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Entry
- #250100 - METACHROMATIC LEUKODYSTROPHY; MLD
- OMIM
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<span class="h4">#250100</span>
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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/250100"><strong>Clinical Synopsis</strong></a>
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<a href="#text"><strong>Text</strong></a>
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<a href="#clinicalFeatures">Clinical Features</a>
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<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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<li role="presentation" style="margin-left: 1em">
<a href="#genotypePhenotypeCorrelations">Genotype/Phenotype Correlations</a>
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<a href="#populationGenetics">Population Genetics</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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<div><a href="https://clinicaltrials.gov/search?cond=METACHROMATIC LEUKODYSTROPHY" 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=21362&Typ=Pat" title="Metachromatic leukodystrophy, late infantile form" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'EuroGentest', 'domain': 'orpha.net'})">Metachromatic leukodystrop…&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=21363&Typ=Pat" title="Metachromatic leukodystrophy, juvenile form" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'EuroGentest', 'domain': 'orpha.net'})">Metachromatic leukodystrop…&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=21364&Typ=Pat" title="Metachromatic leukodystrophy, adult form" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'EuroGentest', 'domain': 'orpha.net'})">Metachromatic leukodystrop…&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=112&Typ=Pat" title="Metachromatic leukodystrophy" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'EuroGentest', 'domain': 'orpha.net'})">Metachromatic leukodystrop…&nbsp;</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/books/NBK1130/" 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/4691" 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/metachromatic-leukodystrophy" 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=250100[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="#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=309256" title="Metachromatic leukodystrophy, late infantile form" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'OrphaNet', 'domain': 'orpha.net'})">Metachromatic leukodystrop…</a></div><div style="margin-left: 0.5em;"><a href="https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=309263" title="Metachromatic leukodystrophy, juvenile form" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'OrphaNet', 'domain': 'orpha.net'})">Metachromatic leukodystrop…</a></div><div style="margin-left: 0.5em;"><a href="https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=309271" title="Metachromatic leukodystrophy, adult form" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'OrphaNet', 'domain': 'orpha.net'})">Metachromatic leukodystrop…</a></div><div style="margin-left: 0.5em;"><a href="https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=512" title="Metachromatic leukodystrophy" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'OrphaNet', 'domain': 'orpha.net'})">Metachromatic leukodystrop…</a></div>
</div>
<div><a href="https://www.possumcore.com/nuxeo/nxdoc/default/bc8786e6-470c-4e3b-89a0-3f588b146534/view_documents?source=omim" class="mim-tip-hint" title="A dysmorphology database of multiple malformations; metabolic, teratogenic, chromosomal, and skeletal syndromes; and their images." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'POSSUM', 'domain': 'possum.net.au'})">POSSUM</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="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:10581" 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/250100" 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:10581" 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:250100" 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> 238031009, 396338004, 44359008, 66521008<br />
<strong>ICD10CM:</strong> E75.25, E75.29<br />
<strong>ORPHA:</strong> 309256, 309263, 309271, 512<br />
<strong>DO:</strong> 10581<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>
250100
</span>
</span>
</div>
</div>
<div>
<a id="preferredTitle" class="mim-anchor"></a>
<h3>
<span class="mim-font">
METACHROMATIC LEUKODYSTROPHY; MLD
</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">
METACHROMATIC LEUKOENCEPHALOPATHY<br />
CEREBRAL SCLEROSIS, DIFFUSE, METACHROMATIC FORM<br />
SULFATIDE LIPIDOSIS<br />
ARYLSULFATASE A DEFICIENCY<br />
ARSA DEFICIENCY<br />
CEREBROSIDE SULFATASE DEFICIENCY
</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">
PSEUDOARYLSULFATASE A DEFICIENCY, INCLUDED
</span>
</div>
<div>
<span class="h4 mim-font">
METACHROMATIC LEUKODYSTROPHY, LATE INFANTILE, INCLUDED<br />
METACHROMATIC LEUKODYSTROPHY, JUVENILE, INCLUDED<br />
METACHROMATIC LEUKODYSTROPHY, ADULT, 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/22/423?start=-3&limit=10&highlight=423">
22q13.33
</a>
</span>
</td>
<td>
<span class="mim-font">
Metachromatic leukodystrophy
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/250100"> 250100 </a>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="Autosomal recessive">AR</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">
ARSA
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/607574"> 607574 </a>
</span>
</td>
</tr>
</tbody>
</table>
</div>
</div>
<div>
<div class="btn-group ">
<a href="/clinicalSynopsis/250100" 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/250100" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Linear'})"> Linear </a></li>
<li><a href="/graph/radial/250100" 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">
- Autosomal recessive <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/258211005" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">258211005</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0441748&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0441748</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000007" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000007</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000007" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000007</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> Eyes </em>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
- Optic atrophy <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/76976005" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">76976005</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/H47.2" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">H47.2</a>, <a href="https://purl.bioontology.org/ontology/ICD10CM/H47.20" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">H47.20</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/377.10" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">377.10</a>, <a href="https://purl.bioontology.org/ontology/ICD9CM/377.1" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">377.1</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0029124&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0029124</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000648" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000648</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000648" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000648</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> Biliary Tract </em>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
- Gallbladder dysfunction <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/51047007" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">51047007</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0232769&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0232769</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0005609" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0005609</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0005609" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0005609</a>]</span><br /> -
Cholecystitis <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/76581006" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">76581006</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/K81.9" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">K81.9</a>, <a href="https://purl.bioontology.org/ontology/ICD10CM/K81" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">K81</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/575.10" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">575.10</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0008325&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0008325</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001082" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001082</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001082" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001082</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> 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">
- Mental deterioration <span class="mim-feature-ids hidden">[UMLS: <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: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 /> -
Hypotonia <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/398151007" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">398151007</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/398152000" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">398152000</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0026827&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0026827</a>, <a href="https://bioportal.bioontology.org/search?q=C1858120&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1858120</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001290" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001290</a>, <a href="https://hpo.jax.org/app/browse/term/HP:0001252" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001252</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001252" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001252</a>]</span><br /> -
Muscle weakness <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/26544005" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">26544005</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0151786&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0151786</a>, <a href="https://bioportal.bioontology.org/search?q=C0030552&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0030552</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001324" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001324</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001324" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001324</a>]</span><br /> -
Gait disturbances <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/22325002" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">22325002</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/781.2" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">781.2</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0575081&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0575081</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001288" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001288</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001288" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001288</a>]</span><br /> -
Hyporeflexia (early) <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1855256&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1855256</a>]</span> <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/835279003" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">835279003</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/405946002" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">405946002</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001265" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001265</a>]</span><br /> -
Dysarthria <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/8011004" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">8011004</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/438.13" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">438.13</a>, <a href="https://purl.bioontology.org/ontology/ICD9CM/784.51" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">784.51</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0013362&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0013362</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001260" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001260</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001260" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001260</a>]</span><br /> -
Dystonia <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/15802004" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">15802004</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/G24.9" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">G24.9</a>, <a href="https://purl.bioontology.org/ontology/ICD10CM/G24" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">G24</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0013421&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0013421</a>, <a href="https://bioportal.bioontology.org/search?q=C0393593&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0393593</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001332" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001332</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001332" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001332</a>]</span><br /> -
Chorea <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/271700006" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">271700006</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/G25.5" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">G25.5</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0008489&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0008489</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002072" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002072</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002072" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002072</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 /> -
Spastic tetraplegia <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/192965001" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">192965001</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0426970&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0426970</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002510" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002510</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002510" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002510</a>]</span><br /> -
Hyperreflexia (later) <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1855257&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1855257</a>]</span> <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/86854008" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">86854008</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001347" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001347</a>]</span><br /> -
Extensor plantar responses (later) <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1855258&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1855258</a>]</span> <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/246586009" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">246586009</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/366575004" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">366575004</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003487" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003487</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 /> -
Bulbar palsies <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> 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 /> -
Progression to tetraplegia and decerebrate state <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1855259&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1855259</a>]</span><br /> -
Cerebral 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 /> -
Elevated CSF protein <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1806780&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1806780</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002922" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002922</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002922" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002922</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">
- Progressive polyneuropathy <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1859178&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1859178</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0007133" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0007133</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0007133" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0007133</a>]</span><br /> -
Demyelination <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/32693004" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">32693004</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0878575&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0878575</a>, <a href="https://bioportal.bioontology.org/search?q=C0011304&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0011304</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0011096" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0011096</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0011096" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0011096</a>]</span><br /> -
EMG shows neuropathic changes <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1842202&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1842202</a>]</span><br /> -
Delayed nerve conduction velocity <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1857640&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1857640</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000762" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000762</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000762" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000762</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 disturbances <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/277843001" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">277843001</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C5886745&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C5886745</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 /> -
Emotional lability <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/18963009" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">18963009</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/R45.86" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">R45.86</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/799.24" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">799.24</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0085633&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0085633</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000712" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000712</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000712" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000712</a>]</span><br /> -
Poor school performance <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1843367&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1843367</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001249" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001249</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001249" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001249</a>]</span><br /> -
Hallucinations <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/7011001" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">7011001</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/R44.3" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">R44.3</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/780.1" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">780.1</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0018524&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0018524</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000738" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000738</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000738" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000738</a>]</span><br /> -
Delusions <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/2073000" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">2073000</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0011253&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0011253</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000746" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000746</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000746" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000746</a>]</span><br /> -
Disorganized thinking <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/736319003" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">736319003</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1855263&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1855263</a>]</span><br />
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<strong> LABORATORY ABNORMALITIES </strong>
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- Metachromatic deposits (sulfatide-containing) in central and peripheral nervous systems and visceral organs <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1855264&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1855264</a>]</span><br /> -
Decreased arylsulfatase A (ARSA) activity in urine, leukocytes, fibroblasts <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1855265&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1855265</a>]</span><br /> -
