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Entry
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- *607574 - ARYLSULFATASE A; ARSA
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- OMIM
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<div id="mimFloatingTocMenu" class="small" role="navigation">
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<p>
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<span class="h4">*607574</span>
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<br />
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<strong>Table of Contents</strong>
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</p>
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<nav>
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<li role="presentation">
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<a href="#title"><strong>Title</strong></a>
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<li role="presentation">
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<a href="#geneMap"><strong>Gene-Phenotype Relationships</strong></a>
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<a href="#text"><strong>Text</strong></a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#description">Description</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#cloning">Cloning and Expression</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#biochemicalFeatures">Biochemical Features</a>
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<a href="#geneStructure">Gene Structure</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#mapping">Mapping</a>
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<a href="#molecularGenetics">Molecular Genetics</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#genotypePhenotypeCorrelations">Genotype/Phenotype Correlations</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#populationGenetics">Population Genetics</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#animalModel">Animal Model</a>
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<li role="presentation">
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<a href="#allelicVariants"><strong>Allelic Variants</strong></a>
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</li>
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<li role="presentation" style="margin-left: 1em">
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<a href="/allelicVariants/607574">Table View</a>
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</li>
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<li role="presentation">
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<a href="#seeAlso"><strong>See Also</strong></a>
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</li>
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<li role="presentation">
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<a href="#references"><strong>References</strong></a>
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</li>
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<li role="presentation">
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<a href="#contributors"><strong>Contributors</strong></a>
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<li role="presentation">
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<a href="#creationDate"><strong>Creation Date</strong></a>
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</li>
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<li role="presentation">
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<a href="#editHistory"><strong>Edit History</strong></a>
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</li>
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</ul>
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<div id="mimFloatingLinksMenu">
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<div class="panel panel-primary" style="margin-bottom: 0px; border-radius: 4px 4px 0px 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimExternalLinks">
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<h4 class="panel-title">
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<a href="#mimExternalLinksFold" id="mimExternalLinksToggle" class="mimTriangleToggle" role="button" data-toggle="collapse">
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<div style="display: table-row">
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<div id="mimExternalLinksToggleTriangle" class="small" style="color: white; display: table-cell;">▼</div>
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<div style="display: table-cell;">External Links</div>
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</div>
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</a>
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</h4>
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</div>
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</div>
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<div id="mimExternalLinksFold" class="collapse in">
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<div class="panel-group" id="mimExternalLinksAccordion" role="tablist" aria-multiselectable="true">
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimGenome">
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<span class="panel-title">
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<span class="small">
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<a href="#mimGenomeLinksFold" id="mimGenomeLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
|
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<span id="mimGenomeLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> Genome
|
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</a>
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</span>
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</span>
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</div>
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<div id="mimGenomeLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="genome">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ensembl.org/Homo_sapiens/Location/View?db=core;g=ENSG00000100299;t=ENST00000216124" class="mim-tip-hint" title="Genome databases for vertebrates and other eukaryotic species." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Ensembl', 'domain': 'ensembl.org'})">Ensembl</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/genome/gdv/browser/gene/?id=410" class="mim-tip-hint" title="Detailed views of the complete genomes of selected organisms from vertebrates to protozoa." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NCBI Genome Viewer', 'domain': 'ncbi.nlm.nih.gov'})">NCBI Genome Viewer</a></div>
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<div><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&hgFind=omimGeneAcc&position=607574" class="mim-tip-hint" title="UCSC Genome Browser; reference sequences and working draft assemblies for a large collection of genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC Genome Browser', 'domain': 'genome.ucsc.edu'})">UCSC Genome Browser</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimDna">
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<span class="panel-title">
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<span class="small">
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<a href="#mimDnaLinksFold" id="mimDnaLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
|
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<span id="mimDnaLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> DNA
|
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</a>
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</span>
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</span>
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</div>
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<div id="mimDnaLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ensembl.org/Homo_sapiens/Transcript/Sequence_cDNA?db=core;g=ENSG00000100299;t=ENST00000216124" class="mim-tip-hint" title="Transcript-based views for coding and noncoding DNA." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Ensembl', 'domain': 'ensembl.org'})">Ensembl (MANE Select)</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/nuccore/NM_000487,NM_001085425,NM_001085426,NM_001085427,NM_001085428,NM_001362782,XM_011530691,XM_024452241,XM_047441363" class="mim-tip-hint" title="A collection of genome, gene, and transcript sequence data from several sources, including GenBank, RefSeq." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NCBI RefSeq', 'domain': 'ncbi.nlm.nih'})">NCBI RefSeq</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/nuccore/NM_000487" class="mim-tip-hint" title="A collection of genome, gene, and transcript sequence data from several sources, including GenBank, RefSeq." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NCBI RefSeq (MANE)', 'domain': 'ncbi.nlm.nih'})">NCBI RefSeq (MANE Select)</a></div>
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<div><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&hgFind=omimGeneAcc&position=607574" class="mim-tip-hint" title="UCSC Genome Browser; reference sequences and working draft assemblies for a large collection of genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC Genome Browser', 'domain': 'genome.ucsc.edu'})">UCSC Genome Browser</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimProtein">
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<span class="panel-title">
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<span class="small">
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<a href="#mimProteinLinksFold" id="mimProteinLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
|
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<span id="mimProteinLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> Protein
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</a>
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</span>
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</span>
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</div>
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<div id="mimProteinLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://hprd.org/summary?hprd_id=09617&isoform_id=09617_1&isoform_name=Isoform_1" class="mim-tip-hint" title="The Human Protein Reference Database; manually extracted and visually depicted information on human proteins." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HPRD', 'domain': 'hprd.org'})">HPRD</a></div>
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<div><a href="https://www.proteinatlas.org/search/ARSA" class="mim-tip-hint" title="The Human Protein Atlas contains information for a large majority of all human protein-coding genes regarding the expression and localization of the corresponding proteins based on both RNA and protein data." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HumanProteinAtlas', 'domain': 'proteinatlas.org'})">Human Protein Atlas</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/protein/28858,28860,114221,1037140,1399961,30016943,33874703,47678297,52545967,119593988,119593989,146229327,189054653,194375169,220983390,308219738,313569791,313569793,313569795,313569797,768031404,957948943,957948946,1233272223,1370482277,1384008275,2217339697" class="mim-tip-hint" title="NCBI protein data." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NCBI Protein', 'domain': 'ncbi.nlm.nih.gov'})">NCBI Protein</a></div>
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<div><a href="https://www.uniprot.org/uniprotkb/P15289" class="mim-tip-hint" title="Comprehensive protein sequence and functional information, including supporting data." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UniProt', 'domain': 'uniprot.org'})">UniProt</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
|
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<div class="panel-heading mim-panel-heading" role="tab" id="mimGeneInfo">
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<span class="panel-title">
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<span class="small">
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<a href="#mimGeneInfoLinksFold" id="mimGeneInfoLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
|
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<div style="display: table-row">
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<div id="mimGeneInfoLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Gene Info</div>
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</div>
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</a>
|
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</span>
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</span>
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</div>
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<div id="mimGeneInfoLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="http://biogps.org/#goto=genereport&id=410" class="mim-tip-hint" title="The Gene Portal Hub; customizable portal of gene and protein function information." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'BioGPS', 'domain': 'biogps.org'})">BioGPS</a></div>
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<div><a href="https://www.ensembl.org/Homo_sapiens/Gene/Summary?db=core;g=ENSG00000100299;t=ENST00000216124" class="mim-tip-hint" title="Orthologs, paralogs, regulatory regions, and splice variants." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Ensembl', 'domain': 'ensembl.org'})">Ensembl</a></div>
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<div><a href="https://www.genecards.org/cgi-bin/carddisp.pl?gene=ARSA" class="mim-tip-hint" title="The Human Genome Compendium; web-based cards integrating automatically mined information on human genes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'GeneCards', 'domain': 'genecards.org'})">GeneCards</a></div>
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<div><a href="http://amigo.geneontology.org/amigo/search/annotation?q=ARSA" class="mim-tip-hint" title="Terms, defined using controlled vocabulary, representing gene product properties (biologic process, cellular component, molecular function) across species." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'GeneOntology', 'domain': 'amigo.geneontology.org'})">Gene Ontology</a></div>
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<div><a href="https://www.genome.jp/dbget-bin/www_bget?hsa+410" class="mim-tip-hint" title="Kyoto Encyclopedia of Genes and Genomes; diagrams of signaling pathways." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'KEGG', 'domain': 'genome.jp'})">KEGG</a></div>
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<dd><a href="http://v1.marrvel.org/search/gene/ARSA" class="mim-tip-hint" title="Model organism Aggregated Resources for Rare Variant ExpLoration." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MARRVEL', 'domain': 'marrvel.org'})">MARRVEL</a></dd>
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<dd><a href="https://monarchinitiative.org/NCBIGene:410" class="mim-tip-hint" title="Monarch Initiative." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Monarch', 'domain': 'monarchinitiative.org'})">Monarch</a></dd>
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<div><a href="https://www.ncbi.nlm.nih.gov/gene/410" class="mim-tip-hint" title="Gene-specific map, sequence, expression, structure, function, citation, and homology data." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NCBI Gene', 'domain': 'ncbi.nlm.nih.gov'})">NCBI Gene</a></div>
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<div><a href="https://genome.ucsc.edu/cgi-bin/hgGene?db=hg38&hgg_chrom=chr22&hgg_gene=ENST00000216124.10&hgg_start=50622754&hgg_end=50628152&hgg_type=knownGene" class="mim-tip-hint" title="UCSC Genome Bioinformatics; gene-specific structure and function information with links to other databases." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC', 'domain': 'genome.ucsc.edu'})">UCSC</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimClinicalResources">
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<span class="panel-title">
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<span class="small">
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<a href="#mimClinicalResourcesLinksFold" id="mimClinicalResourcesLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimClinicalResourcesLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Clinical Resources</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimClinicalResourcesLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="clinicalResources">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://search.clinicalgenome.org/kb/gene-dosage/HGNC:713" class="mim-tip-hint" title="A ClinGen curated resource of genes and regions of the genome that are dosage sensitive and should be targeted on a cytogenomic array." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinGen Dosage', 'domain': 'dosage.clinicalgenome.org'})">ClinGen Dosage</a></div>
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<div><a href="https://search.clinicalgenome.org/kb/genes/HGNC:713" class="mim-tip-hint" title="A ClinGen curated resource of ratings for the strength of evidence supporting or refuting the clinical validity of the claim(s) that variation in a particular gene causes disease." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinGen Validity', 'domain': 'search.clinicalgenome.org'})">ClinGen Validity</a></div>
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<div><a href="https://medlineplus.gov/genetics/gene/arsa" 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>
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<div><a href="https://www.ncbi.nlm.nih.gov/gtr/all/tests/?term=607574[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>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimVariation">
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<span class="panel-title">
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<span class="small">
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<a href="#mimVariationLinksFold" id="mimVariationLinksToggle" class=" mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimVariationLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">▼</span> Variation
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</a>
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</span>
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</span>
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</div>
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<div id="mimVariationLinksFold" class="panel-collapse collapse in mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ncbi.nlm.nih.gov/clinvar?term=607574[MIM]" class="mim-tip-hint" title="ClinVar aggregates information about sequence variation and its relationship to human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">ClinVar</a></div>
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<div><a href="https://gnomad.broadinstitute.org/gene/ENSG00000100299" class="mim-tip-hint" title="The Genome Aggregation Database (gnomAD), Broad Institute." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'gnomAD', 'domain': 'gnomad.broadinstitute.org'})">gnomAD</a></div>
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<div><a href="https://www.ebi.ac.uk/gwas/search?query=ARSA" class="mim-tip-hint" title="GWAS Catalog; NHGRI-EBI Catalog of published genome-wide association studies." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'GWAS Catalog', 'domain': 'gwascatalog.org'})">GWAS Catalog </a></div>
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<div><a href="https://www.gwascentral.org/search?q=ARSA" class="mim-tip-hint" title="GWAS Central; summary level genotype-to-phenotype information from genetic association studies." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'GWAS Central', 'domain': 'gwascentral.org'})">GWAS Central </a></div>
