deletions point to a gene location in Xq28.&lt;/strong&gt; Biochem. Biophys. Res. Commun. 191: 955-960, 1993.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/8466536/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;8466536&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1006/bbrc.1993.1310&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="8466536">Sack and Morrell (1993)</a> found normal hybridization using a probe situated 30 kb centromeric to the color pigment genes. However, using a probe located 100 kb further centromeric, they found 2 overlapping deletions in 2 patients. Additional study indicated that the telomeric ends of the 2 deletions were 8 kb apart. Thus, the location of the ALD gene appeared to have been defined as approximately 150 kb centromeric of the color pigment genes. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=8466536+1671851+3856557+2883927" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#101" class="mim-tip-reference" title="Mosser, J., Douar, A.-M., Sarde, C.-O., Kioschis, P., Feil, R., Moser, H., Poustka, A.-M., Mandel, J.-L., Aubourg, P. &lt;strong&gt;Putative X-linked adrenoleukodystrophy gene shares unexpected homology with ABC transporters.&lt;/strong&gt; Nature 361: 726-730, 1993.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/8441467/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;8441467&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1038/361726a0&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="8441467">Mosser et al. (1993)</a> identified the ALD gene by positional cloning. <a href="#131" class="mim-tip-reference" title="Sarde, C.-O., Mosser, J., Kioschis, P., Kretz, C., Vicaire, S., Aubourg, P., Poustka, A., Mandel, J.-L. &lt;strong&gt;Genomic organization of the adrenoleukodystrophy gene.&lt;/strong&gt; Genomics 22: 13-20, 1994.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/7959759/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;7959759&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1006/geno.1994.1339&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="7959759">Sarde et al. (1994)</a> determined that the ALD gene is 720 kb proximal to the R/GCP genes and other genes lie between the two. Thus the occurrence of color vision abnormalities in ALD is not secondary to localization. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=8441467+7959759" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="pathogenesis" class="mim-anchor"></a>
<h4 href="#mimPathogenesisFold" id="mimPathogenesisToggle" class="mimTriangleToggle" style="cursor: pointer;" data-toggle="collapse">
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<strong>Pathogenesis</strong>
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<p><a href="#58" class="mim-tip-reference" title="Hoefnagel, D., Van den Noort, S., Ingbar, S. H. &lt;strong&gt;Diffuse cerebral sclerosis with endocrine abnormalities in young males.&lt;/strong&gt; Brain 85: 553-568, 1962.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/13963828/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;13963828&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1093/brain/85.3.553&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="13963828">Hoefnagel et al. (1962)</a> described the histologic findings in endocrine glands, especially the pituitary and adrenal. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=13963828" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#124" class="mim-tip-reference" title="Ropers, H.-H., Zimmermann, J., Wienker, T. &lt;strong&gt;Adrenoleukodystrophy (Siemerling-Creutzfeldt disease): heterozygote with two clonal fibroblast populations.&lt;/strong&gt; Clin. Genet. 11: 114-118, 1977.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/837560/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;837560&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1111/j.1399-0004.1977.tb01287.x&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="837560">Ropers et al. (1977)</a> described typical morphologic changes in cultured fibroblasts on light microscopy. The changes, seen only 4 or 5 days after subculture, consisted of expansion of the cells, which appeared abnormally large. Lyonization was demonstrated in cultured fibroblasts of the mother. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=837560" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#56" class="mim-tip-reference" title="Ho, J. K., Moser, H., Kishimoto, Y., Hamilton, J. A. &lt;strong&gt;Interactions of a very long chain fatty acid with model membranes and serum albumin: implications for the pathogenesis of adrenoleukodystrophy.&lt;/strong&gt; J. Clin. Invest. 96: 1455-1463, 1995.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/7657817/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;7657817&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1172/JCI118182&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="7657817">Ho et al. (1995)</a> predicted that disruptive effects of the accumulation of very long chain saturated fatty acids on cell membrane structure and function may explain the neurologic manifestations of ALD patients. Especially the 26-carbon acid, hexacosanoic acid, is involved. They studied the interaction of radiolabelled hexacosanoic acid with model membranes and bovine serum albumin by NMR spectroscopy to compare properties of the hexacosanoic acid with those of typical dietary fatty acids. Desorption of hexacosanoic acid from membranes was orders of magnitude slower than that of shorter-chain fatty acids and binding to serum albumin was ineffective. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7657817" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#41" class="mim-tip-reference" title="Federico, A., Dotti, M. T., Annunziata, P., Bonuccelli, U., Fenzi, G., Ciacci, G., Malandrini, A., Meucci, G., Guazzi, G. C. &lt;strong&gt;Adrenomyeloneurodystrophy with late cerebral involvement and evidence of a multiple autoimmune disorder.&lt;/strong&gt; J. Inherit. Metab. Dis. 11 (suppl. 2): 169-172, 1988.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/3141701/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;3141701&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1007/BF01804227&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="3141701">Federico et al. (1988)</a> added to the evidence for autoimmune factors in the pathogenesis of ALD by the description of a 53-year-old man with CNS white matter demyelination and evidence of a multisystem immunologic disorder including autoimmune thyroiditis, antigastric mucosa antibodies, and antismooth muscle antibodies. The cerebrospinal fluid showed a marked increase in IgG index and several oligoclonal bands with an alkaline isoelectric point. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=3141701" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In a review of brain autopsy material from 9 cases of ALD, <a href="#37" class="mim-tip-reference" title="Eichler, F. S., Ren, J.-Q., Cossoy, M., Rietsch, A. M., Nagpal, S., Moser, A. B., Frosch, M. P., Ransohoff, R. M. &lt;strong&gt;Is microglial apoptosis an early pathogenic change in cerebral X-linked adrenoleukodystrophy?&lt;/strong&gt; Ann. Neurol. 63: 729-742, 2008.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/18571777/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;18571777&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ana.21391&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="18571777">Eichler et al. (2008)</a> observed marked demyelinative lesions in the white matter with sparing of the subcortical white matter. One additional case of pure adrenomyeloneuropathy did not show white matter demyelination. The lesion edges were regions of active demyelination with macrophages containing granules consisting of lipid inclusions consistent with myelin debris. Dense perivascular aggregates of macrophages and lymphocytes were closer to the lesion, but macrophages were less prominent within the cores of lesions. These findings suggested that macrophages played a phagocytic role but not a role in active myelin destruction. Further studies showed that white matter areas beyond the actively demyelinating edge were essentially devoid of microglia due to apoptosis, whereas microglia density was normal in remote normal brain tissue. Injection of lysophosphatidylcholine in mouse brains induced microglial apoptosis. <a href="#37" class="mim-tip-reference" title="Eichler, F. S., Ren, J.-Q., Cossoy, M., Rietsch, A. M., Nagpal, S., Moser, A. B., Frosch, M. P., Ransohoff, R. M. &lt;strong&gt;Is microglial apoptosis an early pathogenic change in cerebral X-linked adrenoleukodystrophy?&lt;/strong&gt; Ann. Neurol. 63: 729-742, 2008.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/18571777/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;18571777&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ana.21391&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="18571777">Eichler et al. (2008)</a> concluded that microglial apoptosis resulting from accumulation of very-long chain fatty acids may be an early change in the pathogenesis of ALD that occurs before demyelination, and that the loss of microglia prevents them from protecting oligodendrocytes and axons. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18571777" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#54" class="mim-tip-reference" title="Hein, S., Schonfeld, P., Kahlert, S., Reiser, G. &lt;strong&gt;Toxic effects of X-linked adrenoleukodystrophy-associated, very long chain fatty acids on glial cells and neurons from rat hippocampus in culture.&lt;/strong&gt; Hum. Molec. Genet. 17: 1750-1761, 2008.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/18344355/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;18344355&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1093/hmg/ddn066&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="18344355">Hein et al. (2008)</a> found that rat oligodendrocytes and astrocytes exposed to VLCFA in culture died within 24 hours, with the greatest effect on myelin-producing oligodendrocytes. VLCFA caused increased intracellular calcium in oligodendrocytes, astrocytes, and neurons. VLCFA also induced depolarization of mitochondria and promoted permeability of the inner mitochondrial membrane. <a href="#54" class="mim-tip-reference" title="Hein, S., Schonfeld, P., Kahlert, S., Reiser, G. &lt;strong&gt;Toxic effects of X-linked adrenoleukodystrophy-associated, very long chain fatty acids on glial cells and neurons from rat hippocampus in culture.&lt;/strong&gt; Hum. Molec. Genet. 17: 1750-1761, 2008.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/18344355/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;18344355&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1093/hmg/ddn066&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="18344355">Hein et al. (2008)</a> concluded that VLCFAs are potently cytotoxic due to mitochondrial dysfunction and calcium deregulation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18344355" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#44" class="mim-tip-reference" title="Fourcade, S., Lopez-Erauskin, J., Galino, J., Duval, C., Naudi, A., Jove, M., Kemp, S., Villarroya, F., Ferrer, I., Pamplona, R., Portero-Otin, M., Pujol, A. &lt;strong&gt;Early oxidative damage underlying neurodegeneration in X-adrenoleukodystrophy.&lt;/strong&gt; Hum. Molec. Genet. 17: 1762-1773, 2008.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/18344354/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;18344354&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1093/hmg/ddn085&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="18344354">Fourcade et al. (2008)</a> found that XLD fibroblasts showed decreased mitochondrial potential and increased sensitivity to oxidative stress. In vitro, the alpha-tocopherol analog Trolox was able to reverse these oxidative defects, as measured by decreased levels of lipoxidative protein damage. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18344354" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div>
<a id="diagnosis" class="mim-anchor"></a>
<h4 href="#mimDiagnosisFold" id="mimDiagnosisToggle" class="mimTriangleToggle" style="cursor: pointer;" data-toggle="collapse">
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<strong>Diagnosis</strong>
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</h4>
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<p><a href="#88" class="mim-tip-reference" title="Moser, H. W., Moser, A. B., Frayer, K. K., Chen, W., Schulman, J. D., O&#x27;Neill, B. P., Kishimoto, Y. &lt;strong&gt;Adrenoleukodystrophy: increased plasma content of saturated very long chain fatty acids.&lt;/strong&gt; Neurology 31: 1241-1249, 1981.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/7202134/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;7202134&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1212/wnl.31.10.1241&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="7202134">Moser et al. (1981)</a> developed a plasma method for the detection of very long chain fatty acids providing for the diagnosis of affected individuals and assisting in carrier identification. <a href="#84" class="mim-tip-reference" title="Moser, A. B., Kreiter, N., Bezman, L., Lu, S., Raymond, G. V., Naidu, S., Moser, H. W. &lt;strong&gt;Plasma very long chain fatty acids in 3,000 peroxisome disease patients and 29,000 controls.&lt;/strong&gt; Ann. Neurol. 45: 100-110, 1999.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/9894883/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;9894883&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/1531-8249(199901)45:1&lt;100::aid-art16&gt;3.0.co;2-u&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="9894883">Moser et al. (1999)</a> reported the results of testing with this assay, the most widely used procedure for the diagnosis of X-linked ALD and other peroxisomal disorders, in 3,000 patients and 29,000 controls. VLCFA levels are elevated at birth, and the assay is highly accurate in hemizygotes. Eighty-five percent of obligate heterozygotes will have an elevated level, but a normal result did not exclude carrier status. A variety of other peroxisomal disorders, including Zellweger syndrome and other single enzyme defects in peroxisomal beta oxidation, also share an elevation of VLCFA levels, but can readily be discerned from ALD by the clinical situation. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=9894883+7202134" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#85" class="mim-tip-reference" title="Moser, A. B., Moser, H. W. &lt;strong&gt;The prenatal diagnosis of X-linked adrenoleukodystrophy.&lt;/strong&gt; Prenatal Diag. 19: 46-48, 1999.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/10073906/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;10073906&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/(sici)1097-0223(199901)19:1&lt;46::aid-pd501&gt;3.0.co;2-e&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="10073906">Moser and Moser (1999)</a> provided an authoritative discussion of the prenatal diagnosis of X-linked ALD. They concluded that measurement of VLCFA levels in cultured amniocytes and chorionic villus cells (the most frequently used procedure) is reliable provided that care is taken to minimize the risk of false-negative results by performance of subcultures in appropriate media. The procedure can be complemented by assays of VLCFA oxidation, and under certain circumstances, immunocytochemical assays for the expression of ALDP. Mutation analysis is the most reliable diagnostic procedure when the nature of the mutation in the at-risk family is known. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10073906" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#61" class="mim-tip-reference" title="Inoue, K., Suzuki, Y., Yajima, S., Shimozawa, N., Tomatsu, S., Orii, T., Kondo, N. &lt;strong&gt;Carrier identification of X-linked adrenoleukodystrophy by measurement of very long chain fatty acids and lignoceric acid oxidation.&lt;/strong&gt; Clin. Genet. 50: 348-352, 1996.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/9007322/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;9007322&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1111/j.1399-0004.1996.tb02386.x&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="9007322">Inoue et al. (1996)</a> found abnormal lignoceric acid oxidation in 19 of 19 ALD patients and in 3 of 3 obligate heterozygous carrier women. Among 10 women at risk of being a carrier, 3 with normal levels of VLCFA had abnormal lignoceric acid oxidation. <a href="#61" class="mim-tip-reference" title="Inoue, K., Suzuki, Y., Yajima, S., Shimozawa, N., Tomatsu, S., Orii, T., Kondo, N. &lt;strong&gt;Carrier identification of X-linked adrenoleukodystrophy by measurement of very long chain fatty acids and lignoceric acid oxidation.&lt;/strong&gt; Clin. Genet. 50: 348-352, 1996.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/9007322/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;9007322&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1111/j.1399-0004.1996.tb02386.x&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="9007322">Inoue et al. (1996)</a> suggested that this combined biochemical procedure could improve the accuracy of carrier detection in ALD. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9007322" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Various techniques have been developed to identify ALD carriers more accurately. <a href="#18" class="mim-tip-reference" title="Boehm, C. D., Cutting, G. R., Lachtermacher, M. B., Moser, H. W., Chong, S. S. &lt;strong&gt;Accurate DNA-based diagnostic and carrier testing for X-linked adrenoleukodystrophy.&lt;/strong&gt; Molec. Genet. Metab. 66: 128-136, 1999.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/10068516/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;10068516&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1006/mgme.1998.2779&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="10068516">Boehm et al. (1999)</a> developed and validated a robust DNA diagnostic test involving nonnested genomic amplification of the ALD gene, followed by fluorescent dye-primer sequencing and analysis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10068516" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#71" class="mim-tip-reference" title="Lachtermacher, M. B. R., Seuanez, H. N., Moser, A. B., Moser, H. W., Smith, K. D. &lt;strong&gt;Determination of 30 X-linked adrenoleukodystrophy mutations, including 15 not previously described.&lt;/strong&gt; Hum. Mutat. 15: 348-353, 2000.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/10737980/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;10737980&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/(SICI)1098-1004(200004)15:4&lt;348::AID-HUMU7&gt;3.0.CO;2-N&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="10737980">Lachtermacher et al. (2000)</a> noted that a very small percentage (0.1%) of affected males had plasma C26:0 levels that are borderline normal, and 15% of obligate female carriers have normal results. Effective mutation detection in these families is therefore fundamental to unambiguous determination of genetic status. Of particular concern are female members of kindreds segregating X-ALD mutations, because normal VLCFA levels do not guarantee lack of carrier status. <a href="#71" class="mim-tip-reference" title="Lachtermacher, M. B. R., Seuanez, H. N., Moser, A. B., Moser, H. W., Smith, K. D. &lt;strong&gt;Determination of 30 X-linked adrenoleukodystrophy mutations, including 15 not previously described.&lt;/strong&gt; Hum. Mutat. 15: 348-353, 2000.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/10737980/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;10737980&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/(SICI)1098-1004(200004)15:4&lt;348::AID-HUMU7&gt;3.0.CO;2-N&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="10737980">Lachtermacher et al. (2000)</a> described a fast method for detection of X-ALD mutations. The method was based on SSCP analysis of nested PCR fragments followed by sequence-determination reactions. Using this method, they found X-ALD mutations in 30 kindreds, including 15 not previously reported. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10737980" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Using records from the Kennedy Krieger Institute between 1981 and 1998 and the Mayo Clinic Rochester from 1996 to 1998, <a href="#15" class="mim-tip-reference" title="Bezman, L., Moser, A. B., Raymond, G. V., Rinaldo, P., Watkins, P. A., Smith, K. D., Kass, N. E., Moser, H. W. &lt;strong&gt;Adrenoleukodystrophy: incidence, new mutation rate, and results of extended family screening.&lt;/strong&gt; Ann. Neurol. 49: 512-517, 2001.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/11310629/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;11310629&lt;/a&gt;]" pmid="11310629">Bezman et al. (2001)</a> estimated that the minimum frequency of X-linked ALD hemizygotes in the US is 1:42,000, and that of hemizygotes plus heterozygotes is 1:16,800. Five percent of male probands were estimated to have new mutations. Extended family testing identified asymptomatic hemizygotes, who could benefit from therapy, and heterozygotes, who could benefit from genetic counseling. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11310629" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div>
<a id="clinicalManagement" class="mim-anchor"></a>
<h4 href="#mimClinicalManagementFold" id="mimClinicalManagementToggle" class="mimTriangleToggle" style="cursor: pointer;" data-toggle="collapse">
<span id="mimClinicalManagementToggleTriangle" class="small mimTextToggleTriangle">&#9660;</span>
<span class="mim-font">
<strong>Clinical Management</strong>
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</h4>
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<div id="mimClinicalManagementFold" class="collapse in mimTextToggleFold">
<span class="mim-text-font">
<p><a href="#67" class="mim-tip-reference" title="Kolodny, E. H. &lt;strong&gt;The adrenoleukodystrophy-adrenomyeloneuropathy complex: is it treatable? (Editorial)&lt;/strong&gt; Ann. Neurol. 21: 230-231, 1987.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/2440377/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;2440377&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ana.410210303&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="2440377">Kolodny (1987)</a> concluded that asymptomatic individuals with the adrenomyeloneuropathy gene, as well as patients with this disorder and heterozygotes, may benefit from a combined oleic acid, VLCFA-restricted diet. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2440377" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#99" class="mim-tip-reference" title="Moser, H. W. &lt;strong&gt;Lorenzo&#x27;s Oil. (Film Review).&lt;/strong&gt; Lancet 341: 544, 1993.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/8094785/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;8094785&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/0140-6736(93)90295-r&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="8094785">Moser (1993)</a> reviewed the film 'Lorenzo's Oil,' a fictionalized account of a family's search for a treatment of ALD, afflicting, in this case, a boy named Lorenzo Odone. <a href="#99" class="mim-tip-reference" title="Moser, H. W. &lt;strong&gt;Lorenzo&#x27;s Oil. (Film Review).&lt;/strong&gt; Lancet 341: 544, 1993.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/8094785/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;8094785&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/0140-6736(93)90295-r&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="8094785">Moser (1993)</a> concluded that it overstated the success that can be achieved with the oil, invented conflicts between the parents and the medical establishment, and presented an inaccurate and malicious portrayal of the United Leukodystrophy Foundation. 'Dr. Nicolai,' played in the film by Peter Ustinov, copied Moser's 'appearance and speech with remarkable accuracy.' In an open trial in 14 men with adrenomyeloneuropathy, 5 symptomatic heterozygous women, and 5 boys (mean age, 13 years) with preclinical adrenomyeloneuropathy, <a href="#4" class="mim-tip-reference" title="Aubourg, P., Adamsbaum, C., Lavallard-Rousseau, M.-C., Rocchiccioli, F., Cartier, N., Jambaque, I., Jakobezak, C., Lemaitre, A., Boureau, F., Wolf, C., Bougneres, P.-F. &lt;strong&gt;A two-year trial of oleic and erucic acids (&#x27;Lorenzo&#x27;s oil&#x27;) as treatment for adrenomyeloneuropathy.&lt;/strong&gt; New Eng. J. Med. 329: 745-752, 1993.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/8350883/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;8350883&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1056/NEJM199309093291101&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="8350883">Aubourg et al. (1993)</a> could find no evidence of a clinically relevant benefit from dietary treatment with oleic and erucic acids (glyceryl trierucate and trioleate oil; 'Lorenzo's oil'). Asymptomatic thrombocytopenia was noted in 6 patients. <a href="#113" class="mim-tip-reference" title="Poulos, A., Gibson, R., Sharp, P., Beckman, K., Grattan-Smith, P. &lt;strong&gt;Very long chain fatty acids in X-linked adrenoleukodystrophy brain after treatment with Lorenzo&#x27;s oil.&lt;/strong&gt; Ann. Neurol. 36: 741-746, 1994.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/7979219/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;7979219&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ana.410360509&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="7979219">Poulos et al. (1994)</a> examined the fatty acid composition of postmortem brain and liver from an adrenoleukodystrophy patient who had received Lorenzo's oil for 9 months. There was improvement in the fatty acid composition of the plasma and liver but not in the brain. This indicated that very little erucic acid crossed the blood-brain barrier. These findings suggested to the authors that dietary supplementation with Lorenzo's oil is of limited value in correcting the accumulation of saturated very long chain fatty acids in the brain of patients with adrenoleukodystrophy. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=8350883+7979219+8094785" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Treatment with Lorenzo's oil normalizes the level of VLCFA in plasma within 4 weeks. In spite of this promising biochemical effect, clinical results have been disappointing when the oils were fed to symptomatic patients (<a href="#4" class="mim-tip-reference" title="Aubourg, P., Adamsbaum, C., Lavallard-Rousseau, M.-C., Rocchiccioli, F., Cartier, N., Jambaque, I., Jakobezak, C., Lemaitre, A., Boureau, F., Wolf, C., Bougneres, P.-F. &lt;strong&gt;A two-year trial of oleic and erucic acids (&#x27;Lorenzo&#x27;s oil&#x27;) as treatment for adrenomyeloneuropathy.&lt;/strong&gt; New Eng. J. Med. 329: 745-752, 1993.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/8350883/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;8350883&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1056/NEJM199309093291101&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="8350883">Aubourg et al., 1993</a>). <a href="#86" class="mim-tip-reference" title="Moser, H. W., Kok, F., Neumann, S., Borel, J., Bergin, A., Mostafa, S. D., Panoscha, R., Davoli, C. T., Shankroff, J., Smith, K. D. &lt;strong&gt;Adrenoleukodystrophy update: genetics and effect of Lorenzo&#x27;s oil therapy in asymptomatic patients.&lt;/strong&gt; Int. Pediat. 9: 196-204, 1994."None>Moser et al. (1994)</a> reported a positive result in patients in whom therapy was begun before neurologic symptoms were present, suggesting that fatty acid abnormality is of pathogenic significance. However, a 3-year follow-up with somatosensory-evoked potentials and motor-evoked potentials of 8 patients by <a href="#121" class="mim-tip-reference" title="Restuccia, D., Di Lazzaro, V., Valeriani, M., Oliviero, A., Le Pera, D., Barba, C., Cappa, M., Bertini, E., Di Capua, M., Tonali, P. &lt;strong&gt;Neurophysiologic follow-up of long-term dietary treatment in adult-onset adrenoleukodystrophy.&lt;/strong&gt; Neurology 52: 810-816, 1999.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/10078732/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;10078732&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1212/wnl.52.4.810&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="10078732">Restuccia et al. (1999)</a> showed no evidence of any benefit of dietary treatment, even when initiated early in the disease before the appearance of inflammatory lesions. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=8350883+10078732" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#93" class="mim-tip-reference" title="Moser, H. W., Raymond, G. V., Lu, S.