Increased CSF protein <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1806780&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1806780</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002922" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002922</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002922" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002922</a>]</span><br /> -
Increased urinary sulfatide excretion <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1855266&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1855266</a>]</span><br />
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<strong> MISCELLANEOUS </strong>
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- Late infantile onset 6-24 months<br /> -
Juvenile onset 4 years to puberty<br /> -
Adult onset after puberty<br /> -
Adult onset form usually presents with psychiatric manifestations<br /> -
Pseudoarylsulfatase A deficiency is an allelic disorder with reduced levels of ARSA activity, but no neurologic manifestations<br />
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<strong> MOLECULAR BASIS </strong>
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- Caused by mutation in the arylsulfatase A gene (ARSA, <a href="/entry/607574#0003">607574.0003</a>)<br />
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<p>A number sign (#) is used with this entry because metachromatic leukodystrophy (MLD) is caused by homozygous or compound heterozygous mutation in the arylsulfatase A gene (ARSA; <a href="/entry/607574">607574</a>) on chromosome 22q13.</p>
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<strong>Description</strong>
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<p>The metachromatic leukodystrophies comprise several allelic disorders. <a href="#56" class="mim-tip-reference" title="Kihara, H. &lt;strong&gt;Genetic heterogeneity in metachromatic leukodystrophy.&lt;/strong&gt; Am. J. Hum. Genet. 34: 171-181, 1982.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/6122378/&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;6122378&lt;/a&gt;]" pmid="6122378">Kihara (1982)</a> recognized 5 allelic forms of MLD: late infantile, juvenile, and adult forms, partial cerebroside sulfate deficiency, and pseudoarylsulfatase A deficiency; and 2 nonallelic forms: metachromatic leukodystrophy due to saposin B deficiency (<a href="/entry/249900">249900</a>) and multiple sulfatase deficiency or juvenile sulfatidosis (<a href="/entry/272200">272200</a>), a disorder that combines features of a mucopolysaccharidosis with those of metachromatic leukodystrophy. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=6122378" 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><strong><em>Late Infantile and Juvenile Forms</em></strong></p><p>
This condition was described by <a href="#39" class="mim-tip-reference" title="Greenfield, J. G. &lt;strong&gt;Form of progressive cerebral sclerosis in infants associated with primary degeneration of interfascicular glia.&lt;/strong&gt; Proc. Roy. Soc. Med. 26: 690-697, 1933.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/19989245/&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;19989245&lt;/a&gt;]" pmid="19989245">Greenfield (1933)</a>. In the late infantile form, onset is usually in the second year of life and death occurs before 5 years in most. Clinical features are motor symptoms, rigidity, mental deterioration, and sometimes convulsions. Early development is normal but onset occurs before 30 months of age. The cerebrospinal fluid contains elevated protein. Galactosphingosulfatides that are strongly metachromatic, doubly refractile in polarized light, and pink with PAS are found in excess in the white matter of the central nervous system, in the kidney, and in the urinary sediment (<a href="#3" class="mim-tip-reference" title="Austin, J. H. &lt;strong&gt;Metachromatic form of diffuse cerebral sclerosis. III. Significance of sulfatide and other lipid abnormalities in white matter and kidney.&lt;/strong&gt; Neurology 10: 470-483, 1960.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/13795190/&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;13795190&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1212/wnl.10.5.470&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="13795190">Austin, 1960</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=13795190+19989245" 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="#63" class="mim-tip-reference" title="Masters, P. L., MacDonald, W. B., Ryan, M. M. P., Cumings, J. N. &lt;strong&gt;Familial leucodystrophy.&lt;/strong&gt; Arch. Dis. Child. 39: 345-355, 1964.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/14206875/&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;14206875&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1136/adc.39.206.345&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="14206875">Masters et al. (1964)</a> described 4 cases in 2 families. Progressive physical and mental deterioration began a few months after birth. Megacolon with attacks of abdominal distention was observed. Sufficient difference from the usual cases existed for the authors to suggest that more than one entity is encompassed by metachromatic leukodystrophy. A curious feature of later bedridden stages of the disease was marked genu recurvatum. The first manifestations, appearing before the second birthday, included hypotonia, muscle weakness and unsteady gait, thus suggesting a myopathy or neuropathy. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14206875" 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="#40" class="mim-tip-reference" title="Gustavson, K.-H., Hagberg, B. &lt;strong&gt;The incidence and genetics of metachromatic leukodystrophy in northern Sweden.&lt;/strong&gt; Acta Paediat. Scand. 60: 585-590, 1971.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/5110535/&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;5110535&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1111/j.1651-2227.1971.tb06994.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="5110535">Gustavson and Hagberg (1971)</a> described 13 cases of late infantile MLD from 11 families. Two pairs of families were related to each other and 3 sets of parents were consanguineous, suggesting autosomal recessive inheritance. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=5110535" 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="Lyon, G., Arthuis, M., Thieffry, S. &lt;strong&gt;Leucodystrophie metachromatique infantile familiale: etude de deux observations, dont une avec examen anatomique et chimique.&lt;/strong&gt; Rev. Neurol. 104: 508-533, 1961.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/14467622/&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;14467622&lt;/a&gt;]" pmid="14467622">Lyon et al. (1961)</a> described affected brothers with onset at 7 and 4 years of age and with marked elevation of protein in the cerebrospinal fluid. <a href="#83" class="mim-tip-reference" title="Schutta, H. S., Pratt, R. T. C., Metz, H., Evans, K. A., Carter, C. O. &lt;strong&gt;A family study of the late infantile and juvenile forms of metachromatic leukodystrophy.&lt;/strong&gt; J. Med. Genet. 3: 86-91, 1966.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/5963214/&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;5963214&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1136/jmg.3.2.86&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="5963214">Schutta et al. (1966)</a> recognized a juvenile form of metachromatic leukodystrophy with onset between ages 4 and 10 years, as compared with the more frequent late infantile form with onset between ages 12 and 24 months. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=14467622+5963214" 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="#65" class="mim-tip-reference" title="Moser, H. W. &lt;strong&gt;Sulfatide lipidosis: metachromatic leukodystrophy. In: Stanbury, J. B.; Wyngaarden, J. B.; Fredrickson, D. S. (eds.): The Metabolic Basis of Inherited Disease. (3rd ed.)&lt;/strong&gt; New York: McGraw-Hill (pub.) 1972. Pp. 688-729."None>Moser (1972)</a> suggested that juvenile cases of MLD, especially those of late juvenile onset, should be classed with the adult form. An alternative possibility was that some of these cases with phenotype intermediate between those of the late infantile and adult forms represented genetic compounds. The same very low levels of arylsulfatase A were found in the infantile, juvenile, and adult forms, and the reason for the differences in age of onset was unknown.</p><p><a href="#89" class="mim-tip-reference" title="von Figura, K., Steckel, F., Conary, J., Hasilik, A., Shaw, E. &lt;strong&gt;Heterogeneity in late-onset metachromatic leukodystrophy: effect of inhibitors of cysteine proteinases.&lt;/strong&gt; Am. J. Hum. Genet. 39: 371-382, 1986.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/2876627/&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;2876627&lt;/a&gt;]" pmid="2876627">Von Figura et al. (1986)</a> pointed out that the late-onset form of MLD is a heterogeneous group in which symptoms may develop at any age beyond 3 years. The age of demarcation of juvenile forms from adult forms is somewhat arbitrarily set at age 16 by some and age 21 by others. In the late-onset forms the disease progresses more slowly, and in mild cases the diagnosis may even go unsuspected during life. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2876627" 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="#1" class="mim-tip-reference" title="Adang, L. A., Groeschel, S., Grzyb, C., D&#x27;Aiello, R., Gavazzi, F., Sherbini, O., Bronner, N., Patel, A., Vincent, A., Sevagamoorthy, A., Mutua, S., Muirhead, K., and 36 others. &lt;strong&gt;Developmental delay can precede neurologic regression in early onset metachromatic leukodystrophy.&lt;/strong&gt; Molec. Genet. Metab. 142: 108521, 2024.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/38964050/&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;38964050&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/j.ymgme.2024.108521&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="38964050">Adang et al. (2024)</a> performed a retrospective analysis of developmental features in patients with MLD prior to their disease diagnosis. There was a significant delay in attainment of developmental milestones in patients with late infantile MLD compared to patients with juvenile-onset or adult-onset MLD. Seventy-four of 194 patients with late infantile MLD had developmental delay or plateau prior to presentation and 73 never achieved ambulation. Developmental delay was reported in 35 of 157 patients with the later onset forms of MLD. Furthermore, a history of developmental delay correlated to an earlier onset of developmental regression. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=38964050" 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>Adult Form</em></strong></p><p>
In the adult form of metachromatic leukodystrophy, initial symptoms, which begin after age 16, are usually psychiatric and may lead to a diagnosis of schizophrenia. Disorders of movement and posture appear late. Differences from the late infantile form also include ability to demonstrate metachromatic material in paraffin- or celloidin-embedded sections and probably greater sulfatide excess in the gray than in the white matter in the adult form. The gallbladder is usually nonfunctional. <a href="#11" class="mim-tip-reference" title="Betts, T. A., Smith, W. T., Kelly, R. E. &lt;strong&gt;Adult metachromatic leukodystrophy (sulphatide lipidosis) simulating acute schizophrenia: report of a case.&lt;/strong&gt; Neurology 18: 1140-1142, 1968.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/5751920/&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;5751920&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1212/wnl.18.11.1140&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="5751920">Betts et al. (1968)</a> described a man who was 28 when admitted to a psychiatric hospital for 'acute schizophrenia' and 35 when he died of bronchopneumonia. <a href="#66" class="mim-tip-reference" title="Muller, D., Pilz, H., Ter Meulen, V. &lt;strong&gt;Studies on adult metachromatic leukodystrophy. I. Clinical, morphological and histochemical observations in two cases.&lt;/strong&gt; J. Neurol. Sci. 9: 567-584, 1969.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/4189441/&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;4189441&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/0022-510x(69)90095-1&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="4189441">Muller et al. (1969)</a> and <a href="#72" class="mim-tip-reference" title="Pilz, H., Muller, D. &lt;strong&gt;Studies on adult metachromatic leukodystrophy. II. Biochemical aspects of adult cases of metachromatic leukodystrophy.&lt;/strong&gt; J. Neurol. Sci. 9: 585-595, 1969.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/5367045/&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;5367045&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/0022-510x(69)90096-3&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="5367045">Pilz and Muller (1969)</a> described 2 unrelated women with this disorder. Affected sibs were recorded by <a href="#2" class="mim-tip-reference" title="Austin, J., Armstrong, D., Fouch, S., Mitchell, C., Stumpf, D. A., Shearer, L., Briner, O. &lt;strong&gt;Metachromatic leukodystrophy (MLD). VIII. MLD in adults: diagnosis and pathogenesis.&lt;/strong&gt; Arch. Neurol. 18: 225-240, 1968.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/5642751/&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;5642751&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1001/archneur.1968.00470330015001&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="5642751">Austin et al. (1968)</a>, among others. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=5751920+5367045+5642751+4189441" 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="Kihara, H., Fluharty, A. L., O&#x27;Brien, J. S., Fish, C. H. &lt;strong&gt;Metachromatic leukodystrophy caused by a partial cerebroside sulfatase defect.&lt;/strong&gt; Clin. Genet. 21: 253-261, 1982.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/6125284/&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;6125284&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1111/j.1399-0004.1982.tb00759.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="6125284">Kihara et al. (1982)</a> found partial cerebroside sulfatase deficiency (10-20% of normal activity in cultured fibroblasts) as the cause of neuropathy and myopathy since infancy in a 37-year-old white female. She had been institutionalized since age 16 for mental retardation. <a href="#91" class="mim-tip-reference" title="Waltz, G., Harik, S. I., Kaufman, B. &lt;strong&gt;Adult metachromatic leukodystrophy: value of computed tomographic scanning and magnetic resonance imaging of the brain.&lt;/strong&gt; Arch. Neurol. 44: 225-227, 1987.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/3813937/&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;3813937&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1001/archneur.1987.00520140083022&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="3813937">Waltz et al. (1987)</a> described a 38-year-old man who had been diagnosed as schizophrenic and was treated for that condition for many years. The diagnosis of adult MLD was suspected because of white matter abnormalities detected by CT and MRI scanning of the brain; this diagnosis was confirmed by discovery of markedly reduced leukocyte arylsulfatase A activity. The man held a master's degree in physical education and worked full-time as a high school physical education teacher. Personality changes were first noted at about age 31. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=6125284+3813937" 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="#77" class="mim-tip-reference" title="Propping, P., Friedl, W., Huschka, M., Schlor, K.-H., Reimer, F., Lee-Vaupel, M., Conzelmann, E., Sandhoff, K. &lt;strong&gt;The influence of low arylsulfatase A activity on neuropsychiatric morbidity: a large-scale screening in patients.&lt;/strong&gt; Hum. Genet. 74: 244-248, 1986.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/2877931/&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;2877931&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1007/BF00282542&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="2877931">Propping et al. (1986)</a> studied consecutive admissions to a state psychiatric hospital and a group of inpatients with chronic psychiatric disorders. The data showed a slight preponderance in the lower levels of arylsulfatase A in leukocytes. <a href="#57" class="mim-tip-reference" title="Kohn, H., Manowitz, P., Miller, M., Kling, A. &lt;strong&gt;Neuropsychological deficits in obligatory heterozygotes for metachromatic leukodystrophy.&lt;/strong&gt; Hum. Genet. 79: 8-12, 1988.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/3366464/&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;3366464&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1007/BF00291701&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="3366464">Kohn et al. (1988)</a> found no neurologic or EEG changes in MLD heterozygotes but found deficits in the neuropsychologic tests involving spatial or constructional components (but not in tests involving language skills). Tay-Sachs heterozygotes (<a href="/entry/272800">272800</a>) showed no consistent deficit in any component of the neurologic or neuropsychologic tests. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=2877931+3366464" 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="Marcao, A. M., Wiest, R., Schindler, K., Wiesmann, U., Weis, J., Schroth, G., Miranda, M. C. S., Sturzenegger, M., Gieselmann, V. &lt;strong&gt;Adult onset metachromatic leukodystrophy without electroclinical peripheral nervous system involvement: a new mutation in the ARSA gene.&lt;/strong&gt; Arch. Neurol. 62: 309-313, 2005.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/15710861/&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;15710861&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1001/archneur.62.2.309&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="15710861">Marcao et al. (2005)</a> reported a woman with adult-onset MLD confirmed by genetic analysis. She presented at age 37 years with dysfunctional and bizarre behavior, including progressive apathy, loss of interest in daily living routines and caring for her 3 children, and memory disturbances. She had no clinical signs of neuropathy, although MRI showed subcortical brain atrophy and periventricular white matter changes. Nerve conduction velocities were normal; sural nerve biopsy findings were consistent with a slowly progressive demyelinating neuropathy. Despite the relatively mild clinical phenotype, ARSA activity was less than 1% of control values. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15710861" 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>Biochemical Features</em></strong></p><p>