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<div><a href="http://www.hgmd.cf.ac.uk/ac/gene.php?gene=ARSA" class="mim-tip-hint" title="Human Gene Mutation Database; published mutations causing or associated with human inherited disease; disease-associated/functional polymorphisms." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGMD', 'domain': 'hgmd.cf.ac.uk'})">HGMD</a></div>
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<div><a href="https://evs.gs.washington.edu/EVS/PopStatsServlet?searchBy=Gene+Hugo&target=ARSA&upstreamSize=0&downstreamSize=0&x=0&y=0" class="mim-tip-hint" title="National Heart, Lung, and Blood Institute Exome Variant Server." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NHLBI EVS', 'domain': 'evs.gs.washington.edu'})">NHLBI EVS</a></div>
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<div><a href="https://www.pharmgkb.org/gene/PA25005" class="mim-tip-hint" title="Pharmacogenomics Knowledge Base; curated and annotated information regarding the effects of human genetic variations on drug response." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PharmGKB', 'domain': 'pharmgkb.org'})">PharmGKB</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimAnimalModels">
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<span class="panel-title">
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<span class="small">
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<a href="#mimAnimalModelsLinksFold" id="mimAnimalModelsLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimAnimalModelsLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Animal Models</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimAnimalModelsLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.alliancegenome.org/gene/HGNC:713" 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>
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<div><a href="https://www.mousephenotype.org/data/genes/MGI:88077" class="mim-tip-hint" title="International Mouse Phenotyping Consortium." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'IMPC', 'domain': 'knockoutmouse.org'})">IMPC</a></div>
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<div><a href="http://v1.marrvel.org/search/gene/ARSA#HomologGenesPanel" class="mim-tip-hint" title="Model organism Aggregated Resources for Rare Variant ExpLoration." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MARRVEL', 'domain': 'marrvel.org'})">MARRVEL</a></div>
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<div><a href="http://www.informatics.jax.org/marker/MGI:88077" class="mim-tip-hint" title="Mouse Genome Informatics; international database resource for the laboratory mouse, including integrated genetic, genomic, and biological data." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MGI Mouse Gene', 'domain': 'informatics.jax.org'})">MGI Mouse Gene</a></div>
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<div><a href="https://www.mmrrc.org/catalog/StrainCatalogSearchForm.php?search_query=" class="mim-tip-hint" title="Mutant Mouse Resource & Research Centers." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MMRRC', 'domain': 'mmrrc.org'})">MMRRC</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/gene/410/ortholog/" class="mim-tip-hint" title="Orthologous genes at NCBI." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NCBI Orthologs', 'domain': 'ncbi.nlm.nih.gov'})">NCBI Orthologs</a></div>
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<div><a href="https://www.orthodb.org/?ncbi=410" class="mim-tip-hint" title="Hierarchical catalogue of orthologs." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'OrthoDB', 'domain': 'orthodb.org'})">OrthoDB</a></div>
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<div><a href="https://wormbase.org/db/gene/gene?name=WBGene00006309;class=Gene" 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'{'name': 'Wormbase Gene', 'domain': 'wormbase.org'})">Wormbase Gene</a></div>
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<div><a href="https://zfin.org/ZDB-GENE-050320-118" class="mim-tip-hint" title="The Zebrafish Model Organism Database." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ZFin', 'domain': 'zfin.org'})">ZFin</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
|
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<div class="panel-heading mim-panel-heading" role="tab" id="mimCellularPathways">
|
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<span class="panel-title">
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<span class="small">
|
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<a href="#mimCellularPathwaysLinksFold" id="mimCellularPathwaysLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
|
|
<div style="display: table-row">
|
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<div id="mimCellularPathwaysLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Cellular Pathways</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimCellularPathwaysLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.genome.jp/dbget-bin/get_linkdb?-t+pathway+hsa:410" class="mim-tip-hint" title="Kyoto Encyclopedia of Genes and Genomes; diagrams of signaling pathways." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'KEGG', 'domain': 'genome.jp'})">KEGG</a></div>
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<div><a href="https://reactome.org/content/query?q=ARSA&species=Homo+sapiens&types=Reaction&types=Pathway&cluster=true" class="definition" title="Protein-specific information in the context of relevant cellular pathways." target="_blank" onclick="gtag('event', 'mim_outbound', {{'name': 'Reactome', 'domain': 'reactome.org'}})">Reactome</a></div>
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</div>
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</div>
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</div>
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</div>
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</div>
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</div>
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<span>
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<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.">
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</span>
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</span>
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</div>
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<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">
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<div>
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<a id="title" class="mim-anchor"></a>
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<div>
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<a id="number" class="mim-anchor"></a>
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<div class="text-right">
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<a href="#" class="mim-tip-icd" qtip_title="<strong>ICD+</strong>" qtip_text="
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<strong>SNOMEDCT:</strong> 24326000, 396338004, 40802007, 44359008, 47683004<br />
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<strong>ICD10CM:</strong> E75.25, E75.29<br />
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">ICD+</a>
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</div>
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<div>
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<span class="h3">
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<span class="mim-font mim-tip-hint" title="Gene description">
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<span class="text-danger"><strong>*</strong></span>
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607574
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</span>
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</span>
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</div>
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</div>
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<div>
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<a id="preferredTitle" class="mim-anchor"></a>
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<h3>
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<span class="mim-font">
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|
ARYLSULFATASE A; ARSA
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</span>
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</h3>
|
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</div>
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<div>
|
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<br />
|
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</div>
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<div>
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<a id="alternativeTitles" class="mim-anchor"></a>
|
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<div>
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<p>
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<span class="mim-font">
|
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<em>Alternative titles; symbols</em>
|
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</span>
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</p>
|
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</div>
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<div>
|
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<h4>
|
|
<span class="mim-font">
|
|
CEREBROSIDE-SULFATASE<br />
|
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CEREBROSIDE 3-SULFATASE
|
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</span>
|
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</h4>
|
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</div>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
|
|
<a id="approvedGeneSymbols" class="mim-anchor"></a>
|
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<p>
|
|
<span class="mim-text-font">
|
|
<strong><em>HGNC Approved Gene Symbol: <a href="https://www.genenames.org/tools/search/#!/genes?query=ARSA" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">ARSA</a></em></strong>
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</span>
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</p>
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</div>
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<div>
|
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<a id="cytogeneticLocation" class="mim-anchor"></a>
|
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<p>
|
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<span class="mim-text-font">
|
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<strong>
|
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<em>
|
|
Cytogenetic location: <a href="/geneMap/22/423?start=-3&limit=10&highlight=423">22q13.33</a>
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|
Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chr22:50622754-50628152&dgv=pack&knownGene=pack&omimGene=pack" class="mim-tip-hint" title="UCSC Genome Browser; reference sequences and working draft assemblies for a large collection of genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC Genome Browser', 'domain': 'genome.ucsc.edu'})">22:50,622,754-50,628,152</a> </span>
|
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</em>
|
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</strong>
|
|
<a href="https://www.ncbi.nlm.nih.gov/" target="_blank" class="small"> (from NCBI) </a>
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</span>
|
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</p>
|
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</div>
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<div>
|
|
<br />
|
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</div>
|
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<div>
|
|
<a id="geneMap" class="mim-anchor"></a>
|
|
<div style="margin-bottom: 10px;">
|
|
<span class="h4 mim-font">
|
|
<strong>Gene-Phenotype Relationships</strong>
|
|
</span>
|
|
</div>
|
|
<div>
|
|
<table class="table table-bordered table-condensed table-hover small mim-table-padding">
|
|
<thead>
|
|
<tr class="active">
|
|
<th>
|
|
Location
|
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</th>
|
|
<th>
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|
Phenotype
|
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</th>
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<th>
|
|
Phenotype <br /> MIM number
|
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</th>
|
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<th>
|
|
Inheritance
|
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</th>
|
|
<th>
|
|
Phenotype <br /> mapping key
|
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</th>
|
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</tr>
|
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</thead>
|
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<tbody>
|
|
|
|
<tr>
|
|
<td rowspan="1">
|
|
<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>
|
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</span>
|
|
</td>
|
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|
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</tr>
|
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</tbody>
|
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</table>
|
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</div>
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</div>
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<div>
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<div class="btn-group">
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<p>The ARSA gene encodes the lysosomal enzyme arylsulfatase A (<a href="https://enzyme.expasy.org/EC/3.1.6.8" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'EC\', \'domain\': \'expasy.org\'})">EC 3.1.6.8</a>).</p>
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<p><a href="#51" class="mim-tip-reference" title="Stein, C., Gieselmann, V., Kreysing, J., Schmidt, B., Pohlmann, R., Waheed, A., Meyer, H. E., O'Brien, J. S., von Figura, K. <strong>Cloning and expression of human arylsulfatase A.</strong> J. Biol. Chem. 264: 1252-1259, 1989.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2562955/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2562955</a>]" pmid="2562955">Stein et al. (1989)</a> cloned and sequenced a full-length cDNA for human arylsulfatase A. The predicted amino acid sequence comprised 507 residues, including a putative signal peptide of 18 residues. The sequence contains 3 potential N-glycosylation sites. The cDNA hybridized to 2.0- and 3.9-kb species in RNA from human fibroblasts and human liver. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2562955" 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="#34" class="mim-tip-reference" title="Kreysing, J., von Figura, K., Gieselmann, V. <strong>Structure of the arylsulfatase A gene.</strong> Europ. J. Biochem. 191: 627-631, 1990.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1975241/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1975241</a>] [<a href="https://doi.org/10.1111/j.1432-1033.1990.tb19167.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1975241">Kreysing et al. (1990)</a> found that 3 different mRNA species of 2.1, 3.7, and 4.8 kb are transcribed from the gene and probably arise from the use of different polyadenylation signals. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1975241" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#37" class="mim-tip-reference" title="Lukatela, G., Krauss, N., Theis, K., Selmer, T., Gieselmann, V., von Figura, K., Saenger, W. <strong>Crystal structure of human arylsulfatase A: the aldehyde function and the metal ion at the active site suggest a novel mechanism for sulfate ester hydrolysis.</strong> Biochemistry 37: 3654-3664, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9521684/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9521684</a>] [<a href="https://doi.org/10.1021/bi9714924" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9521684">Lukatela et al. (1998)</a> determined the crystal structure of ARSA at 2.1 angstrom resolution. The core of the enzyme consists of 2 beta-pleated sheets, linked by several hydrogen bonds and 1 disulfide bridge. The large central beta-pleated sheet is associated with several helices on each side, resembling bacterial alkaline phosphatase. The quaternary structure of ARSA is highly pH dependent and oscillates between 2 states: at neutral pH, it is predominantly dimeric, and at lysosomal acid pH, it is predominantly a homo-octamer, composed of 4 dimers arranged in a ring-like structure. The dimer-octamer equilibrium is regulated by deprotonation-protonation of glu424. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9521684" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#34" class="mim-tip-reference" title="Kreysing, J., von Figura, K., Gieselmann, V. <strong>Structure of the arylsulfatase A gene.</strong> Europ. J. Biochem. 191: 627-631, 1990.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1975241/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1975241</a>] [<a href="https://doi.org/10.1111/j.1432-1033.1990.tb19167.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1975241">Kreysing et al. (1990)</a> determined that the ARSA gene contains 8 exons. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1975241" 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>By somatic cell hybridization methods, <a href="#11" class="mim-tip-reference" title="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.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/36611/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">36611</a>] [<a href="https://doi.org/10.1073/pnas.76.4.1957" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="36611">DeLuca et al. (1979)</a> assigned arylsulfatases A and B (<a href="/entry/611542">611542</a>) to chromosome 22 and 5, respectively. Using somatic cell hybrids, <a href="#28" class="mim-tip-reference" title="Hors-Cayla, M. C., Heuertz, S., Van Cong, N., Weil, D., Frezal, J. <strong>Confirmation of the assignment of the gene for arylsulfatase A to chromosome 22 using somatic cell hybrids.</strong> Hum. Genet. 49: 33-39, 1979.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/38202/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">38202</a>] [<a href="https://doi.org/10.1007/BF00277684" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="38202">Hors-Cayla et al. (1979)</a> confirmed the assignment of human ARSA to chromosome 22. From study of human-rodent hybrid clones, <a href="#16" class="mim-tip-reference" title="Geurts van Kessel, A. H. M., Westerveld, A., de Groot, P. G., Meera Khan, P., Hagemeijer, A. <strong>Regional localization of the genes coding for human ACO2, ARSA, and NAGA on chromosome 22.</strong> Cytogenet. Cell Genet. 28: 169-172, 1980.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7192199/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7192199</a>] [<a href="https://doi.org/10.1159/000131527" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7192199">Geurts van Kessel et al. (1980)</a> concluded that arylsulfatase A is located distal to 22q13. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=7192199+36611+38202" 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 an infant with deletion of 22q13.31-qter, <a href="#42" class="mim-tip-reference" title="Narahara, K., Takahashi, Y., Murakami, M., Tsuji, K., Yokoyama, Y., Murakami, R., Ninomiya, S., Seino, Y. <strong>Terminal 22q deletion associated with a partial deficiency of arylsulphatase A.</strong> J. Med. Genet. 29: 432-433, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1352356/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1352356</a>] [<a href="https://doi.org/10.1136/jmg.29.6.432" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1352356">Narahara et al. (1992)</a> found partial deficiency of ARSA, indicating that the ARSA locus was in the deleted region. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1352356" 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>In fibroblasts of 2 patients with metachromatic leukodystrophy (MLD; <a href="/entry/250100">250100</a>), <a href="#51" class="mim-tip-reference" title="Stein, C., Gieselmann, V., Kreysing, J., Schmidt, B., Pohlmann, R., Waheed, A., Meyer, H. E., O'Brien, J. S., von Figura, K. <strong>Cloning and expression of human arylsulfatase A.</strong> J. Biol. Chem. 264: 1252-1259, 1989.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2562955/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2562955</a>]" pmid="2562955">Stein et al. (1989)</a> detected ARSA RNA species of similar size. One was a form in which synthesis of ARSA polypeptides was not detectable, and the second was a form in which catalytically active enzyme was synthesized but was unstable in lysosomes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2562955" 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>In patients with MLD, <a href="#46" class="mim-tip-reference" title="Polten, A., Fluharty, A. L., Fluharty, C. B., Kappler, J., von Figura, K., Gieselmann, V. <strong>Molecular basis of different forms of metachromatic leukodystrophy.</strong> New Eng. J. Med. 324: 18-22, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1670590/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1670590</a>] [<a href="https://doi.org/10.1056/NEJM199101033240104" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1670590">Polten et al. (1991)</a>, <a href="#17" class="mim-tip-reference" title="Gieselmann, V., Fluharty, A. L., Tonnesen, T., Von Figura, K. <strong>Mutations in the arylsulfatase A pseudodeficiency allele causing metachromatic leukodystrophy.</strong> Am. J. Hum. Genet. 49: 407-413, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1678251/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1678251</a>]" pmid="1678251">Gieselmann et al. (1991)</a>, <a href="#32" class="mim-tip-reference" title="Kondo, R., Wakamatsu, N., Yoshino, H., Fukuhara, N., Miyatake, T., Tsuji, S. <strong>Identification of a mutation in the arylsulfatase A gene of a patient with adult-type metachromatic leukodystrophy.</strong> Am. J. Hum. Genet. 48: 971-978, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1673291/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1673291</a>]" pmid="1673291">Kondo et al. (1991)</a>, <a href="#6" class="mim-tip-reference" title="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.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1676699/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1676699</a>] [<a href="https://doi.org/10.1007/BF00204172" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1676699">Bohne et al. (1991)</a>, and <a href="#14" class="mim-tip-reference" title="Fluharty, A. L., Fluharty, C. B., Bohne, W., von Figura, K., Gieselmann, V. <strong>Two new arylsulfatase A (ARSA) mutations in a juvenile metachromatic leukodystrophy (MLD) patient.</strong> Am. J. Hum. Genet. 49: 1340-1350, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1684088/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1684088</a>]" pmid="1684088">Fluharty et al. (1991)</a> identified mutations in the ARSA gene (e.g., <a href="#0003">607574.0003</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=1684088+1670590+1676699+1678251+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>
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<p><a href="#19" class="mim-tip-reference" title="Gieselmann, V., Zlotogora, J., Harris, A., Wenger, D. A., Morris, C. P. <strong>Molecular genetics of metachromatic leukodystrophy.</strong> Hum. Mutat. 4: 233-242, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7866401/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7866401</a>] [<a href="https://doi.org/10.1002/humu.1380040402" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" 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>
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<p><a href="#30" class="mim-tip-reference" title="Kappler, J., Sommerlade, H. J., von Figura, K., Gieselmann, V. <strong>Complex arylsulfatase A alleles causing metachromatic leukodystrophy.</strong> Hum. Mutat. 4: 119-127, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7981715/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7981715</a>] [<a href="https://doi.org/10.1002/humu.1380040205" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7981715">Kappler et al. (1994)</a> found that a patient with late infantile MLD was a genetic compound for 2 alleles, each of which carried 2 deleterious mutations. One allele carried 2 missense mutations; the other allele bore a splice donor site mutation and a missense mutation, both of which had previously been described but on different alleles. When ARSA cDNAs carrying these mutations, separately or in combination, were transfected into baby hamster kidney cells, expression of arylsulfatase A activity could not be detected. Among the lysosomal storage disorders, a single allele with 2 disease-causing mutations had been described for the GLA gene in Fabry disease (<a href="/entry/301500#0011">301500.0011</a>) and in the complex glucocerebrosidase alleles associated with Gaucher disease (<a href="/entry/230800#0009">230800.0009</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7981715" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#3" class="mim-tip-reference" title="Barth, M. L., Fensom, A., Harris, A. <strong>Identification of seven novel mutations associated with metachromatic leukodystrophy.</strong> Hum. Mutat. 6: 170-176, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7581401/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7581401</a>] [<a href="https://doi.org/10.1002/humu.1380060210" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7581401">Barth et al. (1995)</a> found 7 novel mutations in ARSA associated with MLD that they had detected by chemical mismatch analysis. <a href="#10" class="mim-tip-reference" title="Coulter-Mackie, M. B., Rip, J., Ludman, M. D., Beis, J., Cole, D. E. C. <strong>Metachromatic leucodystrophy (MLD) in a patient with a constitutional ring chromosome 22.</strong> J. Med. Genet. 32: 787-791, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8558556/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8558556</a>] [<a href="https://doi.org/10.1136/jmg.32.10.787" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8558556">Coulter-Mackie et al. (1995)</a> described a child with MLD who had inherited a common splicing mutation, termed the 'I' allele, from the father and had a ring chromosome 22 from which the arylsulfatase A gene was deleted. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=8558556+7581401" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#12" class="mim-tip-reference" title="Draghia, R., Letourneur, F., Drugan, C., Manicom, J., Blanchot, C., Kahn, A., Poenaru, L., Caillaud, C. <strong>Metachromatic leukodystrophy: identification of the first deletion in exon 1 and of nine novel point mutations in the arylsulfatase gene.</strong> Hum. Mutat. 9: 234-242, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9090526/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9090526</a>] [<a href="https://doi.org/10.1002/(SICI)1098-1004(1997)9:3<234::AID-HUMU4>3.0.CO;2-7" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9090526">Draghia et al. (1997)</a> described 10 novel and 5 previously described mutations in 21 MLD patients (14 late infantile and 7 juvenile cases), confirming the heterogeneity of mutations causing MLD. One of the 10 novel mutations was an R496H missense change. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9090526" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#21" class="mim-tip-reference" title="Gomez-Lira, M., Perusi, C., Mottes, M., Pignatti, P. F., Manfredi, M., Rizzuto, N., Salviati, A. <strong>Molecular genetic characterization of two metachromatic leukodystrophy patients who carry the T799G mutation and show different phenotypes; description of a novel null-type mutation.</strong> Hum. Genet. 102: 459-463, 1998. Note: Erratum: Hum. Genet. 102: 602 only, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9600244/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9600244</a>] [<a href="https://doi.org/10.1007/s004390050721" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9600244">Gomez-Lira et al. (1998)</a> described mutations in the ARSA gene in 2 Italian patients with metachromatic leukodystrophy, one with juvenile onset and the other with adult onset. Both carried the ile179-to-ser mutation (<a href="#0008">607574.0008</a>) in compound heterozygosity with distinct null mutations. The patient with juvenile onset also had a previously described splice site mutation, 459+1G-A (<a href="#0003">607574.0003</a>), and the patient with adult onset had a previously undescribed mutation, pro135 to leu (<a href="#0042">607574.0042</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9600244" 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><strong><em>Pseudoarylsulfatase A Deficiency Alleles</em></strong>
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<div class="mim-changed mim-change"><p><a href="#18" class="mim-tip-reference" title="Gieselmann, V., Polten, A., Kreysing, J., von Figura, K. <strong>Arylsulfatase A pseudodeficiency: loss of a polyadenylylation (sic) signal and N-glycosylation site.</strong> Proc. Nat. Acad. Sci. 86: 9436-9440, 1989.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2574462/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2574462</a>] [<a href="https://doi.org/10.1073/pnas.86.23.9436" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2574462">Gieselmann et al. (1989)</a> found that the pseudoarylsulfatase A deficiency (<a href="/entry/250100">250100</a>) allele had 2 A-to-G transitions: one, an asn350-to-ser mutation in exon 6, causing the loss of an N-glycosylation site (<a href="#0002">607574.0002</a>), and the other occurring in exon 8 at the 3-prime end of the gene, causing the loss of a polyadenylation signal (<a href="#0001">607574.0001</a>). <a href="#20" class="mim-tip-reference" title="Gieselmann, V. <strong>An assay for the rapid detection of the arylsulfatase A pseudodeficiency allele facilitates diagnosis and genetic counseling for metachromatic leukodystrophy.</strong> Hum. Genet. 86: 251-255, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1671769/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1671769</a>] [<a href="https://doi.org/10.1007/BF00202403" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1671769">Gieselmann (1991)</a> found that these 2 mutations could be detected simultaneously with a rapid 3-prime-mismatch polymerase chain reaction. <a href="#50" class="mim-tip-reference" title="Shen, N., Li, Z.-G., Waye, J. S., Francis, G., Chang, P. L. <strong>Complications in the genotypic molecular diagnosis of pseudo arylsulfatase A deficiency.</strong> Am. J. Med. Genet. 45: 631-637, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8456837/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8456837</a>] [<a href="https://doi.org/10.1002/ajmg.1320450523" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8456837">Shen et al. (1993)</a> found another complication: a pseudodeficiency allele in which only 1 of the 2 A-to-G mutations was present. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=8456837+2574462+1671769" 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></div>
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<p>Although the ARSA pseudodeficiency allele contains 2 sequence alterations, a polyadenylation defect (<a href="#0001">607574.0001</a>) and an amino acid substitution, N350S (<a href="#0002">607574.0002</a>), the reduction in arylsulfatase activity had previously been attributed to the polyadenylation defect which reduces the amount of ARSA mRNA and hence arylsulfatase A protein by approximately 90%. <a href="#22" class="mim-tip-reference" title="Harvey, J. S., Carey, W. F., Morris, C. P. <strong>Importance of the glycosylation and polyadenylation variants in metachromatic leukodystrophy pseudodeficiency phenotype.</strong> Hum. Molec. Genet. 7: 1215-1219, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9668161/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9668161</a>] [<a href="https://doi.org/10.1093/hmg/7.8.1215" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9668161">Harvey et al. (1998)</a> performed ribonuclease protection assay analysis of ARSA mRNA transcripts and investigated the activity and lysosomal localization of protein expressed by an ARSA expression construct containing the N350S variant. They concluded that both the N350S and the polyadenylation defect play roles in biochemically defining the pseudodeficiency phenotype. The combined effect of the reduction in ARSA mRNA due to the polyadenylation defect and the lowering of ARSA activity and aberrant targeting of the expressed N350S ARSA protein to the lysosome was estimated to reduce ARSA activity in the pseudodeficiency homozygote to approximately 8% of normal. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9668161" 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>In 34 individuals with low ASA activity, <a href="#29" class="mim-tip-reference" title="Kappler, J., Leinekugel, P., Conzelmann, E., Kleijer, W. J., Kohlschutter, A., Tonnesen, T., Rochel, M., Freycon, F., Propping, P. <strong>Genotype-phenotype relationship in various degrees of arylsulfatase A deficiency.</strong> Hum. Genet. 86: 463-470, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1673113/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1673113</a>] [<a href="https://doi.org/10.1007/BF00194634" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" 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="#5" class="mim-tip-reference" title="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> Hum. Mutat. 13: 61-68, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9888390/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9888390</a>] [<a href="https://doi.org/10.1002/(SICI)1098-1004(1999)13:1<61::AID-HUMU7>3.0.CO;2-H" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" 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. The late infantile patient inherited from his mother the frequent IVS2DS+1G-A mutation (<a href="#0003">607574.0003</a>), and from his father a novel, single basepair microdeletion of guanine at nucleotide 7 in exon 1 (7delG). The 2 clinically unaffected sibs carried the maternal mutation IVS2DS+1G-A and, on their paternal allele, a novel C-to-T transition at nucleotide 2435 in exon 8, resulting in an ala464-to-val amino acid substitution. The father's genotype thus was 7delG/A464V. The A464V mutation was not found in 18 unrelated MLD patients and 50 controls. A464V, although clearly modifying ARSA and GS levels, apparently has little significance for clinical manifestation of MLD, mimicking the frequent ARSA pseudodeficiency allele (<a href="#0001">607574.0001</a>). 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 similar to A464V may exist which, together with 0-type mutations such as IVS2DS+1G-A, 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="#48" class="mim-tip-reference" title="Regis, S., Corsolini, F., Stroppiano, M., Cusano, R., Filocamo, M. <strong>Contribution of arylsulfatase A mutations located on the same allele to enzyme activity reduction and metachromatic leukodystrophy severity.</strong> Hum. Genet. 110: 351-355, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11941485/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11941485</a>] [<a href="https://doi.org/10.1007/s00439-002-0701-y" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11941485">Regis et al. (2002)</a> identified a late infantile MLD patient carrying on one allele a novel E253K mutation (<a href="#0044">607574.0044</a>) and the known T391S polymorphism, and on the other allele the common P426L mutation (<a href="#0004">607574.0004</a>), usually associated with the adult or juvenile form of the disease, and the N350S (<a href="#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="#47" 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. <strong>Late-onset metachromatic leukodystrophy: genotype strongly influences phenotype.</strong> Neurology 67: 859-863, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16966551/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16966551</a>] [<a href="https://doi.org/10.1212/01.wnl.0000234129.97727.4d" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" 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 who were compound heterozygous for I179S (<a href="#0008">607574.0008</a>) and another pathogenic ARSA mutation. Patients homozygous for the P426L mutation presented with progressive gait disturbance caused by spasticity 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>
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<p><a href="#49" class="mim-tip-reference" title="Ricketts, M. H., Poretz, R. D., Manowitz, P. <strong>The R496H mutation of arylsulfatase A does not cause metachromatic leukodystrophy.</strong> Hum. Mutat. 12: 238-239, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9744473/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9744473</a>] [<a href="https://doi.org/10.1002/(SICI)1098-1004(1998)12:4<238::AID-HUMU3>3.0.CO;2-B" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9744473">Ricketts et al. (1998)</a> demonstrated that the ARSA polymorphism R496H has a relatively high frequency in an African American population, i.e., a frequency of 0.09 in 61 subjects tested. One normal 21-year-old subject was homozygous for the R496H mutation without evidence of MLD. The ARSA enzyme activity in subjects with or without R496H was found to be normal. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9744473" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#41" 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. <strong>Enzyme replacement improves nervous system pathology and function in a mouse model for metachromatic leukodystrophy.</strong> Hum. Molec. Genet. 14: 1139-1152, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15772092/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15772092</a>] [<a href="https://doi.org/10.1093/hmg/ddi126" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" 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. The 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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<strong>ALLELIC VARIANTS (<a href="/help/faq#1_4"></strong>
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<strong>47 Selected Examples</a>):</strong>
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<strong>.0001 ARYLSULFATASE A PSEUDODEFICIENCY</strong>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000003190 OR RCV000020309 OR RCV000180167 OR RCV000246300" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000003190, RCV000020309, RCV000180167, RCV000246300" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000003190...</a>