-E., Muenz, L. R., Moser, A. B., Xu, J., Jones, R. O., Loes, D. J., Melhem, E. R., Dubey, P., Bezman, L., Brereton, N. H., Odone, A. &lt;strong&gt;Follow-up of 89 asymptomatic patients with adrenoleukodystrophy treated with Lorenzo&#x27;s oil.&lt;/strong&gt; Arch. Neurol. 62: 1073-1080, 2005.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/16009761/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;16009761&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1001/archneur.62.7.1073&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="16009761">Moser et al. (2005)</a> identified asymptomatic boys with X-linked adrenoleukodystrophy who had a normal MRI and assessed the effect of Lorenzo's oil (4:1 glyceryl trioleate-glyceryl trierucate) on disease progression. By a plasma very long chain fatty acids assay used to screen at-risk boys, 89 affected boys were identified, and all were treated with Lorenzo's oil and moderate fat restriction. Plasma fatty acids and clinical status were followed for 6.9 +/- 2.7 years. Of the 89 boys, 24% developed MRI abnormalities and 11% developed neurologic and MRI abnormalities. <a href="#93" class="mim-tip-reference" title="Moser, H. W., Raymond, G. V., Lu, S.-E., Muenz, L. R., Moser, A. B., Xu, J., Jones, R. O., Loes, D. J., Melhem, E. R., Dubey, P., Bezman, L., Brereton, N. H., Odone, A. &lt;strong&gt;Follow-up of 89 asymptomatic patients with adrenoleukodystrophy treated with Lorenzo&#x27;s oil.&lt;/strong&gt; Arch. Neurol. 62: 1073-1080, 2005.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/16009761/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;16009761&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1001/archneur.62.7.1073&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="16009761">Moser et al. (2005)</a> concluded that reduction of hexacosanoic acid by Lorenzo's oil was associated with reduced risk of developing MRI abnormalities. They recommended therapy with Lorenzo's oil in asymptomatic boys with X-linked adrenoleukodystrophy who had normal brain MRI results. Their experience with other ALD patients and that of <a href="#122" class="mim-tip-reference" title="Rizzo, W. B., Leshner, R. T., Odone, A., Dammann, A. L., Craft, D. A., Jensen, M. E., Jennings, S. S., Davis, S., Jaitly, R., Sgro, J. A. &lt;strong&gt;Dietary erucic acid therapy for X-linked adrenoleukodystrophy.&lt;/strong&gt; Neurology 39: 1415-1422, 1989.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/2682348/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;2682348&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1212/wnl.39.11.1415&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="2682348">Rizzo et al. (1989)</a> indicated that total fat intake in excess of 30 to 35% of total calories may counteract or nullify the C26:0-reducing effect of Lorenzo's oil. Those patients who developed progressive MRI abnormalities should be considered for hematopoietic stem cell transplantation (HSCT) as recommended by <a href="#112" class="mim-tip-reference" title="Peters, C., Charnas, L. R., Tan, Y., Ziegler, R. S., Shapiro, E. G., DeFor, T., Grewal, S. S., Orchard, P. J., Abel, S. L., Goldman, A. I., Ramsay, N. K. C., Dusenbery, K. E., Loes, D. J., Lockman, L. A., Kato, S., Aubourg, P. R., Moser, H. W., Krivit, W. &lt;strong&gt;Cerebral X-linked adrenoleukodystrophy: the international hematopoietic cell transplantation experience from 1982 to 1999.&lt;/strong&gt; Blood 104: 881-888, 2004. Note: Erratum: Blood 104: 3857 only, 2004.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/15073029/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;15073029&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1182/blood-2003-10-3402&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="15073029">Peters et al. (2004)</a>. Adrenal function must be monitored since 80% asymptomatic patients with ALD develop evidence of adrenal insufficiency (<a href="#33" class="mim-tip-reference" title="Dubey, P., Raymond, G., Moser, A. B., Kharkar, S., Bezman, L., Moser, H. W. &lt;strong&gt;Adrenal insufficiency in asymptomatic adrenoleukodystrophy patients identified by very long-chain fatty acid screening.&lt;/strong&gt; J. Pediat. 146: 528-532, 2005.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/15812458/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;15812458&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/j.jpeds.2004.10.067&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="15812458">Dubey et al., 2005</a>) and adrenal hormone replacement therapy should be provided when indicated by laboratory findings. Thus, a 3-prong therapeutic approach is recommended. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=2682348+16009761+15073029+15812458" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#5" class="mim-tip-reference" title="Aubourg, P., Blanche, S., Jambaque, I., Rocchiccioli, F., Kalifa, G., Naud-Saudreau, C., Rolland, M.-O., Debre, M., Chaussain, J.-L., Griscelli, C., Fischer, A., Bougneres, P.-F. &lt;strong&gt;Reversal of early neurologic and neuroradiologic manifestations of X-linked adrenoleukodystrophy by bone marrow transplantation.&lt;/strong&gt; New Eng. J. Med. 322: 1860-1866, 1990.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/2348839/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;2348839&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1056/NEJM199006283222607&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="2348839">Aubourg et al. (1990)</a> achieved reversal of early neurologic and neuroradiologic features in an 8-year-old boy who received bone marrow transplantation (BMT) from his fraternal twin brother. <a href="#77" class="mim-tip-reference" title="Malm, G., Ringden, O., Anvret, M., von Dobeln, U., Hagenfeldt, L., Isberg, B., Knuutila, S., Nennesmo, I., Winiarski, J., Marcus, C. &lt;strong&gt;Treatment of adrenoleukodystrophy with bone marrow transplantation.&lt;/strong&gt; Acta Paediat. 86: 484-492, 1997.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/9183487/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;9183487&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1111/j.1651-2227.1997.tb08918.x&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="9183487">Malm et al. (1997)</a> described experience with bone marrow transplantation in 3 children with ALD. They concluded that BMT must be considered very early, even in a child without symptoms but with signs of demyelination on MRI, if a suitable donor is available. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=9183487+2348839" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#139" class="mim-tip-reference" title="Shapiro, E., Krivit, W., Lockman, L., Jambaque, I., Peters, C., Cowan, M., Harris, R., Blanche, S., Bordigoni, P., Loes, D., Ziegler, R., Crittenden, M., Ris, D., Berg, B., Cox, C., Moser, H., Fischer, A., Aubourg, P. &lt;strong&gt;Long-term effect of bone-marrow transplantation for childhood-onset cerebral X-linked adrenoleukodystrophy.&lt;/strong&gt; Lancet 356: 713-714, 2000.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/11085690/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;11085690&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/S0140-6736(00)02629-5&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="11085690">Shapiro et al. (2000)</a> discussed the experience of BMT in 12 patients over an extended period of time and came to the conclusion that it did result in improved outcome if performed early in the course of symptomatic disease. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11085690" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#70" class="mim-tip-reference" title="Kruse, B., Barker, P. B., van Zijl, P. C. M., Duyn, J. H., Moonen, C. T. W., Moser, H. W. &lt;strong&gt;Multislice proton magnetic resonance spectroscopic imaging in X-linked adrenoleukodystrophy.&lt;/strong&gt; Ann. Neurol. 36: 595-608, 1994.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/7944292/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;7944292&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ana.410360408&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="7944292">Kruse et al. (1994)</a> systematically studied 25 patients with adrenoleukodystrophy. Using multislice proton magnetic resonance spectroscopy, they demonstrated a reduction in N-acetyl aspartate, an increase in choline, and occasionally an increase in lactate. They concluded that magnetic resonance spectroscopic imaging is a more sensitive indicator of early neurologic involvement than is magnetic resonance imaging and therefore a more useful gauge of demyelination by which therapeutic approaches could be judged. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7944292" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Because of the circumstantial evidence that immunologic factors contribute to the pathogenesis of the CNS lesions in ALD, <a href="#102" class="mim-tip-reference" title="Naidu, S., Bresnan, M. J., Griffin, D., O&#x27;Toole, S., Moser, H. W. &lt;strong&gt;Childhood adrenoleukodystrophy: failure of intensive immunosuppression to arrest neurologic progression.&lt;/strong&gt; Arch. Neurol. 45: 846-848, 1988.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/3293554/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;3293554&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1001/archneur.1988.00520320032011&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="3293554">Naidu et al. (1988)</a> administered cyclophosphamide for 5 to 11 days to 4 patients with childhood ALD and to 1 patient with the adult cerebral form. The rate of neurologic progression in the 4 patients with childhood disease did not differ from that in 167 untreated patients with childhood disease surveyed previously. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=3293554" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#24" class="mim-tip-reference" title="Cappa, M., Bertini, E., del Balzo, P., Cambiaso, P., Di Biase, A., Salvati, S. &lt;strong&gt;High dose immunoglobulin IV treatment in adrenoleukodystrophy.&lt;/strong&gt; J. Neurol. Neurosurg. Psychiat. 57 (suppl.): 69-70, 1994.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/7964860/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;7964860&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1136/jnnp.57.suppl.69&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="7964860">Cappa et al. (1994)</a> gave intravenous high-dose immunoglobulins to 6 patients with adrenoleukodystrophy who were already on a restricted very long chain fatty acid diet supplemented with glycerol trioleate/erucic acid. The MRI and symptoms deteriorated in this group at the same rate as they did in 6 control patients on the same restricted/supplemented diet who did not receive immunoglobulins. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7964860" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#38" class="mim-tip-reference" title="El-Deiry, S. S., Naidu, S., Blevins, L. S., Ladenson, P. W. &lt;strong&gt;Assessment of adrenal function in women heterozygous for adrenoleukodystrophy.&lt;/strong&gt; J. Clin. Endocr. Metab. 82: 856-860, 1997.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/9062496/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;9062496&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1210/jcem.82.3.3802&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="9062496">El-Deiry et al. (1997)</a> studied the prevalence of adrenal dysfunction in 71 females who were obligate carriers of the X-linked trait by pedigree analysis and whose plasma very long chain fatty acid levels were consistent with a heterozygote status. The authors concluded that, in ALD heterozygotes, adrenal cortical insufficiency rarely develops, although isolated mineralocorticoid insufficiency may occur in these individuals. Furthermore, they inferred that ALD heterozygotes may be predisposed to hypoaldosteronism related to the use of nonsteroidal antiinflammatory agents. A subclinical decrease in glucocorticoid reserve, as measured by synthetic ovine corticotropin releasing hormone testing, may be present in a majority of these women. The authors suggested that aldosterone levels be included in ACTH stimulation testing done to detect adrenal insufficiency in affected women. Nonsteroidal antiinflammatory agents should be considered a risk factor for the development of hypoaldosteronism in women heterozygous for ALD. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9062496" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#112" class="mim-tip-reference" title="Peters, C., Charnas, L. R., Tan, Y., Ziegler, R. S., Shapiro, E. G., DeFor, T., Grewal, S. S., Orchard, P. J., Abel, S. L., Goldman, A. I., Ramsay, N. K. C., Dusenbery, K. E., Loes, D. J., Lockman, L. A., Kato, S., Aubourg, P. R., Moser, H. W., Krivit, W. &lt;strong&gt;Cerebral X-linked adrenoleukodystrophy: the international hematopoietic cell transplantation experience from 1982 to 1999.&lt;/strong&gt; Blood 104: 881-888, 2004. Note: Erratum: Blood 104: 3857 only, 2004.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/15073029/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;15073029&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1182/blood-2003-10-3402&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="15073029">Peters et al. (2004)</a> reviewed results in 126 boys with X-ALD who received hematopoietic cell transplantation from 1982 to 1999. Complete data were available and analyzed for 94 boys with cerebral X-ALD. The estimated 5- and 8-year survival was 56%. The leading cause of death was disease progression. Donor-derived engraftment occurred in 86% of patients. Demyelination involved parietal-occipital lobes in 90%, leading to visual and auditory processing deficits in many boys. <a href="#112" class="mim-tip-reference" title="Peters, C., Charnas, L. R., Tan, Y., Ziegler, R. S., Shapiro, E. G., DeFor, T., Grewal, S. S., Orchard, P. J., Abel, S. L., Goldman, A. I., Ramsay, N. K. C., Dusenbery, K. E., Loes, D. J., Lockman, L. A., Kato, S., Aubourg, P. R., Moser, H. W., Krivit, W. &lt;strong&gt;Cerebral X-linked adrenoleukodystrophy: the international hematopoietic cell transplantation experience from 1982 to 1999.&lt;/strong&gt; Blood 104: 881-888, 2004. Note: Erratum: Blood 104: 3857 only, 2004.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/15073029/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;15073029&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1182/blood-2003-10-3402&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="15073029">Peters et al. (2004)</a> concluded that boys with early-stage disease benefit from hematopoietic cell transplantation, whereas boys with advanced disease may be candidates for experimental therapies. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15073029" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#137" class="mim-tip-reference" title="Schonberger, S., Roerig, P., Schneider, D. T., Reifenberger, G., Gobel, U., Gartner, J. &lt;strong&gt;Genotype and protein expression after bone marrow transplantation for adrenoleukodystrophy.&lt;/strong&gt; Arch. Neurol. 64: 651-657, 2007.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/17353371/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;17353371&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1001/archneur.64.5.noc60105&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="17353371">Schonberger et al. (2007)</a> reported a boy with childhood ALD who underwent hematopoietic stem cell transplantation but died from transplant-related complications 76 days later. Postmortem examination showed mixed chimerism of the mutant and wildtype alleles in 23 tissue samples examined, including 12 CNS samples. Normal ALD protein was localized to peroxisomes within multiple cell types, including neurons. <a href="#137" class="mim-tip-reference" title="Schonberger, S., Roerig, P., Schneider, D. T., Reifenberger, G., Gobel, U., Gartner, J. &lt;strong&gt;Genotype and protein expression after bone marrow transplantation for adrenoleukodystrophy.&lt;/strong&gt; Arch. Neurol. 64: 651-657, 2007.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/17353371/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;17353371&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1001/archneur.64.5.noc60105&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="17353371">Schonberger et al. (2007)</a> noted that detection of ALD protein so soon after transplant may indicate that healthy donor cells assisted affected recipient cells in metabolic function. Peripheral blood samples from an affected male cousin who had successful HSCT showed the wildtype ALD allele exclusively. There was no clinical disease progression after transplant. The findings in both patients indicated that HSCT can result in restoration and widespread presence of intact donor ALD protein in various recipient tissues. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17353371" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#25" class="mim-tip-reference" title="Cartier, N., Hacein-Bey-Abina, S., Bartholomae, C. C., Veres, G., Schmidt, M., Kutschera, I., Vidaud, M., Abel, U., Dal-Cortivo, L., Caccavelli, L., Mahlaoui, N., Kiermer, V., and 14 others. &lt;strong&gt;Hematopoietic stem cell gene therapy with a lentiviral vector in X-linked adrenoleukodystrophy.&lt;/strong&gt; Science 326: 818-823, 2009.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/19892975/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;19892975&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1126/science.1171242&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="19892975">Cartier et al. (2009)</a> initiated a gene therapy trial in 2 ALD patients for whom there were no matched donors for hematopoietic stem cell transplantation. Autologous CD34(+) cells were removed from the patients, genetically corrected ex vivo with a lentiviral vector encoding wildtype ABCD1, and then reinfused into the patients after they had received myeloablative treatment. Over a span of 24 to 30 months of follow-up, <a href="#25" class="mim-tip-reference" title="Cartier, N., Hacein-Bey-Abina, S., Bartholomae, C. C., Veres, G., Schmidt, M., Kutschera, I., Vidaud, M., Abel, U., Dal-Cortivo, L., Caccavelli, L., Mahlaoui, N., Kiermer, V., and 14 others. &lt;strong&gt;Hematopoietic stem cell gene therapy with a lentiviral vector in X-linked adrenoleukodystrophy.&lt;/strong&gt; Science 326: 818-823, 2009.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/19892975/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;19892975&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1126/science.1171242&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="19892975">Cartier et al. (2009)</a> detected polyclonal reconstitution, with 9 to 14% of granulocytes, monocytes, and T and B lymphocytes expressing the ALD protein. <a href="#25" class="mim-tip-reference" title="Cartier, N., Hacein-Bey-Abina, S., Bartholomae, C. C., Veres, G., Schmidt, M., Kutschera, I., Vidaud, M., Abel, U., Dal-Cortivo, L., Caccavelli, L., Mahlaoui, N., Kiermer, V., and 14 others. &lt;strong&gt;Hematopoietic stem cell gene therapy with a lentiviral vector in X-linked adrenoleukodystrophy.&lt;/strong&gt; Science 326: 818-823, 2009.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/19892975/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;19892975&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1126/science.1171242&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="19892975">Cartier et al. (2009)</a> concluded that their results strongly suggested that hematopoietic stem cells were transduced in the patients. Beginning from 14 to 16 months after infusion of the genetically corrected cells, progressive cerebral demyelination in the 2 patients stopped, a clinical outcome comparable to that achieved by allogeneic hematopoietic stem cell transplant. Thus, <a href="#25" class="mim-tip-reference" title="Cartier, N., Hacein-Bey-Abina, S., Bartholomae, C. C., Veres, G., Schmidt, M., Kutschera, I., Vidaud, M., Abel, U., Dal-Cortivo, L., Caccavelli, L., Mahlaoui, N., Kiermer, V., and 14 others. &lt;strong&gt;Hematopoietic stem cell gene therapy with a lentiviral vector in X-linked adrenoleukodystrophy.&lt;/strong&gt; Science 326: 818-823, 2009.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/19892975/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;19892975&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1126/science.1171242&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="19892975">Cartier et al. (2009)</a> concluded that lentiviral-mediated gene therapy of hematopoietic stem cells can provide clinical benefits in ALD. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19892975" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#39" class="mim-tip-reference" title="Engelen, M., Ofman, R., Dijkgraaf, M. G. W., Hijzen, M., van der Wardt, L. A., van Geel, B. M., de Visser, M., Wanders, R. J. A., Poll-The, B. T., Kemp, S. &lt;strong&gt;Lovastatin in X-linked adrenoleukodystrophy. (Letter)&lt;/strong&gt; New Eng. J. Med. 362: 276-277, 2010.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/20089986/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;20089986&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1056/NEJMc0907735&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="20089986">Engelen et al. (2010)</a> reported the results of a randomized control trial of 40 mg daily lovastatin in 14 patients with ALD. Treatment with lovastatin resulted in a small decrease of plasma C24:0 and C26:0, likely due to a decrease in LDL cholesterol. Levels of C18:1 were also slightly reduced. However, there was no effect on C26:0 in erythrocytes or lymphocytes or on VLCFAs in the LDL lipoprotein fraction. These data indicated lovastatin should not be prescribed as a therapy to lower levels of VLCFAs in patients with ALD. No adverse events were observed. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20089986" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#45" class="mim-tip-reference" title="Fourcade, S., Ruiz, M., Guilera, C., Hahnen, E., Brichta, L., Naudi, A., Portero-Otin, M., Dacremont, G., Cartier, N., Wanders, R., Kemp, S., Mandel, J. L., Wirth, B., Pamplona, R., Aubourg, P., Pujol, A. &lt;strong&gt;Valproic acid induces antioxidant effects in X-linked adrenoleukodystrophy.&lt;/strong&gt; Hum. Molec. Genet. 19: 2005-2014, 2010.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/20179078/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;20179078&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1093/hmg/ddq082&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="20179078">Fourcade et al. (2010)</a> demonstrated that valproic acid (VPA), a widely used antiepileptic drug with histone deacetylase inhibitor properties, induced the expression of the ABCD2 peroxisomal transporter (<a href="/entry/601081">601081</a>). VPA corrected the oxidative damage in ALD human fibroblasts and decreased the levels of monounsaturated VLCFA (C26:1 n-9), but not saturated VLCFA. Overexpression of ABCD2 alone prevented oxidative lesions to proteins in a mouse model of ALD. A 6-month pilot trial of VPA in ALD patients resulted in reversion of the oxidative damage to proteins in peripheral blood mononuclear cells. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20179078" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Elivaldogene autotemcel (eli-cel) gene therapy consists of autologous CD34+ cells transduced with Lenti-D lentiviral vector containing ABCD1 cDNA. <a href="#34" class="mim-tip-reference" title="Duncan, C. N., Bledsoe, J. R., Grzywacz, B., Beckman, A., Bonner, M., Eichler, F. S., Kuhl, J. S., Harris, M. H., Slauson, S., Colvin, R. A., Prasad, V. K., Downey, G. F., and 11 others. &lt;strong&gt;Hematologic cancer after gene therapy for cerebral adrenoleukodystrophy.&lt;/strong&gt; New Eng. J. Med. 391: 1287-1301, 2024.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/39383458/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;39383458&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1056/NEJMoa2405541&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="39383458">Duncan et al. (2024)</a> performed integration-site analysis, genetic studies, flow cytometry, and morphologic studies in peripheral blood and bone marrow samples from patients who received eli-cel therapy in 2 completed phase 2-3 studies (ALD-102 and ALD-104) and an ongoing follow-up study (LTF-304, <a href="#35" class="mim-tip-reference" title="Eichler, F., Duncan, C. N., Musolino, P. L., Lund, T. C., Gupta, A. O., De Oliveira, S., Thrasher, A. J., Aubourg, P., Kuhl, J. S., Loes, D. J., Amartino, H., Smith, N., and 14 others. &lt;strong&gt;Lentiviral gene therapy for cerebral adrenoleukodystrophy.&lt;/strong&gt; New Eng. J. Med. 391: 1302-1312, 2024.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/39383459/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;39383459&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1056/NEJMoa2400442&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="39383459">Eichler et al., 2024</a>) involving the patients in both ALD-102 and ALD-104. Hematologic cancer developed in 7 of 67 patients after the receipt of eli-cel (1 of 32 patients in the ALD-102 study and 6 of 35 patients in the ALD-104 study): myelodysplastic syndrome (MDS) with unilineage dysplasia in 2 patients at 14 and 26 months; MDS with excess blasts in 3 patients at 28, 42, and 92 months; MDS in 1 patient at 36 months; and acute myeloid leukemia (AML) in 1 patient at 57 months. In the 6 patients with available data, predominant clones contained lentiviral vector insertions at multiple loci, including at either MECOM (<a href="/entry/165215">165215</a>) in 5 patients or PRDM16 (<a href="/entry/605557">605557</a>) in 1 patient. Several patients had cytopenias, and most had vector insertions in multiple genes within the same clone; 6 of the 7 patients also had somatic mutations (KRAS, <a href="/entry/190070">190070</a>; NRAS, <a href="/entry/164790">164790</a>; WT1, <a href="/entry/607102">607102</a>; CDKN2A, <a href="/entry/600160">600160</a> or CDKN2B, <a href="/entry/600431">600431</a>; or RUNX1, <a href="/entry/151385">151385</a>), and 1 of the 7 patients had monosomy 7. Of the 5 patients with MDS with excess blasts or MDS with unilineage dysplasia who underwent allogeneic hematopoietic stem cell transplantation (HSCT), 4 patients remained free of MDS without recurrence of symptoms of cerebral adrenoleukodystrophy, and 1 patient died from presumed graft-versus-host disease 20 months after HSCT (49 months after receiving eli-cel). The patient with AML was alive and had full donor chimerism after HSCT; the patient with the most recent case of MDS was alive and awaiting HSCT. The authors concluded that hematologic cancer developed in a subgroup of patients who were treated with eli-cel; the cases were associated with clonal vector insertions within oncogenes and clonal evolution with acquisition of somatic genetic defects. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=39383459+39383458" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In a phase 2-3 study, <a href="#35" class="mim-tip-reference" title="Eichler, F., Duncan, C. N., Musolino, P. L., Lund, T. C., Gupta, A. O., De Oliveira, S., Thrasher, A. J., Aubourg, P., Kuhl, J. S., Loes, D. J., Amartino, H., Smith, N., and 14 others. &lt;strong&gt;Lentiviral gene therapy for cerebral adrenoleukodystrophy.&lt;/strong&gt; New Eng. J. Med. 391: 1302-1312, 2024.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/39383459/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;39383459&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1056/NEJMoa2400442&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="39383459">Eichler et al. (2024)</a> evaluated the efficacy and safety of eli-cel therapy in boys with early-stage cerebral adrenoleukodystrophy and evidence of active inflammation on magnetic resonance imaging (MRI). The primary efficacy end point was survival without any of 6 major functional disabilities at month 24. The secondary end points included overall survival at month 24 and the change from baseline to month 24 in the total neurologic function score. A total of 32 patients received eli-cel; 29 patients (91%) completed the 24-month study and are being monitored in a 13-year long-term follow-up study. At month 24, none of these 29 patients had major functional disabilities; overall survival was 94%. At the most recent assessment (median follow-up, 6 years), the neurologic function score was stable as compared with the baseline score in 30 of 32 patients (94%); 26 patients (81%) had no major functional disabilities. Four patients had adverse events that were directly related to eli-cel. Myelodysplastic syndrome (MDS) with excess blasts developed in 1 patient at month 92; the patient underwent allogeneic hematopoietic stem cell transplantation and did not have MDS at the most recent follow-up. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=39383459" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#90" class="mim-tip-reference" title="Moser, H. W., Moser, A. B., Naidu, S., Bergin, A. &lt;strong&gt;Clinical aspects of adrenoleukodystrophy and adrenomyeloneuropathy.&lt;/strong&gt; Dev. Neurosci. 13: 254-261, 1991.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/1817030/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;1817030&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1159/000112170&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="1817030">Moser et al. (1991)</a> reported that their laboratory had identified more than 900 hemizygotes and 1,000 heterozygotes. Approximately 50% of the hemizygotes had a rapidly progressive childhood or adolescent form of the disease. In 25% of males, a slowly progressive paraparesis was the clinical picture. The illness occasionally presented as Addison disease without apparent neurologic involvement. Approximately 15% of heterozygotes developed moderately severe spastic paraparesis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1817030" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In studies of 30 Dutch kindreds, <a href="#149" class="mim-tip-reference" title="van Geel, B. M., Assies, J., Weverling, G. J., Barth, P. G. &lt;strong&gt;Predominance of the adrenomyeloneuropathy phenotype of X-linked adrenoleukodystrophy in the Netherlands: a survey of 30 kindreds.&lt;/strong&gt; Neurology 44: 2343-2346, 1994.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/7991123/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;7991123&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1212/wnl.44.12.2343&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="7991123">van Geel et al. (1994)</a> phenotyped 77 affected males and found that 35 (46%) had adrenomyeloneuropathy and 24 (31%) had the childhood or adolescent cerebral ALD. These percentages differed significantly from previous reports in which 25 to 28% of the patients developed AMN and 53 to 57% developed childhood or adolescent cerebral ALD. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7991123" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In studies in Australasia and Spain, <a href="#64" class="mim-tip-reference" title="Kirk, E. P. E., Fletcher, J. M., Sharp, P., Carey, B., Poulos, A. &lt;strong&gt;X-linked adrenoleukodystrophy: the Australasian experience.&lt;/strong&gt; Am. J. Med. Genet. 76: 420-423, 1998.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/9556302/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;9556302&lt;/a&gt;]" pmid="9556302">Kirk et al. (1998)</a> and <a href="#126" class="mim-tip-reference" title="Ruiz, M., Coll, M. J., Pampols, T., Giros, M. &lt;strong&gt;X-linked adrenoleukodystrophy: phenotype distribution and expression of ALDP in Spanish kindreds.&lt;/strong&gt; Am. J. Med. Genet. 76: 424-427, 1998.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/9556303/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;9556303&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/(sici)1096-8628(19980413)76:5&lt;424::aid-ajmg11&gt;3.0.co;2-o&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="9556303">Ruiz et al. (1998)</a>, respectively, provided new information about the epidemiology of ALD and the relative frequency of ALD phenotypes. The first study originated from the unit that had served as the ALD Referral Center in Australasia for the previous 15 years. Based on the number of ALD cases identified during this period and the number of live births, they arrived at a minimum incidence of 1.6 per 100,000 live births, slightly higher than the 1.1 per 100,000 based on similar analyses in the United States (<a href="#94" class="mim-tip-reference" title="Moser, H. W., Smith, K. D., Moser, A. B. &lt;strong&gt;X-linked adrenoleukodystrophy. In: Scriver, C. R.; Beaudet, A. L.; Sly, W. S.; Valle, D. (eds): The Metabolic and Molecular Bases of Inherited Disease.&lt;/strong&gt; New York: McGraw-Hill 1995. Pp. 2325-2349."None>Moser et al., 1995</a>) and considerably higher than the estimated 1 per 200,000 males in the Netherlands (<a href="#149" class="mim-tip-reference" title="van Geel, B. M., Assies, J., Weverling, G. J., Barth, P. G. &lt;strong&gt;Predominance of the adrenomyeloneuropathy phenotype of X-linked adrenoleukodystrophy in the Netherlands: a survey of 30 kindreds.&lt;/strong&gt; Neurology 44: 2343-2346, 1994.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/7991123/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;7991123&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1212/wnl.44.12.2343&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="7991123">van Geel et al., 1994</a>). Of the 95 affected males studied by <a href="#64" class="mim-tip-reference" title="Kirk, E. P. E., Fletcher, J. M., Sharp, P., Carey, B., Poulos, A. &lt;strong&gt;X-linked adrenoleukodystrophy: the Australasian experience.&lt;/strong&gt; Am. J. Med. Genet. 76: 420-423, 1998.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/9556302/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;9556302&lt;/a&gt;]" pmid="9556302">Kirk et al. (1998)</a>, 51 had cerebral adrenoleukodystrophy, 24 had adrenomyeloneuropathy, 15 had Addison disease only, and 5 remained asymptomatic when last examined. Of the 60 patients belonging to 48 kindreds studied by <a href="#126" class="mim-tip-reference" title="Ruiz, M., Coll, M. J., Pampols, T., Giros, M. &lt;strong&gt;X-linked adrenoleukodystrophy: phenotype distribution and expression of ALDP in Spanish kindreds.&lt;/strong&gt; Am. J. Med. Genet. 76: 424-427, 1998.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/9556303/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;9556303&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/(sici)1096-8628(19980413)76:5&lt;424::aid-ajmg11&gt;3.0.co;2-o&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="9556303">Ruiz et al. (1998)</a>, 33% had childhood cerebral ALD plus adolescent cerebral ALD, 16% had adult cerebral ALD, 27% had adrenomyeloneuropathy, 12% had Addison disease only, and 12% had presymptomatic ALD. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=7991123+9556303+9556302" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#16" class="mim-tip-reference" title="Bezman, L., Moser, H. W. &lt;strong&gt;Incidence of X-linked adrenoleukodystrophy and the relative frequency of its phenotypes. (Editorial)&lt;/strong&gt; Am. J. Med. Genet. 76: 415-419, 1998.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/9556301/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;9556301&lt;/a&gt;]" pmid="9556301">Bezman and Moser (1998)</a> reviewed the relative frequency of phenotypes in 388 patients from 253 sibships from the United States and Canada in whom the genotype and phenotype of every male was known. This determination of every male eliminated the ascertainment bias introduced by other series in which ALD status was not known. When the proband was excluded, the phenotypic breakdown was 33% with childhood cerebral ALD, 26% with adrenomyeloneuropathy, 14% Addison only, 13% asymptomatic, 4% adolescent, and 2% adult cerebral. These numbers were very similar to the series from the Netherlands in which there was an attempt to identify everyone in the country with ALD. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9556301" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#15" class="mim-tip-reference" title="Bezman, L., Moser, A. B., Raymond, G. V., Rinaldo, P., Watkins, P. A., Smith, K. D., Kass, N. E., Moser, H. W. &lt;strong&gt;Adrenoleukodystrophy: incidence, new mutation rate, and results of extended family screening.&lt;/strong&gt; Ann. Neurol. 49: 512-517, 2001.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/11310629/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;11310629&lt;/a&gt;]" pmid="11310629">Bezman et al. (2001)</a> determined the minimum frequency of hemizygotes in the United States to be 1:42,000 and that of hemizygotes and heterozygotes to be 1:16,800. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11310629" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In a retrospective hospital- and clinic-based study involving 122 children with an inherited leukodystrophy, <a href="#19" class="mim-tip-reference" title="Bonkowsky, J. L., Nelson, C., Kingston, J. L., Filloux, F. M., Mundorff, M. B., Srivastava, R. &lt;strong&gt;The burden of inherited leukodystrophies in children.&lt;/strong&gt; Neurology 75: 718-725, 2010.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/20660364/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;20660364&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1212/WNL.0b013e3181eee46b&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="20660364">Bonkowsky et al. (2010)</a> found that the most common diagnoses were metachromatic leukodystrophy (<a href="/entry/250100">250100</a>) (8.2%), Pelizaeus-Merzbacher disease (<a href="/entry/312080">312080</a>) (7.4%), mitochondrial diseases (4.9%), and adrenoleukodystrophy (4.1%). No final diagnosis was reported in 51% of patients. The disorder was severe: epilepsy was found in 49%, mortality was 34%, and the average age at death was 8.2 years. The population incidence of leukodystrophy in general was found to be 1 in 7,663 live births. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20660364" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#69" class="mim-tip-reference" title="Koto, Y., Sakai, N., Lee, Y., Kakee, N., Matsuda, J., Tsuboi, K., Shimozawa, N., Okuyama, T., Nakamura, K., Narita, A., kobayashi, H., Uehara, R., Nakamura, Y., Kato, K., Eto, Y. &lt;strong&gt;Prevalence of patients with lysosomal storage disorders and peroxisomal disorders: a nationwide survey in Japan.&lt;/strong&gt; Molec. Genet. Metab. 133: 277-288, 2021.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/34090759/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;34090759&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/j.ymgme.2021.05.004&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="34090759">Koto et al. (2021)</a> surveyed hospitals in Japan for information about patients with peroxisomal disorders treated between 2013-2016 and 2018-2019. Adrenoleukodystrophy was identified in 73 patients, of whom 52.1% had the childhood cerebral form, 16.4% had the adolescent cerebral form, 11% had adrenomyeloneuropathy, 1.4% had the adult cerebral form, 8.2% had Addison disease, 1.4% were symptomatic females, 5.5% had prenatal onset, and 4.1% had unknown onset. When these data were extrapolated across Japan, <a href="#69" class="mim-tip-reference" title="Koto, Y., Sakai, N., Lee, Y., Kakee, N., Matsuda, J., Tsuboi, K., Shimozawa, N., Okuyama, T., Nakamura, K., Narita, A., kobayashi, H., Uehara, R., Nakamura, Y., Kato, K., Eto, Y. &lt;strong&gt;Prevalence of patients with lysosomal storage disorders and peroxisomal disorders: a nationwide survey in Japan.&lt;/strong&gt; Molec. Genet. Metab. 133: 277-288, 2021.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/34090759/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;34090759&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/j.ymgme.2021.05.004&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="34090759">Koto et al. (2021)</a> estimated that there were 262 patients with adrenoleukodystrophy, and they calculated a birth prevalence in Japan of 0.2 per 100,000. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=34090759" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>Animal Model</strong>
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<p><a href="#43" class="mim-tip-reference" title="Forss-Petter, S., Werner, H., Berger, J., Lassmann, H., Molzer, B., Schwab, M. H., Bernheimer, H., Zimmermann, F., Nave, K.-A. &lt;strong&gt;Targeted inactivation of the X-linked adrenoleukodystrophy gene in mice.&lt;/strong&gt; J. Neurosci. Res. 50: 829-843, 1997.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/9418970/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;9418970&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/(SICI)1097-4547(19971201)50:5&lt;829::AID-JNR19&gt;3.0.CO;2-W&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="9418970">Forss-Petter et al. (1997)</a> and <a href="#74" class="mim-tip-reference" title="Lu, J. F., Lawler, A. M., Watkins, P. A., Powers, J. M., Moser, A. B., Moser, H. W., Smith, K. D. &lt;strong&gt;A mouse model for X-linked adrenoleukodystrophy.&lt;/strong&gt; Proc. Nat. Acad. Sci. 94: 9366-9371, 1997.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/9256488/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;9256488&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=9256488[PMID]&amp;report=imagesdocsum&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed Image&#x27;, &#x27;domain&#x27;: &#x27;ncbi.nlm.nih.gov&#x27;})&quot;&gt;images&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1073/pnas.94.17.9366&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="9256488">Lu et al. (1997)</a> generated mice deficient in ALDP by targeted disruption. Motor functions in Aldp-deficient mice developed on schedule, and unexpectedly, adult animals appeared unaffected by neurologic symptoms up to 6 months of age. Biochemical analyses demonstrated impaired beta-oxidation in mutant fibroblasts and abnormal accumulation of very long chain fatty acids in the CNS and kidney. In 6-month-old mutants, adrenal cortex cells displayed a ballooned morphology and needle-like lipid inclusions, also found in testis and ovaries. However, lipid inclusions and demyelinating lesions of the CNS were not a feature. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=9418970+9256488" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Contrary to the original suggestion that there was no phenotype associated with these mice, <a href="#120" class="mim-tip-reference" title="Pujol, A., Hindelang, C., Callizot, N., Bartsch, U., Schachner, M., Mandel, J. L. &lt;strong&gt;Late onset neurological phenotype of the X-ALD gene inactivation in mice: a mouse model for adrenomyeloneuropathy.&lt;/strong&gt; Hum. Molec. Genet. 11: 499-505, 2002.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/11875044/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;11875044&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1093/hmg/11.5.499&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="11875044">Pujol et al. (2002)</a> determined that older mice have changes resembling AMN. Older Aldp-deficient mice exhibited an abnormal neurologic and behavioral phenotype, starting at around 15 months. This was correlated with slower nerve conduction and with myelin and axonal anomalies detectable in the spinal cord and sciatic nerve, but not in brain. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11875044" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>The Drosophila recessive mutant 'bubblegum' (bgm) exhibits adult neurodegeneration, with marked dilation of photoreceptor axons. This mutant shows elevated levels of VLCFAs, as seen in ALD. <a href="#83" class="mim-tip-reference" title="Min, K.-T., Benzer, S. &lt;strong&gt;Preventing neurodegeneration in the Drosophila mutant bubblegum.&lt;/strong&gt; Science 284: 1985-1988, 1999.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/10373116/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;10373116&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1126/science.284.5422.1985&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="10373116">Min and Benzer (1999)</a> found that feeding the fly mutant one of the components of 'Lorenzo's oil,' glyceryl trioleate oil, blocked the accumulation of excess VLCFAs as well as development of the pathology. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10373116" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In Abcd1-knockout mice, <a href="#119" class="mim-tip-reference" title="Pujol, A., Ferrer, I., Camps, C., Metzger, E., Hindelang, C., Callizot, N., Ruiz, M., Pampols, T., Giros, M., Mandel, J. L. &lt;strong&gt;Functional overlap between ABCD1 (ALD) and ABCD2 (ALDR) transporters: a therapeutic target for X-adrenoleukodystrophy.&lt;/strong&gt; Hum. Molec. Genet. 13: 2997-3006, 2004.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/15489218/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;15489218&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1093/hmg/ddh323&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="15489218">Pujol et al. (2004)</a> demonstrated that axonal damage was the first pathologic event in this model, followed by myelin degeneration. The phenotype could be modulated through expression levels of Abcd2 (<a href="/entry/601081">601081</a>). Overexpression of Abcd2 in Abcd1-knockout mice prevented both VLCFA accumulation and neurodegenerative features, whereas Abcd1/Abcd2 double mutants exhibited an earlier onset and more severe disease. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15489218" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#109" class="mim-tip-reference" title="Oezen, I., Rossmanith, W., Forss-Petter, S., Kemp, S., Voigtlander, T., Moser-Thier, K., Wanders, R. J., Bittner, R. E., Berger, J. &lt;strong&gt;Accumulation of very long-chain fatty acids does not affect mitochondrial function in adrenoleukodystrophy protein deficiency.&lt;/strong&gt; Hum. Molec. Genet. 14: 1127-1137, 2005.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/15772093/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;15772093&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1093/hmg/ddi125&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="15772093">Oezen et al. (2005)</a> reported normal VLCFA levels in mitochondria of Abcd1-deficient mice. Polarographic analysis of the respiratory chain as well as enzymatic assays of isolated muscle mitochondria revealed no differences between Abcd1-deficient and control mice. Ultrastructural analysis revealed normal size, structure, and localization of mitochondria in muscle of both groups. Mitochondrial enzyme activity in brain homogenates of Abcd1-deficient and wildtype animals also did not differ, and studies on mitochondrial oxidative phosphorylation in permeabilized human skin fibroblasts of ALD patients and controls revealed no abnormalities. <a href="#109" class="mim-tip-reference" title="Oezen, I., Rossmanith, W., Forss-Petter, S., Kemp, S., Voigtlander, T., Moser-Thier, K., Wanders, R. J., Bittner, R. E., Berger, J. &lt;strong&gt;Accumulation of very long-chain fatty acids does not affect mitochondrial function in adrenoleukodystrophy protein deficiency.&lt;/strong&gt; Hum. Molec. Genet. 14: 1127-1137, 2005.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/15772093/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;15772093&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1093/hmg/ddi125&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="15772093">Oezen et al. (2005)</a> concluded that accumulation of VLCFA per se does not cause mitochondrial abnormalities, and vice versa mitochondrial abnormalities are not responsible for the accumulation of VLCFA in Abcd1-deficient mice. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15772093" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#44" class="mim-tip-reference" title="Fourcade, S., Lopez-Erauskin, J., Galino, J., Duval, C., Naudi, A., Jove, M., Kemp, S., Villarroya, F., Ferrer, I., Pamplona, R., Portero-Otin, M., Pujol, A. &lt;strong&gt;Early oxidative damage underlying neurodegeneration in X-adrenoleukodystrophy.&lt;/strong&gt; Hum. Molec. Genet. 17: 1762-1773, 2008.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/18344354/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;18344354&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1093/hmg/ddn085&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="18344354">Fourcade et al. (2008)</a> found evidence of lipoxidative protein damage in the spinal cord of Abcd1-null mice as early as 3.5 months of age before the onset of neurologic symptoms. At 12 months, Abcd1-null mice had accumulated additional proteins affected by oxidative damage. Abcd1-null mice, spinal cord slices from these mice, and human ALD fibroblasts all showed a defective antioxidant response to VLCFA. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18344354" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In early symptomatic Abcd1/Abcd2 double-knockout mice, <a href="#79" class="mim-tip-reference" title="Mastroeni, R., Bensadoun, J.-C., Charvin, D., Aebischer, P., Pujol, A., Raoul, C. &lt;strong&gt;Insulin-like growth factor-1 and neurotrophin-3 gene therapy prevents motor decline in an X-linked adrenoleukodystrophy mouse model.&lt;/strong&gt; Ann. Neurol. 66: 117-122, 2009.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/19670442/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;19670442&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ana.21677&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="19670442">Mastroeni et al. (2009)</a> demonstrated that intracisternal injection of an adeno-associated viral vector engineered to express human IGF1 (<a href="/entry/147440">147440</a>) and NTF3 (<a href="/entry/162660">162660</a>), 2 potent inducers of myelin formation and oligodendrocyte survival, resulted in protective effects against the demyelination process and amelioration of disease progression. Studies of CSF showed persistent expression of the genes after 20 weeks, suggesting effective transduction of leptomeningeal cells and a long-lasting effect. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19670442" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#100" class="mim-tip-reference" title="Moser, H. W. &lt;strong&gt;Adrenoleukodystrophy: phenotype, genetics, pathogenesis and therapy.&lt;/strong&gt; Brain 120: 1485-1508, 1997.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/9278636/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;9278636&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1093/brain/120.8.1485&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="9278636">Moser (1997)</a> suggested that the first patient with X-ALD was described by <a href="#49" class="mim-tip-reference" title="Haberfeld, W., Spieler, F. &lt;strong&gt;Zur diffusen Hirn-Ruckenmarksklerose im Kindesalter.&lt;/strong&gt; Dt. Z. Nervheilk 40: 436-463, 1910."None>Haberfeld and Spieler (1910)</a>. A previously normal boy developed disturbances in eye movement and vision at the age of 6 years, became apathetic, and showed deterioration of school work. Four months later his gait became spastic, and this progressed to an inability to walk. He was hospitalized at 7 years of age. Dark skin was noted. He died 8 months later. An older brother had died of a similar illness at 8.5 years. The postmortem brain was studied by <a href="#136" class="mim-tip-reference" title="Schilder, P. &lt;strong&gt;Zur Frage der Encephalitis Periaxialis Diffusa (Sogenannte Diffuse Sklerose).&lt;/strong&gt; Z. ges Neurol. Psychiat. 15: 359-376, 1913."None>Schilder (1913)</a> and reported as the second of 3 cases that he referred to as 'encephalitis periaxialis diffusa,' characterized by diffuse involvement of the cerebral hemispheres in children with severe loss of myelin, which resembled multiple sclerosis because of the relative preservation of axons and the accumulation of lymphocytes, fat-laden phagocytes, and glial cells. The findings in the adrenal gland were not reported. Involvement of the adrenal gland was reported by <a href="#140" class="mim-tip-reference" title="Siemerling, E., Creutzfeldt, H. G. &lt;strong&gt;Bronzekrankheit und sklerosierende Encephalomyelitis.&lt;/strong&gt; Arch. Psychiat. Nervkrankh. 68: 217-244, 1923."None>Siemerling and Creutzfeldt (1923)</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9278636" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#17" class="mim-tip-reference" title="Blaw, M. E. &lt;strong&gt;Melanodermic type leucodystrophy (adrenoleukodystrophy). In: Vinken, P. J.; Bruyn, G. W. (eds.): Handbook of Clinical Neurology. Vol. 10.&lt;/strong&gt; Amsterdam: North Holland 1970. Pp. 128-133."None>Blaw (1970)</a> coined the name 'adrenoleukodystrophy.'</p><p><a href="#48" class="mim-tip-reference" title="Gumbinas, M., Liu, H. M., Dawson, G., Larsen, M., Green, O. &lt;strong&gt;Progressive spastic aparaparesis and adrenal insufficiency.&lt;/strong&gt; Arch. Neurol. 33: 678-680, 1976.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/973804/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;973804&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1001/archneur.1976.00500100012006&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="973804">Gumbinas et al. (1976)</a> suggested that progressive spastic paraparesis with adrenal insufficiency is 'a distinct disease, differing importantly from adrenoleukodystrophy.' <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=973804" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<h4 href="#mimSeeAlsoFold" id="mimSeeAlsoToggle" class="mimTriangleToggle" style="cursor: pointer;" data-toggle="collapse">
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<strong>See Also:</strong>
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<span class="mim-text-font">
<a href="#Aguilar1967" class="mim-tip-reference" title="Aguilar, M. J., O&#x27;Brien, J. S., Taber, P. &lt;strong&gt;The syndrome of familial leukodystrophy, adrenal insufficiency and cutaneous melanosis. In: Aronson, S. M.; Volk, B. W.: Inborn Disorders of Sphingolipid Metabolism.&lt;/strong&gt; Oxford: Pergamon Press (pub.) 1967. Pp. 149-166.">Aguilar et al. (1967)</a>; <a href="#ASHG1998">ASHG statement (1998)</a>; <a href="#Aubourg1990" class="mim-tip-reference" title="Aubourg, P., Feil, R., Guidoux, S., Kaplan, J.-C., Moser, H., Kahn, A., Mandel, J.-L. &lt;strong&gt;The red-green visual pigment gene region in adrenoleukodystrophy.&lt;/strong&gt; Am. J. Hum. Genet. 46: 459-469, 1990.">Aubourg et al. (1990)</a>; <a href="#Aubourg1993" class="mim-tip-reference" title="Aubourg, P., Mosser, J., Douar, A. M., Sarde, C. O., Lopez, J., Mandel, J. L. &lt;strong&gt;Adrenoleukodystrophy gene: unexpected homology to a protein involved in peroxisome biogenesis.&lt;/strong&gt; Biochimie 75: 293-302, 1993.">Aubourg et al. (1993)</a>; <a href="#Barcelo1994" class="mim-tip-reference" title="Barcelo, A., Giros, M., Sarde, C. O., Martinez-Bermejo, A., Mandel, J. L., Pampols, T., Estivill, X. &lt;strong&gt;Identification of a new frameshift mutation (1801delAG) in the ALD gene.&lt;/strong&gt; Hum. Molec. Genet. 3: 1889-1890, 1994.">Barcelo et al. (1994)</a>; <a href="#Barcelo1994" class="mim-tip-reference" title="Barcelo, A., Giros, M., Sarde, C. O., Martinez-Bermejo, A., Mandel, J. L., Pampols, T., Estivill, X. &lt;strong&gt;Identification of a new frameshift mutation (1801delAG) in the ALD gene.&lt;/strong&gt; Hum. Molec. Genet. 3: 1889-1890, 1994.">Barcelo et al. (1994)</a>; <a href="#Berger1994" class="mim-tip-reference" title="Berger, J., Molzer, B., Fae, I., Bernheimer, H. &lt;strong&gt;X-linked adrenoleukodystrophy (ALD): a novel mutation of the ALD gene in 6 members of a family presenting with 5 different phenotypes.&lt;/strong&gt; Biochem. Biophys. Res. Commun. 205: 1638-1643, 1994.">Berger et al. (1994)</a>; <a href="#Brady1976" class="mim-tip-reference" title="Brady, R. O. &lt;strong&gt;Inherited metabolic diseases of the nervous system.&lt;/strong&gt; Science 193: 733-739, 1976.">Brady (1976)</a>; <a href="#Braun1995" class="mim-tip-reference" title="Braun, A., Ambach, H., Kammerer, S., Rolinski, B., Stockler, S., Rabl, W., Gartner, J., Zierz, S., Roscher, A. A. &lt;strong&gt;Mutations in the gene for X-linked adrenoleukodystrophy in patients with different clinical phenotypes.&lt;/strong&gt; Am. J. Hum. Genet. 56: 854-861, 1995.">Braun et al. (1995)</a>; <a href="#Cartier1993" class="mim-tip-reference" title="Cartier, N., Sarde, C.-O., Douar, A.-M., Mosser, J., Mandel, J.-L., Aubourg, P. &lt;strong&gt;Abnormal messenger RNA expression and a missense mutation in patients with X-linked adrenoleukodystrophy.&lt;/strong&gt; Hum. Molec. Genet. 2: 1949-1951, 1993.">Cartier et
al. (1993)</a>; <a href="#Di1980" class="mim-tip-reference" title="Di Chiro, G., Eiben, R. M., Manz, H. J., Jacobs, I. B., Schellinger, D. &lt;strong&gt;A new CT pattern in adrenoleukodystrophy.&lt;/strong&gt; Radiology 137: 687-692, 1980.">Di Chiro et al. (1980)</a>; <a href="#Dodd1997" class="mim-tip-reference" title="Dodd, A., Rowland, S. A., Hawkes, S. L. J., Kennedy, M. A., Love, D. R. &lt;strong&gt;Mutations in the adrenoleukodystrophy gene.&lt;/strong&gt; Hum. Mutat. 9: 500-511, 1997.">Dodd et al. (1997)</a>; <a href="#Fuchs1994" class="mim-tip-reference" title="Fuchs, S., Sarde, C. O., Wedemann, H., Schwinger, E., Mandel, J. L., Gal, A. &lt;strong&gt;Missense mutations are frequent in the gene for X-chromosomal adrenoleukodystrophy (ALD).&lt;/strong&gt; Hum. Molec. Genet. 3: 1903-1905, 1994.">Fuchs et al.