<a href="#5" class="mim-tip-reference" title="Austin, J., McAfee, D., Armstrong, D., O&#x27;Rourke, M., Shearer, L., Bachhawat, B. K. &lt;strong&gt;Abnormal sulphatase activities in two human diseases (metachromatic leukodystrophy and gargoylism).&lt;/strong&gt; Biochem. J. 93: 15C-17C, 1964.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/4953831/&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;4953831&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1042/bj0930015c&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="4953831">Austin et al. (1964)</a> determined that the defect in MLD involves the lysosomal enzyme arylsulfatase A. Since the metachromatic material is cerebroside sulfate, MLD is a sulfatide lipidosis. <a href="#85" class="mim-tip-reference" title="Stumpf, D. A., Austin, J. &lt;strong&gt;Metachromatic leukodystrophy (MLD). IX. Qualitative and quantitative differences in urinary arylsulfatase A in different forms of MLD.&lt;/strong&gt; Arch. Neurol. 24: 117-124, 1971.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/5540376/&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;5540376&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1001/archneur.1971.00480320045004&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="5540376">Stumpf and Austin (1971)</a> presented evidence suggesting that the abnormality in arylsulfatase A is quantitatively and qualitatively different in the late infantile and juvenile forms of metachromatic leukodystrophy. <a href="#69" class="mim-tip-reference" title="Percy, A. K., Kaback, M. M. &lt;strong&gt;Infantile and adult-onset metachromatic leukodystrophy: biochemical comparisons and predictive diagnosis.&lt;/strong&gt; New Eng. J. Med. 285: 785-787, 1971.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/5567265/&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;5567265&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1056/NEJM197109302851407&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="5567265">Percy and Kaback (1971)</a> found no difference in enzyme levels between the infantile and adult-onset types, and concluded that some other factor must account for the difference in age of onset. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=5567265+4953831+5540376" 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="#75" class="mim-tip-reference" title="Porter, M. T., Fluharty, A. L., Kihara, H. &lt;strong&gt;Correction of abnormal cerebroside sulfate metabolism in cultured metachromatic leukodystrophy fibroblasts.&lt;/strong&gt; Science 172: 1263-1265, 1971.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/5576165/&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;5576165&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1126/science.172.3989.1263&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="5576165">Porter et al. (1971)</a> corrected the metabolic defect in cultured fibroblasts by addition of arylsulfatase A to the medium. They found that cultured fibroblasts from late-onset metachromatic leukodystrophy hydrolyzed appreciable amounts of exogenous cerebroside sulfate, whereas fibroblasts from patients with the early-onset form hydrolyzed none. Studies of cell-free preparations showed no cerebroside sulfatase activity. <a href="#68" class="mim-tip-reference" title="Percy, A. K., Kaback, M. M., Herndon, R. M. &lt;strong&gt;Metachromatic leukodystrophy: comparison of early- and late-onset forms.&lt;/strong&gt; Neurology 27: 933-941, 1977.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/561906/&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;561906&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1212/wnl.27.10.933&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="561906">Percy et al. (1977)</a> found that cultured skin fibroblasts from the adult-onset patients, although clearly abnormal, were able to catabolize sulfatide significantly more effectively than cultured skin fibroblasts from late infantile patients. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=561906+5576165" 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 the technique of isoelectric focusing on cellulose acetate membranes, <a href="#31" class="mim-tip-reference" title="Farrell, D. F., MacMartin, M. P., Clark, A. F. &lt;strong&gt;Multiple molecular forms of arylsulfatase A in different forms of metachromatic leukodystrophy (MLD).&lt;/strong&gt; Neurology 29: 16-20, 1979.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/34126/&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;34126&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1212/wnl.29.1.16&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="34126">Farrell et al. (1979)</a> found differences in arylsulfatase A isozymes that correlated with the clinical type of metachromatic leukodystrophy, i.e., juvenile or late infantile. <a href="#23" class="mim-tip-reference" title="Chang, P. L., Rosa, N. E., Davidson, R. G. &lt;strong&gt;Somatic cell hybridization studies on the genetic regulation and allelic mutations in metachromatic leukodystrophy.&lt;/strong&gt; Hum. Genet. 61: 231-235, 1982.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/7173866/&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;7173866&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1007/BF00296448&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="7173866">Chang et al. (1982)</a> showed that fusion of cells from the infantile and juvenile forms of MLD did not result in complementation of arylsulfatase A activity, and concluded that they are allelic disorders. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=34126+7173866" 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 the cells from patients with juvenile and adult forms of MLD, <a href="#90" class="mim-tip-reference" title="von Figura, K., Steckel, F., Hasilik, A. &lt;strong&gt;Juvenile and adult metachromatic leukodystrophy: partial restoration of arylsulfatase A (cerebroside sulfatase) activity by inhibitors of thiol proteinases.&lt;/strong&gt; Proc. Nat. Acad. Sci. 80: 6066-6070, 1983.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/6136972/&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;6136972&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1073/pnas.80.19.6066&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="6136972">von Figura et al. (1983)</a> found severe deficiency in the arylsulfatase polypeptide but a rate of synthesis that was 20 to 50% of control. In the absence of NH4Cl, the mutant enzyme was rapidly degraded upon transport into lysosomes. In the presence of inhibitors of thiol proteases, e.g., leupeptin, arylsulfatase A polypeptides were partially protected from degradation with increase in catalytic activity of arylsulfatase A and improved ability of the cells to degrade cerebroside sulfates. Therapeutic use of this approach was suggested. The approach might be useful in other lysosomal storage diseases in which an unstable mutant enzyme is produced, e.g., the late form of glycogen storage disease II (<a href="/entry/232300">232300</a>). In a study of 8 patients with the juvenile form of MLD, <a href="#89" class="mim-tip-reference" title="von Figura, K., Steckel, F., Conary, J., Hasilik, A., Shaw, E. &lt;strong&gt;Heterogeneity in late-onset metachromatic leukodystrophy: effect of inhibitors of cysteine proteinases.&lt;/strong&gt; Am. J. Hum. Genet. 39: 371-382, 1986.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/2876627/&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;2876627&lt;/a&gt;]" pmid="2876627">von Figura et al. (1986)</a> found that the mutation leads to the synthesis of arylsulfatase A polypeptides with increased susceptibility to cysteine proteinases. Multiple allelic mutations within this group were suggested by clinical heterogeneity, variability in residual activity, and response to inhibitors (cysteine proteinases). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=6136972+2876627" 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>Pseudoarylsulfatase A deficiency</em></strong></p><p>
Pseudoarylsulfatase A deficiency refers to a condition of apparent ARSA enzyme deficiency in persons without neurologic abnormalities. <a href="#29" class="mim-tip-reference" title="Dubois, G., Harzer, K., Baumann, N. &lt;strong&gt;Very low arylsulfatase A and cerebroside sulfatase activities in leukocytes of healthy members of metachromatic leukodystrophy family.&lt;/strong&gt; Am. J. Hum. Genet. 29: 191-194, 1977.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/15452/&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;15452&lt;/a&gt;]" pmid="15452">Dubois et al. (1977)</a> described very low arylsulfatase A and cerebroside sulfatase activities in leukocytes of healthy members of a metachromatic leukodystrophy family. <a href="#60" class="mim-tip-reference" title="Langenbeck, U., Dunker, P., Heipertz, R., Pilz, H. &lt;strong&gt;Inheritance of metachromatic leukodystrophy. (Letter)&lt;/strong&gt; Am. J. Hum. Genet. 29: 639-640, 1977.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/930929/&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;930929&lt;/a&gt;]" pmid="930929">Langenbeck et al. (1977)</a> proposed a one locus, multiple allele hypothesis to explain the peculiar findings in that kindred. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=15452+930929" 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="#19" class="mim-tip-reference" title="Butterworth, J., Broadhead, D. M., Keay, A. J. &lt;strong&gt;Low arylsulphatase A activity in a family without metachromatic leukodystrophy.&lt;/strong&gt; Clin. Genet. 14: 213-218, 1978.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/699360/&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;699360&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1111/j.1399-0004.1978.tb02133.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="699360">Butterworth et al. (1978)</a> reported a child with very low levels of the enzyme whose mother was, seemingly, heterozygous and whose father carried a variant gene giving a very low in vitro level. They concluded that low arylsulfatase A is not necessarily indicative of this disease, which should be taken into consideration when screening for the disease. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=699360" 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 pseudodeficiency allele at the arylsulfatase A locus was delineated by <a href="#82" class="mim-tip-reference" title="Schaap, T., Zlotogora, J., Elian, E., Barak, Y., Bach, G. &lt;strong&gt;The genetics of the aryl sulfatase A locus.&lt;/strong&gt; Am. J. Hum. Genet. 33: 531-539, 1981.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/6114634/&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;6114634&lt;/a&gt;]" pmid="6114634">Schaap et al. (1981)</a>. Clinically healthy persons with ARSA levels in the range of MLD patients have been found among the relatives of MLD patients. Cultured fibroblasts from persons with pseudodeficiency catabolize cerebroside sulfate; fibroblasts from MLD patients do not. <a href="#95" class="mim-tip-reference" title="Zlotogora, J., Bach, G. &lt;strong&gt;Deficiency of lysosomal hydrolases in apparently healthy individuals.&lt;/strong&gt; Am. J. Med. Genet. 14: 73-80, 1983.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/6131608/&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;6131608&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ajmg.1320140112&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="6131608">Zlotogora and Bach (1983)</a> pointed out that lysosomal hydrolases deficient in cases of metachromatic leukodystrophy, Tay-Sachs disease, Fabry disease, and Krabbe disease have also been found to be deficient in healthy persons. The authors suggested that most of the latter cases represent the compound heterozygote for the deficient allele and another allele coding for an in vitro low enzyme activity (pseudodeficiency). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=6114634+6131608" 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="#22" class="mim-tip-reference" title="Chang, P. L., Davidson, R. G. &lt;strong&gt;Pseudo arylsulfatase-A deficiency in healthy individuals: genetic and biochemical relationship to metachromatic leukodystrophy.&lt;/strong&gt; Proc. Nat. Acad. Sci. 80: 7323-7327, 1983.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/6580647/&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;6580647&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1073/pnas.80.23.7323&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="6580647">Chang and Davidson (1983)</a> could demonstrate no restoration of activity of arylsulfatase A in hybrid cells created from cells of individuals with MLD and individuals with pseudo-ARSA deficiency. They concluded, therefore, that the 2 mutations are allelic. They showed that the 2 conditions can be distinguished in the laboratory by a simple electrophoretic analysis of residual ARSA activity. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=6580647" 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="Kihara, H., Meek, W. E., Fluharty, A. L. &lt;strong&gt;Attenuated activities and structural alterations of arylsulfatase A in tissues from subjects with pseudo arylsulfatase A deficiency.&lt;/strong&gt; Hum. Genet. 74: 59-62, 1986.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/2875937/&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;2875937&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1007/BF00278786&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="2875937">Kihara et al. (1986)</a> noted that the apparent enzyme deficiency in persons without neurologic abnormalities is due in part to the nonspecificity of the synthetic substrates used for assays and in part to a high redundancy of arylsulfatase A. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2875937" 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="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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<p><a href="#5" class="mim-tip-reference" title="Austin, J., McAfee, D., Armstrong, D., O&#x27;Rourke, M., Shearer, L., Bachhawat, B. K. &lt;strong&gt;Abnormal sulphatase activities in two human diseases (metachromatic leukodystrophy and gargoylism).&lt;/strong&gt; Biochem. J. 93: 15C-17C, 1964.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/4953831/&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;4953831&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1042/bj0930015c&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="4953831">Austin et al. (1964)</a> determined that the defect concerns the lysosomal enzyme arylsulfatase A. Austin's test to demonstrate absence of arylsulfatase A activity in the urine was useful in early diagnosis (<a href="#38" class="mim-tip-reference" title="Greene, H., Hug, G., Schubert, W. K. &lt;strong&gt;Arylsulfatase A in the urine and metachromatic leukodystrophy.&lt;/strong&gt; J. Pediat. 71: 709-711, 1967.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/6054756/&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;6054756&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/s0022-3476(67)80207-5&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="6054756">Greene et al., 1967</a>). <a href="#50" class="mim-tip-reference" title="Kaback, M. M., Howell, R. R. &lt;strong&gt;Infantile metachromatic leukodystrophy: heterozygote detection in skin fibroblasts and possible applications to intrauterine diagnosis.&lt;/strong&gt; New Eng. J. Med. 282: 1336-1340, 1970.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/4192207/&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;4192207&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1056/NEJM197006112822403&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="4192207">Kaback and Howell (1970)</a> demonstrated profound deficiency of arylsulfatase A in cultured skin fibroblasts of patients and an intermediate deficiency in carriers. Normally enzyme levels are low in midtrimester amniotic cells; hence, homozygotes cannot be reliably identified by amniocentesis. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=6054756+4953831+4192207" 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>Prenatal Diagnosis</em></strong></p><p>
<a href="#73" class="mim-tip-reference" title="Poenaru, L., Castelnau, L., Besancon, A.-M., Nicolesco, H., Akli, S., Theophil, D. &lt;strong&gt;First trimester prenatal diagnosis of metachromatic leukodystrophy on chorionic villi by &#x27;immunoprecipitation-electrophoresis.&#x27;.&lt;/strong&gt; J. Inherit. Metab. Dis. 11: 123-130, 1988.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/2902245/&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;2902245&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1007/BF01799861&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="2902245">Poenaru et al. (1988)</a> described a method of first-trimester prenatal diagnosis of metachromatic leukodystrophy using immunoprecipitation-electrophoresis on chorionic villus material. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2902245" 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="#7" class="mim-tip-reference" title="Baldinger, S., Pierpont, M. E., Wenger, D. A. &lt;strong&gt;Pseudodeficiency of arylsulfatase A: a counseling dilemma.&lt;/strong&gt; Clin. Genet. 31: 70-76, 1987.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/2881636/&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;2881636&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1111/j.1399-0004.1987.tb02772.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="2881636">Baldinger et al. (1987)</a> discussed the complications of genetic counseling and prenatal diagnosis resulting from the occurrence of the pseudodeficiency phenotype. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2881636" 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="clinicalManagement" class="mim-anchor"></a>
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<strong>Clinical Management</strong>
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<p><a href="#8" class="mim-tip-reference" title="Bayever, E., Ladisch, S., Philippart, M., Brill, N., Nuwer, M., Sparkes, R. S., Feig, S. A. &lt;strong&gt;Bone-marrow transplantation for metachromatic leucodystrophy.&lt;/strong&gt; Lancet 326: 471-473, 1985. Note: Originally Volume II.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/2863494/&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;2863494&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/s0140-6736(85)90402-7&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="2863494">Bayever et al. (1985)</a> observed apparent improvement (i.e., continued developmental progress) in a boy with late infantile MLD given a bone marrow transplant from an HLA-identical sister. <a href="#59" class="mim-tip-reference" title="Krivit, W., Shapiro, E., Kennedy, W., Lipton, M., Lockman, L., Smith, S., Summers, C. G., Wenger, D. A., Tsai, M. Y., Ramsay, N. K. C., Kersey, J. H., Yao, J. K., Kaye, E. &lt;strong&gt;Treatment of late infantile metachromatic leukodystrophy by bone marrow transplantation.&lt;/strong&gt; New Eng. J. Med. 322: 28-32, 1990.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/1967188/&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;1967188&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1056/NEJM199001043220106&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="1967188">Krivit et al. (1990)</a> reported improvement in neurophysiologic function and sulfatide metabolism in an affected 10-year-old girl who had received a bone marrow transplant 5 years previously. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=2863494+1967188" 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="Pierson, T. M., Bonnemann, C. G., Finkel, R. S., Bunin, N., Tennekoon, G. I. &lt;strong&gt;Umbilical cord blood transplantation for juvenile metachromatic leukodystrophy.&lt;/strong&gt; Ann. Neurol. 64: 583-587, 2008.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/19067349/&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;19067349&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ana.21522&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="19067349">Pierson et al. (2008)</a> reported 3 sibs with juvenile MLD who received unrelated umbilical cord blood transplantation at different stages of disease: they were 8, 6, and 4 years old, respectively, at the time of treatment. The 8-year-old boy had an IQ of 59, spasticity, and white matter lesions on MRI before transplant and experienced disease progression after transplant. His 6-year-old brother had an IQ of 88 and moderate white matter lesions before transplant, but remained neurologically stable and showed some improvement in nerve conduction velocity and near resolution of white matter lesions after transplant. His 4-year-old sister had no neurologic impairment or white matter lesions before transplant, and remained normal after transplant. She developed mild white matter lesions about 6 months after transplant, but these resolved within the following 6 months. <a href="#70" class="mim-tip-reference" title="Pierson, T. M., Bonnemann, C. G., Finkel, R. S., Bunin, N., Tennekoon, G. I. &lt;strong&gt;Umbilical cord blood transplantation for juvenile metachromatic leukodystrophy.&lt;/strong&gt; Ann. Neurol. 64: 583-587, 2008.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/19067349/&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;19067349&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ana.21522&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="19067349">Pierson et al. (2008)</a> concluded that pretransplantation neurologic status is the best predictor of outcome following cord blood transplant and that cord blood transplant can stop disease progression in MLD. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19067349" 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="Wang, R. Y., Bodamer, O. A., Watson, M. S., Wilcox, W. R. &lt;strong&gt;Lysosomal storage diseases: diagnostic confirmation and management of presymptomatic individuals.&lt;/strong&gt; Genet. Med. 13: 457-484, 2011.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/21502868/&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;21502868&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1097/GIM.0b013e318211a7e1&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="21502868">Wang et al. (2011)</a> described the ACMG standards and guidelines for the diagnostic confirmation and management of presymptomatic individuals with lysosomal storage diseases. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21502868" 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="Biffi, A., Montini, E., Lorioli, L., Cesani, M., Fumagalli, F., Plati, T., Baldoli, C., Martino, S., Calabria, A., Canale, S., Benedicenti, F., Vallanti, G., and 25 others. &lt;strong&gt;Lentiviral hematopoietic stem cell gene therapy benefits metachromatic leukodystrophy.&lt;/strong&gt; Science 341: 1233158, 2013. Note: Electronic Article.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/23845948/&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;23845948&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1126/science.1233158&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="23845948">Biffi et al. (2013)</a> performed lentiviral hematopoietic stem cell (HSC) gene therapy on 3 asymptomatic children with ARSA deficiency known because of older sibs with early-onset MLD carrying the same mutations. Following myeloablative busulfan conditioning, patients were transduced with hematopoietic stem cells with the lentiviral gene. There was high-level stable engraftment of the transduced HSCs in bone marrow and peripheral blood of all patients at all times tested, with 45 to 80% of bone marrow-derived hematopoietic colonies harboring the vector. ARSA activity was reconstituted to above-normal values in the hematopoietic lineages and in the cerebrospinal fluid. None of the 3 patients had progression of disease at up to 24 months after treatment, even after the time of onset projected from sib cases. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23845948" 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="#26" class="mim-tip-reference" title="Dali, C., Sevin, C., Krageloh-Mann, I., Giugliani, R., Sakai, N., Wu, J., Wasilewski, M. &lt;strong&gt;Safety of intrathecal delivery of recombinant human arylsulfatase A in children with metachromatic leukodystrophy: results from a phase 1/2 clinical trial.&lt;/strong&gt; Molec. Genet. Metab. 131: 235-244, 2020.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/32792226/&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;32792226&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/j.ymgme.2020.07.002&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="32792226">Dali et al. (2020)</a> tested the safety of intrathecal administration of recombinant human arylsulfatase A (rhASA) in 24 children with MLD in an open-label, 38-week study. Patients were assigned to cohorts and treated with either 10, 30, or 100 mg of rhASA every other week. There were no deaths and no drug-related serious adverse events, although 25% of patients had a serious adverse event associated with the intrathecal device or drug delivery method. Ten patients developed treatment-induced anti-rhASA antibodies in serum, but there was no correlation between serum antibody response and adverse events. <a href="#26" class="mim-tip-reference" title="Dali, C., Sevin, C., Krageloh-Mann, I., Giugliani, R., Sakai, N., Wu, J., Wasilewski, M. &lt;strong&gt;Safety of intrathecal delivery of recombinant human arylsulfatase A in children with metachromatic leukodystrophy: results from a phase 1/2 clinical trial.