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<p>In an individual homozygous for the ARSA pseudodeficiency (<a href="/entry/250100">250100</a>) allele, <a href="#18" class="mim-tip-reference" title="Gieselmann, V., Polten, A., Kreysing, J., von Figura, K. <strong>Arylsulfatase A pseudodeficiency: loss of a polyadenylylation (sic) signal and N-glycosylation site.</strong> Proc. Nat. Acad. Sci. 86: 9436-9440, 1989.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2574462/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2574462</a>] [<a href="https://doi.org/10.1073/pnas.86.23.9436" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2574462">Gieselmann et al. (1989)</a> found 2 A-to-G transitions: one changed asn350 to serine, leading to loss of an N-glycosylation site (<a href="#0002">607574.0002</a>). This loss explained the smaller size of ARSA in ARSA pseudodeficient fibroblasts. Introduction of ser350 into normal ARSA cDNA did not affect the rate of synthesis, stability, or catalytic properties of ARSA in stably transfected baby hamster kidney cells, however. The other A-to-G transition changed the first polyadenylation signal downstream of the stop codon from AATAAC to AGTAAC. The latter change caused a severe deficiency of a 2.1-kb RNA species. The deficiency of the 2.1-kb RNA species explained the diminished synthesis of ARSA in pseudodeficiency fibroblasts. The same change was found in 4 unrelated individuals with pseudodeficiency. In those who are homozygous for the pseudodeficiency allele or carry it in heterozygous state with a normal allele, enough arylsulfatase A is synthesized to prevent clinically apparent disease. In combination with other mutant alleles, it may cause metachromatic leukodystrophy. <a href="#43" class="mim-tip-reference" title="Nelson, P. V., Carey, W. F., Morris, C. P. <strong>Population frequency of the arylsulphatase A pseudo-deficiency allele.</strong> Hum. Genet. 87: 87-88, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1674719/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1674719</a>] [<a href="https://doi.org/10.1007/BF01213099" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1674719">Nelson et al. (1991)</a> likewise found the A-to-G change at nucleotide 1620 in the first polyadenylation signal of the ARSA gene resulting in loss of its major mRNA species and a greatly reduced level of enzyme activity. This change was found to be closely linked to another A-to-G transition at nucleotide 1049 which changed asparagine-350 to serine but did not affect ARSA activity. The findings of <a href="#43" class="mim-tip-reference" title="Nelson, P. V., Carey, W. F., Morris, C. P. <strong>Population frequency of the arylsulphatase A pseudo-deficiency allele.</strong> Hum. Genet. 87: 87-88, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1674719/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1674719</a>] [<a href="https://doi.org/10.1007/BF01213099" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1674719">Nelson et al. (1991)</a> supported the conclusion of <a href="#18" class="mim-tip-reference" title="Gieselmann, V., Polten, A., Kreysing, J., von Figura, K. <strong>Arylsulfatase A pseudodeficiency: loss of a polyadenylylation (sic) signal and N-glycosylation site.</strong> Proc. Nat. Acad. Sci. 86: 9436-9440, 1989.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2574462/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2574462</a>] [<a href="https://doi.org/10.1073/pnas.86.23.9436" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2574462">Gieselmann et al. (1989)</a> that the change in nucleotide 1620 is always associated with that at nucleotide 1049. <a href="#4" class="mim-tip-reference" title="Barth, M. L., Ward, C., Harris, A., Saad, A., Fensom, A. <strong>Frequency of arylsulphatase A pseudodeficiency associated mutations in a healthy population.</strong> J. Med. Genet. 31: 667-671, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7815433/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7815433</a>] [<a href="https://doi.org/10.1136/jmg.31.9.667" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7815433">Barth et al. (1994)</a> stated that the 2 mutations do not always occur together and that at least the N350S mutation may be found alone. The carrier frequency of the ARSA pseudodeficiency mutation in Australia was estimated to be about 20%. <a href="#35" class="mim-tip-reference" title="Li, Z. G., Waye, J. S., Chang, P. L. <strong>Diagnosis of arylsulfatase A deficiency.</strong> Am. J. Med. Genet. 43: 976-982, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1357970/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1357970</a>] [<a href="https://doi.org/10.1002/ajmg.1320430614" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1357970">Li et al. (1992)</a> described a polymerase chain reaction (PCR)-based method for genotypically identifying pseudodeficiency. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=1357970+1674719+7815433+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><p><a href="#4" class="mim-tip-reference" title="Barth, M. L., Ward, C., Harris, A., Saad, A., Fensom, A. <strong>Frequency of arylsulphatase A pseudodeficiency associated mutations in a healthy population.</strong> J. Med. Genet. 31: 667-671, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7815433/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7815433</a>] [<a href="https://doi.org/10.1136/jmg.31.9.667" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7815433">Barth et al. (1994)</a> used PCR and restriction endonuclease digestion to determine the frequency of A-to-G transitions at bases 1049 (N350S) and 1620 in healthy persons from England. Mutations were found in 24 of 77 screened persons. Two were homozygous for both mutations, 16 were heterozygous for both, 5 were heterozygous for the N350S mutation alone, and 1 was homozygous for the N350S mutation. Study of the 16 persons heterozygous for both mutations showed that in 15 persons both mutations were located on the same chromosome, and in 1 person the mutations were located on different chromosomes. Persons homozygous for both mutations had the lowest activities of ARSA. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7815433" 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="Harvey, J. S., Carey, W. F., Morris, C. P. <strong>Importance of the glycosylation and polyadenylation variants in metachromatic leukodystrophy pseudodeficiency phenotype.</strong> Hum. Molec. Genet. 7: 1215-1219, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9668161/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9668161</a>] [<a href="https://doi.org/10.1093/hmg/7.8.1215" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9668161">Harvey et al. (1998)</a> presented evidence that the combined effect of reduction in ARSA mRNA due to the polyadenylation defect and the lowering of ARSA activity and aberrant targeting of the expressed N350S ARSA protein (<a href="#0002">607574.0002</a>) to the lysosome was estimated to reduce ARSA activity in pseudodeficiency homozygotes to approximately 8% of normal. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9668161" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs2071421 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs2071421;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs2071421?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs2071421" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs2071421" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000020310 OR RCV000078931 OR RCV000249834 OR RCV001357207" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000020310, RCV000078931, RCV000249834, RCV001357207" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000020310...</a>
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<p>In a homozygote for ARSA deficiency (<a href="/entry/250100">250100</a>), <a href="#18" class="mim-tip-reference" title="Gieselmann, V., Polten, A., Kreysing, J., von Figura, K. <strong>Arylsulfatase A pseudodeficiency: loss of a polyadenylylation (sic) signal and N-glycosylation site.</strong> Proc. Nat. Acad. Sci. 86: 9436-9440, 1989.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2574462/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2574462</a>] [<a href="https://doi.org/10.1073/pnas.86.23.9436" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2574462">Gieselmann et al. (1989)</a> demonstrated that an A-to-G transition in the polyadenylation signal downstream of the stop codon, from AATAAC to AGTAAC, was responsible for the severe deficiency of a 2.1-kb RNA species and the diminished synthesis of ARSA (<a href="#0001">607574.0001</a>). A second mutation, asn350-to-serine, resulting from an A-to-G transition, appeared to be responsible for the small size of ARSA produced by pseudodeficiency fibroblasts because it led to loss of an N-glycosylation site. It was not, however, responsible for the defective synthesis of enzyme. The asn350-to-ser mutation is a polymorphism that does not affect the activity or stability of the enzyme, whereas the other mutation causes the loss of about 90% of ARSA mRNA, which explains the loss of 90% of ARSA crossreacting material and enzyme activity. <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><p>The 'pseudodeficiency' allele, found in a frequency of approximately 10% in many populations, is associated with 2 A-to-G transitions in cis in the ARSA gene causing the simultaneous loss of an N-glycosylation and a polyadenylation signal. To understand the evolutionary relationship between such common and tightly linked mutations, <a href="#44" class="mim-tip-reference" title="Ott, R., Waye, J. S., Chang, P. L. <strong>Evolutionary origins of two tightly linked mutations in arylsulfatase-A pseudodeficiency.</strong> Hum. Genet. 101: 135-140, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9402957/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9402957</a>] [<a href="https://doi.org/10.1007/s004390050602" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9402957">Ott et al. (1997)</a> studied 400 individuals in the African, European, Indian, and East Asian populations and found none carrying the polyadenylation mutation alone. However, the N-glycosylation mutation could occur independently. Its frequency varies from 0.01 in Indians and 0.06 in Europeans to 0.21 in East Asians and 0.32 in Africans. The frequencies of both mutations occurring together range from almost nonexistent in the Africans and East Asians, to 0.075 in Europeans and 0.125 in Indians. These frequencies were significantly different among populations. Haplotype analysis among homozygous pseudodeficiency individuals and 8 multigeneration families with 6 polymorphism-identifying restriction enzymes showed that, of the 5 haplotypes found in the general population, only 1 was linked to the double mutations. Alleles among the 4 populations with only the N-glycosylation mutation also supported linkage to the same haplotype except in some Europeans, whose alleles were discordant. These results were considered consistent with the hypothesis that the N-glycosylation mutation may be a recurrent event among Europeans but first occurred in an ancestral allele before the emergence of modern Homo sapiens from Africa approximately 100,000 to 200,000 years ago. Subsequently, the polyadenylation mutation occurred in this ancient allele with the N-glycosylation mutation, an event that likely took place after the divergence between the European and East Asian lineages. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9402957" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs80338815 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs80338815;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs80338815?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs80338815" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs80338815" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000003192 OR RCV000003194 OR RCV000020319 OR RCV000335617 OR RCV001251910 OR RCV001267384 OR RCV001778645 OR RCV002251862 OR RCV003934795" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000003192, RCV000003194, RCV000020319, RCV000335617, RCV001251910, RCV001267384, RCV001778645, RCV002251862, RCV003934795" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000003192...</a>
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<p>In a patient with juvenile-onset metachromatic leukodystrophy (<a href="/entry/250100">250100</a>), <a href="#46" class="mim-tip-reference" title="Polten, A., Fluharty, A. L., Fluharty, C. B., Kappler, J., von Figura, K., Gieselmann, V. <strong>Molecular basis of different forms of metachromatic leukodystrophy.</strong> New Eng. J. Med. 324: 18-22, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1670590/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1670590</a>] [<a href="https://doi.org/10.1056/NEJM199101033240104" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1670590">Polten et al. (1991)</a> found 2 different metachromatic leukodystrophy alleles. One, designated allele I, differed in 3 positions from the published sequence for the ARSA gene. Two of the substitutions represented functionally silent changes; only the loss of a splice donor site in allele I was considered to be relevant to metachromatic leukodystrophy. Specifically, a G-to-A transition destroyed the splice donor site of exon 2 by changing the classic exon-intron boundary consensus sequence from AGgt to AGat. In all 6 instances of homozygosity for allele I, <a href="#46" class="mim-tip-reference" title="Polten, A., Fluharty, A. L., Fluharty, C. B., Kappler, J., von Figura, K., Gieselmann, V. <strong>Molecular basis of different forms of metachromatic leukodystrophy.</strong> New Eng. J. Med. 324: 18-22, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1670590/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1670590</a>] [<a href="https://doi.org/10.1056/NEJM199101033240104" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1670590">Polten et al. (1991)</a> reported that the clinical picture was that of the late infantile form of metachromatic leukodystrophy. <a href="#26" class="mim-tip-reference" title="Heinisch, U., Zlotogora, J., Kafert, S., Gieselmann, V. <strong>Multiple mutations are responsible for the high frequency of metachromatic leukodystrophy in a small geographic area.</strong> Am. J. Hum. Genet. 56: 51-57, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7825603/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7825603</a>]" pmid="7825603">Heinisch et al. (1995)</a> found this mutation in homozygous state in 3 separate Arab families living in the Jerusalem area. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=1670590+7825603" 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="Draghia, R., Letourneur, F., Drugan, C., Manicom, J., Blanchot, C., Kahn, A., Poenaru, L., Caillaud, C. <strong>Metachromatic leukodystrophy: identification of the first deletion in exon 1 and of nine novel point mutations in the arylsulfatase gene.</strong> Hum. Mutat. 9: 234-242, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9090526/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9090526</a>] [<a href="https://doi.org/10.1002/(SICI)1098-1004(1997)9:3<234::AID-HUMU4>3.0.CO;2-7" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9090526">Draghia et al. (1997)</a>, who referred to this mutation as 459+1G-A, cited reports stating that it, and the P426L mutation (<a href="#0004">607574.0004</a>), have the highest frequency in MLD, each accounting for 25% of mutant alleles among Caucasian patients (<a href="#46" class="mim-tip-reference" title="Polten, A., Fluharty, A. L., Fluharty, C. B., Kappler, J., von Figura, K., Gieselmann, V. <strong>Molecular basis of different forms of metachromatic leukodystrophy.</strong> New Eng. J. Med. 324: 18-22, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1670590/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1670590</a>] [<a href="https://doi.org/10.1056/NEJM199101033240104" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1670590">Polten et al., 1991</a>; <a href="#2" class="mim-tip-reference" title="Barth, M. L., Fensom, A., Harris, A. <strong>Prevalence of common mutations in the arylsulphatase A gene in metachromatic leukodystrophy patients diagnosed in Britain.</strong> Hum. Genet. 91: 73-77, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8095918/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8095918</a>] [<a href="https://doi.org/10.1007/BF00230227" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8095918">Barth et al., 1993</a>). The remaining 50% of alleles are very heterogeneous, most of them being found in only 1 or 2 patients (<a href="#19" class="mim-tip-reference" title="Gieselmann, V., Zlotogora, J., Harris, A., Wenger, D. A., Morris, C. P. <strong>Molecular genetics of metachromatic leukodystrophy.</strong> Hum. Mutat. 4: 233-242, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7866401/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7866401</a>] [<a href="https://doi.org/10.1002/humu.1380040402" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7866401">Gieselmann et al., 1994</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=1670590+8095918+9090526+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><a href="#9" class="mim-tip-reference" title="Comabella, M., Waye, J. S., Raguer, N., Eng, B., Dominguez, C., Navarro, C., Borras, C., Krivit, W., Montalban, X. <strong>Late-onset metachromatic leukodystrophy clinically presenting as isolated peripheral neuropathy: compound heterozygosity for the IVS2+1G-to-A mutation and a newly identified missense mutation (thr408-to-ile) in a Spanish family.</strong> Ann. Neurol. 50: 108-112, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11456299/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11456299</a>]" pmid="11456299">Comabella et al. (2001)</a> reported a consanguineous Spanish family in which a proband and her daughter had atypical adult-onset metachromatic leukodystrophy presenting as isolated peripheral neuropathy. Electrophysiologic studies were consistent with a chronic acquired demyelinating polyneuropathy. Both patients were compound heterozygotes for this mutation and a 1223C-T transition resulting in a thr408-to-ile (T408I; <a href="#0045">607574.0045</a>) substitution in the ARSA gene. The mutations segregated independently; the unaffected father was a carrier for this mutation and 2 daughters from the proband's second marriage were each carriers for one or the other of the mutations. Noting that homozygosity for this mutation results in severe infantile disease, the authors concluded that the T408I mutation has a relatively mild effect. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11456299" 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 an Italian patient with juvenile-onset metachromatic leukodystrophy, <a href="#21" class="mim-tip-reference" title="Gomez-Lira, M., Perusi, C., Mottes, M., Pignatti, P. F., Manfredi, M., Rizzuto, N., Salviati, A. <strong>Molecular genetic characterization of two metachromatic leukodystrophy patients who carry the T799G mutation and show different phenotypes; description of a novel null-type mutation.</strong> Hum. Genet. 102: 459-463, 1998. Note: Erratum: Hum. Genet. 102: 602 only, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9600244/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9600244</a>] [<a href="https://doi.org/10.1007/s004390050721" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9600244">Gomez-Lira et al. (1998)</a> identified compound heterozygosity for the 459+1G-A and the I179S (<a href="#0008">607574.0008</a>) mutations in the ARSA gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9600244" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs28940893 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs28940893;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs28940893?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs28940893" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs28940893" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000003195 OR RCV000003196 OR RCV000003197 OR RCV000020314 OR RCV000392246 OR RCV001251909 OR RCV004755702 OR RCV004797751" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000003195, RCV000003196, RCV000003197, RCV000020314, RCV000392246, RCV001251909, RCV004755702, RCV004797751" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000003195...</a>