(1994)</a>; <a href="#Harris-Jones1955" class="mim-tip-reference" title="Harris-Jones, J. N., Nixon, P. G. F. &lt;strong&gt;Familial Addison&#x27;s disease with spastic paraplegia.&lt;/strong&gt; J. Clin. Endocr. 15: 739-744, 1955.">Harris-Jones and Nixon (1955)</a>; <a href="#Hoefnagel1967" class="mim-tip-reference" title="Hoefnagel, D., Brun, A., Ingbar, S. H., Goldman, H. &lt;strong&gt;Addison&#x27;s disease and diffuse cerebral sclerosis.&lt;/strong&gt; J. Neurol. Neurosurg. Psychiat. 30: 56-60, 1967.">Hoefnagel et al. (1967)</a>; <a href="#Kano1998" class="mim-tip-reference" title="Kano, S., Watanabe, M., Kanai, M., Koike, R., Onodera, O., Tsuji, S., Okamoto, K., Shoji, M. &lt;strong&gt;A Japanese family with adrenoleukodystrophy with a codon 291 deletion: a clinical, biochemical, pathological, and genetic report.&lt;/strong&gt; J. Neurol. Sci. 158: 187-192, 1998.">Kano
et al. (1998)</a>; <a href="#Kobayashi1994" class="mim-tip-reference" title="Kobayashi, T., Yamada, T., Yasutake, T., Shinnoh, N., Goto, I., Iwaki, T. &lt;strong&gt;Adrenoleukodystrophy gene encodes an 80 kDa membrane protein.&lt;/strong&gt; Biochem. Biophys. Res. Commun. 201: 1029-1034, 1994.">Kobayashi et al. (1994)</a>; <a href="#Martin1980" class="mim-tip-reference" title="Martin, J. J., Dompas, B., Ceuterick, C., Jacobs, K. &lt;strong&gt;Adrenomyeloneuropathy and adrenoleukodystrophy in two brothers.&lt;/strong&gt; Europ. Neurol. 19: 281-287, 1980.">Martin et al. (1980)</a>; <a href="#Menkes1977" class="mim-tip-reference" title="Menkes, J. H., Corbo, L. M. &lt;strong&gt;Adrenoleukodystrophy: accumulation of cholesterol esters with very long chain fatty acids.&lt;/strong&gt; Neurology 27: 928-932, 1977.">Menkes
and Corbo (1977)</a>; <a href="#Moser1984" class="mim-tip-reference" title="Moser, H. W., Tutschka, P. J., Brown, F. R., III, Moser, A. E., Yeager, A. M., Singh, I., Mark, S. A., Kumar, A. A. J., McDonnell, J. M., White, C. L., III, Maumenee, I. H., Green, W. R., Powers, J. M., Santos, G. W. &lt;strong&gt;Bone marrow transplant in adrenoleukodystrophy.&lt;/strong&gt; Neurology 34: 1410-1417, 1984.">Moser et al. (1984)</a>; <a href="#Moser1984" class="mim-tip-reference" title="Moser, H. W., Tutschka, P. J., Brown, F. R., III, Moser, A. E., Yeager, A. M., Singh, I., Mark, S. A., Kumar, A. A. J., McDonnell, J. M., White, C. L., III, Maumenee, I. H., Green, W. R., Powers, J. M., Santos, G. W. &lt;strong&gt;Bone marrow transplant in adrenoleukodystrophy.&lt;/strong&gt; Neurology 34: 1410-1417, 1984.">Moser et al. (1984)</a>; <a href="#O'Neill1981" class="mim-tip-reference" title="O&#x27;Neill, B. P., Marmion, L. C., Feringa, E. R. &lt;strong&gt;The adrenoleukomyeloneuropathy complex: expression in four generations.&lt;/strong&gt; Neurology 31: 151-156, 1981.">O'Neill
et al. (1981)</a>; <a href="#O'Neill1982" class="mim-tip-reference" title="O&#x27;Neill, B. P., Moser, H. W., Saxena, K. M. &lt;strong&gt;Familial X-linked Addison disease as an expression of adrenoleukodystrophy (ALD): elevated C26 fatty acid in cultured skin fibroblasts.&lt;/strong&gt; Neurology 32: 543-547, 1982.">O'Neill et al. (1982)</a>; <a href="#Peckham1982" class="mim-tip-reference" title="Peckham, R. S., Marshall, M. C., Jr., Rosman, P. M., Farag, A., Kabadi, U., Wallace, E. Z. &lt;strong&gt;A variant of adrenomyeloneuropathy with hypothalamic-pituitary dysfunction and neurologic remission after glucocorticoid replacement therapy.&lt;/strong&gt; Am. J. Med. 72: 173-176, 1982.">Peckham et al. (1982)</a>; <a href="#Penman1960" class="mim-tip-reference" title="Penman, R. W. B. &lt;strong&gt;Addison&#x27;s disease in association with spastic paraplegia.&lt;/strong&gt; Brit. Med. J. 1: 402, 1960.">Penman
(1960)</a>; <a href="#Powers1980" class="mim-tip-reference" title="Powers, J. M., Schaumburg, H. H. &lt;strong&gt;A fatal cause of sexual inadequacy in men: adreno-leukodystrophy.&lt;/strong&gt; J. Urol. 124: 583-585, 1980.">Powers et al. (1980)</a>; <a href="#Powers1974" class="mim-tip-reference" title="Powers, J. M., Schaumburg, H. H. &lt;strong&gt;Adreno-leukodystrophy (sex-linked Schilder&#x27;s disease): a pathogenic hypothesis based on ultrastructural lesions in adrenal cortex, peripheral nerve and testis.&lt;/strong&gt; Am. J. Path. 76: 481-500, 1974.">Powers and Schaumburg (1974)</a>; <a href="#Powers1980" class="mim-tip-reference" title="Powers, J. M., Schaumburg, H. H. &lt;strong&gt;A fatal cause of sexual inadequacy in men: adreno-leukodystrophy.&lt;/strong&gt; J. Urol. 124: 583-585, 1980.">Powers
and Schaumburg (1980)</a>; <a href="#Powers1981" class="mim-tip-reference" title="Powers, J. M., Schaumburg, H. H. &lt;strong&gt;The testis in adreno-leukodystrophy.&lt;/strong&gt; Am. J. Path. 102: 90-98, 1981.">Powers and Schaumburg (1981)</a>; <a href="#Probst1980" class="mim-tip-reference" title="Probst, A., Ulrich, J., Heitz, P. U., Herschkowitz, N. &lt;strong&gt;Adrenomyeloneuropathy: a protracted, pseudosystematic variant of adrenoleukodystrophy.&lt;/strong&gt; Acta Neuropath. 49: 105-115, 1980.">Probst et al.
(1980)</a>; <a href="#Ropers1975" class="mim-tip-reference" title="Ropers, H.-H., Burmeister, P., von Petrykowski, W., Schindera, F. &lt;strong&gt;Leukodystrophy, skin hyperpigmentation, and adrenal atrophy: Siemerling-Creutzfeldt disease: transmission through several generations in two families.&lt;/strong&gt; Am. J. Hum. Genet. 27: 547-553, 1975.">Ropers et al. (1975)</a>; <a href="#Rosen1985" class="mim-tip-reference" title="Rosen, N. L., Lechtenberg, R., Wisniewski, K., Pullarkat, R., Bennett, H. S. &lt;strong&gt;Adrenoleukomyeloneuropathy with onset in early childhood.&lt;/strong&gt; Ann. Neurol. 17: 311-312, 1985.">Rosen et al. (1985)</a>; <a href="#Sarde1994" class="mim-tip-reference" title="Sarde, C.-O., Thomas, J., Sadoulet, H., Garnier, J.-M., Mandel, J.-L. &lt;strong&gt;cDNA sequence of Aldgh, the mouse homolog of the X-linked adrenoleukodystrophy gene.&lt;/strong&gt; Mammalian Genome 5: 810-813, 1994.">Sarde et al.
(1994)</a>; <a href="#Schaumburg1972" class="mim-tip-reference" title="Schaumburg, H. H., Richardson, E. P., Jr., Johnson, P. C., Cohen, R. B., Powers, J. M., Raine, C. S. &lt;strong&gt;Schilder&#x27;s disease: sex-linked recessive transmission with specific adrenal changes.&lt;/strong&gt; Arch. Neurol. 27: 458-460, 1972.">Schaumburg et al. (1972)</a>; <a href="#Seneca1995" class="mim-tip-reference" title="Seneca, S., Lissens, W. &lt;strong&gt;DNA diagnosis of X-linked adrenoleukodystrophy.&lt;/strong&gt; J. Inherit. Metab. Dis. 18 (suppl. 1): 34-44, 1995.">Seneca and Lissens (1995)</a>; <a href="#Takano1999" class="mim-tip-reference" title="Takano, H., Koike, R., Onodera, O., Sasaki, R., Tsuji, S. &lt;strong&gt;Mutational analysis and genotype-phenotype correlation of 29 unrelated Japanese patients with X-linked adrenoleukodystrophy.&lt;/strong&gt; Arch. Neurol. 56: 295-300, 1999.">Takano
et al. (1999)</a>; <a href="#Turkington1966" class="mim-tip-reference" title="Turkington, R. W., Stempfel, R. S., Jr. &lt;strong&gt;Adrenocortical atrophy and diffuse cerebral sclerosis (Addison-Schilder&#x27;s disease).&lt;/strong&gt; J. Pediat. 69: 406-412, 1966.">Turkington and Stempfel (1966)</a>; <a href="#Unterrainer2000" class="mim-tip-reference" title="Unterrainer, G., Molzer, B., Forss-Petter, S., Berger, J. &lt;strong&gt;Co-expression of mutated and normal adrenoleukodystrophy protein reduces protein function: implications for gene therapy of X-linked adrenoleukodystrophy.&lt;/strong&gt; Hum. Molec. Genet. 9: 2609-2616, 2000.">Unterrainer et al.
(2000)</a>; <a href="#Walsh1980" class="mim-tip-reference" title="Walsh, P. J. &lt;strong&gt;Adrenoleukodystrophy: report of two cases with relapsing and remitting courses.&lt;/strong&gt; Arch. Neurol. 37: 448-450, 1980.">Walsh (1980)</a>; <a href="#Wanders1987" class="mim-tip-reference" title="Wanders, R. J. A., van Roermund, C. W. T., van Wijland, M. J. A., Schutgens, R. B. H., Heikoop, J., van den Bosch, H., Schram, A. W., Tager, J. M. &lt;strong&gt;Peroxisomal fatty acid beta-oxidation in relation to the accumulation of very long chain fatty acids in cultured skin fibroblasts from patients with Zellweger syndrome and other peroxisomal disorders.&lt;/strong&gt; J. Clin. Invest. 80: 1778-1783, 1987.">Wanders et al. (1987)</a>; <a href="#Wray1976" class="mim-tip-reference" title="Wray, S. H., Cogan, D. G., Kuwabara, T., Schaumburg, H. H., Powers, J. M. &lt;strong&gt;Adrenoleukodystrophy with disease of the eye and optic nerve.&lt;/strong&gt; Am. J. Ophthal. 82: 480-485, 1976.">Wray et al. (1976)</a>
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<strong>REFERENCES</strong>
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<a id="1" class="mim-anchor"></a>
<a id="Aguilar1967" class="mim-anchor"></a>
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Aguilar, M. J., O'Brien, J. S., Taber, P.
<strong>The syndrome of familial leukodystrophy, adrenal insufficiency and cutaneous melanosis. In: Aronson, S. M.; Volk, B. W.: Inborn Disorders of Sphingolipid Metabolism.</strong>
Oxford: Pergamon Press (pub.) 1967. Pp. 149-166.
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<a id="Alpern1993" class="mim-anchor"></a>
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Alpern, M., Sack, G. H., Jr., Krantz, D. H., Jenness, J., Zhang, H., Moser, H. W.
<strong>Chromosomal rearrangement segregating with adrenoleukodystrophy: associated changes in color vision.</strong>
Proc. Nat. Acad. Sci. 90: 9494-9498, 1993.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8415729/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8415729</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8415729" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1073/pnas.90.20.9494" target="_blank">Full Text</a>]
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<a id="{ASHG statement}1998" class="mim-anchor"></a>
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ASHG statement.
<strong>Professional disclosure of familial genetic information: the American Society of Human Genetics Social Issues Subcommittee on Familial Disclosure.</strong>
Am. J. Hum. Genet. 62: 474-483, 1998.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9537923/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9537923</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9537923" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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<a id="Aubourg1993" class="mim-anchor"></a>
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Aubourg, P., Adamsbaum, C., Lavallard-Rousseau, M.-C., Rocchiccioli, F., Cartier, N., Jambaque, I., Jakobezak, C., Lemaitre, A., Boureau, F., Wolf, C., Bougneres, P.-F.
<strong>A two-year trial of oleic and erucic acids ('Lorenzo's oil') as treatment for adrenomyeloneuropathy.</strong>
New Eng. J. Med. 329: 745-752, 1993.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8350883/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8350883</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8350883" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1056/NEJM199309093291101" target="_blank">Full Text</a>]
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<a id="Aubourg1990" class="mim-anchor"></a>
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Aubourg, P., Blanche, S., Jambaque, I., Rocchiccioli, F., Kalifa, G., Naud-Saudreau, C., Rolland, M.-O., Debre, M., Chaussain, J.-L., Griscelli, C., Fischer, A., Bougneres, P.-F.
<strong>Reversal of early neurologic and neuroradiologic manifestations of X-linked adrenoleukodystrophy by bone marrow transplantation.</strong>
New Eng. J. Med. 322: 1860-1866, 1990.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2348839/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2348839</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2348839" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1056/NEJM199006283222607" target="_blank">Full Text</a>]
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<a id="Aubourg1982" class="mim-anchor"></a>
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[<a href="https://doi.org/10.1016/0002-9343(79)90562-x" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1002/ana.1220" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1056/NEJMoa2400442" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1093/hmg/ddn066" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1212/01.wnl.0000257129.51273.73" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1016/s0022-510x(98)00120-8" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1006/bbrc.1994.1805" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1210/jcem.81.2.8636252" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1111/j.1651-2227.1997.tb08918.x" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1212/wnl.27.10.928" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1073/pnas.78.8.5066" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1126/science.284.5422.1985" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1002/1531-8249(199901)45:1&lt;100::aid-art16&gt;3.0.co;2-u" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1002/(sici)1097-0223(199901)19:1&lt;46::aid-pd501&gt;3.0.co;2-e" target="_blank">Full Text</a>]
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Moser, H. W., Loes, D. J., Melhem, E. R., Raymond, G. V., Bezman, L., Cox, C. S., Lu, S. E.
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[<a href="https://doi.org/10.1055/s-2000-9236" target="_blank">Full Text</a>]
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Moser, H. W., Moser, A. B., Frayer, K. K., Chen, W., Schulman, J. D., O'Neill, B. P., Kishimoto, Y.
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[<a href="https://doi.org/10.1212/wnl.31.10.1241" target="_blank">Full Text</a>]
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Moser, H. W., Moser, A. B., Kawamura, N., Murphy, J., Suzuki, K., Schaumburg, H., Kishimoto, Y.
<strong>Adrenoleukodystrophy: elevated C26 fatty acid in cultured skin fibroblasts.</strong>
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[<a href="https://doi.org/10.1002/ana.410070607" target="_blank">Full Text</a>]
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Moser, H. W., Moser, A. B., Naidu, S., Bergin, A.
<strong>Clinical aspects of adrenoleukodystrophy and adrenomyeloneuropathy.</strong>
Dev. Neurosci. 13: 254-261, 1991.
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[<a href="https://doi.org/10.1159/000112170" target="_blank">Full Text</a>]
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Moser, H. W., Moser, A. E., Singh, I., O'Neill, B. P.
<strong>Adrenoleukodystrophy: survey of 303 cases: biochemistry, diagnosis, and therapy.</strong>
Ann. Neurol. 16: 628-641, 1984.
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[<a href="https://doi.org/10.1002/ana.410160603" target="_blank">Full Text</a>]
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Moser, H. W., Raymond, G. V., Dubey, P.
<strong>Adrenoleukodystrophy: new approaches to a neurodegenerative disease.</strong>
JAMA 294: 3131-3134, 2005.
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[<a href="https://doi.org/10.1001/jama.294.24.3131" target="_blank">Full Text</a>]
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Moser, H. W., Raymond, G. V., Lu, S.-E., Muenz, L. R., Moser, A. B., Xu, J., Jones, R. O., Loes, D. J., Melhem, E. R., Dubey, P., Bezman, L., Brereton, N. H., Odone, A.
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[<a href="https://doi.org/10.1001/archneur.62.7.1073" target="_blank">Full Text</a>]
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Moser, H. W., Smith, K. D., Moser, A. B.
<strong>X-linked adrenoleukodystrophy. In: Scriver, C. R.; Beaudet, A. L.; Sly, W. S.; Valle, D. (eds): The Metabolic and Molecular Bases of Inherited Disease.</strong>
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Moser, H. W., Tutschka, P. J., Brown, F. R., III, Moser, A. E., Yeager, A. M., Singh, I., Mark, S. A., Kumar, A. A. J., McDonnell, J. M., White, C. L., III, Maumenee, I. H., Green, W. R., Powers, J. M., Santos, G. W.
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[<a href="https://doi.org/10.1212/wnl.34.11.1410" target="_blank">Full Text</a>]
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Moser, H. W.
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Baltimore, Md. 1980.
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Moser, H. W.
<strong>Personal Communication.</strong>
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Moser, H. W.
<strong>Personal Communication.</strong>
Baltimore, Md. 6/29/1989.
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Moser, H. W.
<strong>Lorenzo's Oil. (Film Review).</strong>
Lancet 341: 544, 1993.
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[<a href="https://doi.org/10.1016/0140-6736(93)90295-r" target="_blank">Full Text</a>]
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Moser, H. W.
<strong>Adrenoleukodystrophy: phenotype, genetics, pathogenesis and therapy.</strong>
Brain 120: 1485-1508, 1997.
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[<a href="https://doi.org/10.1093/brain/120.8.1485" target="_blank">Full Text</a>]
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<p class="mim-text-font">
Mosser, J., Douar, A.-M., Sarde, C.-O., Kioschis, P., Feil, R., Moser, H., Poustka, A.-M., Mandel, J.-L., Aubourg, P.
<strong>Putative X-linked adrenoleukodystrophy gene shares unexpected homology with ABC transporters.</strong>
Nature 361: 726-730, 1993.
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Naidu, S., Bresnan, M. J., Griffin, D., O'Toole, S., Moser, H. W.
<strong>Childhood adrenoleukodystrophy: failure of intensive immunosuppression to arrest neurologic progression.</strong>
Arch. Neurol. 45: 846-848, 1988.
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[<a href="https://doi.org/10.1001/archneur.1988.00520320032011" target="_blank">Full Text</a>]
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<strong>Adrenoleukodystrophy carrier state presenting as a chronic nonprogressive spinal cord disorder.</strong>
Arch. Neurol. 44: 566-567, 1987.