&lt;/strong&gt; Molec. Genet. Metab. 131: 235-244, 2020.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/32792226/&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;32792226&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/j.ymgme.2020.07.002&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="32792226">Dali et al. (2020)</a> found dose- and time-dependent reductions in CSF sulfatide and lysosulfatide levels at all doses, with levels reduced to the normal range in patients receiving the 100 mg dose. <a href="#26" class="mim-tip-reference" title="Dali, C., Sevin, C., Krageloh-Mann, I., Giugliani, R., Sakai, N., Wu, J., Wasilewski, M. &lt;strong&gt;Safety of intrathecal delivery of recombinant human arylsulfatase A in children with metachromatic leukodystrophy: results from a phase 1/2 clinical trial.&lt;/strong&gt; Molec. Genet. Metab. 131: 235-244, 2020.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/32792226/&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;32792226&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/j.ymgme.2020.07.002&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="32792226">Dali et al. (2020)</a> concluded that rhASA was generally well-tolerated at doses up to 100 mg administered every other week. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=32792226" 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="#51" class="mim-tip-reference" title="Kaminski, D., Yaghootfam, C., Matthes, F., Ressing, A., Gieselmann, V., Matzner, U. &lt;strong&gt;Brain cell type-specific endocytosis of arylsulfatase A identifies limitations of enzyme-based therapies for metachromatic leukodystrophy.&lt;/strong&gt; Hum. Molec. Genet. 29: 3807-3817, 2020.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/33367737/&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;33367737&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1093/hmg/ddaa277&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="33367737">Kaminski et al. (2020)</a> examined the in vitro uptake of arylsulfatase A by different brain-derived cell lines and primary murine brain cells. Endocytosis of human ASA expressed by Chinese hamster ovary (CHO) cells was highest in primary murine neurons and astrocytes and lowest in oligodendrocytes. Immature oligodendrocytes were able to endocytose this form of ASA. Mannose 6-phosphate (M6P) was able to inhibit ASA uptake by nonglial cells, indicating that the mechanism of uptake of ASA was through M6P receptor-mediated endocytosis. Primary murine microglial cells were found to employ a combination of M6P-receptors, mannose receptors, and scavenger receptors to endocytose ASA. As opposed to the ASA expressed by CHO cells, ASA expressed by microglial cells was not taken up in an M6P-dependent fashion by mouse embryonic fibroblasts, indicating failure of metabolic cross-correction by receptor-mediated endocytosis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=33367737" 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="molecularGenetics" class="mim-anchor"></a>
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<strong>Molecular Genetics</strong>
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<p>In patients with MLD, <a href="#74" class="mim-tip-reference" title="Polten, A., Fluharty, A. L., Fluharty, C. B., Kappler, J., von Figura, K., Gieselmann, V. &lt;strong&gt;Molecular basis of different forms of metachromatic leukodystrophy.&lt;/strong&gt; New Eng. J. Med. 324: 18-22, 1991.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/1670590/&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;1670590&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1056/NEJM199101033240104&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="1670590">Polten et al. (1991)</a>, <a href="#34" class="mim-tip-reference" title="Gieselmann, V., Fluharty, A. L., Tonnesen, T., Von Figura, K. &lt;strong&gt;Mutations in the arylsulfatase A pseudodeficiency allele causing metachromatic leukodystrophy.&lt;/strong&gt; Am. J. Hum. Genet. 49: 407-413, 1991.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/1678251/&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;1678251&lt;/a&gt;]" pmid="1678251">Gieselmann et al. (1991)</a>, <a href="#58" class="mim-tip-reference" title="Kondo, R., Wakamatsu, N., Yoshino, H., Fukuhara, N., Miyatake, T., Tsuji, S. &lt;strong&gt;Identification of a mutation in the arylsulfatase A gene of a patient with adult-type metachromatic leukodystrophy.&lt;/strong&gt; Am. J. Hum. Genet. 48: 971-978, 1991.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/1673291/&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;1673291&lt;/a&gt;]" pmid="1673291">Kondo et al. (1991)</a>, <a href="#15" class="mim-tip-reference" title="Bohne, W., von Figura, K., Gieselmann, V. &lt;strong&gt;An 11-bp deletion in the arylsulfatase A gene of a patient with late infantile metachromatic leukodystrophy.&lt;/strong&gt; Hum. Genet. 87: 155-158, 1991.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/1676699/&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;1676699&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1007/BF00204172&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="1676699">Bohne et al. (1991)</a>, and <a href="#33" class="mim-tip-reference" title="Fluharty, A. L., Fluharty, C. B., Bohne, W., von Figura, K., Gieselmann, V. &lt;strong&gt;Two new arylsulfatase A (ARSA) mutations in a juvenile metachromatic leukodystrophy (MLD) patient.&lt;/strong&gt; Am. J. Hum. Genet. 49: 1340-1350, 1991.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/1684088/&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;1684088&lt;/a&gt;]" pmid="1684088">Fluharty et al. (1991)</a> identified mutations in the ARSA gene (e.g., <a href="/entry/607574#0003">607574.0003</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=1678251+1684088+1676699+1670590+1673291" 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="Gieselmann, V., Zlotogora, J., Harris, A., Wenger, D. A., Morris, C. P. &lt;strong&gt;Molecular genetics of metachromatic leukodystrophy.&lt;/strong&gt; Hum. Mutat. 4: 233-242, 1994.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/7866401/&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;7866401&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/humu.1380040402&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="7866401">Gieselmann et al. (1994)</a> stated that 31 amino acid substitutions, 1 nonsense mutation, 3 small deletions, 3 splice donor site mutations, and 1 combined missense/splice donor site mutation had been identified in the ARSA gene in metachromatic leukodystrophy. Two of these mutant alleles account for about 25% of MLD alleles each. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7866401" 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>Pseudodeficiency Alleles</em></strong></p><p>
<a href="#35" class="mim-tip-reference" title="Gieselmann, V., Polten, A., Kreysing, J., von Figura, K. &lt;strong&gt;Arylsulfatase A pseudodeficiency: loss of a polyadenylylation (sic) signal and N-glycosylation site.&lt;/strong&gt; Proc. Nat. Acad. Sci. 86: 9436-9440, 1989.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/2574462/&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;2574462&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1073/pnas.86.23.9436&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="2574462">Gieselmann et al. (1989)</a> determined 2 pseudodeficiency alleles of the ARSA gene (<a href="/entry/607574#0001">607574.0001</a>-<a href="/entry/607574#0002">607574.0002</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2574462" 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="genotypePhenotypeCorrelations" class="mim-anchor"></a>
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<strong>Genotype/Phenotype Correlations</strong>
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<p><a href="#47" class="mim-tip-reference" title="Hohenschutz, C., Friedl, W., Schlor, K.-H., Waheed, A., Conzelmann, E., Sandhoff, K., Propping, P. &lt;strong&gt;Probable metachromatic leukodystrophy/pseudodeficiency compound heterozygote at the arylsulfatase A locus with neurological and psychiatric symptomatology.&lt;/strong&gt; Am. J. Med. Genet. 31: 169-175, 1988.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/2906225/&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;2906225&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ajmg.1320310120&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="2906225">Hohenschutz et al. (1988)</a> described a probable case of the genetic compound between metachromatic leukodystrophy and pseudodeficiency. The patient developed slight spasticity of the left leg at the age of 36 years and left-sided retrobulbar neuritis at the age of 62, together with slight spasticity of both legs. The diagnosis of encephalomyelitis disseminata was made. There were psychiatric manifestations as well. Based on the facts that the pseudodeficiency allele at the ARSA locus is common (gene frequency = 13.7 to 17%), that genetic compounds between the pseudodeficiency allele and the true deficiency allele may be as frequent as 0.073%, and that the residual enzyme activity may fall below a critical threshold in such individuals, <a href="#46" class="mim-tip-reference" title="Hohenschutz, C., Eich, P., Friedl, W., Waheed, A., Conzelmann, E., Propping, P. &lt;strong&gt;Pseudodeficiency of arylsulfatase A: a common genetic polymorphism with possible disease implications.&lt;/strong&gt; Hum. Genet. 82: 45-48, 1989.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/2565866/&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;2565866&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1007/BF00288270&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="2565866">Hohenschutz et al. (1989)</a> suggested that the compound heterozygote genotype might be associated with neuropsychiatric disorders of late onset. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=2906225+2565866" 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 34 individuals with low ASA activity, <a href="#52" class="mim-tip-reference" title="Kappler, J., Leinekugel, P., Conzelmann, E., Kleijer, W. J., Kohlschutter, A., Tonnesen, T., Rochel, M., Freycon, F., Propping, P. &lt;strong&gt;Genotype-phenotype relationship in various degrees of arylsulfatase A deficiency.&lt;/strong&gt; Hum. Genet. 86: 463-470, 1991.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/1673113/&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;1673113&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1007/BF00194634&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="1673113">Kappler et al. (1991)</a> identified 3 different classes: homozygosity for the pseudodeficiency allele (ASAp/ASAp) (10 individuals), compound heterozygosity for ASAp and ASA- (6 individuals), and homozygosity of ASA- (16 individuals). The genotypes exhibited different levels of residual ASA activity. ASAp/ASAp was associated with normal sulfatide degrading capacity and a reduced ASA activity that was the highest of the 3 classes (10-50% of normal). ASAp/ASAp subjects showed no evidence of MLD. ASAp/ASA- subjects showed mildly reduced sulfatide degrading capacity and a reduced ASA activity that was in between the other 2 classes (10% of controls). ASAp/ASA- subjects were either healthy or showed mild neurologic abnormalities. ASA-/ASA- subjects showed markedly reduced sulfatide degradation and markedly reduced ASA activity. Only the ASA-/ASA- genotype was associated with the development of both early- and late-onset MLD, including neuropsychiatric symptoms. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1673113" 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="#10" class="mim-tip-reference" title="Berger, J., Gmach, M., Mayr, U., Molzer, B., Bernheimer, H. &lt;strong&gt;Coincidence of two novel arylsulfatase A alleles and mutation 459+1G-A within a family with metachromatic leukodystrophy: molecular basis of phenotypic heterogeneity.&lt;/strong&gt; Hum. Mutat. 13: 61-68, 1999.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/9888390/&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;9888390&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/(SICI)1098-1004(1999)13:1&lt;61::AID-HUMU7&gt;3.0.CO;2-H&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="9888390">Berger et al. (1999)</a> described a family with 3 sibs, 1 of whom developed classic late infantile MLD, fatal at age 5 years, with deficient ARSA activity and increased galactosylsulfatide (GS) excretion. The other 2 sibs, apparently healthy at 12.5 and 15 years, and their father, apparently healthy as well, presented ARSA and GS values within the range of MLD patients. Mutation analysis demonstrated that 3 different ARSA mutations accounted for the intrafamilial phenotypic heterogeneity. One of the mutations, although clearly modifying ARSA and GS levels, apparently had little significance for clinical manifestation of MLD, The results demonstrated that in certain genetic conditions the ARSA and GS values may not be paralleled by clinical disease, a finding with serious diagnostic and prognostic implications. Moreover, further ARSA alleles functionally may exist which, together with 0-type mutations may cause ARSA and GS levels in the pathologic range but no clinical manifestation of the disease. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9888390" 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="#80" class="mim-tip-reference" title="Regis, S., Corsolini, F., Stroppiano, M., Cusano, R., Filocamo, M. &lt;strong&gt;Contribution of arylsulfatase A mutations located on the same allele to enzyme activity reduction and metachromatic leukodystrophy severity.&lt;/strong&gt; Hum. Genet. 110: 351-355, 2002.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/11941485/&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;11941485&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1007/s00439-002-0701-y&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="11941485">Regis et al. (2002)</a> identified a late infantile MLD patient carrying on one allele a novel E253K mutation (<a href="/entry/607574#0044">607574.0044</a>) and the known T391S polymorphism, and on the other allele the common P426L mutation (<a href="/entry/607574#0004">607574.0004</a>), usually associated with the adult or juvenile form of the disease, and the N350S (<a href="/entry/607574#0002">607574.0002</a>) and *96A-G pseudodeficiency mutations. To analyze the contribution of mutations based on the same allele to enzyme activity reduction, as well as the possible phenotype implications, they performed transient expression experiments using ARSA cDNAs carrying the identified mutations separately or in combination. Their results indicated that mutants carrying multiple mutations cause greater reduction of ARSA activity than do the corresponding single mutants, the total deficiency likely corresponding to the sum of the reductions attributed to each mutation. Consequently, each mutation may contribute to the ARSA activity reduction, and, therefore, to the degree of disease severity. This is particularly important for the alleles containing a disease-causing mutation and the pseudodeficiency mutations: in these alleles pseudodeficiency could play a role in affecting the clinical phenotype. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11941485" 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="#79" class="mim-tip-reference" title="Rauschka, H., Colsch, B., Baumann, N., Wevers, R., Schmidbauer, M., Krammer, M., Turpin, J.-C., Lefevre, M., Olivier, C., Tardieu, S., Krivit, W., Moser, H., and 10 others. &lt;strong&gt;Late-onset metachromatic leukodystrophy: genotype strongly influences phenotype.&lt;/strong&gt; Neurology 67: 859-863, 2006.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/16966551/&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;16966551&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1212/01.wnl.0000234129.97727.4d&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="16966551">Rauschka et al. (2006)</a> evaluated 42 patients with late-onset MLD, 22 of whom were homozygous for the P426L mutation and 20 of whom were compound heterozygous for I179S (<a href="/entry/607574#0008">607574.0008</a>) and another pathogenic ARSA mutation. Patients homozygous for the P426L mutation presented with progressive gait disturbance caused by spastic paraparesis or cerebellar ataxia; mental disturbance was absent or insignificant at disease onset but became more apparent as the disease evolved. Peripheral nerve conduction velocities were decreased. In contrast, patients who were heterozygous for I179S presented with schizophrenia-like behavior changes, social dysfunction, and mental decline, but motor deficits were scarce. There was less residual ARSA activity in those with P426L mutations compared to those with I179S mutations. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16966551" 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="#12" class="mim-tip-reference" title="Biffi, A., Cesani, M., Fumagalli, F., Del Carro, U., Baldoli, C., Canale, S., Gerevini, S., Amadio, S., Falautano, M., Rovelli, A., Comi, G., Roncarolo, M. G., Sessa, M. &lt;strong&gt;Metachromatic leukodystrophy-mutation analysis provides further evidence of genotype-phenotype correlation.&lt;/strong&gt; Clin. Genet. 74: 349-357, 2008.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/18786133/&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;18786133&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1111/j.1399-0004.2008.01058.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="18786133">Biffi et al. (2008)</a> reported 26 patients with MLD who were classified clinically according to age at onset into late-infantile (17), early juvenile (6), late-juvenile (2), and adult (1). These patients were found to carry 18 mutations in the ARSA gene, including 10 rare and 8 novel mutations, that were classified as null '0' alleles lacking residual activity and 'R' alleles with residual activity. The null/null homozygous patients were the most severely affected with severe clinical manifestations, profound motor and cognitive deficits, and rapid disease progression. Patients who were null/R compound heterozygous showed a similar presentation and disease evolution, although less rapid, to null/null homozygotes. Despite some variability, all R/R homozygous patients showed a milder disease burden and slower progression when compared with null/null and null/R subjects. <a href="#12" class="mim-tip-reference" title="Biffi, A., Cesani, M., Fumagalli, F., Del Carro, U., Baldoli, C., Canale, S., Gerevini, S., Amadio, S., Falautano, M., Rovelli, A., Comi, G., Roncarolo, M. G., Sessa, M. &lt;strong&gt;Metachromatic leukodystrophy-mutation analysis provides further evidence of genotype-phenotype correlation.&lt;/strong&gt; Clin. Genet. 74: 349-357, 2008.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/18786133/&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;18786133&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1111/j.1399-0004.2008.01058.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="18786133">Biffi et al. (2008)</a> observed early involvement of the peripheral nervous system in all patients with at least 1 null allele, and the authors suggested that evaluation of nerve conduction velocities could be used as a frontline test for all MLD patients, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18786133" 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="populationGenetics" class="mim-anchor"></a>
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<strong>Population Genetics</strong>