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<p>In a patient with juvenile-onset metachromatic leukodystrophy (<a href="/entry/250100">250100</a>), <a href="#46" class="mim-tip-reference" title="Polten, A., Fluharty, A. L., Fluharty, C. B., Kappler, J., von Figura, K., Gieselmann, V. <strong>Molecular basis of different forms of metachromatic leukodystrophy.</strong> New Eng. J. Med. 324: 18-22, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1670590/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1670590</a>] [<a href="https://doi.org/10.1056/NEJM199101033240104" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1670590">Polten et al. (1991)</a> found compound heterozygosity for 2 mutations in the ARSA gene: a splice site mutation, referred to as 'allele I' (<a href="#0003">607574.0003</a>) and a C-to-T transition, resulting in a pro426-to-leu (P426L) substitution, referred to as 'allele A.' To test the functional consequence of this mutation, <a href="#46" class="mim-tip-reference" title="Polten, A., Fluharty, A. L., Fluharty, C. B., Kappler, J., von Figura, K., Gieselmann, V. <strong>Molecular basis of different forms of metachromatic leukodystrophy.</strong> New Eng. J. Med. 324: 18-22, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1670590/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1670590</a>] [<a href="https://doi.org/10.1056/NEJM199101033240104" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1670590">Polten et al. (1991)</a> introduced it into arylsulfatase A cDNA by site-directed mutagenesis, and the mutated cDNA was transiently expressed in baby-hamster kidney cells after transfection. Only a small increase in the activity of arylsulfatase A was observed in the transfected cells (3%; range, 2-5). <a href="#46" class="mim-tip-reference" title="Polten, A., Fluharty, A. L., Fluharty, C. B., Kappler, J., von Figura, K., Gieselmann, V. <strong>Molecular basis of different forms of metachromatic leukodystrophy.</strong> New Eng. J. Med. 324: 18-22, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1670590/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1670590</a>] [<a href="https://doi.org/10.1056/NEJM199101033240104" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1670590">Polten et al. (1991)</a> determined the frequency of alleles I and A by allele-specific oligonucleotide hybridization. Of 68 patients studied, 50 carried at least 1 of the 2 alleles. In 23 patients, they found homozygosity for one or the other allele or compound heterozygosity for the 2. Neither allele was found in 18 of the 68 patients. In total, 37 I alleles and 36 A alleles were found. In 8 instances of homozygosity for allele A, <a href="#46" class="mim-tip-reference" title="Polten, A., Fluharty, A. L., Fluharty, C. B., Kappler, J., von Figura, K., Gieselmann, V. <strong>Molecular basis of different forms of metachromatic leukodystrophy.</strong> New Eng. J. Med. 324: 18-22, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1670590/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1670590</a>] [<a href="https://doi.org/10.1056/NEJM199101033240104" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1670590">Polten et al. (1991)</a> found that in 5 it was associated with the adult form and in 3 with the juvenile form of the disease. Compound heterozygosity for allele A and allele I resulted in the juvenile form of metachromatic leukodystrophy in 7 of 7 instances. Heterozygosity for allele I (with the other allele unknown) was usually associated with late infantile disease, and heterozygosity for allele A with later onset of the disease. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1670590" 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="Draghia, R., Letourneur, F., Drugan, C., Manicom, J., Blanchot, C., Kahn, A., Poenaru, L., Caillaud, C. <strong>Metachromatic leukodystrophy: identification of the first deletion in exon 1 and of nine novel point mutations in the arylsulfatase gene.</strong> Hum. Mutat. 9: 234-242, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9090526/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9090526</a>] [<a href="https://doi.org/10.1002/(SICI)1098-1004(1997)9:3<234::AID-HUMU4>3.0.CO;2-7" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9090526">Draghia et al. (1997)</a>, cited reports stating that the P426L mutation and a splice site mutation (<a href="#0003">607574.0003</a>) have the highest frequency in MLD, each accounting for 25% of mutant alleles among Caucasian patients (<a href="#46" class="mim-tip-reference" title="Polten, A., Fluharty, A. L., Fluharty, C. B., Kappler, J., von Figura, K., Gieselmann, V. <strong>Molecular basis of different forms of metachromatic leukodystrophy.</strong> New Eng. J. Med. 324: 18-22, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1670590/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1670590</a>] [<a href="https://doi.org/10.1056/NEJM199101033240104" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1670590">Polten et al., 1991</a>; <a href="#2" class="mim-tip-reference" title="Barth, M. L., Fensom, A., Harris, A. <strong>Prevalence of common mutations in the arylsulphatase A gene in metachromatic leukodystrophy patients diagnosed in Britain.</strong> Hum. Genet. 91: 73-77, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8095918/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8095918</a>] [<a href="https://doi.org/10.1007/BF00230227" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8095918">Barth et al., 1993</a>). The remaining 50% of alleles are very heterogeneous, most of them being found in only 1 or 2 patients (<a href="#19" class="mim-tip-reference" title="Gieselmann, V., Zlotogora, J., Harris, A., Wenger, D. A., Morris, C. P. <strong>Molecular genetics of metachromatic leukodystrophy.</strong> Hum. Mutat. 4: 233-242, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7866401/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7866401</a>] [<a href="https://doi.org/10.1002/humu.1380040402" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7866401">Gieselmann et al., 1994</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=1670590+8095918+9090526+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>
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<strong>.0005 METACHROMATIC LEUKODYSTROPHY, ADULT</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs74315455 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs74315455;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs74315455?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs74315455" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs74315455" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000003198 OR RCV000020318 OR RCV000724149" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000003198, RCV000020318, RCV000724149" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000003198...</a>
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<p>In a Japanese patient with adult-type metachromatic leukodystrophy (<a href="/entry/250100">250100</a>), <a href="#32" class="mim-tip-reference" title="Kondo, R., Wakamatsu, N., Yoshino, H., Fukuhara, N., Miyatake, T., Tsuji, S. <strong>Identification of a mutation in the arylsulfatase A gene of a patient with adult-type metachromatic leukodystrophy.</strong> Am. J. Hum. Genet. 48: 971-978, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1673291/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1673291</a>]" pmid="1673291">Kondo et al. (1991)</a> identified a G-to-A transition in exon 2, which resulted in amino acid substitution of aspartic acid for glycine-99. In transient expression studies, COS cells transfected with the mutant cDNA carrying gly99-to-asp did not show increase of ARSA activity, thus confirming that the mutation was the cause of MLD. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=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>
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<strong>.0006 METACHROMATIC LEUKODYSTROPHY, LATE INFANTILE</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs74315456 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs74315456;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs74315456?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs74315456" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs74315456" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000003199 OR RCV000020317 OR RCV000723374" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000003199, RCV000020317, RCV000723374" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000003199...</a>
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<p>In a patient with the late infantile form of metachromatic leukodystrophy (<a href="/entry/250100">250100</a>), <a href="#17" class="mim-tip-reference" title="Gieselmann, V., Fluharty, A. L., Tonnesen, T., Von Figura, K. <strong>Mutations in the arylsulfatase A pseudodeficiency allele causing metachromatic leukodystrophy.</strong> Am. J. Hum. Genet. 49: 407-413, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1678251/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1678251</a>]" pmid="1678251">Gieselmann et al. (1991)</a> found homozygosity for the mutations characteristic of the arylsulfatase A pseudodeficiency allele but, in addition, a C-to-T transition in exon 2 causing a substitution of phenylalanine for serine-96. <a href="#17" class="mim-tip-reference" title="Gieselmann, V., Fluharty, A. L., Tonnesen, T., Von Figura, K. <strong>Mutations in the arylsulfatase A pseudodeficiency allele causing metachromatic leukodystrophy.</strong> Am. J. Hum. Genet. 49: 407-413, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1678251/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1678251</a>]" pmid="1678251">Gieselmann et al. (1991)</a> pointed out the necessity for care in not overlooking a mutation causing severe deficiency associated with the changes of pseudodeficiency. This can be a serious problem since homozygous pseudodeficiency is present in 1 to 2% of the population. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1678251" 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>.0007 METACHROMATIC LEUKODYSTROPHY, LATE INFANTILE</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs80338823 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs80338823;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs80338823" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs80338823" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000180166 OR RCV000723834 OR RCV002265665" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000180166, RCV000723834, RCV002265665" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000180166...</a>
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<p><a href="#6" class="mim-tip-reference" title="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.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1676699/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1676699</a>] [<a href="https://doi.org/10.1007/BF00204172" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1676699">Bohne et al. (1991)</a> demonstrated an 11-bp deletion in exon 8 of one allele of the ARSA gene in a patient with the late infantile form of MLD (<a href="/entry/250100">250100</a>). Although this allele produced normal amounts of mRNA, no arylsulfatase A crossreacting material could be detected in cultured fibroblasts from the patient. The 11-bp deletion was found between nucleotides 2506 and 2516. It caused a frameshift downstream of the codon for amino acid 467. The polypeptide encoded by the mutant allele should be 29 amino acids longer than wildtype ASA. The other allele, which had been inherited from the father, had a splice donor site mutation in exon 7. This allele is known also to generate no ASA polypeptide. Thus, this was another example where absence of ASA polypeptide correlated with the severe late infantile form of MLD. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1676699" 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>.0008 METACHROMATIC LEUKODYSTROPHY, JUVENILE</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs74315457 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs74315457;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs74315457?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs74315457" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs74315457" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000003202 OR RCV000003203 OR RCV000020320 OR RCV000657846 OR RCV001267385" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000003202, RCV000003203, RCV000020320, RCV000657846, RCV001267385" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000003202...</a>
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<p>In a patient with juvenile-onset metachromatic leukodystrophy (<a href="/entry/250100">250100</a>), <a href="#14" class="mim-tip-reference" title="Fluharty, A. L., Fluharty, C. B., Bohne, W., von Figura, K., Gieselmann, V. <strong>Two new arylsulfatase A (ARSA) mutations in a juvenile metachromatic leukodystrophy (MLD) patient.</strong> Am. J. Hum. Genet. 49: 1340-1350, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1684088/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1684088</a>]" pmid="1684088">Fluharty et al. (1991)</a> identified a T-to-G transversion at nucleotide 799, resulting in a change from isoleucine to serine in exon 3. They designated this mutation E3P799 according to the following scheme: location in the gene, e.g., E3 = exon 3 or its immediately adjacent splice-recognition sequence; type of alteration, e.g., P = point mutation leading to amino acid substitution, or S = mutation in splice recognition sequence; and number of initial nucleotide in the altered sequence, e.g., 799 = 799th nucleotide beyond start of initiation codon. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1684088" 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="Lugowska, A., Berger, J., Tylki-Szymanska, A., Czartoryska, B., Loschl, B., Molzer, B. <strong>High prevalence of I179S mutation in patients with late-onset metachromatic leukodystrophy. (Letter)</strong> Clin. Genet. 61: 389-390, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12081727/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12081727</a>] [<a href="https://doi.org/10.1034/j.1399-0004.2002.610514.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12081727">Lugowska et al. (2002)</a> pointed out that this mutation, designated I179S in the accepted terminology, had been described in 15 of 130 MLD patients in the literature. All of them were found to have been heterozygous for this mutation. <a href="#36" class="mim-tip-reference" title="Lugowska, A., Berger, J., Tylki-Szymanska, A., Czartoryska, B., Loschl, B., Molzer, B. <strong>High prevalence of I179S mutation in patients with late-onset metachromatic leukodystrophy. (Letter)</strong> Clin. Genet. 61: 389-390, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12081727/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12081727</a>] [<a href="https://doi.org/10.1034/j.1399-0004.2002.610514.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12081727">Lugowska et al. (2002)</a> stated that, according to the Hardy-Weinberg law for 2 alleles, 1 homozygote I179S/I179S among 12 late juveniles and adults studied by them should have been found. Thus, they speculated that the residual ARSA activity in an I179S homozygote might be similar to that found in an individual homozygous for the ARSA pseudodeficiency allele (<a href="#0001">607574.0001</a>) who does not present with clinical symptoms of classic MLD. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12081727" 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 2 Italian patients with metachromatic leukodystrophy, one with adult onset and the other with juvenile onset, <a href="#21" class="mim-tip-reference" title="Gomez-Lira, M., Perusi, C., Mottes, M., Pignatti, P. F., Manfredi, M., Rizzuto, N., Salviati, A. <strong>Molecular genetic characterization of two metachromatic leukodystrophy patients who carry the T799G mutation and show different phenotypes; description of a novel null-type mutation.</strong> Hum. Genet. 102: 459-463, 1998. Note: Erratum: Hum. Genet. 102: 602 only, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9600244/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9600244</a>] [<a href="https://doi.org/10.1007/s004390050721" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9600244">Gomez-Lira et al. (1998)</a> identified compound heterozygosity for mutations in the ARSA gene. Both carried the I179S mutation (<a href="#0008">607574.0008</a>); the patient with juvenile onset had the common 459+1G-A (<a href="#0003">607574.0003</a>) mutation, and the patient with adult onset had a pro135-to-leu mutation (<a href="#0042">607574.0042</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9600244" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs80338820 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs80338820;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs80338820?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs80338820" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs80338820" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000003204 OR RCV000020312 OR RCV000723835" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000003204, RCV000020312, RCV000723835" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000003204...</a>
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<p>In a patient with juvenile-onset metachromatic leukodystrophy (<a href="/entry/250100">250100</a>), <a href="#14" class="mim-tip-reference" title="Fluharty, A. L., Fluharty, C. B., Bohne, W., von Figura, K., Gieselmann, V. <strong>Two new arylsulfatase A (ARSA) mutations in a juvenile metachromatic leukodystrophy (MLD) patient.</strong> Am. J. Hum. Genet. 49: 1340-1350, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1684088/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1684088</a>]" pmid="1684088">Fluharty et al. (1991)</a> found compound heterozygosity for a point mutation (see <a href="#0008">607574.0008</a>) and for a G-to-A transition that resulted in an altered splice-recognition sequence between exon 7 and the following intron. The mutation involved nucleotide 2195, the first nucleotide in intron 7. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1684088" 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>.0010 METACHROMATIC LEUKODYSTROPHY, LATE-ONSET</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs74315458 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs74315458;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs74315458?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs74315458" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs74315458" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000003205 OR RCV000020316 OR RCV000723563" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000003205, RCV000020316, RCV000723563" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000003205...</a>
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<p><a href="#31" class="mim-tip-reference" title="Kappler, J., von Figura, K., Gieselmann, V. <strong>Late-onset metachromatic leukodystrophy: molecular pathology in two siblings.</strong> Ann. Neurol. 31: 256-261, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1353340/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1353340</a>] [<a href="https://doi.org/10.1002/ana.410310305" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1353340">Kappler et al. (1992)</a> described an arg84-to-gln mutation in 2 sisters with late-onset metachromatic leukodystrophy (<a href="/entry/250100">250100</a>). One sister developed abnormal behavior at the age of 14 years and was thought to have 'frontal lobe syndrome.' Later she developed peripheral neuropathy and dementia. At the age of 30 she was bedridden. The other sister presented similar biochemical alterations. In spite of cranial CT alterations characteristic of MLD, her clinical status was almost normal when she was 21 years old. At the age of 29 years, she was still without complaints. Both sisters showed residual ARSA activity, further validating the concept that different degrees of residual ARSA activity account for phenotypic variation in this disorder. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1353340" 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>.0011 METACHROMATIC LEUKODYSTROPHY, LATE INFANTILE</strong>
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ARSA, GLY309SER