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[<a href="https://doi.org/10.1001/archneur.1987.00520170092031" target="_blank">Full Text</a>]
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<strong>The adrenoleukomyeloneuropathy complex: expression in four generations.</strong>
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O'Neill, B. P., Moser, H. W., Marmion, L. C.
<strong>Adrenoleukodystrophy: elevated C26 fatty acid in cultured skin fibroblasts and correlation with disease expression in three generations of a kindred.</strong>
Neurology 32: 540-542, 1982.
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<strong>Familial X-linked Addison disease as an expression of adrenoleukodystrophy (ALD): elevated C26 fatty acid in cultured skin fibroblasts.</strong>
Neurology 32: 543-547, 1982.
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O'Neill, B. P., Swanson, J. W., Brown, F. R., III, Griffin, J. W., Moser, H. W.
<strong>Familial spastic paraparesis: an adrenoleukodystrophy phenotype?</strong>
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Oezen, I., Rossmanith, W., Forss-Petter, S., Kemp, S., Voigtlander, T., Moser-Thier, K., Wanders, R. J., Bittner, R. E., Berger, J.
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<strong>A variant of adrenomyeloneuropathy with hypothalamic-pituitary dysfunction and neurologic remission after glucocorticoid replacement therapy.</strong>
Am. J. Med. 72: 173-176, 1982.
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Peters, C., Charnas, L. R., Tan, Y., Ziegler, R. S., Shapiro, E. G., DeFor, T., Grewal, S. S., Orchard, P. J., Abel, S. L., Goldman, A. I., Ramsay, N. K. C., Dusenbery, K. E., Loes, D. J., Lockman, L. A., Kato, S., Aubourg, P. R., Moser, H. W., Krivit, W.
<strong>Cerebral X-linked adrenoleukodystrophy: the international hematopoietic cell transplantation experience from 1982 to 1999.</strong>
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Poulos, A., Gibson, R., Sharp, P., Beckman, K., Grattan-Smith, P.
<strong>Very long chain fatty acids in X-linked adrenoleukodystrophy brain after treatment with Lorenzo's oil.</strong>
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Powers, J. M., Schaumburg, H. H., Gaffney, C. L.
<strong>Kluver-Bucy syndrome caused by adreno-leukodystrophy.</strong>
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Powers, J. M., Schaumburg, H. H.
<strong>Adreno-leukodystrophy (sex-linked Schilder's disease): a pathogenic hypothesis based on ultrastructural lesions in adrenal cortex, peripheral nerve and testis.</strong>
Am. J. Path. 76: 481-500, 1974.
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Powers, J. M., Schaumburg, H. H.
<strong>A fatal cause of sexual inadequacy in men: adreno-leukodystrophy.</strong>
J. Urol. 124: 583-585, 1980.
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Powers, J. M., Schaumburg, H. H.
<strong>The testis in adreno-leukodystrophy.</strong>
Am. J. Path. 102: 90-98, 1981.
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Probst, A., Ulrich, J., Heitz, P. U., Herschkowitz, N.
<strong>Adrenomyeloneuropathy: a protracted, pseudosystematic variant of adrenoleukodystrophy.</strong>
Acta Neuropath. 49: 105-115, 1980.
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Pujol, A., Ferrer, I., Camps, C., Metzger, E., Hindelang, C., Callizot, N., Ruiz, M., Pampols, T., Giros, M., Mandel, J. L.
<strong>Functional overlap between ABCD1 (ALD) and ABCD2 (ALDR) transporters: a therapeutic target for X-adrenoleukodystrophy.</strong>
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Pujol, A., Hindelang, C., Callizot, N., Bartsch, U., Schachner, M., Mandel, J. L.
<strong>Late onset neurological phenotype of the X-ALD gene inactivation in mice: a mouse model for adrenomyeloneuropathy.</strong>
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Restuccia, D., Di Lazzaro, V., Valeriani, M., Oliviero, A., Le Pera, D., Barba, C., Cappa, M., Bertini, E., Di Capua, M., Tonali, P.
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Rizzo, W. B., Leshner, R. T., Odone, A., Dammann, A. L., Craft, D. A., Jensen, M. E., Jennings, S. S., Davis, S., Jaitly, R., Sgro, J. A.
<strong>Dietary erucic acid therapy for X-linked adrenoleukodystrophy.</strong>
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Ropers, H.-H., Burmeister, P., von Petrykowski, W., Schindera, F.
<strong>Leukodystrophy, skin hyperpigmentation, and adrenal atrophy: Siemerling-Creutzfeldt disease: transmission through several generations in two families.</strong>
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<strong>Adrenoleukodystrophy (Siemerling-Creutzfeldt disease): heterozygote with two clonal fibroblast populations.</strong>
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Rosen, N. L., Lechtenberg, R., Wisniewski, K., Pullarkat, R., Bennett, H. S.
<strong>Adrenoleukomyeloneuropathy with onset in early childhood.</strong>
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Ruiz, M., Coll, M. J., Pampols, T., Giros, M.
<strong>X-linked adrenoleukodystrophy: phenotype distribution and expression of ALDP in Spanish kindreds.</strong>
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[<a href="https://doi.org/10.1002/(sici)1096-8628(19980413)76:5&lt;424::aid-ajmg11&gt;3.0.co;2-o" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1073/pnas.90.20.9489" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1006/bbrc.1993.1310" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1056/NEJM199001043220103" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1006/geno.1994.1339" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1007/BF00292021" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1212/wnl.27.12.1114" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1001/archneur.1975.00490510033001" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1001/archneur.1972.00490170090014" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1016/S0140-6736(00)02629-5" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1016/s0140-6736(71)92776-0" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1023/a:1013992224811" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1001/archneur.56.3.295" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1016/s0022-3476(66)80085-9" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1093/hmg/9.18.2609" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1212/wnl.43.6.1249" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1212/wnl.44.12.2343" target="_blank">Full Text</a>]
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<div class="">
<p class="mim-text-font">
van Oost, B. A., van Zandvoort, P., Hoogeboom, A., Bakkeren, J., Hamel, B., Brunner, H., Knoers, N., Ropers, H. H.
<strong>Tight linkage between adrenoleukodystrophy and DXS 52. (Abstract)</strong>
Cytogenet. Cell Genet. 46: 708 only, 1987.
</p>
</div>
</li>
<li>
<a id="152" class="mim-anchor"></a>
<a id="van Oost1991" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
van Oost, B. A., van Zandvoort, P. M., Tunte, W., Brunner, H. G., Hoogeboom, A. J. M., Maaswinkel-Mooy, P. D., Bakkeren, J., Hamel, B., Ropers, H. H.
<strong>Linkage analysis in X-linked adrenoleukodystrophy and application in post- and prenatal diagnosis.</strong>
Hum. Genet. 86: 404-407, 1991.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1671851/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1671851</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1671851" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1007/BF00201845" target="_blank">Full Text</a>]
</p>
</div>
</li>
<li>
<a id="153" class="mim-anchor"></a>
<a id="Walsh1980" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Walsh, P. J.
<strong>Adrenoleukodystrophy: report of two cases with relapsing and remitting courses.</strong>
Arch. Neurol. 37: 448-450, 1980.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/6248004/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">6248004</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=6248004" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1001/archneur.1980.00500560078013" target="_blank">Full Text</a>]
</p>
</div>
</li>
<li>
<a id="154" class="mim-anchor"></a>
<a id="Wanders1987" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Wanders, R. J. A., van Roermund, C. W. T., van Wijland, M. J. A., Nijenhuis, A. A., Tromp, A., Schutgens, R. B. H., Brouwer-Kelder, E. M., Schram, A. W., Tager, J. M., van den Bosch, H., Schalkwijk, C.
<strong>X-linked adrenoleukodystrophy: defective peroxisomal oxidation of very long chain fatty acids but not of very long chain fatty acyl-CoA esters.</strong>
Clin. Chim. Acta 165: 321-329, 1987.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3652454/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3652454</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=3652454" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1016/0009-8981(87)90177-x" target="_blank">Full Text</a>]
</p>
</div>
</li>
<li>
<a id="155" class="mim-anchor"></a>
<a id="Wanders1987" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Wanders, R. J. A., van Roermund, C. W. T., van Wijland, M. J. A., Schutgens, R. B. H., Heikoop, J., van den Bosch, H., Schram, A. W., Tager, J. M.
<strong>Peroxisomal fatty acid beta-oxidation in relation to the accumulation of very long chain fatty acids in cultured skin fibroblasts from patients with Zellweger syndrome and other peroxisomal disorders.</strong>
J. Clin. Invest. 80: 1778-1783, 1987.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3680527/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3680527</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=3680527" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1172/JCI113271" target="_blank">Full Text</a>]
</p>
</div>
</li>
<li>
<a id="156" class="mim-anchor"></a>
<a id="Wanders1988" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Wanders, R. J. A., van Roermund, C. W. T., van Wijland, M. J. A., Schutgens, R. B. H., van den Bosch, H., Schram, A. W., Tager, J. M.
<strong>Direct demonstration that the deficient oxidation of very long chain fatty acids in X-linked adrenoleukodystrophy is due to an impaired ability of peroxisomes to activate very long chain fatty acids.</strong>
Biochem. Biophys. Res. Commun. 153: 618-624, 1988.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3382393/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3382393</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=3382393" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1016/s0006-291x(88)81140-9" target="_blank">Full Text</a>]
</p>
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<a id="157" class="mim-anchor"></a>
<a id="Watkiss1993" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Watkiss, E., Webb, T., Bundey, S.
<strong>Is skewed X inactivation responsible for symptoms in female carriers for adrenoleucodystrophy?</strong>
J. Med. Genet. 30: 651-654, 1993.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8411051/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8411051</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8411051" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1136/jmg.30.8.651" target="_blank">Full Text</a>]
</p>
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<a id="158" class="mim-anchor"></a>
<a id="Wilichowski1998" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Wilichowski, E., Ohlenbusch, A., Korenke, G. C., Hunneman, D. H., Hanefeld, F.
<strong>Identical mitochondrial DNA in monozygotic twins with discordant adrenoleukodystrophy phenotype. (Letter)</strong>
Ann. Neurol. 43: 835-836, 1998.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9629856/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9629856</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9629856" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1002/ana.410430621" target="_blank">Full Text</a>]
</p>
</div>
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<li>
<a id="159" class="mim-anchor"></a>
<a id="Willems1990" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Willems, P. J., Vits, L., Wanders, R. J. A., Coucke, P. J., Van der Auwera, B. J., Van Elsen, A. F., Raeymaekers, P., Van Broeckhoven, C., Schutgens, R. B. H., Dacremont, G., Leroy, J. G., Martin, J.-J., Dumon, J. E.
<strong>Linkage of DNA markers at Xq28 to adrenoleukodystrophy and adrenomyeloneuropathy present within the same family.</strong>
Arch. Neurol. 47: 665-669, 1990.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2161209/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2161209</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2161209" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1001/archneur.1990.00530060077022" target="_blank">Full Text</a>]
</p>
</div>
</li>
<li>
<a id="160" class="mim-anchor"></a>
<a id="Wray1976" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Wray, S. H., Cogan, D. G., Kuwabara, T., Schaumburg, H. H., Powers, J. M.
<strong>Adrenoleukodystrophy with disease of the eye and optic nerve.</strong>
Am. J. Ophthal. 82: 480-485, 1976.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/961799/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">961799</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=961799" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1016/0002-9394(76)90498-0" target="_blank">Full Text</a>]
</p>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
<span class="mim-text-font">
Ada Hamosh - updated : 10/21/2024
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<div class="row collapse" id="mimCollapseContributors">
<div class="col-lg-offset-2 col-md-offset-4 col-sm-offset-4 col-xs-offset-2 col-lg-6 col-md-6 col-sm-6 col-xs-6">
<span class="mim-text-font">
Hilary J. Vernon - updated : 09/13/2021<br>George E. Tiller - updated : 09/09/2013<br>George E. Tiller - updated : 8/15/2013<br>Cassandra L. Kniffin - updated : 1/25/2011<br>Cassandra L. Kniffin - updated : 10/20/2010<br>Cassandra L. Kniffin - updated : 1/21/2010<br>Ada Hamosh - updated : 1/5/2010<br>Cassandra L. Kniffin - updated : 12/8/2009<br>Cassandra L. Kniffin - updated : 3/24/2009<br>George E. Tiller - updated : 5/19/2008<br>Cassandra L. Kniffin - updated : 3/25/2008<br>Cassandra L. Kniffin - updated : 12/17/2007<br>George E. Tiller - updated : 5/21/2007<br>Cassandra L. Kniffin - updated : 7/17/2006<br>Victor A. McKusick - updated : 12/5/2005<br>Victor A. McKusick - updated : 10/20/2004<br>Victor A. McKusick - updated : 3/5/2004<br>Ada Hamosh - updated : 10/2/2003<br>Cassandra L. Kniffin - updated : 4/2/2003<br>Cassandra L. Kniffin - updated : 1/29/2003<br>Gerald V. Raymond - reorganized : 1/13/2003<br>Gerald V. Raymond - updated : 1/13/2003<br>Victor A. McKusick - updated : 1/4/2002<br>Victor A. McKusick - updated : 1/2/2002<br>Victor A. McKusick - updated : 12/27/2001<br>Victor A. McKusick - updated : 11/6/2001<br>Victor A. McKusick - updated : 7/24/2001<br>George E. Tiller - updated : 1/24/2001<br>Ada Hamosh - updated : 1/10/2001<br>Victor A. McKusick - updated : 4/19/2000<br>Orest Hurko - updated : 7/1/1999<br>Victor A. McKusick - updated : 6/18/1999<br>Victor A. McKusick - updated : 6/7/1999<br>Victor A. McKusick - updated : 6/4/1999<br>Orest Hurko - updated : 5/24/1999<br>Victor A. McKusick - updated : 4/21/1998<br>Victor A. McKusick - updated : 9/9/1997<br>Victor A. McKusick - updated : 8/15/1997<br>Victor A. McKusick - updated : 6/23/1997<br>John A. Phillips, III - updated : 4/29/1997<br>Victor A. McKusick - updated : 4/11/1997<br>Stylianos E. Antonarakis - updated : 7/5/1996<br>Moyra Smith - updated : 4/19/1996<br>Alan F. Scott - updated : 4/12/1996<br>Orest Hurko - updated : 9/21/1995
</span>
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<a id="creationDate" class="mim-anchor"></a>
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Creation Date:
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
<span class="mim-text-font">
Victor A. McKusick : 6/4/1986
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alopez : 10/21/2024
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carol : 09/12/2024<br>carol : 03/01/2024<br>carol : 01/17/2023<br>carol : 01/13/2023<br>carol : 09/13/2021<br>carol : 03/07/2018<br>alopez : 02/21/2017<br>alopez : 02/21/2017<br>carol : 09/09/2016<br>alopez : 09/09/2013<br>tpirozzi : 8/16/2013<br>tpirozzi : 8/15/2013<br>carol : 8/6/2013<br>terry : 3/14/2013<br>terry : 1/18/2012<br>wwang : 2/17/2011<br>ckniffin : 1/25/2011<br>wwang : 10/29/2010<br>ckniffin : 10/20/2010<br>terry : 10/13/2010<br>terry : 5/12/2010<br>wwang : 1/25/2010<br>ckniffin : 1/21/2010<br>carol : 1/5/2010<br>alopez : 1/5/2010<br>wwang : 1/4/2010<br>ckniffin : 12/8/2009<br>wwang : 3/31/2009<br>terry : 3/26/2009<br>ckniffin : 3/24/2009<br>wwang : 5/20/2008<br>terry : 5/19/2008<br>wwang : 4/2/2008<br>ckniffin : 3/25/2008<br>ckniffin : 3/25/2008<br>wwang : 1/7/2008<br>ckniffin : 12/17/2007<br>wwang : 6/1/2007<br>terry : 5/21/2007<br>carol : 7/19/2006<br>ckniffin : 7/17/2006<br>alopez : 12/7/2005<br>terry : 12/5/2005<br>carol : 9/28/2005<br>tkritzer : 10/21/2004<br>terry : 10/20/2004<br>tkritzer : 3/8/2004<br>terry : 3/5/2004<br>carol : 3/4/2004<br>cwells : 10/2/2003<br>carol : 6/16/2003<br>carol : 4/18/2003<br>tkritzer : 4/8/2003<br>tkritzer : 4/4/2003<br>ckniffin : 4/4/2003<br>ckniffin : 4/2/2003<br>ckniffin : 1/29/2003<br>carol : 1/15/2003<br>carol : 1/13/2003<br>carol : 1/13/2003<br>carol : 11/5/2002<br>carol : 1/16/2002<br>mcapotos : 1/4/2002<br>terry : 1/4/2002<br>terry : 1/2/2002<br>carol : 1/2/2002<br>terry : 12/27/2001<br>carol : 11/8/2001<br>mcapotos : 11/6/2001<br>mcapotos : 8/8/2001<br>mcapotos : 7/31/2001<br>terry : 7/24/2001<br>mcapotos : 1/25/2001<br>mcapotos : 1/24/2001<br>cwells : 1/18/2001<br>terry : 1/10/2001<br>mcapotos : 5/19/2000<br>mcapotos : 5/17/2000<br>terry : 4/19/2000<br>carol : 11/9/1999<br>mgross : 7/6/1999<br>mgross : 7/2/1999<br>kayiaros : 7/1/1999<br>jlewis : 6/24/1999<br>terry : 6/18/1999<br>mgross : 6/17/1999<br>terry : 6/7/1999<br>mgross : 6/4/1999<br>carol : 5/24/1999<br>alopez : 11/24/1998<br>carol : 6/25/1998<br>alopez : 5/21/1998<br>carol : 5/1/1998<br>terry : 4/21/1998<br>mark : 9/9/1997<br>mark : 9/9/1997<br>jenny : 8/19/1997<br>terry : 8/15/1997<br>mark : 7/8/1997<br>jenny : 6/23/1997<br>mark : 6/16/1997<br>jenny : 5/14/1997<br>jenny : 4/29/1997<br>mark : 4/11/1997<br>alopez : 4/2/1997<br>alopez : 4/2/1997<br>terry : 4/1/1997<br>carol : 7/5/1996<br>terry : 7/3/1996<br>carol : 5/22/1996<br>carol : 4/19/1996<br>mark : 4/12/1996<br>terry : 4/12/1996<br>terry : 4/11/1996<br>terry : 4/11/1996<br>mark : 4/10/1996<br>terry : 4/8/1996<br>mark : 3/28/1996<br>terry : 3/20/1996<br>mark : 2/16/1996<br>mark : 2/13/1996<br>mark : 2/7/1996<br>terry : 1/31/1996<br>terry : 11/6/1995<br>mark : 10/12/1995<br>jason : 7/18/1994<br>warfield : 4/20/1994<br>mimadm : 4/14/1994
</span>
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<h3>
<span class="mim-font">
<strong>#</strong> 300100
</span>
</h3>
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<h3>
<span class="mim-font">
ADRENOLEUKODYSTROPHY; ALD
</span>
</h3>
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<div >
<p>
<span class="mim-font">
<em>Alternative titles; symbols</em>
</span>
</p>
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<div>
<h4>
<span class="mim-font">
X-ALD<br />
ADDISON DISEASE AND CEREBRAL SCLEROSIS<br />
SIEMERLING-CREUTZFELDT DISEASE<br />
BRONZE SCHILDER DISEASE<br />
MELANODERMIC LEUKODYSTROPHY
</span>
</h4>
</div>
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<br />
</div>
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<p>
<span class="mim-font">
Other entities represented in this entry:
</span>
</p>
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<div>
<span class="h3 mim-font">
ADRENOMYELONEUROPATHY, INCLUDED; AMN, INCLUDED
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<br />
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<p>
<span class="mim-text-font">
<strong>SNOMEDCT:</strong> 1269423000, 65389002; &nbsp;
<strong>ICD10CM:</strong> E71.52, E71.522, E71.529; &nbsp;
<strong>ORPHA:</strong> 139396, 139399, 43; &nbsp;
<strong>DO:</strong> 10588; &nbsp;
</span>
</p>
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<h4>
<span class="mim-font">
<strong>Phenotype-Gene Relationships</strong>
</span>
</h4>
<div>
<table class="table table-bordered table-condensed small mim-table-padding">
<thead>
<tr class="active">
<th>
Location
</th>
<th>
Phenotype
</th>
<th>
Phenotype <br /> MIM number
</th>
<th>
Inheritance
</th>
<th>
Phenotype <br /> mapping key
</th>
<th>
Gene/Locus
</th>
<th>
Gene/Locus <br /> MIM number
</th>
</tr>
</thead>
<tbody>
<tr>
<td>
<span class="mim-font">
Xq28
</span>
</td>
<td>
<span class="mim-font">
Adrenomyeloneuropathy, adult
</span>
</td>
<td>
<span class="mim-font">
300100
</span>
</td>
<td>
<span class="mim-font">
X-linked recessive
</span>
</td>
<td>
<span class="mim-font">
3
</span>
</td>
<td>
<span class="mim-font">
ABCD1
</span>
</td>
<td>
<span class="mim-font">
300371
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
Xq28
</span>
</td>
<td>
<span class="mim-font">
Adrenoleukodystrophy
</span>
</td>
<td>
<span class="mim-font">
300100
</span>
</td>
<td>
<span class="mim-font">
X-linked recessive
</span>
</td>
<td>
<span class="mim-font">
3
</span>
</td>
<td>
<span class="mim-font">
ABCD1
</span>
</td>
<td>
<span class="mim-font">
300371
</span>
</td>
</tr>
</tbody>
</table>
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<h4>
<span class="mim-font">
<strong>TEXT</strong>
</span>
</h4>
<span class="mim-text-font">
<p>A number sign (#) is used with this entry because of evidence that adrenoleukodystrophy (ALD) and adrenomyeloneuropathy (AMN) are caused by mutation in the ABCD1 gene (300371) on chromosome Xq28.</p>
</span>
<div>
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<div>
<h4>
<span class="mim-font">
<strong>Description</strong>
</span>
</h4>
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<p>Adrenoleukodystrophy (ALD) is an X-linked disorder which is secondary to a mutation in the ABCD1 gene and results in the apparent defect in peroxisomal beta oxidation and the accumulation of the saturated very long chain fatty acids (VLCFA) in all tissues of the body. The manifestations of the disorder occur primarily in the adrenal cortex, the myelin of the central nervous system, and the Leydig cells of the testes.</p><p>ABCD1 is an ATPase binding cassette protein in the same category of transporter proteins such as the CFTR and MDR proteins.</p><p>Identification of X-ALD as a lipid-storage disease, as a defect in the capacity to degrade VLCFAs, and its characterization as a peroxisomal disorder was reviewed by Moser (1997). </p><p>Moser et al. (2005) provided a clinical review of ALD. </p>
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<strong>Clinical Features</strong>
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<p>Adrenoleukodystrophy can present at a variety of ages and with different manifestations depending on the presence and type of neurologic findings. Moser et al. (2000) stated that there are 7 phenotypes, which include the childhood cerebral form, adrenomyeloneuropathy (AMN), adult cerebral, adolescent, adrenal insufficiency without neurologic disease, asymptomatic, and heterozygotes. </p><p>The clinical presentation can vary within the same family. One male may have the childhood form of the disorder and his brother may have the adult form. It is apparent that neither the genetic mutation nor the level of biochemical abnormality predicts the phenotypic presentation.</p><p>Davis et al. (1979) observed a family with 4 cases of adrenoleukodystrophy and 1 of adrenomyeloneuropathy, suggesting the fundamental identity of the 2 disorders. The patient with adrenomyeloneuropathy was well until age 21 years when he developed spastic paraparesis. He subsequently fathered 2 daughters and a stillborn child. He was 41 years old at the time of study and showed no clinical manifestations of adrenal insufficiency. A brother of his developed paraparesis at age 13 and progressed to death at age 19. A nephew became ill at age 4 and died at age 7. Autopsy showed atrophic adrenals although no clinical signs of adrenal insufficiency were observed. </p><p>O'Neill et al. (1982) studied a kindred in which 14 members were affected with a variable combination of neurologic and adrenal manifestations. Abnormality was identified by increased content of C(26:0) fatty acid (hexacosanoic acid) in cultured skin fibroblasts and abnormal C26/C22 fatty acid ratios. The latter ratios were not proportional to severity of disease, duration, or character of the neurologic syndrome. In the family reported by O'Neill et al. (1980, 1982), clinically apparent Addison disease without neurologic involvement was the expression of adrenoleukodystrophy in males, and spastic paraplegia and sphincter disturbances occurred in female carriers. </p><p>Berg et al. (1989) described phenotypic features of a 362-member kindred spanning 6 generations. They observed clustering of phenotypes within individual sibships of the pedigree.</p><p>Willems et al. (1990) showed that patients with ALD and AMN in the same pedigree had identical haplotypes, demonstrating that they are not caused by different allelic mutations. </p><p>Holmberg et al. (1991) described a remarkable family in Sweden in which there was Addison disease in a 13-year-old boy, adrenomyeloneuropathy in a 58-year-old man, and spastic paraparesis and peripheral neuropathy in at least 3 heterozygous females, including the 85-year-old mother of the man with AMN. </p><p>Sobue et al. (1994) described considerable phenotypic heterogeneity between 2 proven monozygotic twins, both of whom had myeloneuropathy. Extensive demyelination in the brain was only prominent in the older twin, while adrenal insufficiency was prominent in the younger twin. They suggested that nongenetic factors were important determinants of the phenotypic variation of the adrenoleukodystrophy gene. Korenke et al. (1996) and Di Rocco et al. (2001) also reported pairs of identical male twins with different clinical expressions of ALD. Wilichowski et al. (1998) found no difference in mitochondrial DNA in the twins reported by Korenke et al. (1996). Di Rocco et al. (2001) stated that the discordant adrenoleukodystrophy phenotypes in 3 pairs of monozygotic twins indicated that modifier genes were not involved in determining the occurrence of CNS degeneration. They suggested that identifying environmental factors could be important for effectively preventing CNS degeneration in this disorder. </p><p>By neuropsychologic testing, Cox et al. (2006) found normal cognitive function in 48 of 52 neurologically asymptomatic boys with ALD (mean age, 6.7 years). All of the patients had normal brain MRI studies. However, there was a negative correlation between age and visual perception as well as age and visuomotor skills. Cox et al. (2006) concluded that a subset of patients with the childhood form of ALD have normal neurodevelopment despite an inherent defect in the ABCD1 gene. </p><p><strong><em>Childhood Cerebral Adrenoleukodystrophy</em></strong></p><p>