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<p>Although MLD occurs panethnically, with an estimated frequency of 1/40,000, <a href="#43" class="mim-tip-reference" title="Heinisch, U., Zlotogora, J., Kafert, S., Gieselmann, V. &lt;strong&gt;Multiple mutations are responsible for the high frequency of metachromatic leukodystrophy in a small geographic area.&lt;/strong&gt; Am. J. Hum. Genet. 56: 51-57, 1995.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/7825603/&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;7825603&lt;/a&gt;]" pmid="7825603">Heinisch et al. (1995)</a> found it to be more frequent among Arabs living in 2 restricted areas in Israel. Ten families with affected children were found, 3 in the Jerusalem region and 7 in a small area in lower Galilee. Whereas all patients from the Jerusalem region were homozygous for the splice donor site mutation at the border of exon/intron 2 (<a href="/entry/607574#0003">607574.0003</a>), 5 different mutations were found in the 7 families from lower Galilee, all of them in homozygous state. Two of the families were Muslim Arabs and 2 were Christian Arabs. Four different haplotypes were represented by the 5 mutations. <a href="#97" class="mim-tip-reference" title="Zlotogora, J., Gieselman, V., von Figura, K., Zeigler, M., Bach, G. &lt;strong&gt;Late infantile metachromatic leukodystrophy in Israel.&lt;/strong&gt; Biomed. Pharmacother. 48: 347-350, 1994.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/7858169/&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;7858169&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/0753-3322(94)90049-3&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="7858169">Zlotogora et al. (1994)</a> studied the ARSA haplotypes defined by 3 intragenic polymorphic sites in 3 Muslim Arab families and 1 Christian Arab family from Jerusalem with the splice donor site mutation at the border of exon/intron 2. The parents were first cousins in all 4 families, but no relationship between these families was known. All 4 patients had the same haplotype, i.e., BglI(1), BamHI(1), BsrI(1), which is rare (3.9%) in the general population. <a href="#96" class="mim-tip-reference" title="Zlotogora, J., Furman-Shaharabani, Y., Harris, A., Barth, M. L., von Figura, K., Gieselmann, V. &lt;strong&gt;A single origin for the most frequent mutation causing late infantile metachromatic leucodystrophy.&lt;/strong&gt; J. Med. Genet. 31: 672-674, 1994.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/7815434/&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;7815434&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1136/jmg.31.9.672&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="7815434">Zlotogora et al. (1994)</a> found the same haplotype in 8 non-Arab patients from the US and Europe who were homozygous for this allele. The strong association between this mutation and haplotype suggested a common origin for the mutation, which may have been introduced into Jerusalem at the time of the Crusades. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=7815434+7825603+7858169" 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="#48" class="mim-tip-reference" title="Holve, S., Hu, D., McCandless, S. E. &lt;strong&gt;Metachromatic leukodystrophy in the Navajo: fallout of the American-Indian Wars of the nineteenth century.&lt;/strong&gt; Am. J. Med. Genet. 101: 203-208, 2001.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/11424134/&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;11424134&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ajmg.1362&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="11424134">Holve et al. (2001)</a> found that cases of MLD among Navajo Indians were clustered in a portion of the western Navajo Nation to which a small number of Navajo fled after armed conflict with the United States Army in the 1860s. The observed incidence of MLD in that region was 1/2,520 live births, with an estimated carrier frequency of 1/25 to 1/50. No cases were observed in the eastern part of the Navajo Nation over a period of 18 years (60,000 births). Bottleneck and founder effect from the mid-19th century could explain the high incidence of MLD as well as a number of other heritable disorders among the Navajo. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11424134" 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 Israel, <a href="#44" class="mim-tip-reference" title="Herz, B., Bach, G. &lt;strong&gt;Arylsulfatase A in pseudodeficiency.&lt;/strong&gt; Hum. Genet. 66: 147-150, 1984.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/6143719/&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;6143719&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1007/BF00286589&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="6143719">Herz and Bach (1984)</a> estimated the frequency of the pseudodeficiency allele to be about 15%. In a Spanish population, <a href="#20" class="mim-tip-reference" title="Chabas, A., Castellvi, S., Bayes, M., Balcells, S., Grinberg, D., Vilageliu, L., Marfany, G., Lissens, W., Gonzalez-Duarte, R. &lt;strong&gt;Frequency of the arylsulphatase A pseudodeficiency allele in the Spanish population.&lt;/strong&gt; Clin. Genet. 44: 320-323, 1993.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/8131304/&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;8131304&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1111/j.1399-0004.1993.tb03908.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="8131304">Chabas et al. (1993)</a> estimated the frequency of the pseudodeficiency allele to be 12.7%. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=6143719+8131304" 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="#16" 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 (8.2%), Pelizaeus-Merzbacher disease (<a href="/entry/312080">312080</a>) (7.4%), mitochondrial diseases (4.9%), and adrenoleukodystrophy (<a href="/entry/300100">300100</a>) (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>
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<strong>History</strong>
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<p><a href="#93" class="mim-tip-reference" title="Yatziv, S., Russell, A. &lt;strong&gt;An unusual form of metachromatic leukodystrophy in three siblings.&lt;/strong&gt; Clin. Genet. 19: 222-227, 1981.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/6115727/&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;6115727&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1111/j.1399-0004.1981.tb00702.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="6115727">Yatziv and Russell (1981)</a> reported 3 adult sibs of Sephardic Jewish extraction who had a form of primary dystonia with onset in childhood. There was a marked deficiency of arylsulfatase A in urine, leukocytes, and fibroblasts. The clinically normal parents both showed a 50% reduction in ARSA activity. <a href="#93" class="mim-tip-reference" title="Yatziv, S., Russell, A. &lt;strong&gt;An unusual form of metachromatic leukodystrophy in three siblings.&lt;/strong&gt; Clin. Genet. 19: 222-227, 1981.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/6115727/&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;6115727&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1111/j.1399-0004.1981.tb00702.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="6115727">Yatziv and Russell (1981)</a> reported the disorder in this family as an 'unusual form of metachromatic leukodystrophy,' but <a href="#53" class="mim-tip-reference" title="Khan, N. L., Wood, N. W., Bhatia, K. P. &lt;strong&gt;Autosomal recessive, DYT2-like primary torsion dystonia: a new family.&lt;/strong&gt; Neurology 61: 1801-1803, 2003.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/14694054/&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;14694054&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1212/01.wnl.0000099076.17187.9a&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="14694054">Khan et al. (2003)</a> later reported that genetic analysis of the family indicated pseudoarylsulfatase A deficiency: the mother and all 3 sibs were homozygous, and the father was heterozygous, for the polyA pseudodeficiency allele (<a href="/entry/607574#0001">607574.0001</a>). <a href="#53" class="mim-tip-reference" title="Khan, N. L., Wood, N. W., Bhatia, K. P. &lt;strong&gt;Autosomal recessive, DYT2-like primary torsion dystonia: a new family.&lt;/strong&gt; Neurology 61: 1801-1803, 2003.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/14694054/&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;14694054&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1212/01.wnl.0000099076.17187.9a&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="14694054">Khan et al. (2003)</a> diagnosed the family with autosomal recessive primary dystonia (DYT2; <a href="/entry/224500">224500</a>); <a href="#24" class="mim-tip-reference" title="Charlesworth, G., Angelova, P. R., Bartolome-Robledo, F., Ryten, M., Trabzuni, D., Stamelou, M., Abramov, A. Y., Bhatia, K. P., Wood, N. W. &lt;strong&gt;Mutations in HPCA cause autosomal-recessive primary isolated dystonia.&lt;/strong&gt; Am. J. Hum. Genet. 96: 657-665, 2015.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/25799108/&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;25799108&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=25799108[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/10.1016/j.ajhg.2015.02.007&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="25799108">Charlesworth et al. (2015)</a> identified a homozygous missense mutation in the HPCA gene (N75K; <a href="/entry/142622#0001">142622.0001</a>) in the affected individuals, thus confirming the diagnosis. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=6115727+25799108+14694054" 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>Since no naturally occurring animal model of metachromatic leukodystrophy is available, <a href="#45" class="mim-tip-reference" title="Hess, B., Saftig, P., Hartmann, D., Coenen, R., Lullmann-Rauch, R., Goebel, H. H., Evers, M., von Figura, K., D&#x27;Hooge, R., Nagels, G., De Deyn, P., Peters, C., Gieselmann, V. &lt;strong&gt;Phenotype of arylsulfatase A-deficient mice: relationship to human metachromatic leukodystrophy.&lt;/strong&gt; Proc. Nat. Acad. Sci. 93: 14821-14826, 1996.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/8962139/&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;8962139&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=8962139[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.93.25.14821&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="8962139">Hess et al. (1996)</a> generated Arsa-deficient mice by targeted disruption of the gene in embryonic stem cells. Deficient animals stored the sphingolipid cerebroside-3-sulfate in various neuronal and nonneuronal tissues. Storage pattern was comparable with that in affected humans, but gross defect of white matter with progressive demyelination was not observed up to the age of 2 years. Reduction of axonal cross-sectional area and astrogliosis were observed in 1-year-old mice; activation of microglia started at 1 year and was generalized at 2 years. Purkinje cell dendrites showed altered morphology. In the acoustic ganglion numbers of neurons and myelinated fibers were severely decreased, which was accompanied by loss of brainstem auditory-evoked potentials. Neurologic examination demonstrated significant impairment of neuromotor coordination. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8962139" 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="#64" class="mim-tip-reference" title="Matzner, U., Herbst, E., Hedayati, K. K., Lullmann-Rauch, R., Wessig, C., Schroeder, S., Eistrup, C., Moeller, C., Fogh, J., Gieselmann, V. &lt;strong&gt;Enzyme replacement improves nervous system pathology and function in a mouse model for metachromatic leukodystrophy.&lt;/strong&gt; Hum. Molec. Genet. 14: 1139-1152, 2005.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/15772092/&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;15772092&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1093/hmg/ddi126&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="15772092">Matzner et al. (2005)</a> treated Arsa-knockout mice by intravenous injection of recombinant human ARSA. Uptake of injected enzyme was high into liver, moderate into peripheral nervous system (PNS) and kidney, and very low into brain. A single injection led to a time- and dose-dependent decline of the excess sulfatide in PNS and kidney by up to 70%, but no reduction was seen in brain. Four weekly injections of 20 mg/kg body weight not only reduced storage in peripheral tissues progressively, but also reduced sulfatide storage in brain and spinal cord. Histopathology of kidney and central nervous system was ameliorated. Improved neuromotor coordination capabilities and normalized peripheral compound motor action potential suggested benefit of enzyme replacement therapy on nervous system function. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15772092" 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="seeAlso" class="mim-anchor"></a>
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<a href="#Austin1967" class="mim-tip-reference" title="Austin, J. H. &lt;strong&gt;Some recent findings in leukodystrophies and in gargoylism. In: Aronson, S. M.; Volk, B. W. (eds.): Inborn Disorders of Sphingolipid Metabolism.&lt;/strong&gt; Oxford: Pergamon Press (pub.) 1967. Pp. 359-387.">Austin (1967)</a>; <a href="#Austin1965" class="mim-tip-reference" title="Austin, J., McAfee, D., Shearer, L. &lt;strong&gt;Metachromatic form of diffuse cerebral sclerosis. IV. Low sulfatase activity in the urine of nine living patients with metachromatic leukodystrophy (MLD).&lt;/strong&gt; Arch. Neurol. 12: 447-455, 1965.">Austin et al. (1965)</a>; <a href="#Beratis1975" class="mim-tip-reference" title="Beratis, N. G., Danesino, C., Hirschhorn, K. &lt;strong&gt;Detection of homozygotes and heterozygotes for metachromatic leukodystrophy in lymphoid cell lines and peripheral leukocytes.&lt;/strong&gt; Ann. Hum. Genet. 38: 485-493, 1975.">Beratis et al. (1975)</a>; <a href="#Black1961" class="mim-tip-reference" title="Black, J. W., Cumings, J. N. &lt;strong&gt;Infantile metachromatic leukodystrophy.&lt;/strong&gt; J. Neurol. Neurosurg. Psychiat. 24: 233-239, 1961.">Black and
Cumings (1961)</a>; <a href="#Bosch1978" class="mim-tip-reference" title="Bosch, E. P., Hart, M. N. &lt;strong&gt;Late adult-onset metachromatic leukodystrophy: dementia and polyneuropathy in a 63-year-old man.&lt;/strong&gt; Arch. Neurol. 35: 475-477, 1978.">Bosch and Hart (1978)</a>; <a href="#Bruns1978" class="mim-tip-reference" title="Bruns, G. A. P., Mintz, B. J., Leary, A. C., Regina, V. M., Gerald, P. S. &lt;strong&gt;Expression of human arylsulfatase A in man-hamster somatic cell hybrids.&lt;/strong&gt; Cytogenet. Cell Genet. 22: 182-185, 1978.">Bruns et al. (1978)</a>; <a href="#Chang1980" class="mim-tip-reference" title="Chang, P. L., Davidson, R. G. &lt;strong&gt;Complementation of arylsulfatase A in somatic hybrids of metachromatic leukodystrophy and multiple sulfatase deficiency disorder fibroblasts.&lt;/strong&gt; Proc. Nat. Acad. Sci. 77: 6166-6170, 1980.">Chang and
Davidson (1980)</a>; <a href="#Cravioto1967" class="mim-tip-reference" title="Cravioto, H., O&#x27;Brien, J., Lockwood, R., Kasten, F. H., Booker, J. &lt;strong&gt;Metachromatic leukodystrophy (sulfatide lipidoses) cultured in vitro.&lt;/strong&gt; Science 156: 243-245, 1967.">Cravioto et al. (1967)</a>; <a href="#DeLuca1979" class="mim-tip-reference" title="DeLuca, C., Brown, J. A., Shows, T. B. &lt;strong&gt;Lysosomal arylsulfatase deficiencies in humans: chromosome assignment of arylsulfatase A and B.&lt;/strong&gt; Proc. Nat. Acad. Sci. 76: 1957-1961, 1979.">DeLuca et al. (1979)</a>; <a href="#DeLuca1977" class="mim-tip-reference" title="DeLuca, C., Champion, M. J., Shows, T. B. &lt;strong&gt;Arylsulfatase-A (ARSA) synteny with beta-glucuronidase (BGUS) indicates assignment to human chromosome 7 in man-Chinese hamster hybrids. (Abstract)&lt;/strong&gt; Gene Mapping Conference, Winnipeg 1977.">DeLuca
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(1977)</a>; <a href="#Hagberg1962" class="mim-tip-reference" title="Hagberg, B., Sourander, P., Svennerholm, L. &lt;strong&gt;Sulfatide lipidosis in childhood.&lt;/strong&gt; Am. J. Dis. Child. 104: 644-656, 1962.">Hagberg et al. (1962)</a>; <a href="#Haltia1980" class="mim-tip-reference" title="Haltia, T., Palo, J., Haltia, M., Icen, A. &lt;strong&gt;Juvenile metachromatic leukodystrophy: clinical, biochemical, and neuropathologic studies in nine new cases.&lt;/strong&gt; Arch. Neurol. 37: 42-46, 1980.">Haltia et al. (1980)</a>; <a href="#Jervis1960" class="mim-tip-reference" title="Jervis, G. A. &lt;strong&gt;Infantile metachromatic leukodystrophy (Greenfield&#x27;s disease).&lt;/strong&gt; J. Neuropath. Exp. Neurol. 19: 323-341, 1960.">Jervis (1960)</a>; <a href="#Percy1968" class="mim-tip-reference" title="Percy, A. K., Brady, R. O. &lt;strong&gt;Metachromatic leukodystrophy: diagnosis with samples of venous blood.&lt;/strong&gt; Science 161: 594-595, 1968.">Percy and Brady (1968)</a>; <a href="#Pilz1977" class="mim-tip-reference" title="Pilz, H., Duensing, I., Heipertz, R., Seidel, D., Lowitsch, K., Hopf, H. C., Goebel, H. H. &lt;strong&gt;Adult metachromatic leukodystrophy. I. Clinical manifestation in a female aged 44 years, previously diagnosed in the preclinical state.&lt;/strong&gt; Europ. Neurol. 15: 301-307, 1977.">Pilz et al. (1977)</a>; <a href="#Porter1971" class="mim-tip-reference" title="Porter, M. T., Fluharty, A. L., Trammell, J., Kihara, H. &lt;strong&gt;A correlation of intracellular cerebroside sulfatase activity in fibroblasts with latency in metachromatic leukodystrophy.&lt;/strong&gt; Biochem. Biophys. Res. Commun. 44: 660-666, 1971.">Porter et al. (1971)</a>; <a href="#Quigley1976" class="mim-tip-reference" title="Quigley, H. A., Green, W. R. &lt;strong&gt;Clinical and ultrastructural ocular histopathologic studies of adult-onset metachromatic leukodystrophy.&lt;/strong&gt; Am. J. Ophthal. 82: 472-479, 1976.">Quigley and Green (1976)</a>; <a href="#Sanguinetti1986" class="mim-tip-reference" title="Sanguinetti, N., Marsh, J., Jackson, M., Fensom, A. H., Warren, R. C., Rodeck, C. H. &lt;strong&gt;The arylsulphatases of chorionic villi: potential problems in the first-trimester diagnosis of metachromatic leucodystrophy and Maroteaux-Lamy disease.&lt;/strong&gt; Clin. Genet. 30: 302-308, 1986.">Sanguinetti et al. (1986)</a>; <a href="#Sourander1962" class="mim-tip-reference" title="Sourander, P., Svennerholm, L. &lt;strong&gt;Sulphatide lipidosis in the adult with the clinical picture of progressive organic dementia with epileptic seizures.&lt;/strong&gt; Acta Neuropath. 1: 384-396, 1962.">Sourander and
Svennerholm (1962)</a>; <a href="#Tonnesen1983" class="mim-tip-reference" title="Tonnesen, T., Bro, P. V., Nielsen, K. B., Lykkelund, C. &lt;strong&gt;Metachromatic leukodystrophy and pseudoarylsulfatase A deficiency in a Danish family.&lt;/strong&gt; Acta Paediat. Scand. 72: 175-178, 1983.">Tonnesen et al. (1983)</a>; <a href="#Tonnesen1984" class="mim-tip-reference" title="Tonnesen, T., Vrang, C., Wiesmann, U. N., Christomanou, H., Lou, H. O. &lt;strong&gt;Atypical metachromatic leukodystrophy? Problems with the biochemical diagnosis.&lt;/strong&gt; Hum. Genet. 67: 170-173, 1984.">Tonnesen et al. (1984)</a>; <a href="#Van1939" class="mim-tip-reference" title="Van Bogaert, L. V., Dewulf, A. &lt;strong&gt;Diffuse progressive leukodystrophy in the adult with production of metachromatic degenerative products (Alzheimer-Baroncini).&lt;/strong&gt; Arch. Neurol. Psychiat. 42: 1083-1097, 1939.">Van Bogaert and Dewulf (1939)</a>; <a href="#Zlotogora1980" class="mim-tip-reference" title="Zlotogora, J., Bach, G., Barak, Y., Elian, E. &lt;strong&gt;Metachromatic leukodystrophy in the Habbanite Jews: high frequency in a genetic isolate and screening for heterozygotes.&lt;/strong&gt; Am. J. Hum. Genet. 32: 663-669, 1980.">Zlotogora et al. (1980)</a>
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<span id="mimReferencesToggleTriangle" class="small mimTextToggleTriangle">&#9660;</span>
<strong>REFERENCES</strong>
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</h4>
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<p class="mim-text-font">
Adang, L. A., Groeschel, S., Grzyb, C., D'Aiello, R., Gavazzi, F., Sherbini, O., Bronner, N., Patel, A., Vincent, A., Sevagamoorthy, A., Mutua, S., Muirhead, K., and 36 others.
<strong>Developmental delay can precede neurologic regression in early onset metachromatic leukodystrophy.</strong>
Molec. Genet. Metab. 142: 108521, 2024.
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[<a href="https://doi.org/10.1016/j.ymgme.2024.108521" target="_blank">Full Text</a>]
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<a id="Austin1968" class="mim-anchor"></a>
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Austin, J., Armstrong, D., Fouch, S., Mitchell, C., Stumpf, D. A., Shearer, L., Briner, O.
<strong>Metachromatic leukodystrophy (MLD). VIII. MLD in adults: diagnosis and pathogenesis.</strong>
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[<a href="https://doi.org/10.1001/archneur.1968.00470330015001" target="_blank">Full Text</a>]
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Austin, J. H.
<strong>Metachromatic form of diffuse cerebral sclerosis. III. Significance of sulfatide and other lipid abnormalities in white matter and kidney.</strong>
Neurology 10: 470-483, 1960.
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[<a href="https://doi.org/10.1212/wnl.10.5.470" target="_blank">Full Text</a>]
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<a id="Austin1967" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Austin, J. H.
<strong>Some recent findings in leukodystrophies and in gargoylism. In: Aronson, S. M.; Volk, B. W. (eds.): Inborn Disorders of Sphingolipid Metabolism.</strong>
Oxford: Pergamon Press (pub.) 1967. Pp. 359-387.
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<a id="Austin1964" class="mim-anchor"></a>
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Austin, J., McAfee, D., Armstrong, D., O'Rourke, M., Shearer, L., Bachhawat, B. K.
<strong>Abnormal sulphatase activities in two human diseases (metachromatic leukodystrophy and gargoylism).</strong>
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[<a href="https://doi.org/10.1042/bj0930015c" target="_blank">Full Text</a>]
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<a id="Austin1965" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Austin, J., McAfee, D., Shearer, L.
<strong>Metachromatic form of diffuse cerebral sclerosis. IV. Low sulfatase activity in the urine of nine living patients with metachromatic leukodystrophy (MLD).</strong>
Arch. Neurol. 12: 447-455, 1965.
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[<a href="https://doi.org/10.1001/archneur.1965.00460290003001" target="_blank">Full Text</a>]
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<a id="Baldinger1987" class="mim-anchor"></a>
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Baldinger, S., Pierpont, M. E., Wenger, D. A.
<strong>Pseudodeficiency of arylsulfatase A: a counseling dilemma.</strong>
Clin. Genet. 31: 70-76, 1987.
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[<a href="https://doi.org/10.1111/j.1399-0004.1987.tb02772.x" target="_blank">Full Text</a>]
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<a id="Bayever1985" class="mim-anchor"></a>
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Bayever, E., Ladisch, S., Philippart, M., Brill, N., Nuwer, M., Sparkes, R. S., Feig, S. A.
<strong>Bone-marrow transplantation for metachromatic leucodystrophy.</strong>
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[<a href="https://doi.org/10.1016/s0140-6736(85)90402-7" target="_blank">Full Text</a>]
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<a id="Beratis1975" class="mim-anchor"></a>
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Beratis, N. G., Danesino, C., Hirschhorn, K.