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs74315459 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs74315459;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs74315459?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs74315459" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs74315459" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000003206 OR RCV000666302 OR RCV000714802 OR RCV001813940 OR RCV002286693" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000003206, RCV000666302, RCV000714802, RCV001813940, RCV002286693" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000003206...</a>
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<p><a href="#33" class="mim-tip-reference" title="Kreysing, J., Bohne, W., Bosenberg, C., Marchesini, S., Turpin, J. C., Baumann, N., von Figura, K., Gieselmann, V. <strong>High residual arylsulfatase A (ARSA) activity in a patient with late-infantile metachromatic leukodystrophy.</strong> Am. J. Hum. Genet. 53: 339-346, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8101038/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8101038</a>]" pmid="8101038">Kreysing et al. (1993)</a> described compound heterozygosity for 2 mutant ARSA alleles in a male patient who presented with gait disturbances at the age of 18 months suggestive of MLD (<a href="/entry/250100">250100</a>). Subsequently he lost acquired capabilities such as walking and sitting, developed spastic paresis, and finally became bedridden. He showed episodes of pain attacks occurring several times per hour. Electromyelography showed signs of denervation and decreased nerve conduction velocity. Sural nerve biopsy demonstrated metachromatic granules. The patient had residual ARSA activity of about 10%. Fibroblasts of the patient showed significant sulfatide degradation activity exceeding that of adult MLD patients. One of the mutant alleles was a G-to-A transition in exon 5 causing a gly309-to-ser substitution. Transient expression of this allele resulted in only 13% enzyme activity as compared with the normal. The mutant enzyme was correctly targeted to the lysosomes but was unstable. The other allele showed a deletion of C447 in exon 2, causing a frameshift and a premature stop codon at amino acid position 105 (<a href="#0012">607574.0012</a>). The findings in this patient contrasted with previous results showing that the late infantile type of MLD is always associated with the complete absence of ARSA activity. In this case, the expression of the mutant ARSA protein may have been influenced by particular features of oligodendrocytes, such that the level of mutant enzyme is lower in these cells than in others. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8101038" 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="0012" class="mim-anchor"></a>
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<span class="mim-font">
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<strong>.0012 METACHROMATIC LEUKODYSTROPHY, LATE INFANTILE</strong>
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ARSA, 1-BP DEL, 447C
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs786204673 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs786204673;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs786204673" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs786204673" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000169476 OR RCV002265656 OR RCV004724964" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000169476, RCV002265656, RCV004724964" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000169476...</a>
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<p>See <a href="#0011">607574.0011</a> and <a href="#33" class="mim-tip-reference" title="Kreysing, J., Bohne, W., Bosenberg, C., Marchesini, S., Turpin, J. C., Baumann, N., von Figura, K., Gieselmann, V. <strong>High residual arylsulfatase A (ARSA) activity in a patient with late-infantile metachromatic leukodystrophy.</strong> Am. J. Hum. Genet. 53: 339-346, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8101038/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8101038</a>]" pmid="8101038">Kreysing et al. (1993)</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8101038" 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>.0013 METACHROMATIC LEUKODYSTROPHY, SEVERE</strong>
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ARSA, GLY86ASP
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs74315460 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs74315460;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs74315460?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs74315460" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs74315460" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000003207 OR RCV001353057" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000003207, RCV001353057" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000003207...</a>
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<p>In Muslim Arab patients with severe metachromatic leukodystrophy (<a href="/entry/250100">250100</a>), <a href="#19" class="mim-tip-reference" title="Gieselmann, V., Zlotogora, J., Harris, A., Wenger, D. A., Morris, C. P. <strong>Molecular genetics of metachromatic leukodystrophy.</strong> Hum. Mutat. 4: 233-242, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7866401/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7866401</a>] [<a href="https://doi.org/10.1002/humu.1380040402" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7866401">Gieselmann et al. (1994)</a> reported a G-to-A substitution of the ARSA gene changing a glycine to aspartic acid at position 86 in exon 2. <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>
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<a id="0014" class="mim-anchor"></a>
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<strong>.0014 METACHROMATIC LEUKODYSTROPHY, SEVERE</strong>
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ARSA, SER96LEU
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs199476371 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs199476371;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs199476371" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs199476371" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000003208 OR RCV000058959" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000003208, RCV000058959" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000003208...</a>
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<span class="mim-text-font">
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<p>In Muslim Arab patients with severe metachromatic leukodystrophy (<a href="/entry/250100">250100</a>), <a href="#19" class="mim-tip-reference" title="Gieselmann, V., Zlotogora, J., Harris, A., Wenger, D. A., Morris, C. P. <strong>Molecular genetics of metachromatic leukodystrophy.</strong> Hum. Mutat. 4: 233-242, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7866401/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7866401</a>] [<a href="https://doi.org/10.1002/humu.1380040402" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7866401">Gieselmann et al. (1994)</a> reported a C-to-T substitution of the ARSA gene changing a serine to a leucine at position 96 in exon 2. <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>
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<a id="0015" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<strong>.0015 METACHROMATIC LEUKODYSTROPHY</strong>
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ARSA, GLY122SER
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs74315461 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs74315461;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs74315461?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs74315461" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs74315461" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000003209 OR RCV000078945 OR RCV000623394 OR RCV003415633" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000003209, RCV000078945, RCV000623394, RCV003415633" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000003209...</a>
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<span class="mim-text-font">
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<p>In Japanese and Caucasian patients with metachromatic leukodystrophy (<a href="/entry/250100">250100</a>), <a href="#27" class="mim-tip-reference" title="Honke, K., Kobayashi, T., Fujii, T., Gasa, S., Xu, M., Takamaru, Y., Kondo, R., Tsuji, S., Makita, A. <strong>An adult-type metachromatic leukodystrophy caused by substitution of serine for glycine-122 in arylsulfatase A.</strong> Hum. Genet. 92: 451-456, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7902317/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7902317</a>] [<a href="https://doi.org/10.1007/BF00216449" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7902317">Honke et al. (1993)</a> and <a href="#30" class="mim-tip-reference" title="Kappler, J., Sommerlade, H. J., von Figura, K., Gieselmann, V. <strong>Complex arylsulfatase A alleles causing metachromatic leukodystrophy.</strong> Hum. Mutat. 4: 119-127, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7981715/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7981715</a>] [<a href="https://doi.org/10.1002/humu.1380040205" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7981715">Kappler et al. (1994)</a> identified a G-to-A substitution of the ARSA gene changing a glycine to serine at position 122 in exon 2. The mutation changes the restriction site BalI. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=7902317+7981715" 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="0016" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<strong>.0016 METACHROMATIC LEUKODYSTROPHY, SEVERE</strong>
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</span>
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</h4>
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<span class="mim-text-font">
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<div style="float: left;">
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ARSA, PRO136LEU
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</span>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs74315462 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs74315462;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs74315462?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs74315462" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs74315462" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000003210 OR RCV000675081" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000003210, RCV000675081" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000003210...</a>
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In Jewish patients with metachromatic leukodystrophy (<a href="/entry/250100">250100</a>), <a href="#19" class="mim-tip-reference" title="Gieselmann, V., Zlotogora, J., Harris, A., Wenger, D. A., Morris, C. P. <strong>Molecular genetics of metachromatic leukodystrophy.</strong> Hum. Mutat. 4: 233-242, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7866401/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7866401</a>] [<a href="https://doi.org/10.1002/humu.1380040402" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7866401">Gieselmann et al. (1994)</a> reported a C-to-T substitution of the ARSA gene changing a proline to leucine at position 136 in exon 2. <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>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<a id="0017" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<strong>.0017 METACHROMATIC LEUKODYSTROPHY</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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<div style="float: left;">
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ARSA, 1-BP DEL, 297C
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</div>
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</span>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000003211" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000003211" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000003211</a>
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In Caucasian patients with metachromatic leukodystrophy (<a href="/entry/250100">250100</a>), <a href="#33" class="mim-tip-reference" title="Kreysing, J., Bohne, W., Bosenberg, C., Marchesini, S., Turpin, J. C., Baumann, N., von Figura, K., Gieselmann, V. <strong>High residual arylsulfatase A (ARSA) activity in a patient with late-infantile metachromatic leukodystrophy.</strong> Am. J. Hum. Genet. 53: 339-346, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8101038/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8101038</a>]" pmid="8101038">Kreysing et al. (1993)</a> identified a 1-bp (C) deletion at position 297 of the coding sequence in exon 2 of the ARSA gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8101038" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<a id="0018" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<strong>.0018 METACHROMATIC LEUKODYSTROPHY</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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<div style="float: left;">
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ARSA, GLY154ASP
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</div>
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</span>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs74315463 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs74315463;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs74315463" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs74315463" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000003212" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000003212" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000003212</a>
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In Caucasian patients with metachromatic leukodystrophy (<a href="/entry/250100">250100</a>), <a href="#30" class="mim-tip-reference" title="Kappler, J., Sommerlade, H. J., von Figura, K., Gieselmann, V. <strong>Complex arylsulfatase A alleles causing metachromatic leukodystrophy.</strong> Hum. Mutat. 4: 119-127, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7981715/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7981715</a>] [<a href="https://doi.org/10.1002/humu.1380040205" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7981715">Kappler et al. (1994)</a> identified a G-to-A substitution of the ARSA gene changing a glycine to aspartic acid at position 154 in exon 3. The mutation changes the restriction site ApaI. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7981715" 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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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<a id="0019" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<strong>.0019 ARYLSULFATASE A PSEUDODEFICIENCY</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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<div style="float: left;">
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ARSA, PRO155ARG
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</div>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs74315464 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs74315464;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs74315464?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs74315464" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs74315464" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000003213" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000003213" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000003213</a>
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In Lebanese patients with arylsulfatase A pseudodeficiency (<a href="/entry/250100">250100</a>), <a href="#19" class="mim-tip-reference" title="Gieselmann, V., Zlotogora, J., Harris, A., Wenger, D. A., Morris, C. P. <strong>Molecular genetics of metachromatic leukodystrophy.</strong> Hum. Mutat. 4: 233-242, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7866401/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7866401</a>] [<a href="https://doi.org/10.1002/humu.1380040402" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7866401">Gieselmann et al. (1994)</a> reported a C-to-G substitution of the ARSA gene changing a proline to arginine at position 155 in exon 3. <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>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<a id="0020" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
|
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<strong>.0020 METACHROMATIC LEUKODYSTROPHY</strong>
|
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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<div style="float: left;">
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ARSA, PRO167ARG
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</div>
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</span>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs74315465 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs74315465;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs74315465" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs74315465" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000003214" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000003214" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000003214</a>
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<p>In Caucasian patients with metachromatic leukodystrophy (<a href="/entry/250100">250100</a>), <a href="#30" class="mim-tip-reference" title="Kappler, J., Sommerlade, H. J., von Figura, K., Gieselmann, V. <strong>Complex arylsulfatase A alleles causing metachromatic leukodystrophy.</strong> Hum. Mutat. 4: 119-127, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7981715/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7981715</a>] [<a href="https://doi.org/10.1002/humu.1380040205" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7981715">Kappler et al. (1994)</a> identified a C-to-G substitution of the ARSA gene changing a proline to arginine at position 167 in exon 3. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7981715" 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="0021" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<strong>.0021 ARYLSULFATASE A PSEUDODEFICIENCY</strong>
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</h4>
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ARSA, ASP169ASN
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</span>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs74315466 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs74315466;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs74315466?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs74315466" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs74315466" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000003215 OR RCV000540770 OR RCV001251908 OR RCV002265546 OR RCV003480017" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000003215, RCV000540770, RCV001251908, RCV002265546, RCV003480017" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000003215...</a>
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</span>
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<span class="mim-text-font">
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<p>In Polynesian patients with arylsulfatase A pseudodeficiency (<a href="/entry/250100">250100</a>), <a href="#19" class="mim-tip-reference" title="Gieselmann, V., Zlotogora, J., Harris, A., Wenger, D. A., Morris, C. P. <strong>Molecular genetics of metachromatic leukodystrophy.</strong> Hum. Mutat. 4: 233-242, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7866401/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7866401</a>] [<a href="https://doi.org/10.1002/humu.1380040402" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7866401">Gieselmann et al. (1994)</a> reported a G-to-A substitution of the ARSA gene changing an aspartic acid to asparagine at position 169 in exon 3. <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>