The classic presentation of childhood cerebral ALD has been analyzed in several large series (Schaumburg et al., 1975; Aubourg et al., 1982). This is the form of the illness that was originally described by Siemerling and Creutzfeldt (1923) and, until it was possible to make the biochemical diagnosis, it was the only form of the disease recognized as adrenoleukodystrophy. It is a rapidly progressive demyelinating condition affecting the cerebral white matter. It is by definition confined to boys who develop cerebral involvement before the age of 10 years. The boys are normal at birth and have unremarkable development. The mean age of onset is approximately 7 years. </p><p>The disease usually manifests itself early with behavioral manifestations including inattention, hyperactivity, and emotional lability. It often becomes apparent through school difficulties. It progresses into visual symptoms, auditory processing difficulties, and motor incoordination. Once the neurologic manifestations appear, progression of the illness is tragically rapid and the child is often in a vegetative state within 1 to 2 years.</p><p>Magnetic resonance imaging is often the first diagnostic study and shows a characteristic pattern of symmetric involvement of the posterior parietooccipital white matter in 85% of patients, frontal involvement in 10%, and an asymmetric pattern in the rest.</p><p><strong><em>Adult/Adrenomyeloneuropathy</em></strong></p><p>
Budka et al. (1976) reported a case they interpreted as an adult variant of adrenoleukodystrophy. At the time, a geneticist could raise the possibility of this form being the consequence of an allelic mutation, but phenotypic variability within families has subsequently been demonstrated. The neurologic picture was dominated by spastic paraplegia. Both clinically and pathologically, absence of diffuse cerebral involvement was noteworthy. The endocrinologic disorder was the particularly striking feature. </p><p>Griffin et al. (1977) and Schaumburg et al. (1977) described a variant that they called adrenomyeloneuropathy. Hypogonadism was present in all cases appropriately studied. Adrenal insufficiency began in childhood and progressive spastic paraparesis in the third decade. Neurologic features included peripheral neuropathy, impotence, and sphincter disturbances. </p><p>O'Neill et al. (1985) found biochemical characteristics of ALD in 2 brothers with spastic paraplegia of onset at age 40 and 50 years. Further study in the family revealed 2 nephews who were also affected as well as asymptomatic carriers in a typical X-linked pedigree pattern. None had symptoms of adrenal insufficiency. Cotrufo et al. (1987) reported the remarkable cases of an uncle and nephew who were completely asymptomatic at ages 25 and 10, respectively, but who showed levels of very long chain fatty acids in plasma consistent with the ALD hemizygote state. Both were found to have adrenocortical insufficiency as evidenced by compensatory high ACTH release. </p><p>Uyama et al. (1993) described a man who had presenile onset (at age 51 years) of the cerebral form of ALD. The first manifestation was difficulty in recalling where he had placed things. Shortly thereafter, he had problems operating farm machinery and gradually developed difficulty seeing clearly and writing at normal speeds. He could dress himself but often put garments on backward or inside out. He later developed Balint syndrome and dementia. (Balint syndrome is an acquired visuospatial disorder characterized by psychic paralysis of visual fixation, optic ataxia, and disturbance of visual attention with relatively intact vision (Hecaen and De Ajuriaguerra, 1954).) MRI demonstrated demyelinating lesions in the bilateral posterior parietooccipital white matter involving the splenium of the corpus callosum. The patient could not move his eyes on command or follow a moving object. He had difficulty in maintaining central fixation. Optic ataxia was also shown by frequent errors when he attempted to grasp an object at which he was looking. The patient was bedridden by age 54 and died at age 55. Tests of adrenal function yielded normal results. Ratios of C26:0 to C22:0 in plasma and in erythrocyte membranes established the diagnosis of ALD in the proband and demonstrated that his mother was a heterozygote. </p><p>Van Geel et al. (2001) studied the evolution of the disease in adults. They studied 129 men retrospectively, with a mean follow-up period of 10.1 +/- 5.0 years. Among 32 neurologically asymptomatic patients, 16 (50%) developed some neurologic involvement. Among 68 men with AMN without cerebral involvement, 13 (19%) developed clinically apparent cerebral demyelination. There was a high risk for adult neurologically asymptomatic patients to develop neurologic deficits and for AMN patients to develop cerebral demyelination. This had implications for the phenotype classification, search for modifying factors, and the development and evaluation of new therapies. </p><p>Eichler et al. (2007) reviewed serial brain MRI scans of 56 adult patients with ALD and white matter abnormalities. Forty-two (75%) of these patients had corticospinal tract involvement, and 21 (50%) of the 42 showed lesion progression over a 3 to 5-year period. Disease progression was slower in adults compared to that previously observed in affected children. Only 3 adult patients showed isolated lesions in the genu or the splenium, all of which developed in childhood or adolescence. The findings suggested that progressive inflammatory demyelination can occur along with the known axonopathy of adulthood. Eichler et al. (2007) suggested that the vulnerability of specific fiber tracts in ALD changes with age. </p><p><strong><em>Adrenal Insufficiency</em></strong></p><p>
Addison disease in young males should prompt consideration of ALD as the underlying abnormality. See also Sadeghi-Nejad and Senior (1990). Laureti et al. (1996) performed biochemical analysis of very long chain fatty acids in 14 male patients (age ranging from 12-45 years at diagnosis) previously diagnosed as having primary idiopathic adrenocortical insufficiency. In 5 of the 14 patients, elevated levels of very long chain fatty acids (VLCFA) were found in plasma; none had adrenocortical antibodies. By electrophysiologic tests and magnetic resonance imaging, it was determined that 2 had cerebral ALD, 1 had adrenomyeloneuropathy with cerebral involvement, and 2 had preclinical AMN. </p><p>Since the adrenal insufficiency may long precede neurologic manifestations and perhaps may occur alone, caution must be exercised in the interpretation of isolated X-linked Addison disease as a separate entity. Of course, autopsy-confirmed adrenal hypoplasia (300200) is a well-established entity.</p><p>The achalasia-Addisonian syndrome (231550), which appears to be autosomal recessive, is another example of combined adrenal and neurologic (autonomic) involvement.</p><p>The postperfusion syndrome is an uncommon event following open-heart surgery with extracorporeal circulation. It is associated with a young age at surgery (less than 1 year) and bypass lasting longer than 60 minutes. Luciani et al. (1997) observed the syndrome in an 18-year-old man who underwent transpulmonary patch repair of a ventricular septal defect with cardiopulmonary bypass for 50 minutes. Preoperatively, the patient exhibited a slight gait disorder and unremarkable EEG and laboratory findings. Twelve hours after surgery he developed hypotension and circulatory collapse. This was treated successfully, but 10 days after discharge the patient was admitted with findings suggesting Addison disease. He showed a worsening disturbance of gait, with ataxia and EEG abnormalities. The diagnosis of adrenoleukodystrophy was supported by MRI of the head and confirmed by increased plasma levels of very long chain saturated fatty acids. Thus, Luciani et al. (1997) concluded that this was a case of Addisonian crisis precipitated by surgery in a patient with previously unrecognized ALD. </p><p><strong><em>Heterozygote</em></strong></p><p>
Women who are carriers for the condition may develop spastic paraparesis with bowel and bladder difficulties. This appears to be partially a function of age.</p><p>Heffungs et al. (1980) observed cerebral sclerosis and Addison disease in a previously healthy 14-year-old sister of an affected boy. They suggested that this was the first documented example of adrenoleukodystrophy in a heterozygote. Several other unusual examples have been published. </p><p>Also see O'Neill et al. (1982). The patient reported by Noetzel et al. (1987) illustrates further the occurrence of a chronic nonprogressive spinal cord syndrome in women heterozygous for ALD. </p><p>Hershkovitz et al. (2002) reported an 8.5-year-old girl who presented with declining school performance and diffuse frontal white matter demyelination. She was known to be at risk for heterozygosity because 2 maternal uncles had ALD. Levels of very long chain fatty acids were elevated. DNA analysis of the patient and her mother showed a cytosine insertion in codon 515 (515insC) of the ABCD1 gene, resulting in a frameshift after amino acid 171 (tyrosine). Immunocytochemical studies showed that ALDP reactivity was lacking in 99% of the fibroblasts analyzed. Cytogenetic analysis showed a deletion at Xq27.2-qter. Both parents were normal. She underwent bone marrow transplantation from a normal sister and at 18 months was stable. Hershkovitz et al. (2002) recommended that cytogenetic studies be performed in the 1% of heterozygotes who show evidence of cerebral involvement. </p><p>Jung et al. (2007) reported 2 unrelated women with heterozygous mutations in the ABCD1 gene. The first patient was diagnosed at age 8 years with manic-hebephrenic disorder and subsequent psychotic episodes. She had spastic paraparesis at age 25 and developed cognitive deficits, cerebellar signs, and more severe spastic paraparesis at age 45. She died of pneumonia at age 52. Her brother had Addison disease at age 47, and later developed spastic paraparesis and polyneuropathy. The second patient developed inability to run at age 35 years, 1 year after her son died of ALD. She was wheelchair-bound by age 48. Later features included bilateral visual loss and mild polyneuropathy. She was cognitively intact. </p><p><strong><em>Other--Spinocerebellar</em></strong></p><p>
Kobayashi et al. (1986) described 2 adult male first cousins with spinocerebellar degeneration manifested by progressive limb and truncal ataxia, slurred speech, and spasticity of the limbs. Brain CT scans showed atrophy of the pons and cerebellum. Very long chain fatty acids were elevated in the plasma and red cell membranes of the affected patients and were increased to intermediate levels in the female carriers. </p>
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<strong>Biochemical Features</strong>
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<p>An important observation was that of Igarashi et al. (1976). They found that cholesterol esters in the brain and adrenals of these patients had an unusually high proportion of fatty acids with a chain length of 24-30 carbon atoms, rather than the usual length of less than 20. This might interfere with myelin formation in the CNS and steroidogenesis in the adrenal. </p><p>Biochemical studies of cerebral white matter showed increased amounts of long chain saturated fatty acids in cholesterol esters.</p><p>ALD is characterized by the accumulation of unbranched saturated fatty acids with a chain length of 24 to 30 carbons, particularly hexacosanoate (C26), in the cholesterol esters of brain white matter and in adrenal cortex and in certain sphingolipids of brain. Accumulation also occurs in plasma-cultured skin fibroblasts and this fact can be used for diagnosis (including prenatal diagnosis) and for the study of the disease's basic mechanisms (Moser et al., 1980). </p><p>It appears that the defect is in the catabolism of the very long chain fatty acids (see 603314) themselves. A parallel to Refsum disease (266500) in which a fatty acid of dietary origin accumulates because of deficiency of an enzyme for its catabolism is suggested by the finding that the accumulating long chain fatty acids are, at least in part, of exogenous origin (Moser, 1980). This finding and analogy suggest that dietary modification may be beneficial in ALD.</p><p>Moser et al. (1981) investigated a possible defect in a peroxisomal beta-oxidation system. </p><p>The work of Hashmi et al. (1986) and of Singh et al. (1988) suggested that the basic defect in X-linked ALD is deficient activity of lignoceroyl-CoA ligase. Singh et al. (1988) and Lazo et al. (1988) presented data demonstrating that the accumulation of very long chain fatty acids in ALD is the result of deficient peroxisomal lignoceroyl-CoA ligase activity. It had previously been thought that the same ligase was responsible for the activation of C16:0 (palmitic acid) and C24:0 (lignoceric acid). Later data indicated that they are separate enzymes. Wanders et al. (1987, 1988) had interpreted their results as indicating that the basic defect in X-linked ALD resides in peroxisomal very long chain fatty acyl-CoA synthetase. This enzyme is present not only in peroxisomes but also in microsomes. </p><p>The identification of the genetic defect and protein abnormality in ALD has resulted, however, in different conclusions. The defect is not in an enzyme, but in a protein, ABCD1, that has a role in peroxisomal beta-oxidation. It has been suggested that the protein has a role in transport.</p><p>Beta-oxidation of fatty acids occurs through a carnitine-dependent pathway in the mitochondria and a carnitine-independent pathway in the peroxisomes. In cell cultures and mouse tissue, McGuinness et al. (2003) showed that the ALDP protein transporter may facilitate an interaction between peroxisomes and mitochondria, which is disturbed in X-linked ALD. </p><p>Stradomska and Tylki-Szymanska (2001) described the results of measuring serum very long chain fatty acid concentrations in 59 females of various ages with heightened risk of carrier status for ALD. In female carriers aged 22 to 50 years, they found serum VLCFA concentrations in a range characteristic of heterozygotes; VLCFA levels were normal in female carriers aged 55 to 64 years. In women aged 37 to 50 years in whom repeat studies of VLCFA concentrations were performed after 5 years, a reduction in VLCFA was observed. Stradomska and Tylki-Szymanska (2001) suggested that the results point to a reduction of serum VLCFA concentrations as X-ALD heterozygotes age. </p>
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<strong>Inheritance</strong>
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<p>Fanconi et al. (1963) suggested X-linked recessive inheritance of a syndrome of Addison disease and cerebral sclerosis. All cases had been male, and in many instances a brother and/or a maternal uncle of the proband has been similarly affected. </p><p>Using content of C26 fatty acids in cultured fibroblasts, Migeon et al. (1981) demonstrated two types of clones in heterozygotes, thus corroborating X-linkage and demonstrating lyonization of the ALD locus. The presence of more mutant than wildtype clones in cultures from most heterozygotes suggested a proliferative advantage of the mutant cells. This advantage appears to exist in vivo also because most heterozygotes showed increased levels of fatty acids in plasma and, in 1 family, women heterozygous for both ALD and G6PD showed an excess of G6PD blood cells of the A (rather than B) type, which was in coupling with the mutant gene. (In Lesch-Nyhan syndrome (308000), it is the wildtype red cell precursors that enjoy a selective advantage so that in heterozygotes the levels of HPRT in red cells are normal.) </p><p>Using the probe M27-beta, Watkiss et al. (1993) found no evidence for skewed X-inactivation in 12 female carriers of ALD. The probe M27-beta detects locus DXS225, which contains a highly polymorphic VNTR sequence. In addition, the locus contains MspI sites that are methylated on the active X chromosome but unmethylated on the inactive X chromosome. Because such sites are vulnerable to digestion by the isoschizomer HpaII only when they are unmethylated, i.e., when they lie on the inactive X chromosome, M27-beta can be used to differentiate between the active and inactive X chromosomes. In the 5 families, they observed 3 manifesting heterozygotes who had presented to a neurologist independently of the illness in affected males in the family. Only 1 of the 3 manifesting carriers showed skewing, but 2 of 9 nonmanifesting carriers did also. </p><p>Maestri and Beaty (1992) examined the implications of a 2-locus model to explain heterogeneity in ALD, i.e., the occurrence of severe childhood form (ALD) and the milder adult-onset form (AMN) in the same family, or even the same sibship. They considered 2 models. Under a dominant epistatic model, a single M allele at an autosomal modifier locus ameliorates the most severe effects of the disease allele, thus leading to the milder AMN phenotype; only males with genotype mm would have ALD. Under a recessive epistatic model, 2 copies of the M allele would be necessary to have the milder AMN phenotype. Maestri and Beaty (1992) showed that the recurrence risk for a second affected male depended on the frequency of the protective allele at this modifier locus. They suggested sampling discordant affected sib pairs as a strategy for detecting linkage between a polymorphic DNA marker and a possible modifier gene. </p>
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<strong>Mapping</strong>
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<p>Close linkage of ALD and G6PD was indicated by the absence of recombination in 18 opportunities. This means that the ALD locus is in the terminal segment of the long arm of the X, i.e., Xq28. That the locus is not closely linked to Xg had been shown by Spira et al. (1971). Close linkage to DXS52 (maximum lod score = 4.17 at theta = 0.0) was found by van Oost et al. (1987). </p><p>Close linkage of ALD to the cluster of colorblindness genes is indicated by the increased frequency of colorblindness in affected males and by the demonstration of deletion of cone pigment genes with the use of DNA probes (Aubourg et al., 1988). Aubourg et al. (1988) studied the red and green visual pigment genes in 8 kindreds with ALD and demonstrated frequent structural changes, including deletions and intragenic recombinations. Sack et al. (1989) found increased frequency of abnormal color vision in men with adrenomyeloneuropathy and pointed to these findings as supporting very close linkage of the ALD and the colorblindness loci, thus giving the opportunity for contiguous gene defects. Aubourg et al. (1990) reported studies on a large number of patients with ALD. No deletions were found with probes that lie 3-prime of the green pigment genes. One of the 8 previously reported ALD patients had a long deletion 5-prime of the red pigment gene, a deletion causing blue cone monochromacy. This finding and the previous finding of a 45% frequency of phenotypic color vision defects in patients with AMN suggested to Aubourg et al. (1990) that the ALD/AMN gene may lie 5-prime to the red pigment gene and that the frequent phenotypic color vision anomalies owe their origin to deleted DNA that includes regulatory genes for color vision. In studies of an ALD patient who also had blue cone monochromacy, Feil et al. (1991) characterized a complex chromosomal rearrangement in band Xq28. Two CpG islands were mapped, at 46 and 115 kb upstream from the visual pigment genes, one or the other of which might mark the location of the ALD gene. Sack et al. (1993) gave a molecular analysis of the chromosomal rearrangement in kindred 'O' reported by Aubourg et al. (1988). Alpern et al. (1993) characterized the physiologic defect in color vision. The DNA in a hemizygous male showed altered restriction fragment sizes compatible with a deletion extending from the 5-prime end of the color pigment gene cluster. The DNA change had removed the red pigment gene and juxtaposed a 15-kb DNA sequence to the remaining pigment gene. Sack et al. (1993) demonstrated linkage with the ALD gene, located centromeric to the color pigment gene cluster; maximum lod = 3.19 at theta = 0.0. On physiologic testing, Alpern et al. (1993) found color matching they interpreted as indicating the presence of an abnormal rudimentary visual pigment. They suggested that this may reflect the presence of a recombinant visual pigment protein or altered regulation of residual pigment genes due to the DNA change: deletion of the long-wave pigment gene and reorganized sequences 5-prime to the pigment gene cluster. </p><p>In several large families with ALD, van Oost et al. (1991) extended the linkage of ALD to DXS52 and arrived at a maximal lod score of 22.5 at 1 cM. They also found tight linkage of ALD to F8C and showed that both ALD and F8C are distal to DXS52. No major structural rearrangement in Xqter was observed; in particular, there were no abnormalities in the color vision genes. The occurrence of several cases in which both ALD and Emery-Dreifuss muscular dystrophy (310300) were thought to be present suggested that these loci are closely situated (Moser, 1987); however, the diagnosis of ALD was not confirmed in these patients, and in testing of additional patients with EMD, none was found to have ALD (Moser, 1989). Using probe St14 (DXS52), Boue et al. (1985) and Aubourg et al. (1987) found a total lod score in their combined families of 13.766 at theta = 0. In an analysis of 59 ALD kindreds, Sack and Morrell (1993) found normal hybridization using a probe situated 30 kb centromeric to the color pigment genes. However, using a probe located 100 kb further centromeric, they found 2 overlapping deletions in 2 patients. Additional study indicated that the telomeric ends of the 2 deletions were 8 kb apart. Thus, the location of the ALD gene appeared to have been defined as approximately 150 kb centromeric of the color pigment genes. </p><p>Mosser et al. (1993) identified the ALD gene by positional cloning. Sarde et al. (1994) determined that the ALD gene is 720 kb proximal to the R/GCP genes and other genes lie between the two. Thus the occurrence of color vision abnormalities in ALD is not secondary to localization. </p>
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<strong>Pathogenesis</strong>
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<p>Hoefnagel et al. (1962) described the histologic findings in endocrine glands, especially the pituitary and adrenal. </p><p>Ropers et al. (1977) described typical morphologic changes in cultured fibroblasts on light microscopy. The changes, seen only 4 or 5 days after subculture, consisted of expansion of the cells, which appeared abnormally large. Lyonization was demonstrated in cultured fibroblasts of the mother. </p><p>Ho et al. (1995) predicted that disruptive effects of the accumulation of very long chain saturated fatty acids on cell membrane structure and function may explain the neurologic manifestations of ALD patients. Especially the 26-carbon acid, hexacosanoic acid, is involved. They studied the interaction of radiolabelled hexacosanoic acid with model membranes and bovine serum albumin by NMR spectroscopy to compare properties of the hexacosanoic acid with those of typical dietary fatty acids. Desorption of hexacosanoic acid from membranes was orders of magnitude slower than that of shorter-chain fatty acids and binding to serum albumin was ineffective. </p><p>Federico et al. (1988) added to the evidence for autoimmune factors in the pathogenesis of ALD by the description of a 53-year-old man with CNS white matter demyelination and evidence of a multisystem immunologic disorder including autoimmune thyroiditis, antigastric mucosa antibodies, and antismooth muscle antibodies. The cerebrospinal fluid showed a marked increase in IgG index and several oligoclonal bands with an alkaline isoelectric point. </p><p>In a review of brain autopsy material from 9 cases of ALD, Eichler et al. (2008) observed marked demyelinative lesions in the white matter with sparing of the subcortical white matter. One additional case of pure adrenomyeloneuropathy did not show white matter demyelination. The lesion edges were regions of active demyelination with macrophages containing granules consisting of lipid inclusions consistent with myelin debris. Dense perivascular aggregates of macrophages and lymphocytes were closer to the lesion, but macrophages were less prominent within the cores of lesions. These findings suggested that macrophages played a phagocytic role but not a role in active myelin destruction. Further studies showed that white matter areas beyond the actively demyelinating edge were essentially devoid of microglia due to apoptosis, whereas microglia density was normal in remote normal brain tissue. Injection of lysophosphatidylcholine in mouse brains induced microglial apoptosis. Eichler et al. (2008) concluded that microglial apoptosis resulting from accumulation of very-long chain fatty acids may be an early change in the pathogenesis of ALD that occurs before demyelination, and that the loss of microglia prevents them from protecting oligodendrocytes and axons. </p><p>Hein et al. (2008) found that rat oligodendrocytes and astrocytes exposed to VLCFA in culture died within 24 hours, with the greatest effect on myelin-producing oligodendrocytes. VLCFA caused increased intracellular calcium in oligodendrocytes, astrocytes, and neurons. VLCFA also induced depolarization of mitochondria and promoted permeability of the inner mitochondrial membrane. Hein et al. (2008) concluded that VLCFAs are potently cytotoxic due to mitochondrial dysfunction and calcium deregulation. </p><p>Fourcade et al. (2008) found that XLD fibroblasts showed decreased mitochondrial potential and increased sensitivity to oxidative stress. In vitro, the alpha-tocopherol analog Trolox was able to reverse these oxidative defects, as measured by decreased levels of lipoxidative protein damage. </p>
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<strong>Diagnosis</strong>