<strong>Detection of homozygotes and heterozygotes for metachromatic leukodystrophy in lymphoid cell lines and peripheral leukocytes.</strong>
Ann. Hum. Genet. 38: 485-493, 1975.
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[<a href="https://doi.org/10.1111/j.1469-1809.1975.tb00638.x" target="_blank">Full Text</a>]
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Berger, J., Gmach, M., Mayr, U., Molzer, B., Bernheimer, H.
<strong>Coincidence of two novel arylsulfatase A alleles and mutation 459+1G-A within a family with metachromatic leukodystrophy: molecular basis of phenotypic heterogeneity.</strong>
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[<a href="https://doi.org/10.1002/(SICI)1098-1004(1999)13:1&lt;61::AID-HUMU7&gt;3.0.CO;2-H" target="_blank">Full Text</a>]
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Betts, T. A., Smith, W. T., Kelly, R. E.
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[<a href="https://doi.org/10.1212/wnl.18.11.1140" target="_blank">Full Text</a>]
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Biffi, A., Cesani, M., Fumagalli, F., Del Carro, U., Baldoli, C., Canale, S., Gerevini, S., Amadio, S., Falautano, M., Rovelli, A., Comi, G., Roncarolo, M. G., Sessa, M.
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[<a href="https://doi.org/10.1111/j.1399-0004.2008.01058.x" target="_blank">Full Text</a>]
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Biffi, A., Montini, E., Lorioli, L., Cesani, M., Fumagalli, F., Plati, T., Baldoli, C., Martino, S., Calabria, A., Canale, S., Benedicenti, F., Vallanti, G., and 25 others.
<strong>Lentiviral hematopoietic stem cell gene therapy benefits metachromatic leukodystrophy.</strong>
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Black, J. W., Cumings, J. N.
<strong>Infantile metachromatic leukodystrophy.</strong>
J. Neurol. Neurosurg. Psychiat. 24: 233-239, 1961.
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[<a href="https://doi.org/10.1136/jnnp.24.3.233" target="_blank">Full Text</a>]
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Bohne, W., von Figura, K., Gieselmann, V.
<strong>An 11-bp deletion in the arylsulfatase A gene of a patient with late infantile metachromatic leukodystrophy.</strong>
Hum. Genet. 87: 155-158, 1991.
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[<a href="https://doi.org/10.1007/BF00204172" target="_blank">Full Text</a>]
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Bonkowsky, J. L., Nelson, C., Kingston, J. L., Filloux, F. M., Mundorff, M. B., Srivastava, R.
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[<a href="https://doi.org/10.1212/WNL.0b013e3181eee46b" target="_blank">Full Text</a>]
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Bosch, E. P., Hart, M. N.
<strong>Late adult-onset metachromatic leukodystrophy: dementia and polyneuropathy in a 63-year-old man.</strong>
Arch. Neurol. 35: 475-477, 1978.
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[<a href="https://doi.org/10.1001/archneur.1978.00500310077017" target="_blank">Full Text</a>]
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Bruns, G. A. P., Mintz, B. J., Leary, A. C., Regina, V. M., Gerald, P. S.
<strong>Expression of human arylsulfatase A in man-hamster somatic cell hybrids.</strong>
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[<a href="https://doi.org/10.1159/000130931" target="_blank">Full Text</a>]
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Butterworth, J., Broadhead, D. M., Keay, A. J.
<strong>Low arylsulphatase A activity in a family without metachromatic leukodystrophy.</strong>
Clin. Genet. 14: 213-218, 1978.
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[<a href="https://doi.org/10.1111/j.1399-0004.1978.tb02133.x" target="_blank">Full Text</a>]
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Chabas, A., Castellvi, S., Bayes, M., Balcells, S., Grinberg, D., Vilageliu, L., Marfany, G., Lissens, W., Gonzalez-Duarte, R.
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[<a href="https://doi.org/10.1111/j.1399-0004.1993.tb03908.x" target="_blank">Full Text</a>]
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Chang, P. L., Davidson, R. G.
<strong>Complementation of arylsulfatase A in somatic hybrids of metachromatic leukodystrophy and multiple sulfatase deficiency disorder fibroblasts.</strong>
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[<a href="https://doi.org/10.1073/pnas.77.10.6166" target="_blank">Full Text</a>]
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Chang, P. L., Davidson, R. G.
<strong>Pseudo arylsulfatase-A deficiency in healthy individuals: genetic and biochemical relationship to metachromatic leukodystrophy.</strong>
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[<a href="https://doi.org/10.1073/pnas.80.23.7323" target="_blank">Full Text</a>]
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Chang, P. L., Rosa, N. E., Davidson, R. G.
<strong>Somatic cell hybridization studies on the genetic regulation and allelic mutations in metachromatic leukodystrophy.</strong>
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[<a href="https://doi.org/10.1007/BF00296448" target="_blank">Full Text</a>]
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Charlesworth, G., Angelova, P. R., Bartolome-Robledo, F., Ryten, M., Trabzuni, D., Stamelou, M., Abramov, A. Y., Bhatia, K. P., Wood, N. W.
<strong>Mutations in HPCA cause autosomal-recessive primary isolated dystonia.</strong>
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[<a href="https://doi.org/10.1016/j.ajhg.2015.02.007" target="_blank">Full Text</a>]
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Cravioto, H., O'Brien, J., Lockwood, R., Kasten, F. H., Booker, J.
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[<a href="https://doi.org/10.1126/science.156.3772.243" target="_blank">Full Text</a>]
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Dali, C., Sevin, C., Krageloh-Mann, I., Giugliani, R., Sakai, N., Wu, J., Wasilewski, M.
<strong>Safety of intrathecal delivery of recombinant human arylsulfatase A in children with metachromatic leukodystrophy: results from a phase 1/2 clinical trial.</strong>
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[<a href="https://doi.org/10.1016/j.ymgme.2020.07.002" target="_blank">Full Text</a>]
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DeLuca, C., Brown, J. A., Shows, T. B.
<strong>Lysosomal arylsulfatase deficiencies in humans: chromosome assignment of arylsulfatase A and B.</strong>
Proc. Nat. Acad. Sci. 76: 1957-1961, 1979.
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[<a href="https://doi.org/10.1073/pnas.76.4.1957" target="_blank">Full Text</a>]
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DeLuca, C., Champion, M. J., Shows, T. B.
<strong>Arylsulfatase-A (ARSA) synteny with beta-glucuronidase (BGUS) indicates assignment to human chromosome 7 in man-Chinese hamster hybrids. (Abstract)</strong>
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Dubois, G., Harzer, K., Baumann, N.
<strong>Very low arylsulfatase A and cerebroside sulfatase activities in leukocytes of healthy members of metachromatic leukodystrophy family.</strong>
Am. J. Hum. Genet. 29: 191-194, 1977.
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Eto, Y., Tahara, T., Koda, N., Yamaguchi, S., Ito, F., Okuno, A.
<strong>Prenatal diagnosis of metachromatic leukodystrophy: a diagnosis by amniotic fluid and its confirmation.</strong>
Arch. Neurol. 39: 29-32, 1982.
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[<a href="https://doi.org/10.1001/archneur.1982.00510130031007" target="_blank">Full Text</a>]
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Farrell, D. F., MacMartin, M. P., Clark, A. F.
<strong>Multiple molecular forms of arylsulfatase A in different forms of metachromatic leukodystrophy (MLD).</strong>
Neurology 29: 16-20, 1979.
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[<a href="https://doi.org/10.1212/wnl.29.1.16" target="_blank">Full Text</a>]
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Farrell, D. F.
<strong>Heterozygote detection in MLD: allelic mutations at the ARA locus.</strong>
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[<a href="https://doi.org/10.1007/BF00293061" target="_blank">Full Text</a>]
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<strong>Two new arylsulfatase A (ARSA) mutations in a juvenile metachromatic leukodystrophy (MLD) patient.</strong>
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Gieselmann, V., Fluharty, A. L., Tonnesen, T., Von Figura, K.
<strong>Mutations in the arylsulfatase A pseudodeficiency allele causing metachromatic leukodystrophy.</strong>
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<a id="Gieselmann1989" class="mim-anchor"></a>
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Gieselmann, V., Polten, A., Kreysing, J., von Figura, K.
<strong>Arylsulfatase A pseudodeficiency: loss of a polyadenylylation (sic) signal and N-glycosylation site.</strong>
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[<a href="https://doi.org/10.1073/pnas.86.23.9436" target="_blank">Full Text</a>]
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<a id="Gieselmann1994" class="mim-anchor"></a>
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[<a href="https://doi.org/10.1002/humu.1380040402" target="_blank">Full Text</a>]
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Goebel, H. H., Pilz, H., Argyrakis, A.
<strong>Adult metachromatic leukodystrophy. II. Ultrastructural findings in peripheral nerve and skeletal muscle.</strong>
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[<a href="https://doi.org/10.1159/000114819" target="_blank">Full Text</a>]
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<strong>Arylsulfatase A in the urine and metachromatic leukodystrophy.</strong>
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[<a href="https://doi.org/10.1016/s0022-3476(67)80207-5" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1111/j.1651-2227.1971.tb06994.x" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1001/archneur.1980.00500500072011" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1007/BF00286589" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1073/pnas.93.25.14821" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1007/BF00288270" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1002/ajmg.1320310120" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1002/ajmg.1362" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1097/00005072-196007000-00001" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1056/NEJM197006112822403" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1093/hmg/ddaa277" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1007/BF00194634" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1212/01.wnl.0000099076.17187.9a" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1111/j.1399-0004.1982.tb00759.x" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1007/BF00278786" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1007/BF00291701" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1056/NEJM199001043220106" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1093/hmg/ddi126" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1016/0022-510x(69)90095-1" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1126/science.161.3841.594" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1212/wnl.27.10.933" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1056/NEJM197109302851407" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1159/000114818" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1016/0022-510x(69)90096-3" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1007/BF01799861" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1126/science.172.3989.1263" target="_blank">Full Text</a>]
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<strong>A correlation of intracellular cerebroside sulfatase activity in fibroblasts with latency in metachromatic leukodystrophy.</strong>
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[<a href="https://doi.org/10.1016/s0006-291x(71)80134-1" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1007/BF00282542" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1016/0002-9394(76)90497-9" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1007/s00439-002-0701-y" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1111/j.1399-0004.1986.tb00611.x" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1136/jmg.3.2.86" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1001/archneur.1971.00480320045004" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1111/j.1651-2227.1983.tb09692.x" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1007/BF00272994" target="_blank">Full Text</a>]
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<a id="89" class="mim-anchor"></a>
<a id="von Figura1986" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
von Figura, K., Steckel, F., Conary, J., Hasilik, A., Shaw, E.
<strong>Heterogeneity in late-onset metachromatic leukodystrophy: effect of inhibitors of cysteine proteinases.</strong>
Am. J. Hum. Genet. 39: 371-382, 1986.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2876627/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2876627</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2876627" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
</p>
</div>
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<li>
<a id="90" class="mim-anchor"></a>
<a id="von Figura1983" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
von Figura, K., Steckel, F., Hasilik, A.
<strong>Juvenile and adult metachromatic leukodystrophy: partial restoration of arylsulfatase A (cerebroside sulfatase) activity by inhibitors of thiol proteinases.</strong>
Proc. Nat. Acad. Sci. 80: 6066-6070, 1983.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/6136972/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">6136972</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=6136972" 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.80.19.6066" target="_blank">Full Text</a>]
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<a id="91" class="mim-anchor"></a>
<a id="Waltz1987" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Waltz, G., Harik, S. I., Kaufman, B.
<strong>Adult metachromatic leukodystrophy: value of computed tomographic scanning and magnetic resonance imaging of the brain.</strong>
Arch. Neurol. 44: 225-227, 1987.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3813937/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3813937</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=3813937" 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.1987.00520140083022" target="_blank">Full Text</a>]
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<a id="92" class="mim-anchor"></a>
<a id="Wang2011" class="mim-anchor"></a>
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<p class="mim-text-font">
Wang, R. Y., Bodamer, O. A., Watson, M. S., Wilcox, W. R.
<strong>Lysosomal storage diseases: diagnostic confirmation and management of presymptomatic individuals.</strong>
Genet. Med. 13: 457-484, 2011.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21502868/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21502868</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21502868" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1097/GIM.0b013e318211a7e1" target="_blank">Full Text</a>]
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<a id="93" class="mim-anchor"></a>
<a id="Yatziv1981" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Yatziv, S., Russell, A.
<strong>An unusual form of metachromatic leukodystrophy in three siblings.</strong>
Clin. Genet. 19: 222-227, 1981.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/6115727/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">6115727</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=6115727" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1111/j.1399-0004.1981.tb00702.x" target="_blank">Full Text</a>]
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<a id="Zlotogora1980" class="mim-anchor"></a>
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Zlotogora, J., Bach, G., Barak, Y., Elian, E.
<strong>Metachromatic leukodystrophy in the Habbanite Jews: high frequency in a genetic isolate and screening for heterozygotes.</strong>
Am. J. Hum. Genet. 32: 663-669, 1980.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/6107044/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">6107044</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=6107044" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
</p>
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<a id="95" class="mim-anchor"></a>
<a id="Zlotogora1983" class="mim-anchor"></a>
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Zlotogora, J., Bach, G.
<strong>Deficiency of lysosomal hydrolases in apparently healthy individuals.</strong>
Am. J. Med. Genet. 14: 73-80, 1983.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/6131608/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">6131608</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=6131608" 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/ajmg.1320140112" target="_blank">Full Text</a>]
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<a id="96" class="mim-anchor"></a>
<a id="Zlotogora1994" class="mim-anchor"></a>
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Zlotogora, J., Furman-Shaharabani, Y., Harris, A., Barth, M. L., von Figura, K., Gieselmann, V.
<strong>A single origin for the most frequent mutation causing late infantile metachromatic leucodystrophy.</strong>
J. Med. Genet. 31: 672-674, 1994.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7815434/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7815434</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7815434" 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.31.9.672" target="_blank">Full Text</a>]
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<a id="97" class="mim-anchor"></a>
<a id="Zlotogora1994" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Zlotogora, J., Gieselman, V., von Figura, K., Zeigler, M., Bach, G.