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</span>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<a id="0022" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<strong>.0022 METACHROMATIC LEUKODYSTROPHY</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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<div style="float: left;">
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ARSA, ALA212VAL
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</div>
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</span>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs74315467 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs74315467;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs74315467?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs74315467" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs74315467" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000003216 OR RCV000723836" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000003216, RCV000723836" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000003216...</a>
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In Caucasian patients with metachromatic leukodystrophy (<a href="/entry/250100">250100</a>), <a href="#1" class="mim-tip-reference" title="Barth, M. L., Fensom, A., Harris, A. <strong>Missense mutations in the arylsulphatase A genes of metachromatic leukodystrophy patients.</strong> Hum. Molec. Genet. 2: 2117-2121, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7906588/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7906588</a>] [<a href="https://doi.org/10.1093/hmg/2.12.2117" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7906588">Barth et al. (1993)</a> identified a G-to-T substitution of the ARSA gene changing an alanine to valine at position 212 in exon 3. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7906588" 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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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<a id="0023" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<strong>.0023 METACHROMATIC LEUKODYSTROPHY</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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<div style="float: left;">
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ARSA, ALA224VAL
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</div>
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</span>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs74315468 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs74315468;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs74315468?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs74315468" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs74315468" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000003217 OR RCV000343115" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000003217, RCV000343115" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000003217...</a>
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In Caucasian patients with metachromatic leukodystrophy (<a href="/entry/250100">250100</a>), <a href="#1" class="mim-tip-reference" title="Barth, M. L., Fensom, A., Harris, A. <strong>Missense mutations in the arylsulphatase A genes of metachromatic leukodystrophy patients.</strong> Hum. Molec. Genet. 2: 2117-2121, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7906588/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7906588</a>] [<a href="https://doi.org/10.1093/hmg/2.12.2117" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7906588">Barth et al. (1993)</a> identified a C-to-T substitution of the ARSA gene changing an alanine to valine at position 224 in exon 3. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7906588" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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</div>
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<div>
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<div>
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<a id="0024" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<strong>.0024 METACHROMATIC LEUKODYSTROPHY</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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<div style="float: left;">
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ARSA, PRO231THR
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</div>
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</span>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs74315469 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs74315469;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs74315469?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs74315469" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs74315469" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000003218 OR RCV003387714" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000003218, RCV003387714" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000003218...</a>
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In a patient with metachromatic leukodystrophy (<a href="/entry/250100">250100</a>), <a href="#8" class="mim-tip-reference" title="Caillaud, C., Blanchor, C., Akli, S., Crosnier, J. M., Puech, J. P., Kahn, A., Poenaru, L. <strong>Molecular basis of late infantile metachromatic leukodystrophy in France. (Abstract)</strong> ESGLD Workshop, Delphi, Greece 1993."None>Caillaud et al. (1993)</a> identified a C-to-A substitution of the ARSA gene changing a proline to threonine at position 231 in exon 4.</p>
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</span>
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</div>
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<div>
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<br />
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<div>
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<a id="0025" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<strong>.0025 METACHROMATIC LEUKODYSTROPHY</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<div style="float: left;">
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ARSA, ARG244CYS
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs74315470 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs74315470;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs74315470?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs74315470" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs74315470" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000003219 OR RCV003993733" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000003219, RCV003993733" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000003219...</a>
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In Caucasian patients with metachromatic leukodystrophy (<a href="/entry/250100">250100</a>), <a href="#19" class="mim-tip-reference" title="Gieselmann, V., Zlotogora, J., Harris, A., Wenger, D. A., Morris, C. P. <strong>Molecular genetics of metachromatic leukodystrophy.</strong> Hum. Mutat. 4: 233-242, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7866401/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7866401</a>] [<a href="https://doi.org/10.1002/humu.1380040402" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7866401">Gieselmann et al. (1994)</a> reported a C-to-T substitution of the ARSA gene changing an arginine to cysteine at position 244 in exon 4. The mutation changes an SstII restriction site. <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>
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<strong>.0026 METACHROMATIC LEUKODYSTROPHY, SEVERE</strong>
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ARSA, GLY245ARG
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs74315471 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs74315471;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs74315471?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs74315471" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs74315471" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000003220 OR RCV000020321 OR RCV000723992" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000003220, RCV000020321, RCV000723992" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000003220...</a>
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<p>In Japanese patients with severe metachromatic leukodystrophy (<a href="/entry/250100">250100</a>), <a href="#24" class="mim-tip-reference" title="Hasegawa, Y., Kawame, H., Eto, Y. <strong>Mutations in the arylsulfatase A gene of Japanese patients with metachromatic leukodystrophy.</strong> DNA Cell Biol. 12: 493-498, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8101083/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8101083</a>] [<a href="https://doi.org/10.1089/dna.1993.12.493" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8101083">Hasegawa et al. (1993)</a> identified a G-to-A substitution of the ARSA gene changing a glycine to arginine at position 245 in exon 4. The mutation changes an SstII restriction site. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8101083" 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="0027" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<strong>.0027 METACHROMATIC LEUKODYSTROPHY, SEVERE</strong>
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</h4>
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ARSA, THR274MET
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs74315472 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs74315472;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs74315472" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs74315472" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000003221 OR RCV000169246 OR RCV000991546 OR RCV003904799" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000003221, RCV000169246, RCV000991546, RCV003904799" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000003221...</a>
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</span>
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<span class="mim-text-font">
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<p>In Lebanese patients with severe metachromatic leukodystrophy (<a href="/entry/250100">250100</a>), <a href="#23" class="mim-tip-reference" title="Harvey, J. S., Nelson, P. V., Carey, W. F., Robertson, E. F., Morris, C. P. <strong>An arylsulfatase A (ARSA) missense mutation (T274M) causing late-infantile metachromatic leukodystrophy.</strong> Hum. Mutat. 2: 261-267, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8104633/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8104633</a>] [<a href="https://doi.org/10.1002/humu.1380020405" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8104633">Harvey et al. (1993)</a> identified a C-to-T change in exon 4 of the ARSA gene, resulting in a thr274-to-met (T274M) substitution. The T274M allele represented 20% of all alleles among Australian patients with metachromatic leukodystrophy, and about 85% of all alleles among Australian Lebanese affected with the disease. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8104633" 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="0028" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<strong>.0028 METACHROMATIC LEUKODYSTROPHY, SEVERE</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<div style="float: left;">
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ARSA, IVS4DS, G-A, +1
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</div>
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</span>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs886041911 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs886041911;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs886041911" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs886041911" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV001192373 OR RCV002221160 OR RCV004590209" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV001192373, RCV002221160, RCV004590209" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV001192373...</a>
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In Caucasian patients with severe metachromatic leukodystrophy (<a href="/entry/250100">250100</a>), <a href="#45" class="mim-tip-reference" title="Pastor-Soler, N. M., Rafi, M. A., Hoffman, J. D., Hu, D., Wenger, D. A. <strong>Metachromatic leukodystrophy in the Navajo Indian population: a splice site mutation in intron 4 of the arylsulfatase A gene.</strong> Hum. Mutat. 4: 199-207, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7833949/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7833949</a>] [<a href="https://doi.org/10.1002/humu.1380040305" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7833949">Pastor-Soler et al. (1994)</a> identified a G-to-A transition of the ARSA gene at nucleotide 848+1 (which is the first nucleotide of the donor splice site) of intron 4, resulting in abnormal splicing. This mutation causes instability of the arylsulfatase A mRNA and was found in all alleles of Navajo Indians patients with late infantile metachromatic leucodystrophy. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7833949" 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="0029" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<strong>.0029 METACHROMATIC LEUKODYSTROPHY</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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<div style="float: left;">
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ARSA, ARG288CYS
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</div>
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</span>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs74315473 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs74315473;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs74315473?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs74315473" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs74315473" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000003223 OR RCV001642197 OR RCV004819990" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000003223, RCV001642197, RCV004819990" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000003223...</a>
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In Caucasian patients with metachromatic leukodystrophy (<a href="/entry/250100">250100</a>), <a href="#19" class="mim-tip-reference" title="Gieselmann, V., Zlotogora, J., Harris, A., Wenger, D. A., Morris, C. P. <strong>Molecular genetics of metachromatic leukodystrophy.</strong> Hum. Mutat. 4: 233-242, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7866401/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7866401</a>] [<a href="https://doi.org/10.1002/humu.1380040402" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7866401">Gieselmann et al. (1994)</a> reported a C-to-T substitution of the ARSA gene changing an arginine to cysteine at position 288 in exon 5. <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>
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</span>
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</div>
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<div>
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<br />
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<a id="0030" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<strong>.0030 METACHROMATIC LEUKODYSTROPHY, SEVERE</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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<div style="float: left;">
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ARSA, SER295TYR
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</div>
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</span>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs74315474 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs74315474;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs74315474" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs74315474" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000003224 OR RCV000492011" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000003224, RCV000492011" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000003224...</a>
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In Saudi Arabian patients with severe metachromatic leukodystrophy (<a href="/entry/250100">250100</a>), <a href="#1" class="mim-tip-reference" title="Barth, M. L., Fensom, A., Harris, A. <strong>Missense mutations in the arylsulphatase A genes of metachromatic leukodystrophy patients.</strong> Hum. Molec. Genet. 2: 2117-2121, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7906588/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7906588</a>] [<a href="https://doi.org/10.1093/hmg/2.12.2117" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7906588">Barth et al. (1993)</a> identified a C-to-A substitution of the ARSA gene changing a serine to tyrosine at position 295 in exon 5. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7906588" 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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</span>
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</div>
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<div>
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<div>
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<a id="0031" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<strong>.0031 ARYLSULFATASE A PSEUDODEFICIENCY</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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ARSA, IVS5DS, G-T, -1, GLY325CYS
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</div>
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</span>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs148092995 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs148092995;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs148092995?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs148092995" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs148092995" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000003225" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000003225" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000003225</a>
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<span class="mim-text-font">
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<p>In Indian patients with arylsulfatase A pseudodeficiency (<a href="/entry/250100">250100</a>), <a href="#19" class="mim-tip-reference" title="Gieselmann, V., Zlotogora, J., Harris, A., Wenger, D. A., Morris, C. P. <strong>Molecular genetics of metachromatic leukodystrophy.</strong> Hum. Mutat. 4: 233-242, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7866401/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7866401</a>] [<a href="https://doi.org/10.1002/humu.1380040402" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7866401">Gieselmann et al. (1994)</a> reported a G-to-T substitution of the last nucleotide of ARSA exon 5, changing a glycine to cysteine at position 325 and concomitantly resulting in aberrant splicing of arylsulfatase A mRNA. <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>
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<a id="0032" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<strong>.0032 METACHROMATIC LEUKODYSTROPHY, SEVERE</strong>
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ARSA, ASP335VAL
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs74315475 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs74315475;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs74315475?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs74315475" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs74315475" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000003226 OR RCV000169024 OR RCV000413321 OR RCV000414806" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000003226, RCV000169024, RCV000413321, RCV000414806" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000003226...</a>
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</span>
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<span class="mim-text-font">