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<p>Moser et al. (1981) developed a plasma method for the detection of very long chain fatty acids providing for the diagnosis of affected individuals and assisting in carrier identification. Moser et al. (1999) reported the results of testing with this assay, the most widely used procedure for the diagnosis of X-linked ALD and other peroxisomal disorders, in 3,000 patients and 29,000 controls. VLCFA levels are elevated at birth, and the assay is highly accurate in hemizygotes. Eighty-five percent of obligate heterozygotes will have an elevated level, but a normal result did not exclude carrier status. A variety of other peroxisomal disorders, including Zellweger syndrome and other single enzyme defects in peroxisomal beta oxidation, also share an elevation of VLCFA levels, but can readily be discerned from ALD by the clinical situation. </p><p>Moser and Moser (1999) provided an authoritative discussion of the prenatal diagnosis of X-linked ALD. They concluded that measurement of VLCFA levels in cultured amniocytes and chorionic villus cells (the most frequently used procedure) is reliable provided that care is taken to minimize the risk of false-negative results by performance of subcultures in appropriate media. The procedure can be complemented by assays of VLCFA oxidation, and under certain circumstances, immunocytochemical assays for the expression of ALDP. Mutation analysis is the most reliable diagnostic procedure when the nature of the mutation in the at-risk family is known. </p><p>Inoue et al. (1996) found abnormal lignoceric acid oxidation in 19 of 19 ALD patients and in 3 of 3 obligate heterozygous carrier women. Among 10 women at risk of being a carrier, 3 with normal levels of VLCFA had abnormal lignoceric acid oxidation. Inoue et al. (1996) suggested that this combined biochemical procedure could improve the accuracy of carrier detection in ALD. </p><p>Various techniques have been developed to identify ALD carriers more accurately. Boehm et al. (1999) developed and validated a robust DNA diagnostic test involving nonnested genomic amplification of the ALD gene, followed by fluorescent dye-primer sequencing and analysis. </p><p>Lachtermacher et al. (2000) noted that a very small percentage (0.1%) of affected males had plasma C26:0 levels that are borderline normal, and 15% of obligate female carriers have normal results. Effective mutation detection in these families is therefore fundamental to unambiguous determination of genetic status. Of particular concern are female members of kindreds segregating X-ALD mutations, because normal VLCFA levels do not guarantee lack of carrier status. Lachtermacher et al. (2000) described a fast method for detection of X-ALD mutations. The method was based on SSCP analysis of nested PCR fragments followed by sequence-determination reactions. Using this method, they found X-ALD mutations in 30 kindreds, including 15 not previously reported. </p><p>Using records from the Kennedy Krieger Institute between 1981 and 1998 and the Mayo Clinic Rochester from 1996 to 1998, Bezman et al. (2001) estimated that the minimum frequency of X-linked ALD hemizygotes in the US is 1:42,000, and that of hemizygotes plus heterozygotes is 1:16,800. Five percent of male probands were estimated to have new mutations. Extended family testing identified asymptomatic hemizygotes, who could benefit from therapy, and heterozygotes, who could benefit from genetic counseling. </p>
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<strong>Clinical Management</strong>
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<span class="mim-text-font">
<p>Kolodny (1987) concluded that asymptomatic individuals with the adrenomyeloneuropathy gene, as well as patients with this disorder and heterozygotes, may benefit from a combined oleic acid, VLCFA-restricted diet. </p><p>Moser (1993) reviewed the film 'Lorenzo's Oil,' a fictionalized account of a family's search for a treatment of ALD, afflicting, in this case, a boy named Lorenzo Odone. Moser (1993) concluded that it overstated the success that can be achieved with the oil, invented conflicts between the parents and the medical establishment, and presented an inaccurate and malicious portrayal of the United Leukodystrophy Foundation. 'Dr. Nicolai,' played in the film by Peter Ustinov, copied Moser's 'appearance and speech with remarkable accuracy.' In an open trial in 14 men with adrenomyeloneuropathy, 5 symptomatic heterozygous women, and 5 boys (mean age, 13 years) with preclinical adrenomyeloneuropathy, Aubourg et al. (1993) could find no evidence of a clinically relevant benefit from dietary treatment with oleic and erucic acids (glyceryl trierucate and trioleate oil; 'Lorenzo's oil'). Asymptomatic thrombocytopenia was noted in 6 patients. Poulos et al. (1994) examined the fatty acid composition of postmortem brain and liver from an adrenoleukodystrophy patient who had received Lorenzo's oil for 9 months. There was improvement in the fatty acid composition of the plasma and liver but not in the brain. This indicated that very little erucic acid crossed the blood-brain barrier. These findings suggested to the authors that dietary supplementation with Lorenzo's oil is of limited value in correcting the accumulation of saturated very long chain fatty acids in the brain of patients with adrenoleukodystrophy. </p><p>Treatment with Lorenzo's oil normalizes the level of VLCFA in plasma within 4 weeks. In spite of this promising biochemical effect, clinical results have been disappointing when the oils were fed to symptomatic patients (Aubourg et al., 1993). Moser et al. (1994) reported a positive result in patients in whom therapy was begun before neurologic symptoms were present, suggesting that fatty acid abnormality is of pathogenic significance. However, a 3-year follow-up with somatosensory-evoked potentials and motor-evoked potentials of 8 patients by Restuccia et al. (1999) showed no evidence of any benefit of dietary treatment, even when initiated early in the disease before the appearance of inflammatory lesions. </p><p>Moser et al. (2005) identified asymptomatic boys with X-linked adrenoleukodystrophy who had a normal MRI and assessed the effect of Lorenzo's oil (4:1 glyceryl trioleate-glyceryl trierucate) on disease progression. By a plasma very long chain fatty acids assay used to screen at-risk boys, 89 affected boys were identified, and all were treated with Lorenzo's oil and moderate fat restriction. Plasma fatty acids and clinical status were followed for 6.9 +/- 2.7 years. Of the 89 boys, 24% developed MRI abnormalities and 11% developed neurologic and MRI abnormalities. Moser et al. (2005) concluded that reduction of hexacosanoic acid by Lorenzo's oil was associated with reduced risk of developing MRI abnormalities. They recommended therapy with Lorenzo's oil in asymptomatic boys with X-linked adrenoleukodystrophy who had normal brain MRI results. Their experience with other ALD patients and that of Rizzo et al. (1989) indicated that total fat intake in excess of 30 to 35% of total calories may counteract or nullify the C26:0-reducing effect of Lorenzo's oil. Those patients who developed progressive MRI abnormalities should be considered for hematopoietic stem cell transplantation (HSCT) as recommended by Peters et al. (2004). Adrenal function must be monitored since 80% asymptomatic patients with ALD develop evidence of adrenal insufficiency (Dubey et al., 2005) and adrenal hormone replacement therapy should be provided when indicated by laboratory findings. Thus, a 3-prong therapeutic approach is recommended. </p><p>Aubourg et al. (1990) achieved reversal of early neurologic and neuroradiologic features in an 8-year-old boy who received bone marrow transplantation (BMT) from his fraternal twin brother. Malm et al. (1997) described experience with bone marrow transplantation in 3 children with ALD. They concluded that BMT must be considered very early, even in a child without symptoms but with signs of demyelination on MRI, if a suitable donor is available. </p><p>Shapiro et al. (2000) discussed the experience of BMT in 12 patients over an extended period of time and came to the conclusion that it did result in improved outcome if performed early in the course of symptomatic disease. </p><p>Kruse et al. (1994) systematically studied 25 patients with adrenoleukodystrophy. Using multislice proton magnetic resonance spectroscopy, they demonstrated a reduction in N-acetyl aspartate, an increase in choline, and occasionally an increase in lactate. They concluded that magnetic resonance spectroscopic imaging is a more sensitive indicator of early neurologic involvement than is magnetic resonance imaging and therefore a more useful gauge of demyelination by which therapeutic approaches could be judged. </p><p>Because of the circumstantial evidence that immunologic factors contribute to the pathogenesis of the CNS lesions in ALD, Naidu et al. (1988) administered cyclophosphamide for 5 to 11 days to 4 patients with childhood ALD and to 1 patient with the adult cerebral form. The rate of neurologic progression in the 4 patients with childhood disease did not differ from that in 167 untreated patients with childhood disease surveyed previously. </p><p>Cappa et al. (1994) gave intravenous high-dose immunoglobulins to 6 patients with adrenoleukodystrophy who were already on a restricted very long chain fatty acid diet supplemented with glycerol trioleate/erucic acid. The MRI and symptoms deteriorated in this group at the same rate as they did in 6 control patients on the same restricted/supplemented diet who did not receive immunoglobulins. </p><p>El-Deiry et al. (1997) studied the prevalence of adrenal dysfunction in 71 females who were obligate carriers of the X-linked trait by pedigree analysis and whose plasma very long chain fatty acid levels were consistent with a heterozygote status. The authors concluded that, in ALD heterozygotes, adrenal cortical insufficiency rarely develops, although isolated mineralocorticoid insufficiency may occur in these individuals. Furthermore, they inferred that ALD heterozygotes may be predisposed to hypoaldosteronism related to the use of nonsteroidal antiinflammatory agents. A subclinical decrease in glucocorticoid reserve, as measured by synthetic ovine corticotropin releasing hormone testing, may be present in a majority of these women. The authors suggested that aldosterone levels be included in ACTH stimulation testing done to detect adrenal insufficiency in affected women. Nonsteroidal antiinflammatory agents should be considered a risk factor for the development of hypoaldosteronism in women heterozygous for ALD. </p><p>Peters et al. (2004) reviewed results in 126 boys with X-ALD who received hematopoietic cell transplantation from 1982 to 1999. Complete data were available and analyzed for 94 boys with cerebral X-ALD. The estimated 5- and 8-year survival was 56%. The leading cause of death was disease progression. Donor-derived engraftment occurred in 86% of patients. Demyelination involved parietal-occipital lobes in 90%, leading to visual and auditory processing deficits in many boys. Peters et al. (2004) concluded that boys with early-stage disease benefit from hematopoietic cell transplantation, whereas boys with advanced disease may be candidates for experimental therapies. </p><p>Schonberger et al. (2007) reported a boy with childhood ALD who underwent hematopoietic stem cell transplantation but died from transplant-related complications 76 days later. Postmortem examination showed mixed chimerism of the mutant and wildtype alleles in 23 tissue samples examined, including 12 CNS samples. Normal ALD protein was localized to peroxisomes within multiple cell types, including neurons. Schonberger et al. (2007) noted that detection of ALD protein so soon after transplant may indicate that healthy donor cells assisted affected recipient cells in metabolic function. Peripheral blood samples from an affected male cousin who had successful HSCT showed the wildtype ALD allele exclusively. There was no clinical disease progression after transplant. The findings in both patients indicated that HSCT can result in restoration and widespread presence of intact donor ALD protein in various recipient tissues. </p><p>Cartier et al. (2009) initiated a gene therapy trial in 2 ALD patients for whom there were no matched donors for hematopoietic stem cell transplantation. Autologous CD34(+) cells were removed from the patients, genetically corrected ex vivo with a lentiviral vector encoding wildtype ABCD1, and then reinfused into the patients after they had received myeloablative treatment. Over a span of 24 to 30 months of follow-up, Cartier et al. (2009) detected polyclonal reconstitution, with 9 to 14% of granulocytes, monocytes, and T and B lymphocytes expressing the ALD protein. Cartier et al. (2009) concluded that their results strongly suggested that hematopoietic stem cells were transduced in the patients. Beginning from 14 to 16 months after infusion of the genetically corrected cells, progressive cerebral demyelination in the 2 patients stopped, a clinical outcome comparable to that achieved by allogeneic hematopoietic stem cell transplant. Thus, Cartier et al. (2009) concluded that lentiviral-mediated gene therapy of hematopoietic stem cells can provide clinical benefits in ALD. </p><p>Engelen et al. (2010) reported the results of a randomized control trial of 40 mg daily lovastatin in 14 patients with ALD. Treatment with lovastatin resulted in a small decrease of plasma C24:0 and C26:0, likely due to a decrease in LDL cholesterol. Levels of C18:1 were also slightly reduced. However, there was no effect on C26:0 in erythrocytes or lymphocytes or on VLCFAs in the LDL lipoprotein fraction. These data indicated lovastatin should not be prescribed as a therapy to lower levels of VLCFAs in patients with ALD. No adverse events were observed. </p><p>Fourcade et al. (2010) demonstrated that valproic acid (VPA), a widely used antiepileptic drug with histone deacetylase inhibitor properties, induced the expression of the ABCD2 peroxisomal transporter (601081). VPA corrected the oxidative damage in ALD human fibroblasts and decreased the levels of monounsaturated VLCFA (C26:1 n-9), but not saturated VLCFA. Overexpression of ABCD2 alone prevented oxidative lesions to proteins in a mouse model of ALD. A 6-month pilot trial of VPA in ALD patients resulted in reversion of the oxidative damage to proteins in peripheral blood mononuclear cells. </p><p>Elivaldogene autotemcel (eli-cel) gene therapy consists of autologous CD34+ cells transduced with Lenti-D lentiviral vector containing ABCD1 cDNA. Duncan et al. (2024) performed integration-site analysis, genetic studies, flow cytometry, and morphologic studies in peripheral blood and bone marrow samples from patients who received eli-cel therapy in 2 completed phase 2-3 studies (ALD-102 and ALD-104) and an ongoing follow-up study (LTF-304, Eichler et al., 2024) involving the patients in both ALD-102 and ALD-104. Hematologic cancer developed in 7 of 67 patients after the receipt of eli-cel (1 of 32 patients in the ALD-102 study and 6 of 35 patients in the ALD-104 study): myelodysplastic syndrome (MDS) with unilineage dysplasia in 2 patients at 14 and 26 months; MDS with excess blasts in 3 patients at 28, 42, and 92 months; MDS in 1 patient at 36 months; and acute myeloid leukemia (AML) in 1 patient at 57 months. In the 6 patients with available data, predominant clones contained lentiviral vector insertions at multiple loci, including at either MECOM (165215) in 5 patients or PRDM16 (605557) in 1 patient. Several patients had cytopenias, and most had vector insertions in multiple genes within the same clone; 6 of the 7 patients also had somatic mutations (KRAS, 190070; NRAS, 164790; WT1, 607102; CDKN2A, 600160 or CDKN2B, 600431; or RUNX1, 151385), and 1 of the 7 patients had monosomy 7. Of the 5 patients with MDS with excess blasts or MDS with unilineage dysplasia who underwent allogeneic hematopoietic stem cell transplantation (HSCT), 4 patients remained free of MDS without recurrence of symptoms of cerebral adrenoleukodystrophy, and 1 patient died from presumed graft-versus-host disease 20 months after HSCT (49 months after receiving eli-cel). The patient with AML was alive and had full donor chimerism after HSCT; the patient with the most recent case of MDS was alive and awaiting HSCT. The authors concluded that hematologic cancer developed in a subgroup of patients who were treated with eli-cel; the cases were associated with clonal vector insertions within oncogenes and clonal evolution with acquisition of somatic genetic defects. </p><p>In a phase 2-3 study, Eichler et al. (2024) evaluated the efficacy and safety of eli-cel therapy in boys with early-stage cerebral adrenoleukodystrophy and evidence of active inflammation on magnetic resonance imaging (MRI). The primary efficacy end point was survival without any of 6 major functional disabilities at month 24. The secondary end points included overall survival at month 24 and the change from baseline to month 24 in the total neurologic function score. A total of 32 patients received eli-cel; 29 patients (91%) completed the 24-month study and are being monitored in a 13-year long-term follow-up study. At month 24, none of these 29 patients had major functional disabilities; overall survival was 94%. At the most recent assessment (median follow-up, 6 years), the neurologic function score was stable as compared with the baseline score in 30 of 32 patients (94%); 26 patients (81%) had no major functional disabilities. Four patients had adverse events that were directly related to eli-cel. Myelodysplastic syndrome (MDS) with excess blasts developed in 1 patient at month 92; the patient underwent allogeneic hematopoietic stem cell transplantation and did not have MDS at the most recent follow-up. </p>
</span>
<div>
<br />
</div>
<div>
<h4>
<span class="mim-font">
<strong>Molecular Genetics</strong>
</span>
</h4>
</div>
<span class="mim-text-font">
<p>See the MOLECULAR GENETICS section in 300371.</p>
</span>
<div>
<br />
</div>
<div>
<h4>
<span class="mim-font">
<strong>Population Genetics</strong>
</span>
</h4>
</div>
<span class="mim-text-font">
<p>Moser et al. (1991) reported that their laboratory had identified more than 900 hemizygotes and 1,000 heterozygotes. Approximately 50% of the hemizygotes had a rapidly progressive childhood or adolescent form of the disease. In 25% of males, a slowly progressive paraparesis was the clinical picture. The illness occasionally presented as Addison disease without apparent neurologic involvement. Approximately 15% of heterozygotes developed moderately severe spastic paraparesis. </p><p>In studies of 30 Dutch kindreds, van Geel et al. (1994) phenotyped 77 affected males and found that 35 (46%) had adrenomyeloneuropathy and 24 (31%) had the childhood or adolescent cerebral ALD. These percentages differed significantly from previous reports in which 25 to 28% of the patients developed AMN and 53 to 57% developed childhood or adolescent cerebral ALD. </p><p>In studies in Australasia and Spain, Kirk et al. (1998) and Ruiz et al. (1998), respectively, provided new information about the epidemiology of ALD and the relative frequency of ALD phenotypes. The first study originated from the unit that had served as the ALD Referral Center in Australasia for the previous 15 years. Based on the number of ALD cases identified during this period and the number of live births, they arrived at a minimum incidence of 1.6 per 100,000 live births, slightly higher than the 1.1 per 100,000 based on similar analyses in the United States (Moser et al., 1995) and considerably higher than the estimated 1 per 200,000 males in the Netherlands (van Geel et al., 1994). Of the 95 affected males studied by Kirk et al. (1998), 51 had cerebral adrenoleukodystrophy, 24 had adrenomyeloneuropathy, 15 had Addison disease only, and 5 remained asymptomatic when last examined. Of the 60 patients belonging to 48 kindreds studied by Ruiz et al. (1998), 33% had childhood cerebral ALD plus adolescent cerebral ALD, 16% had adult cerebral ALD, 27% had adrenomyeloneuropathy, 12% had Addison disease only, and 12% had presymptomatic ALD. </p><p>Bezman and Moser (1998) reviewed the relative frequency of phenotypes in 388 patients from 253 sibships from the United States and Canada in whom the genotype and phenotype of every male was known. This determination of every male eliminated the ascertainment bias introduced by other series in which ALD status was not known. When the proband was excluded, the phenotypic breakdown was 33% with childhood cerebral ALD, 26% with adrenomyeloneuropathy, 14% Addison only, 13% asymptomatic, 4% adolescent, and 2% adult cerebral. These numbers were very similar to the series from the Netherlands in which there was an attempt to identify everyone in the country with ALD. </p><p>Bezman et al. (2001) determined the minimum frequency of hemizygotes in the United States to be 1:42,000 and that of hemizygotes and heterozygotes to be 1:16,800. </p><p>In a retrospective hospital- and clinic-based study involving 122 children with an inherited leukodystrophy, Bonkowsky et al. (2010) found that the most common diagnoses were metachromatic leukodystrophy (250100) (8.2%), Pelizaeus-Merzbacher disease (312080) (7.4%), mitochondrial diseases (4.9%), and adrenoleukodystrophy (4.1%). No final diagnosis was reported in 51% of patients. The disorder was severe: epilepsy was found in 49%, mortality was 34%, and the average age at death was 8.2 years. The population incidence of leukodystrophy in general was found to be 1 in 7,663 live births. </p><p>Koto et al. (2021) surveyed hospitals in Japan for information about patients with peroxisomal disorders treated between 2013-2016 and 2018-2019. Adrenoleukodystrophy was identified in 73 patients, of whom 52.1% had the childhood cerebral form, 16.4% had the adolescent cerebral form, 11% had adrenomyeloneuropathy, 1.4% had the adult cerebral form, 8.2% had Addison disease, 1.4% were symptomatic females, 5.5% had prenatal onset, and 4.1% had unknown onset. When these data were extrapolated across Japan, Koto et al. (2021) estimated that there were 262 patients with adrenoleukodystrophy, and they calculated a birth prevalence in Japan of 0.2 per 100,000. </p>
</span>
<div>
<br />
</div>
<div>
<h4>
<span class="mim-font">
<strong>Animal Model</strong>
</span>
</h4>
</div>
<span class="mim-text-font">
<p>Forss-Petter et al. (1997) and Lu et al. (1997) generated mice deficient in ALDP by targeted disruption. Motor functions in Aldp-deficient mice developed on schedule, and unexpectedly, adult animals appeared unaffected by neurologic symptoms up to 6 months of age. Biochemical analyses demonstrated impaired beta-oxidation in mutant fibroblasts and abnormal accumulation of very long chain fatty acids in the CNS and kidney. In 6-month-old mutants, adrenal cortex cells displayed a ballooned morphology and needle-like lipid inclusions, also found in testis and ovaries. However, lipid inclusions and demyelinating lesions of the CNS were not a feature. </p><p>Contrary to the original suggestion that there was no phenotype associated with these mice, Pujol et al. (2002) determined that older mice have changes resembling AMN. Older Aldp-deficient mice exhibited an abnormal neurologic and behavioral phenotype, starting at around 15 months. This was correlated with slower nerve conduction and with myelin and axonal anomalies detectable in the spinal cord and sciatic nerve, but not in brain. </p><p>The Drosophila recessive mutant 'bubblegum' (bgm) exhibits adult neurodegeneration, with marked dilation of photoreceptor axons. This mutant shows elevated levels of VLCFAs, as seen in ALD. Min and Benzer (1999) found that feeding the fly mutant one of the components of 'Lorenzo's oil,' glyceryl trioleate oil, blocked the accumulation of excess VLCFAs as well as development of the pathology. </p><p>In Abcd1-knockout mice, Pujol et al. (2004) demonstrated that axonal damage was the first pathologic event in this model, followed by myelin degeneration. The phenotype could be modulated through expression levels of Abcd2 (601081). Overexpression of Abcd2 in Abcd1-knockout mice prevented both VLCFA accumulation and neurodegenerative features, whereas Abcd1/Abcd2 double mutants exhibited an earlier onset and more severe disease. </p><p>Oezen et al. (2005) reported normal VLCFA levels in mitochondria of Abcd1-deficient mice. Polarographic analysis of the respiratory chain as well as enzymatic assays of isolated muscle mitochondria revealed no differences between Abcd1-deficient and control mice. Ultrastructural analysis revealed normal size, structure, and localization of mitochondria in muscle of both groups. Mitochondrial enzyme activity in brain homogenates of Abcd1-deficient and wildtype animals also did not differ, and studies on mitochondrial oxidative phosphorylation in permeabilized human skin fibroblasts of ALD patients and controls revealed no abnormalities. Oezen et al. (2005) concluded that accumulation of VLCFA per se does not cause mitochondrial abnormalities, and vice versa mitochondrial abnormalities are not responsible for the accumulation of VLCFA in Abcd1-deficient mice. </p><p>Fourcade et al. (2008) found evidence of lipoxidative protein damage in the spinal cord of Abcd1-null mice as early as 3.5 months of age before the onset of neurologic symptoms. At 12 months, Abcd1-null mice had accumulated additional proteins affected by oxidative damage. Abcd1-null mice, spinal cord slices from these mice, and human ALD fibroblasts all showed a defective antioxidant response to VLCFA. </p><p>In early symptomatic Abcd1/Abcd2 double-knockout mice, Mastroeni et al. (2009) demonstrated that intracisternal injection of an adeno-associated viral vector engineered to express human IGF1 (147440) and NTF3 (162660), 2 potent inducers of myelin formation and oligodendrocyte survival, resulted in protective effects against the demyelination process and amelioration of disease progression. Studies of CSF showed persistent expression of the genes after 20 weeks, suggesting effective transduction of leptomeningeal cells and a long-lasting effect. </p>
</span>
<div>
<br />
</div>
<div>
<h4>
<span class="mim-font">
<strong>History</strong>
</span>
</h4>
</div>
<span class="mim-text-font">
<p>Moser (1997) suggested that the first patient with X-ALD was described by Haberfeld and Spieler (1910). A previously normal boy developed disturbances in eye movement and vision at the age of 6 years, became apathetic, and showed deterioration of school work. Four months later his gait became spastic, and this progressed to an inability to walk. He was hospitalized at 7 years of age. Dark skin was noted. He died 8 months later. An older brother had died of a similar illness at 8.5 years. The postmortem brain was studied by Schilder (1913) and reported as the second of 3 cases that he referred to as 'encephalitis periaxialis diffusa,' characterized by diffuse involvement of the cerebral hemispheres in children with severe loss of myelin, which resembled multiple sclerosis because of the relative preservation of axons and the accumulation of lymphocytes, fat-laden phagocytes, and glial cells. The findings in the adrenal gland were not reported. Involvement of the adrenal gland was reported by Siemerling and Creutzfeldt (1923). </p><p>Blaw (1970) coined the name 'adrenoleukodystrophy.'</p><p>Gumbinas et al. (1976) suggested that progressive spastic paraparesis with adrenal insufficiency is 'a distinct disease, differing importantly from adrenoleukodystrophy.' </p>
</span>
<div>
<br />
</div>
</div>
<div>
<h4>
<span class="mim-font">
<strong>See Also:</strong>
</span>
</h4>
<span class="mim-text-font">
Aguilar et al. (1967); ASHG statement (1998); Aubourg et al. (1990);
Aubourg et al. (1993); Barcelo et al. (1994); Barcelo et al. (1994);
Berger et al. (1994); Brady (1976); Braun et al. (1995); Cartier et
al. (1993); Di Chiro et al. (1980); Dodd et al. (1997); Fuchs et al.