<strong>Late infantile metachromatic leukodystrophy in Israel.</strong>
Biomed. Pharmacother. 48: 347-350, 1994.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7858169/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7858169</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7858169" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1016/0753-3322(94)90049-3" target="_blank">Full Text</a>]
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Hilary J. Vernon - updated : 09/30/2024
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Hilary J. Vernon - updated : 09/30/2021<br>Hilary J. Vernon - updated : 09/30/2020<br>Cassandra L. Kniffin - updated : 4/28/2015<br>Ada Hamosh - updated : 1/6/2014<br>Ada Hamosh - updated : 10/3/2012<br>Cassandra L. Kniffin - updated : 10/20/2010<br>Cassandra L. Kniffin - updated : 6/26/2009<br>Cassandra L. Kniffin - updated : 2/13/2009<br>George E. Tiller - updated : 5/19/2008<br>Cassandra L. Kniffin - updated : 7/31/2007<br>Cassandra L. Kniffin - updated : 6/27/2005<br>Cassandra L. Kniffin - updated : 2/3/2004<br>Cassandra L. Kniffin - reorganized : 2/28/2003<br>Cassandra L. Kniffin - updated : 1/28/2003<br>Victor A. McKusick - updated : 8/27/2002<br>Victor A. McKusick - updated : 5/13/2002<br>Victor A. McKusick - updated : 7/31/2001<br>Majed J. Dasouki - updated : 4/13/2001<br>Victor A. McKusick - updated : 1/12/1999<br>Victor A. McKusick - updated : 9/29/1998<br>Victor A. McKusick - updated : 9/18/1998<br>Clair A. Francomano - updated : 5/27/1998<br>Victor A. McKusick - updated : 12/2/1997<br>Victor A. McKusick - updated : 5/8/1997<br>Iosif W. Lurie - updated : 9/15/1996<br>Stylianos E. Antonarakis - updated : 7/6/1996
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Victor A. McKusick : 6/4/1986
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carol : 09/30/2024
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carol : 09/16/2024<br>alopez : 09/13/2024<br>carol : 09/30/2021<br>alopez : 02/19/2021<br>carol : 09/30/2020<br>carol : 10/14/2016<br>carol : 07/09/2016<br>carol : 5/27/2016<br>alopez : 5/1/2015<br>mcolton : 4/30/2015<br>ckniffin : 4/28/2015<br>alopez : 1/6/2014<br>alopez : 10/3/2012<br>wwang : 10/29/2010<br>ckniffin : 10/20/2010<br>wwang : 7/23/2009<br>ckniffin : 6/26/2009<br>terry : 3/5/2009<br>wwang : 2/19/2009<br>ckniffin : 2/13/2009<br>wwang : 5/21/2008<br>terry : 5/19/2008<br>carol : 1/21/2008<br>wwang : 8/23/2007<br>ckniffin : 7/31/2007<br>wwang : 7/1/2005<br>wwang : 6/29/2005<br>ckniffin : 6/27/2005<br>terry : 2/22/2005<br>carol : 11/18/2004<br>tkritzer : 2/9/2004<br>ckniffin : 2/3/2004<br>ckniffin : 2/3/2004<br>carol : 2/28/2003<br>ckniffin : 2/27/2003<br>ckniffin : 2/27/2003<br>ckniffin : 2/27/2003<br>carol : 2/10/2003<br>tkritzer : 1/31/2003<br>ckniffin : 1/28/2003<br>tkritzer : 9/10/2002<br>tkritzer : 8/30/2002<br>terry : 8/27/2002<br>terry : 8/27/2002<br>alopez : 5/16/2002<br>terry : 5/13/2002<br>cwells : 8/10/2001<br>cwells : 8/1/2001<br>terry : 7/31/2001<br>carol : 4/13/2001<br>carol : 9/22/1999<br>carol : 4/2/1999<br>carol : 1/14/1999<br>terry : 1/12/1999<br>carol : 9/30/1998<br>terry : 9/29/1998<br>carol : 9/22/1998<br>terry : 9/18/1998<br>dkim : 9/10/1998<br>carol : 7/16/1998<br>carol : 6/19/1998<br>terry : 6/16/1998<br>terry : 6/16/1998<br>terry : 6/3/1998<br>dholmes : 5/28/1998<br>dholmes : 5/27/1998<br>dholmes : 5/21/1998<br>mark : 12/9/1997<br>terry : 12/2/1997<br>terry : 12/2/1997<br>alopez : 7/10/1997<br>terry : 7/9/1997<br>jenny : 6/23/1997<br>mark : 6/23/1997<br>jenny : 6/17/1997<br>mark : 6/17/1997<br>mark : 5/8/1997<br>alopez : 5/6/1997<br>jamie : 1/7/1997<br>jamie : 1/7/1997<br>terry : 1/3/1997<br>carol : 9/15/1996<br>mark : 11/6/1995<br>pfoster : 9/30/1994<br>davew : 6/3/1994<br>terry : 4/18/1994<br>mimadm : 4/17/1994<br>warfield : 3/9/1994
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<h3>
<span class="mim-font">
<strong>#</strong> 250100
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<span class="mim-font">
METACHROMATIC LEUKODYSTROPHY; MLD
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<em>Alternative titles; symbols</em>
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METACHROMATIC LEUKOENCEPHALOPATHY<br />
CEREBRAL SCLEROSIS, DIFFUSE, METACHROMATIC FORM<br />
SULFATIDE LIPIDOSIS<br />
ARYLSULFATASE A DEFICIENCY<br />
ARSA DEFICIENCY<br />
CEREBROSIDE SULFATASE DEFICIENCY
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Other entities represented in this entry:
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<span class="h3 mim-font">
PSEUDOARYLSULFATASE A DEFICIENCY, INCLUDED
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<span class="h4 mim-font">
METACHROMATIC LEUKODYSTROPHY, LATE INFANTILE, INCLUDED<br />
METACHROMATIC LEUKODYSTROPHY, JUVENILE, INCLUDED<br />
METACHROMATIC LEUKODYSTROPHY, ADULT, INCLUDED
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<strong>SNOMEDCT:</strong> 238031009, 396338004, 44359008, 66521008; &nbsp;
<strong>ICD10CM:</strong> E75.25, E75.29; &nbsp;
<strong>ORPHA:</strong> 309256, 309263, 309271, 512; &nbsp;
<strong>DO:</strong> 10581; &nbsp;
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<strong>Phenotype-Gene Relationships</strong>
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Location
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Phenotype
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Phenotype <br /> MIM number
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Inheritance
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Phenotype <br /> mapping key
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Gene/Locus
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Gene/Locus <br /> MIM number
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<td>
<span class="mim-font">
22q13.33
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Metachromatic leukodystrophy
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250100
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Autosomal recessive
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3
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ARSA
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607574
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<strong>TEXT</strong>
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<p>A number sign (#) is used with this entry because metachromatic leukodystrophy (MLD) is caused by homozygous or compound heterozygous mutation in the arylsulfatase A gene (ARSA; 607574) on chromosome 22q13.</p>
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<strong>Description</strong>
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<p>The metachromatic leukodystrophies comprise several allelic disorders. Kihara (1982) recognized 5 allelic forms of MLD: late infantile, juvenile, and adult forms, partial cerebroside sulfate deficiency, and pseudoarylsulfatase A deficiency; and 2 nonallelic forms: metachromatic leukodystrophy due to saposin B deficiency (249900) and multiple sulfatase deficiency or juvenile sulfatidosis (272200), a disorder that combines features of a mucopolysaccharidosis with those of metachromatic leukodystrophy. </p>
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<strong>Clinical Features</strong>
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<p><strong><em>Late Infantile and Juvenile Forms</em></strong></p><p>
This condition was described by Greenfield (1933). In the late infantile form, onset is usually in the second year of life and death occurs before 5 years in most. Clinical features are motor symptoms, rigidity, mental deterioration, and sometimes convulsions. Early development is normal but onset occurs before 30 months of age. The cerebrospinal fluid contains elevated protein. Galactosphingosulfatides that are strongly metachromatic, doubly refractile in polarized light, and pink with PAS are found in excess in the white matter of the central nervous system, in the kidney, and in the urinary sediment (Austin, 1960). </p><p>Masters et al. (1964) described 4 cases in 2 families. Progressive physical and mental deterioration began a few months after birth. Megacolon with attacks of abdominal distention was observed. Sufficient difference from the usual cases existed for the authors to suggest that more than one entity is encompassed by metachromatic leukodystrophy. A curious feature of later bedridden stages of the disease was marked genu recurvatum. The first manifestations, appearing before the second birthday, included hypotonia, muscle weakness and unsteady gait, thus suggesting a myopathy or neuropathy. </p><p>Gustavson and Hagberg (1971) described 13 cases of late infantile MLD from 11 families. Two pairs of families were related to each other and 3 sets of parents were consanguineous, suggesting autosomal recessive inheritance. </p><p>Lyon et al. (1961) described affected brothers with onset at 7 and 4 years of age and with marked elevation of protein in the cerebrospinal fluid. Schutta et al. (1966) recognized a juvenile form of metachromatic leukodystrophy with onset between ages 4 and 10 years, as compared with the more frequent late infantile form with onset between ages 12 and 24 months. </p><p>Moser (1972) suggested that juvenile cases of MLD, especially those of late juvenile onset, should be classed with the adult form. An alternative possibility was that some of these cases with phenotype intermediate between those of the late infantile and adult forms represented genetic compounds. The same very low levels of arylsulfatase A were found in the infantile, juvenile, and adult forms, and the reason for the differences in age of onset was unknown.</p><p>Von Figura et al. (1986) pointed out that the late-onset form of MLD is a heterogeneous group in which symptoms may develop at any age beyond 3 years. The age of demarcation of juvenile forms from adult forms is somewhat arbitrarily set at age 16 by some and age 21 by others. In the late-onset forms the disease progresses more slowly, and in mild cases the diagnosis may even go unsuspected during life. </p><p>Adang et al. (2024) performed a retrospective analysis of developmental features in patients with MLD prior to their disease diagnosis. There was a significant delay in attainment of developmental milestones in patients with late infantile MLD compared to patients with juvenile-onset or adult-onset MLD. Seventy-four of 194 patients with late infantile MLD had developmental delay or plateau prior to presentation and 73 never achieved ambulation. Developmental delay was reported in 35 of 157 patients with the later onset forms of MLD. Furthermore, a history of developmental delay correlated to an earlier onset of developmental regression. </p><p><strong><em>Adult Form</em></strong></p><p>
In the adult form of metachromatic leukodystrophy, initial symptoms, which begin after age 16, are usually psychiatric and may lead to a diagnosis of schizophrenia. Disorders of movement and posture appear late. Differences from the late infantile form also include ability to demonstrate metachromatic material in paraffin- or celloidin-embedded sections and probably greater sulfatide excess in the gray than in the white matter in the adult form. The gallbladder is usually nonfunctional. Betts et al. (1968) described a man who was 28 when admitted to a psychiatric hospital for 'acute schizophrenia' and 35 when he died of bronchopneumonia. Muller et al. (1969) and Pilz and Muller (1969) described 2 unrelated women with this disorder. Affected sibs were recorded by Austin et al. (1968), among others. </p><p>Kihara et al. (1982) found partial cerebroside sulfatase deficiency (10-20% of normal activity in cultured fibroblasts) as the cause of neuropathy and myopathy since infancy in a 37-year-old white female. She had been institutionalized since age 16 for mental retardation. Waltz et al. (1987) described a 38-year-old man who had been diagnosed as schizophrenic and was treated for that condition for many years. The diagnosis of adult MLD was suspected because of white matter abnormalities detected by CT and MRI scanning of the brain; this diagnosis was confirmed by discovery of markedly reduced leukocyte arylsulfatase A activity. The man held a master's degree in physical education and worked full-time as a high school physical education teacher. Personality changes were first noted at about age 31. </p><p>Propping et al. (1986) studied consecutive admissions to a state psychiatric hospital and a group of inpatients with chronic psychiatric disorders. The data showed a slight preponderance in the lower levels of arylsulfatase A in leukocytes. Kohn et al. (1988) found no neurologic or EEG changes in MLD heterozygotes but found deficits in the neuropsychologic tests involving spatial or constructional components (but not in tests involving language skills). Tay-Sachs heterozygotes (272800) showed no consistent deficit in any component of the neurologic or neuropsychologic tests. </p><p>Marcao et al. (2005) reported a woman with adult-onset MLD confirmed by genetic analysis. She presented at age 37 years with dysfunctional and bizarre behavior, including progressive apathy, loss of interest in daily living routines and caring for her 3 children, and memory disturbances. She had no clinical signs of neuropathy, although MRI showed subcortical brain atrophy and periventricular white matter changes. Nerve conduction velocities were normal; sural nerve biopsy findings were consistent with a slowly progressive demyelinating neuropathy. Despite the relatively mild clinical phenotype, ARSA activity was less than 1% of control values. </p><p><strong><em>Biochemical Features</em></strong></p><p>
Austin et al. (1964) determined that the defect in MLD involves the lysosomal enzyme arylsulfatase A. Since the metachromatic material is cerebroside sulfate, MLD is a sulfatide lipidosis. Stumpf and Austin (1971) presented evidence suggesting that the abnormality in arylsulfatase A is quantitatively and qualitatively different in the late infantile and juvenile forms of metachromatic leukodystrophy. Percy and Kaback (1971) found no difference in enzyme levels between the infantile and adult-onset types, and concluded that some other factor must account for the difference in age of onset. </p><p>Porter et al. (1971) corrected the metabolic defect in cultured fibroblasts by addition of arylsulfatase A to the medium. They found that cultured fibroblasts from late-onset metachromatic leukodystrophy hydrolyzed appreciable amounts of exogenous cerebroside sulfate, whereas fibroblasts from patients with the early-onset form hydrolyzed none. Studies of cell-free preparations showed no cerebroside sulfatase activity. Percy et al. (1977) found that cultured skin fibroblasts from the adult-onset patients, although clearly abnormal, were able to catabolize sulfatide significantly more effectively than cultured skin fibroblasts from late infantile patients. </p><p>By the technique of isoelectric focusing on cellulose acetate membranes, Farrell et al. (1979) found differences in arylsulfatase A isozymes that correlated with the clinical type of metachromatic leukodystrophy, i.e., juvenile or late infantile. Chang et al. (1982) showed that fusion of cells from the infantile and juvenile forms of MLD did not result in complementation of arylsulfatase A activity, and concluded that they are allelic disorders. </p><p>In the cells from patients with juvenile and adult forms of MLD, von Figura et al. (1983) found severe deficiency in the arylsulfatase polypeptide but a rate of synthesis that was 20 to 50% of control. In the absence of NH4Cl, the mutant enzyme was rapidly degraded upon transport into lysosomes. In the presence of inhibitors of thiol proteases, e.g., leupeptin, arylsulfatase A polypeptides were partially protected from degradation with increase in catalytic activity of arylsulfatase A and improved ability of the cells to degrade cerebroside sulfates. Therapeutic use of this approach was suggested. The approach might be useful in other lysosomal storage diseases in which an unstable mutant enzyme is produced, e.g., the late form of glycogen storage disease II (232300). In a study of 8 patients with the juvenile form of MLD, von Figura et al. (1986) found that the mutation leads to the synthesis of arylsulfatase A polypeptides with increased susceptibility to cysteine proteinases. Multiple allelic mutations within this group were suggested by clinical heterogeneity, variability in residual activity, and response to inhibitors (cysteine proteinases). </p><p><strong><em>Pseudoarylsulfatase A deficiency</em></strong></p><p>
Pseudoarylsulfatase A deficiency refers to a condition of apparent ARSA enzyme deficiency in persons without neurologic abnormalities. Dubois et al. (1977) described very low arylsulfatase A and cerebroside sulfatase activities in leukocytes of healthy members of a metachromatic leukodystrophy family. Langenbeck et al. (1977) proposed a one locus, multiple allele hypothesis to explain the peculiar findings in that kindred. </p><p>Butterworth et al. (1978) reported a child with very low levels of the enzyme whose mother was, seemingly, heterozygous and whose father carried a variant gene giving a very low in vitro level. They concluded that low arylsulfatase A is not necessarily indicative of this disease, which should be taken into consideration when screening for the disease. </p><p>A pseudodeficiency allele at the arylsulfatase A locus was delineated by Schaap et al. (1981). Clinically healthy persons with ARSA levels in the range of MLD patients have been found among the relatives of MLD patients. Cultured fibroblasts from persons with pseudodeficiency catabolize cerebroside sulfate; fibroblasts from MLD patients do not. Zlotogora and Bach (1983) pointed out that lysosomal hydrolases deficient in cases of metachromatic leukodystrophy, Tay-Sachs disease, Fabry disease, and Krabbe disease have also been found to be deficient in healthy persons. The authors suggested that most of the latter cases represent the compound heterozygote for the deficient allele and another allele coding for an in vitro low enzyme activity (pseudodeficiency). </p><p>Chang and Davidson (1983) could demonstrate no restoration of activity of arylsulfatase A in hybrid cells created from cells of individuals with MLD and individuals with pseudo-ARSA deficiency. They concluded, therefore, that the 2 mutations are allelic. They showed that the 2 conditions can be distinguished in the laboratory by a simple electrophoretic analysis of residual ARSA activity. </p><p>Kihara et al. (1986) noted that the apparent enzyme deficiency in persons without neurologic abnormalities is due in part to the nonspecificity of the synthetic substrates used for assays and in part to a high redundancy of arylsulfatase A. </p>
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<h4>
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<strong>Diagnosis</strong>
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<p>Austin et al. (1964) determined that the defect concerns the lysosomal enzyme arylsulfatase A. Austin's test to demonstrate absence of arylsulfatase A activity in the urine was useful in early diagnosis (Greene et al., 1967). Kaback and Howell (1970) demonstrated profound deficiency of arylsulfatase A in cultured skin fibroblasts of patients and an intermediate deficiency in carriers. Normally enzyme levels are low in midtrimester amniotic cells; hence, homozygotes cannot be reliably identified by amniocentesis. </p><p><strong><em>Prenatal Diagnosis</em></strong></p><p>
Poenaru et al. (1988) described a method of first-trimester prenatal diagnosis of metachromatic leukodystrophy using immunoprecipitation-electrophoresis on chorionic villus material. </p><p>Baldinger et al. (1987) discussed the complications of genetic counseling and prenatal diagnosis resulting from the occurrence of the pseudodeficiency phenotype. </p>
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<strong>Clinical Management</strong>