(1994); Harris-Jones and Nixon (1955); Hoefnagel et al. (1967); Kano
et al. (1998); Kobayashi et al. (1994); Martin et al. (1980); Menkes
and Corbo (1977); Moser et al. (1984); Moser et al. (1984); O&#x27;Neill
et al. (1981); O&#x27;Neill et al. (1982); Peckham et al. (1982); Penman
(1960); Powers et al. (1980); Powers and Schaumburg (1974); Powers
and Schaumburg (1980); Powers and Schaumburg (1981); Probst et al.
(1980); Ropers et al. (1975); Rosen et al. (1985); Sarde et al.
(1994); Schaumburg et al. (1972); Seneca and Lissens (1995); Takano
et al. (1999); Turkington and Stempfel (1966); Unterrainer et al.
(2000); Walsh (1980); Wanders et al. (1987); Wray et al. (1976)
</span>
<div>
<br />
</div>
</div>
<div>
<h4>
<span class="mim-font">
<strong>REFERENCES</strong>
</span>
</h4>
<div>
<p />
</div>
<div>
<ol>
<li>
<p class="mim-text-font">
Aguilar, M. J., O'Brien, J. S., Taber, P.
<strong>The syndrome of familial leukodystrophy, adrenal insufficiency and cutaneous melanosis. In: Aronson, S. M.; Volk, B. W.: Inborn Disorders of Sphingolipid Metabolism.</strong>
Oxford: Pergamon Press (pub.) 1967. Pp. 149-166.
</p>
</li>
<li>
<p class="mim-text-font">
Alpern, M., Sack, G. H., Jr., Krantz, D. H., Jenness, J., Zhang, H., Moser, H. W.
<strong>Chromosomal rearrangement segregating with adrenoleukodystrophy: associated changes in color vision.</strong>
Proc. Nat. Acad. Sci. 90: 9494-9498, 1993.
[PubMed: 8415729]
[Full Text: https://doi.org/10.1073/pnas.90.20.9494]
</p>
</li>
<li>
<p class="mim-text-font">
ASHG statement.
<strong>Professional disclosure of familial genetic information: the American Society of Human Genetics Social Issues Subcommittee on Familial Disclosure.</strong>
Am. J. Hum. Genet. 62: 474-483, 1998.
[PubMed: 9537923]
</p>
</li>
<li>
<p class="mim-text-font">
Aubourg, P., Adamsbaum, C., Lavallard-Rousseau, M.-C., Rocchiccioli, F., Cartier, N., Jambaque, I., Jakobezak, C., Lemaitre, A., Boureau, F., Wolf, C., Bougneres, P.-F.
<strong>A two-year trial of oleic and erucic acids (&#x27;Lorenzo&#x27;s oil&#x27;) as treatment for adrenomyeloneuropathy.</strong>
New Eng. J. Med. 329: 745-752, 1993.
[PubMed: 8350883]
[Full Text: https://doi.org/10.1056/NEJM199309093291101]
</p>
</li>
<li>
<p class="mim-text-font">
Aubourg, P., Blanche, S., Jambaque, I., Rocchiccioli, F., Kalifa, G., Naud-Saudreau, C., Rolland, M.-O., Debre, M., Chaussain, J.-L., Griscelli, C., Fischer, A., Bougneres, P.-F.
<strong>Reversal of early neurologic and neuroradiologic manifestations of X-linked adrenoleukodystrophy by bone marrow transplantation.</strong>
New Eng. J. Med. 322: 1860-1866, 1990.
[PubMed: 2348839]
[Full Text: https://doi.org/10.1056/NEJM199006283222607]
</p>
</li>
<li>
<p class="mim-text-font">
Aubourg, P., Chaussain, J. L., Dulac, O., Arthuis, M.
<strong>Adrenoleukodystrophy in children: apropos of 20 cases.</strong>
Arch. Franc. Pediat. 39: 663-669, 1982.
[PubMed: 6299222]
</p>
</li>
<li>
<p class="mim-text-font">
Aubourg, P., Feil, R., Guidoux, S., Kaplan, J.-C., Moser, H., Kahn, A., Mandel, J.-L.
<strong>The red-green visual pigment gene region in adrenoleukodystrophy.</strong>
Am. J. Hum. Genet. 46: 459-469, 1990.
[PubMed: 2309698]
</p>
</li>
<li>
<p class="mim-text-font">
Aubourg, P., Mosser, J., Douar, A. M., Sarde, C. O., Lopez, J., Mandel, J. L.
<strong>Adrenoleukodystrophy gene: unexpected homology to a protein involved in peroxisome biogenesis.</strong>
Biochimie 75: 293-302, 1993.
[PubMed: 8507690]
[Full Text: https://doi.org/10.1016/0300-9084(93)90089-b]
</p>
</li>
<li>
<p class="mim-text-font">
Aubourg, P. R., Sack, G. H., Jr., Meyers, D. A., Lease, J. J., Moser, H. W.
<strong>Linkage of adrenoleukodystrophy to a polymorphic DNA probe.</strong>
Ann. Neurol. 21: 349-352, 1987.
[PubMed: 2883927]
[Full Text: https://doi.org/10.1002/ana.410210406]
</p>
</li>
<li>
<p class="mim-text-font">
Aubourg, P. R., Sack, G. H., Jr., Moser, H.
<strong>Frequent alterations of visual pigment genes in adrenoleukodystrophy.</strong>
Am. J. Hum. Genet. 42: 408-413, 1988.
[PubMed: 2894755]
</p>
</li>
<li>
<p class="mim-text-font">
Barcelo, A., Giros, M., Martinez-Bermejo, A., Sarde, C.-O., Coll, M. J., Moser, J., Mandel, J. L., Estivill, X., Pampols, T.
<strong>A frame shift mutation in the candidate gene of X-linked adrenoleukodystrophy.</strong>
International Congress of Inborn Errors of Metabolism, Milano, Italy 1994. P. 228.
</p>
</li>
<li>
<p class="mim-text-font">
Barcelo, A., Giros, M., Sarde, C. O., Martinez-Bermejo, A., Mandel, J. L., Pampols, T., Estivill, X.
<strong>Identification of a new frameshift mutation (1801delAG) in the ALD gene.</strong>
Hum. Molec. Genet. 3: 1889-1890, 1994.
[PubMed: 7849718]
[Full Text: https://doi.org/10.1093/hmg/3.10.1889]
</p>
</li>
<li>
<p class="mim-text-font">
Berg, K. A., Beaty, T. H., Raven, M. B., Moser, A. B., Moser, H. W.
<strong>X-linked adrenoleukodystrophy in a 362 member kindred. (Abstract)</strong>
Am. J. Hum. Genet. 45 (suppl.): A39, 1989.
</p>
</li>
<li>
<p class="mim-text-font">
Berger, J., Molzer, B., Fae, I., Bernheimer, H.
<strong>X-linked adrenoleukodystrophy (ALD): a novel mutation of the ALD gene in 6 members of a family presenting with 5 different phenotypes.</strong>
Biochem. Biophys. Res. Commun. 205: 1638-1643, 1994.
[PubMed: 7811247]
[Full Text: https://doi.org/10.1006/bbrc.1994.2855]
</p>
</li>
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</li>
<li>
<p class="mim-text-font">
Sack, G. H., Jr., Raven, M. B., Moser, H. W.
<strong>Color vision defects in adrenomyeloneuropathy.</strong>
Am. J. Hum. Genet. 44: 794-798, 1989.
[PubMed: 2729274]
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<li>
<p class="mim-text-font">
Sadeghi-Nejad, A., Senior, B.
<strong>Adrenomyeloneuropathy presenting as Addison&#x27;s disease in childhood.</strong>
New Eng. J. Med. 322: 13-16, 1990.
[PubMed: 2294415]
[Full Text: https://doi.org/10.1056/NEJM199001043220103]
</p>
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<li>
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Sarde, C.-O., Mosser, J., Kioschis, P., Kretz, C., Vicaire, S., Aubourg, P., Poustka, A., Mandel, J.-L.
<strong>Genomic organization of the adrenoleukodystrophy gene.</strong>
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</li>
<li>
<p class="mim-text-font">
Sarde, C.-O., Thomas, J., Sadoulet, H., Garnier, J.-M., Mandel, J.-L.
<strong>cDNA sequence of Aldgh, the mouse homolog of the X-linked adrenoleukodystrophy gene.</strong>
Mammalian Genome 5: 810-813, 1994.
[PubMed: 7894167]
[Full Text: https://doi.org/10.1007/BF00292021]
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<li>
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Schaumburg, H. H., Powers, J. M., Raine, C. S., Spencer, P. S., Griffin, J. W., Prineas, J. W., Boehme, D. M.
<strong>Adrenomyeloneuropathy: a probable variant of adrenoleukodystrophy. II. General pathologic, neuropathologic, and biochemical aspects.</strong>
Neurology 27: 1114-1119, 1977.
[PubMed: 200862]
[Full Text: https://doi.org/10.1212/wnl.27.12.1114]
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Schaumburg, H. H., Powers, J. M., Raine, C. S., Suzuki, K., Richardson, E. P., Jr.
<strong>Adrenoleukodystrophy: a clinical and pathological study of 17 cases.</strong>
Arch. Neurol. 32: 577-591, 1975.
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Schaumburg, H. H., Richardson, E. P., Jr., Johnson, P. C., Cohen, R. B., Powers, J. M., Raine, C. S.
<strong>Schilder&#x27;s disease: sex-linked recessive transmission with specific adrenal changes.</strong>
Arch. Neurol. 27: 458-460, 1972.
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<p class="mim-text-font">
Schilder, P.
<strong>Zur Frage der Encephalitis Periaxialis Diffusa (Sogenannte Diffuse Sklerose).</strong>
Z. ges Neurol. Psychiat. 15: 359-376, 1913.
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Siemerling, E., Creutzfeldt, H. G.
<strong>Bronzekrankheit und sklerosierende Encephalomyelitis.</strong>
Arch. Psychiat. Nervkrankh. 68: 217-244, 1923.
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Singh, I., Lazo, O., Contreras, M., Hashmi, M., Stanley, W. S.
<strong>Peroxisomal lignoceroyl-CoA ligase deficiency in X-linked adrenoleukodystrophy. (Abstract)</strong>
Am. J. Hum. Genet. 43: A16, 1988.
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<strong>Recombination between cerebral sclerosis--Addison&#x27;s disease and the Xg blood-groups. (Letter)</strong>
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Turkington, R. W., Stempfel, R. S., Jr.
<strong>Adrenocortical atrophy and diffuse cerebral sclerosis (Addison-Schilder&#x27;s disease).</strong>
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Unterrainer, G., Molzer, B., Forss-Petter, S., Berger, J.
<strong>Co-expression of mutated and normal adrenoleukodystrophy protein reduces protein function: implications for gene therapy of X-linked adrenoleukodystrophy.</strong>
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Uyama, E., Iwagoe, H., Maeda, J., Nakamura, M., Terasaki, T., Ando, M.
<strong>Presenile-onset cerebral adrenoleukodystrophy presenting as Balint&#x27;s syndrome and dementia.</strong>
Neurology 43: 1249-1251, 1993.
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[Full Text: https://doi.org/10.1212/wnl.43.6.1249]
</p>
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van Geel, B. M., Assies, J., Weverling, G. J., Barth, P. G.
<strong>Predominance of the adrenomyeloneuropathy phenotype of X-linked adrenoleukodystrophy in the Netherlands: a survey of 30 kindreds.</strong>
Neurology 44: 2343-2346, 1994.
[PubMed: 7991123]
[Full Text: https://doi.org/10.1212/wnl.44.12.2343]
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van Geel, B. M., Bezman, L., Loes, D. J., Moser, H. W., Raymond, G. V.
<strong>Evolution of phenotypes in adult male patients with X-linked adrenoleukodystrophy.</strong>
Ann. Neurol. 49: 186-194, 2001.
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<p class="mim-text-font">
van Oost, B. A., van Zandvoort, P., Hoogeboom, A., Bakkeren, J., Hamel, B., Brunner, H., Knoers, N., Ropers, H. H.
<strong>Tight linkage between adrenoleukodystrophy and DXS 52. (Abstract)</strong>
Cytogenet. Cell Genet. 46: 708 only, 1987.
</p>
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<p class="mim-text-font">
van Oost, B. A., van Zandvoort, P. M., Tunte, W., Brunner, H. G., Hoogeboom, A. J. M., Maaswinkel-Mooy, P. D., Bakkeren, J., Hamel, B., Ropers, H. H.
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Hum. Genet. 86: 404-407, 1991.
[PubMed: 1671851]
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</p>
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<li>
<p class="mim-text-font">
Walsh, P. J.
<strong>Adrenoleukodystrophy: report of two cases with relapsing and remitting courses.</strong>
Arch. Neurol. 37: 448-450, 1980.
[PubMed: 6248004]
[Full Text: https://doi.org/10.1001/archneur.1980.00500560078013]
</p>
</li>
<li>
<p class="mim-text-font">
Wanders, R. J. A., van Roermund, C. W. T., van Wijland, M. J. A., Nijenhuis, A. A., Tromp, A., Schutgens, R. B. H., Brouwer-Kelder, E. M., Schram, A. W., Tager, J. M., van den Bosch, H., Schalkwijk, C.
<strong>X-linked adrenoleukodystrophy: defective peroxisomal oxidation of very long chain fatty acids but not of very long chain fatty acyl-CoA esters.</strong>
Clin. Chim. Acta 165: 321-329, 1987.
[PubMed: 3652454]
[Full Text: https://doi.org/10.1016/0009-8981(87)90177-x]
</p>
</li>
<li>
<p class="mim-text-font">
Wanders, R. J. A., van Roermund, C. W. T., van Wijland, M. J. A., Schutgens, R. B. H., Heikoop, J., van den Bosch, H., Schram, A. W., Tager, J. M.
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J. Clin. Invest. 80: 1778-1783, 1987.
[PubMed: 3680527]
[Full Text: https://doi.org/10.1172/JCI113271]
</p>
</li>
<li>
<p class="mim-text-font">
Wanders, R. J. A., van Roermund, C. W. T., van Wijland, M. J. A., Schutgens, R. B. H., van den Bosch, H., Schram, A. W., Tager, J. M.
<strong>Direct demonstration that the deficient oxidation of very long chain fatty acids in X-linked adrenoleukodystrophy is due to an impaired ability of peroxisomes to activate very long chain fatty acids.</strong>
Biochem. Biophys. Res. Commun. 153: 618-624, 1988.
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Watkiss, E., Webb, T., Bundey, S.
<strong>Is skewed X inactivation responsible for symptoms in female carriers for adrenoleucodystrophy?</strong>
J. Med. Genet. 30: 651-654, 1993.
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[Full Text: https://doi.org/10.1136/jmg.30.8.651]
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Wilichowski, E., Ohlenbusch, A., Korenke, G. C., Hunneman, D. H., Hanefeld, F.
<strong>Identical mitochondrial DNA in monozygotic twins with discordant adrenoleukodystrophy phenotype. (Letter)</strong>
Ann. Neurol. 43: 835-836, 1998.
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[Full Text: https://doi.org/10.1002/ana.410430621]
</p>
</li>
<li>
<p class="mim-text-font">
Willems, P. J., Vits, L., Wanders, R. J. A., Coucke, P. J., Van der Auwera, B. J., Van Elsen, A. F., Raeymaekers, P., Van Broeckhoven, C., Schutgens, R. B. H., Dacremont, G., Leroy, J. G., Martin, J.-J., Dumon, J. E.
<strong>Linkage of DNA markers at Xq28 to adrenoleukodystrophy and adrenomyeloneuropathy present within the same family.</strong>
Arch. Neurol. 47: 665-669, 1990.
[PubMed: 2161209]
[Full Text: https://doi.org/10.1001/archneur.1990.00530060077022]
</p>
</li>
<li>
<p class="mim-text-font">
Wray, S. H., Cogan, D. G., Kuwabara, T., Schaumburg, H. H., Powers, J. M.
<strong>Adrenoleukodystrophy with disease of the eye and optic nerve.</strong>
Am. J. Ophthal. 82: 480-485, 1976.
[PubMed: 961799]
[Full Text: https://doi.org/10.1016/0002-9394(76)90498-0]
</p>
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Ada Hamosh - updated : 10/21/2024<br>Hilary J. Vernon - updated : 09/13/2021<br>George E. Tiller - updated : 09/09/2013<br>George E. Tiller - updated : 8/15/2013<br>Cassandra L. Kniffin - updated : 1/25/2011<br>Cassandra L. Kniffin - updated : 10/20/2010<br>Cassandra L. Kniffin - updated : 1/21/2010<br>Ada Hamosh - updated : 1/5/2010<br>Cassandra L. Kniffin - updated : 12/8/2009<br>Cassandra L. Kniffin - updated : 3/24/2009<br>George E. Tiller - updated : 5/19/2008<br>Cassandra L. Kniffin - updated : 3/25/2008<br>Cassandra L. Kniffin - updated : 12/17/2007<br>George E. Tiller - updated : 5/21/2007<br>Cassandra L. Kniffin - updated : 7/17/2006<br>Victor A. McKusick - updated : 12/5/2005<br>Victor A. McKusick - updated : 10/20/2004<br>Victor A. McKusick - updated : 3/5/2004<br>Ada Hamosh - updated : 10/2/2003<br>Cassandra L. Kniffin - updated : 4/2/2003<br>Cassandra L. Kniffin - updated : 1/29/2003<br>Gerald V. Raymond - reorganized : 1/13/2003<br>Gerald V. Raymond - updated : 1/13/2003<br>Victor A. McKusick - updated : 1/4/2002<br>Victor A. McKusick - updated : 1/2/2002<br>Victor A. McKusick - updated : 12/27/2001<br>Victor A. McKusick - updated : 11/6/2001<br>Victor A. McKusick - updated : 7/24/2001<br>George E. Tiller - updated : 1/24/2001<br>Ada Hamosh - updated : 1/10/2001<br>Victor A. McKusick - updated : 4/19/2000<br>Orest Hurko - updated : 7/1/1999<br>Victor A. McKusick - updated : 6/18/1999<br>Victor A. McKusick - updated : 6/7/1999<br>Victor A. McKusick - updated : 6/4/1999<br>Orest Hurko - updated : 5/24/1999<br>Victor A. McKusick - updated : 4/21/1998<br>Victor A. McKusick - updated : 9/9/1997<br>Victor A. McKusick - updated : 8/15/1997<br>Victor A. McKusick - updated : 6/23/1997<br>John A. Phillips, III - updated : 4/29/1997<br>Victor A. McKusick - updated : 4/11/1997<br>Stylianos E. Antonarakis - updated : 7/5/1996<br>Moyra Smith - updated : 4/19/1996<br>Alan F. Scott - updated : 4/12/1996<br>Orest Hurko - updated : 9/21/1995
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