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<p>Bayever et al. (1985) observed apparent improvement (i.e., continued developmental progress) in a boy with late infantile MLD given a bone marrow transplant from an HLA-identical sister. Krivit et al. (1990) reported improvement in neurophysiologic function and sulfatide metabolism in an affected 10-year-old girl who had received a bone marrow transplant 5 years previously. </p><p>Pierson et al. (2008) reported 3 sibs with juvenile MLD who received unrelated umbilical cord blood transplantation at different stages of disease: they were 8, 6, and 4 years old, respectively, at the time of treatment. The 8-year-old boy had an IQ of 59, spasticity, and white matter lesions on MRI before transplant and experienced disease progression after transplant. His 6-year-old brother had an IQ of 88 and moderate white matter lesions before transplant, but remained neurologically stable and showed some improvement in nerve conduction velocity and near resolution of white matter lesions after transplant. His 4-year-old sister had no neurologic impairment or white matter lesions before transplant, and remained normal after transplant. She developed mild white matter lesions about 6 months after transplant, but these resolved within the following 6 months. Pierson et al. (2008) concluded that pretransplantation neurologic status is the best predictor of outcome following cord blood transplant and that cord blood transplant can stop disease progression in MLD. </p><p>Wang et al. (2011) described the ACMG standards and guidelines for the diagnostic confirmation and management of presymptomatic individuals with lysosomal storage diseases. </p><p>Biffi et al. (2013) performed lentiviral hematopoietic stem cell (HSC) gene therapy on 3 asymptomatic children with ARSA deficiency known because of older sibs with early-onset MLD carrying the same mutations. Following myeloablative busulfan conditioning, patients were transduced with hematopoietic stem cells with the lentiviral gene. There was high-level stable engraftment of the transduced HSCs in bone marrow and peripheral blood of all patients at all times tested, with 45 to 80% of bone marrow-derived hematopoietic colonies harboring the vector. ARSA activity was reconstituted to above-normal values in the hematopoietic lineages and in the cerebrospinal fluid. None of the 3 patients had progression of disease at up to 24 months after treatment, even after the time of onset projected from sib cases. </p><p>Dali et al. (2020) tested the safety of intrathecal administration of recombinant human arylsulfatase A (rhASA) in 24 children with MLD in an open-label, 38-week study. Patients were assigned to cohorts and treated with either 10, 30, or 100 mg of rhASA every other week. There were no deaths and no drug-related serious adverse events, although 25% of patients had a serious adverse event associated with the intrathecal device or drug delivery method. Ten patients developed treatment-induced anti-rhASA antibodies in serum, but there was no correlation between serum antibody response and adverse events. Dali et al. (2020) found dose- and time-dependent reductions in CSF sulfatide and lysosulfatide levels at all doses, with levels reduced to the normal range in patients receiving the 100 mg dose. Dali et al. (2020) concluded that rhASA was generally well-tolerated at doses up to 100 mg administered every other week. </p><p>Kaminski et al. (2020) examined the in vitro uptake of arylsulfatase A by different brain-derived cell lines and primary murine brain cells. Endocytosis of human ASA expressed by Chinese hamster ovary (CHO) cells was highest in primary murine neurons and astrocytes and lowest in oligodendrocytes. Immature oligodendrocytes were able to endocytose this form of ASA. Mannose 6-phosphate (M6P) was able to inhibit ASA uptake by nonglial cells, indicating that the mechanism of uptake of ASA was through M6P receptor-mediated endocytosis. Primary murine microglial cells were found to employ a combination of M6P-receptors, mannose receptors, and scavenger receptors to endocytose ASA. As opposed to the ASA expressed by CHO cells, ASA expressed by microglial cells was not taken up in an M6P-dependent fashion by mouse embryonic fibroblasts, indicating failure of metabolic cross-correction by receptor-mediated endocytosis. </p>
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<h4>
<span class="mim-font">
<strong>Molecular Genetics</strong>
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<p>In patients with MLD, Polten et al. (1991), Gieselmann et al. (1991), Kondo et al. (1991), Bohne et al. (1991), and Fluharty et al. (1991) identified mutations in the ARSA gene (e.g., 607574.0003). </p><p>Gieselmann et al. (1994) stated that 31 amino acid substitutions, 1 nonsense mutation, 3 small deletions, 3 splice donor site mutations, and 1 combined missense/splice donor site mutation had been identified in the ARSA gene in metachromatic leukodystrophy. Two of these mutant alleles account for about 25% of MLD alleles each. </p><p><strong><em>Pseudodeficiency Alleles</em></strong></p><p>
Gieselmann et al. (1989) determined 2 pseudodeficiency alleles of the ARSA gene (607574.0001-607574.0002). </p>
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<h4>
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<strong>Genotype/Phenotype Correlations</strong>
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<span class="mim-text-font">
<p>Hohenschutz et al. (1988) described a probable case of the genetic compound between metachromatic leukodystrophy and pseudodeficiency. The patient developed slight spasticity of the left leg at the age of 36 years and left-sided retrobulbar neuritis at the age of 62, together with slight spasticity of both legs. The diagnosis of encephalomyelitis disseminata was made. There were psychiatric manifestations as well. Based on the facts that the pseudodeficiency allele at the ARSA locus is common (gene frequency = 13.7 to 17%), that genetic compounds between the pseudodeficiency allele and the true deficiency allele may be as frequent as 0.073%, and that the residual enzyme activity may fall below a critical threshold in such individuals, Hohenschutz et al. (1989) suggested that the compound heterozygote genotype might be associated with neuropsychiatric disorders of late onset. </p><p>In 34 individuals with low ASA activity, Kappler et al. (1991) identified 3 different classes: homozygosity for the pseudodeficiency allele (ASAp/ASAp) (10 individuals), compound heterozygosity for ASAp and ASA- (6 individuals), and homozygosity of ASA- (16 individuals). The genotypes exhibited different levels of residual ASA activity. ASAp/ASAp was associated with normal sulfatide degrading capacity and a reduced ASA activity that was the highest of the 3 classes (10-50% of normal). ASAp/ASAp subjects showed no evidence of MLD. ASAp/ASA- subjects showed mildly reduced sulfatide degrading capacity and a reduced ASA activity that was in between the other 2 classes (10% of controls). ASAp/ASA- subjects were either healthy or showed mild neurologic abnormalities. ASA-/ASA- subjects showed markedly reduced sulfatide degradation and markedly reduced ASA activity. Only the ASA-/ASA- genotype was associated with the development of both early- and late-onset MLD, including neuropsychiatric symptoms. </p><p>Berger et al. (1999) described a family with 3 sibs, 1 of whom developed classic late infantile MLD, fatal at age 5 years, with deficient ARSA activity and increased galactosylsulfatide (GS) excretion. The other 2 sibs, apparently healthy at 12.5 and 15 years, and their father, apparently healthy as well, presented ARSA and GS values within the range of MLD patients. Mutation analysis demonstrated that 3 different ARSA mutations accounted for the intrafamilial phenotypic heterogeneity. One of the mutations, although clearly modifying ARSA and GS levels, apparently had little significance for clinical manifestation of MLD, The results demonstrated that in certain genetic conditions the ARSA and GS values may not be paralleled by clinical disease, a finding with serious diagnostic and prognostic implications. Moreover, further ARSA alleles functionally may exist which, together with 0-type mutations may cause ARSA and GS levels in the pathologic range but no clinical manifestation of the disease. </p><p>Regis et al. (2002) identified a late infantile MLD patient carrying on one allele a novel E253K mutation (607574.0044) and the known T391S polymorphism, and on the other allele the common P426L mutation (607574.0004), usually associated with the adult or juvenile form of the disease, and the N350S (607574.0002) and *96A-G pseudodeficiency mutations. To analyze the contribution of mutations based on the same allele to enzyme activity reduction, as well as the possible phenotype implications, they performed transient expression experiments using ARSA cDNAs carrying the identified mutations separately or in combination. Their results indicated that mutants carrying multiple mutations cause greater reduction of ARSA activity than do the corresponding single mutants, the total deficiency likely corresponding to the sum of the reductions attributed to each mutation. Consequently, each mutation may contribute to the ARSA activity reduction, and, therefore, to the degree of disease severity. This is particularly important for the alleles containing a disease-causing mutation and the pseudodeficiency mutations: in these alleles pseudodeficiency could play a role in affecting the clinical phenotype. </p><p>Rauschka et al. (2006) evaluated 42 patients with late-onset MLD, 22 of whom were homozygous for the P426L mutation and 20 of whom were compound heterozygous for I179S (607574.0008) and another pathogenic ARSA mutation. Patients homozygous for the P426L mutation presented with progressive gait disturbance caused by spastic paraparesis or cerebellar ataxia; mental disturbance was absent or insignificant at disease onset but became more apparent as the disease evolved. Peripheral nerve conduction velocities were decreased. In contrast, patients who were heterozygous for I179S presented with schizophrenia-like behavior changes, social dysfunction, and mental decline, but motor deficits were scarce. There was less residual ARSA activity in those with P426L mutations compared to those with I179S mutations. </p><p>Biffi et al. (2008) reported 26 patients with MLD who were classified clinically according to age at onset into late-infantile (17), early juvenile (6), late-juvenile (2), and adult (1). These patients were found to carry 18 mutations in the ARSA gene, including 10 rare and 8 novel mutations, that were classified as null '0' alleles lacking residual activity and 'R' alleles with residual activity. The null/null homozygous patients were the most severely affected with severe clinical manifestations, profound motor and cognitive deficits, and rapid disease progression. Patients who were null/R compound heterozygous showed a similar presentation and disease evolution, although less rapid, to null/null homozygotes. Despite some variability, all R/R homozygous patients showed a milder disease burden and slower progression when compared with null/null and null/R subjects. Biffi et al. (2008) observed early involvement of the peripheral nervous system in all patients with at least 1 null allele, and the authors suggested that evaluation of nerve conduction velocities could be used as a frontline test for all MLD patients, </p>
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<h4>
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<strong>Population Genetics</strong>
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<p>Although MLD occurs panethnically, with an estimated frequency of 1/40,000, Heinisch et al. (1995) found it to be more frequent among Arabs living in 2 restricted areas in Israel. Ten families with affected children were found, 3 in the Jerusalem region and 7 in a small area in lower Galilee. Whereas all patients from the Jerusalem region were homozygous for the splice donor site mutation at the border of exon/intron 2 (607574.0003), 5 different mutations were found in the 7 families from lower Galilee, all of them in homozygous state. Two of the families were Muslim Arabs and 2 were Christian Arabs. Four different haplotypes were represented by the 5 mutations. Zlotogora et al. (1994) studied the ARSA haplotypes defined by 3 intragenic polymorphic sites in 3 Muslim Arab families and 1 Christian Arab family from Jerusalem with the splice donor site mutation at the border of exon/intron 2. The parents were first cousins in all 4 families, but no relationship between these families was known. All 4 patients had the same haplotype, i.e., BglI(1), BamHI(1), BsrI(1), which is rare (3.9%) in the general population. Zlotogora et al. (1994) found the same haplotype in 8 non-Arab patients from the US and Europe who were homozygous for this allele. The strong association between this mutation and haplotype suggested a common origin for the mutation, which may have been introduced into Jerusalem at the time of the Crusades. </p><p>Holve et al. (2001) found that cases of MLD among Navajo Indians were clustered in a portion of the western Navajo Nation to which a small number of Navajo fled after armed conflict with the United States Army in the 1860s. The observed incidence of MLD in that region was 1/2,520 live births, with an estimated carrier frequency of 1/25 to 1/50. No cases were observed in the eastern part of the Navajo Nation over a period of 18 years (60,000 births). Bottleneck and founder effect from the mid-19th century could explain the high incidence of MLD as well as a number of other heritable disorders among the Navajo. </p><p>In Israel, Herz and Bach (1984) estimated the frequency of the pseudodeficiency allele to be about 15%. In a Spanish population, Chabas et al. (1993) estimated the frequency of the pseudodeficiency allele to be 12.7%. </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 (8.2%), Pelizaeus-Merzbacher disease (312080) (7.4%), mitochondrial diseases (4.9%), and adrenoleukodystrophy (300100) (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>
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<h4>
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<strong>History</strong>
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<p>Yatziv and Russell (1981) reported 3 adult sibs of Sephardic Jewish extraction who had a form of primary dystonia with onset in childhood. There was a marked deficiency of arylsulfatase A in urine, leukocytes, and fibroblasts. The clinically normal parents both showed a 50% reduction in ARSA activity. Yatziv and Russell (1981) reported the disorder in this family as an 'unusual form of metachromatic leukodystrophy,' but Khan et al. (2003) later reported that genetic analysis of the family indicated pseudoarylsulfatase A deficiency: the mother and all 3 sibs were homozygous, and the father was heterozygous, for the polyA pseudodeficiency allele (607574.0001). Khan et al. (2003) diagnosed the family with autosomal recessive primary dystonia (DYT2; 224500); Charlesworth et al. (2015) identified a homozygous missense mutation in the HPCA gene (N75K; 142622.0001) in the affected individuals, thus confirming the diagnosis. </p>
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<h4>
<span class="mim-font">
<strong>Animal Model</strong>
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</h4>
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<span class="mim-text-font">
<p>Since no naturally occurring animal model of metachromatic leukodystrophy is available, Hess et al. (1996) generated Arsa-deficient mice by targeted disruption of the gene in embryonic stem cells. Deficient animals stored the sphingolipid cerebroside-3-sulfate in various neuronal and nonneuronal tissues. Storage pattern was comparable with that in affected humans, but gross defect of white matter with progressive demyelination was not observed up to the age of 2 years. Reduction of axonal cross-sectional area and astrogliosis were observed in 1-year-old mice; activation of microglia started at 1 year and was generalized at 2 years. Purkinje cell dendrites showed altered morphology. In the acoustic ganglion numbers of neurons and myelinated fibers were severely decreased, which was accompanied by loss of brainstem auditory-evoked potentials. Neurologic examination demonstrated significant impairment of neuromotor coordination. </p><p>Matzner et al. (2005) treated Arsa-knockout mice by intravenous injection of recombinant human ARSA. Uptake of injected enzyme was high into liver, moderate into peripheral nervous system (PNS) and kidney, and very low into brain. A single injection led to a time- and dose-dependent decline of the excess sulfatide in PNS and kidney by up to 70%, but no reduction was seen in brain. Four weekly injections of 20 mg/kg body weight not only reduced storage in peripheral tissues progressively, but also reduced sulfatide storage in brain and spinal cord. Histopathology of kidney and central nervous system was ameliorated. Improved neuromotor coordination capabilities and normalized peripheral compound motor action potential suggested benefit of enzyme replacement therapy on nervous system function. </p>
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<div>
<h4>
<span class="mim-font">
<strong>See Also:</strong>
</span>
</h4>
<span class="mim-text-font">
Austin (1967); Austin et al. (1965); Beratis et al. (1975); Black and
Cumings (1961); Bosch and Hart (1978); Bruns et al. (1978); Chang and
Davidson (1980); Cravioto et al. (1967); DeLuca et al. (1979); DeLuca
et al. (1977); Eto et al. (1982); Farrell (1981); Goebel et al.
(1977); Hagberg et al. (1962); Haltia et al. (1980); Jervis (1960);
Percy and Brady (1968); Pilz et al. (1977); Porter et al. (1971);
Quigley and Green (1976); Sanguinetti et al. (1986); Sourander and
Svennerholm (1962); Tonnesen et al. (1983); Tonnesen et al. (1984);
Van Bogaert and Dewulf (1939); Zlotogora et al. (1980)
</span>
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</div>
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<div>
<h4>
<span class="mim-font">
<strong>REFERENCES</strong>
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</h4>
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</div>
<div>
<ol>
<li>
<p class="mim-text-font">
Adang, L. A., Groeschel, S., Grzyb, C., D'Aiello, R., Gavazzi, F., Sherbini, O., Bronner, N., Patel, A., Vincent, A., Sevagamoorthy, A., Mutua, S., Muirhead, K., and 36 others.
<strong>Developmental delay can precede neurologic regression in early onset metachromatic leukodystrophy.</strong>
Molec. Genet. Metab. 142: 108521, 2024.
[PubMed: 38964050]
[Full Text: https://doi.org/10.1016/j.ymgme.2024.108521]
</p>
</li>
<li>
<p class="mim-text-font">
Austin, J., Armstrong, D., Fouch, S., Mitchell, C., Stumpf, D. A., Shearer, L., Briner, O.
<strong>Metachromatic leukodystrophy (MLD). VIII. MLD in adults: diagnosis and pathogenesis.</strong>
Arch. Neurol. 18: 225-240, 1968.
[PubMed: 5642751]
[Full Text: https://doi.org/10.1001/archneur.1968.00470330015001]
</p>
</li>
<li>
<p class="mim-text-font">
Austin, J. H.
<strong>Metachromatic form of diffuse cerebral sclerosis. III. Significance of sulfatide and other lipid abnormalities in white matter and kidney.</strong>
Neurology 10: 470-483, 1960.
[PubMed: 13795190]
[Full Text: https://doi.org/10.1212/wnl.10.5.470]
</p>
</li>
<li>
<p class="mim-text-font">
Austin, J. H.
<strong>Some recent findings in leukodystrophies and in gargoylism. In: Aronson, S. M.; Volk, B. W. (eds.): Inborn Disorders of Sphingolipid Metabolism.</strong>
Oxford: Pergamon Press (pub.) 1967. Pp. 359-387.
</p>
</li>
<li>
<p class="mim-text-font">
Austin, J., McAfee, D., Armstrong, D., O'Rourke, M., Shearer, L., Bachhawat, B. K.
<strong>Abnormal sulphatase activities in two human diseases (metachromatic leukodystrophy and gargoylism).</strong>
Biochem. J. 93: 15C-17C, 1964.
[PubMed: 4953831]
[Full Text: https://doi.org/10.1042/bj0930015c]
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<li>
<p class="mim-text-font">
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