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<p>In Caucasian patients with severe metachromatic leukodystrophy (<a href="/entry/250100">250100</a>), <a href="#19" class="mim-tip-reference" title="Gieselmann, V., Zlotogora, J., Harris, A., Wenger, D. A., Morris, C. P. <strong>Molecular genetics of metachromatic leukodystrophy.</strong> Hum. Mutat. 4: 233-242, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7866401/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7866401</a>] [<a href="https://doi.org/10.1002/humu.1380040402" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7866401">Gieselmann et al. (1994)</a> reported an A-to-T substitution of the ARSA gene changing an aspartic acid to valine at position 335 in exon 6. <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>
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<br />
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<a id="0033" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<strong>.0033 METACHROMATIC LEUKODYSTROPHY, SEVERE</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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<div style="float: left;">
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ARSA, ARG370TRP
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</div>
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</span>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs74315476 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs74315476;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs74315476?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs74315476" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs74315476" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000003227 OR RCV000078933 OR RCV000723522" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000003227, RCV000078933, RCV000723522" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000003227...</a>
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In Christian Arab patients with severe metachromatic leukodystrophy (<a href="/entry/250100">250100</a>), <a href="#19" class="mim-tip-reference" title="Gieselmann, V., Zlotogora, J., Harris, A., Wenger, D. A., Morris, C. P. <strong>Molecular genetics of metachromatic leukodystrophy.</strong> Hum. Mutat. 4: 233-242, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7866401/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7866401</a>] [<a href="https://doi.org/10.1002/humu.1380040402" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7866401">Gieselmann et al. (1994)</a> reported a C-to-T substitution of the ARSA gene changing an arginine to tryptophan at position 370 in exon 7. <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>
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</span>
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</div>
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<div>
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<br />
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<div>
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<div>
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<a id="0034" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<strong>.0034 METACHROMATIC LEUKODYSTROPHY, MILD</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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<div style="float: left;">
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ARSA, ARG370GLN
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</div>
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</span>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs74315477 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs74315477;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs74315477?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs74315477" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs74315477" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000003228 OR RCV000544790" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000003228, RCV000544790" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000003228...</a>
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In Jewish patients with mild metachromatic leukodystrophy (<a href="/entry/250100">250100</a>), <a href="#19" class="mim-tip-reference" title="Gieselmann, V., Zlotogora, J., Harris, A., Wenger, D. A., Morris, C. P. <strong>Molecular genetics of metachromatic leukodystrophy.</strong> Hum. Mutat. 4: 233-242, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7866401/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7866401</a>] [<a href="https://doi.org/10.1002/humu.1380040402" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7866401">Gieselmann et al. (1994)</a> reported a G-to-A substitution of the ARSA gene changing an arginine to glutamine at position 370 in exon 7. <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>
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</span>
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</div>
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<div>
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<br />
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</div>
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<div>
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<div>
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<a id="0035" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<strong>.0035 ARYLSULFATASE A PSEUDODEFICIENCY, SEVERE</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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<div style="float: left;">
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ARSA, PRO377LEU
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</div>
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</span>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs74315478 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs74315478;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs74315478?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs74315478" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs74315478" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000003229 OR RCV002512051 OR RCV003500499" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000003229, RCV002512051, RCV003500499" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000003229...</a>
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In Habbanite Jewish patients with severe arylsulfatase A pseudodeficiency (<a href="/entry/250100">250100</a>), <a href="#53" class="mim-tip-reference" title="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://doi.org/10.1016/0753-3322(94)90049-3" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7858169">Zlotogora et al. (1994)</a> identified a C-to-T substitution of the ARSA gene changing a proline to leucine at position 377 in exon 7. This mutation has a high frequency among the small population of Habbanite Jews (1 in 75 live births). <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'})"><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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</span>
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</div>
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<div>
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<a id="0036" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<strong>.0036 ARYLSULFATASE A PSEUDODEFICIENCY, INTERMEDIATE</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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<div style="float: left;">
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ARSA, GLU382LYS
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</div>
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</span>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs74315479 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs74315479;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs74315479?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs74315479" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs74315479" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000003230 OR RCV000078936 OR RCV000723624" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000003230, RCV000078936, RCV000723624" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000003230...</a>
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<p>In Caucasian patients with intermediate arylsulfatase A pseudodeficiency (<a href="/entry/250100">250100</a>), <a href="#4" class="mim-tip-reference" title="Barth, M. L., Ward, C., Harris, A., Saad, A., Fensom, A. <strong>Frequency of arylsulphatase A pseudodeficiency associated mutations in a healthy population.</strong> J. Med. Genet. 31: 667-671, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7815433/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7815433</a>] [<a href="https://doi.org/10.1136/jmg.31.9.667" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7815433">Barth et al. (1994)</a> identified a G-to-A substitution of the ARSA gene changing a glutamic acid to lysine at position 382 in exon 7. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7815433" 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="0037" class="mim-anchor"></a>
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<strong>.0037 METACHROMATIC LEUKODYSTROPHY</strong>
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ARSA, ARG390TRP
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs74315480 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs74315480;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs74315480?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs74315480" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs74315480" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000003231 OR RCV000723375" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000003231, RCV000723375" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000003231...</a>
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<p>In Indian patients with metachromatic leukodystrophy (<a href="/entry/250100">250100</a>), <a href="#19" class="mim-tip-reference" title="Gieselmann, V., Zlotogora, J., Harris, A., Wenger, D. A., Morris, C. P. <strong>Molecular genetics of metachromatic leukodystrophy.</strong> Hum. Mutat. 4: 233-242, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7866401/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7866401</a>] [<a href="https://doi.org/10.1002/humu.1380040402" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7866401">Gieselmann et al. (1994)</a> reported a C-to-T substitution of the ARSA gene changing an arginine to tryptophan at position 390 in exon 7. <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>
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<a id="0038" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<strong>.0038 METACHROMATIC LEUKODYSTROPHY</strong>
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</h4>
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</div>
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<span class="mim-text-font">
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<div style="float: left;">
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ARSA, 3-BP DEL, PHE398DEL
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</div>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs1569077723 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1569077723;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs1569077723" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs1569077723" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000003232" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000003232" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000003232</a>
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</span>
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</div>
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<span class="mim-text-font">
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<p>In Polynesian patients with metachromatic leukodystrophy (<a href="/entry/250100">250100</a>), <a href="#19" class="mim-tip-reference" title="Gieselmann, V., Zlotogora, J., Harris, A., Wenger, D. A., Morris, C. P. <strong>Molecular genetics of metachromatic leukodystrophy.</strong> Hum. Mutat. 4: 233-242, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7866401/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7866401</a>] [<a href="https://doi.org/10.1002/humu.1380040402" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7866401">Gieselmann et al. (1994)</a> reported an in frame deletion of 3 bp of the ARSA gene corresponding to codon 398 (TTC) in exon 7. The mutation causes a deletion of phenylalanine at position 398. <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>
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<a id="0039" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<strong>.0039 METACHROMATIC LEUKODYSTROPHY, MILD</strong>
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</h4>
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ARSA, THR409ILE
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs74315481 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs74315481;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs74315481?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs74315481" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs74315481" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000003233 OR RCV000020313" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000003233, RCV000020313" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000003233...</a>
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In Japanese patients with mild metachromatic leukodystrophy (<a href="/entry/250100">250100</a>), <a href="#25" class="mim-tip-reference" title="Hasegawa, Y., Kawame, H., Ida, H., Ohashi, T., Eto, Y. <strong>Single exon mutation in arylsulfatase A gene has two effects: loss of enzyme activity and aberrant splicing.</strong> Hum. Genet. 93: 415-420, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7909527/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7909527</a>] [<a href="https://doi.org/10.1007/BF00201666" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7909527">Hasegawa et al. (1994)</a> identified a C-to-T substitution of the ARSA gene changing a threonine to isoleucine at position 409 in exon 8. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7909527" 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="0040" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<strong>.0040 ARYLSULFATASE A PSEUDODEFICIENCY</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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<div style="float: left;">
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ARSA, GLN486TER
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs74315482 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs74315482;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs74315482" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs74315482" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000003234" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000003234" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000003234</a>
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In Caucasian patients with arylsulfatase A pseudodeficiency (<a href="/entry/250100">250100</a>), <a href="#19" class="mim-tip-reference" title="Gieselmann, V., Zlotogora, J., Harris, A., Wenger, D. A., Morris, C. P. <strong>Molecular genetics of metachromatic leukodystrophy.</strong> Hum. Mutat. 4: 233-242, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7866401/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7866401</a>] [<a href="https://doi.org/10.1002/humu.1380040402" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7866401">Gieselmann et al. (1994)</a> reported a C-to-A substitution at nucleotide 1456 in ARSA exon 8, resulting in a stop codon at position 486. <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>
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</span>
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</div>
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<div>
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<br />
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<div>
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<div>
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<a id="0041" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<strong>.0041 MOVED TO <a href="/entry/607574#0008">607574.0008</a></strong>
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</span>
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</h4>
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<a id="0042" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<strong>.0042 METACHROMATIC LEUKODYSTROPHY, ADULT</strong>
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</span>
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</h4>
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ARSA, PRO135LEU
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs121434215 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121434215;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs121434215" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs121434215" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000003235" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000003235" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000003235</a>
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In an Italian patient with adult-onset metachromatic leukodystrophy (<a href="/entry/250100">250100</a>), <a href="#21" class="mim-tip-reference" title="Gomez-Lira, M., Perusi, C., Mottes, M., Pignatti, P. F., Manfredi, M., Rizzuto, N., Salviati, A. <strong>Molecular genetic characterization of two metachromatic leukodystrophy patients who carry the T799G mutation and show different phenotypes; description of a novel null-type mutation.</strong> Hum. Genet. 102: 459-463, 1998. Note: Erratum: Hum. Genet. 102: 602 only, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9600244/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9600244</a>] [<a href="https://doi.org/10.1007/s004390050721" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9600244">Gomez-Lira et al. (1998)</a> identified compound heterozygosity for mutations in the ARSA gene: the previously described I179S mutation (<a href="#0008">607574.0008</a>) and a 556T-C transition in exon 2 resulting in a leu135-to-pro substitution. In an erratum, the authors stated that this was a 553T-C transition, according to the nomenclature of <a href="#19" class="mim-tip-reference" title="Gieselmann, V., Zlotogora, J., Harris, A., Wenger, D. A., Morris, C. P. <strong>Molecular genetics of metachromatic leukodystrophy.</strong> Hum. Mutat. 4: 233-242, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7866401/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7866401</a>] [<a href="https://doi.org/10.1002/humu.1380040402" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7866401">Gieselmann et al. (1994)</a>, and results in a pro135-to-leu (P135L) substitution. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=9600244+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>
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<strong>.0043 METACHROMATIC LEUKODYSTROPHY, ADULT</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs28940894 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs28940894;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs28940894?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs28940894" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs28940894" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000003236 OR RCV000795605 OR RCV004755703" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000003236, RCV000795605, RCV004755703" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000003236...</a>
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<p><a href="#13" class="mim-tip-reference" title="Felice, K. J., Gomez Lira, M., Natowicz, M., Grunnet, M. L., Tsongalis, G. J., Sima, A. A. F., Kaplan, R. F. <strong>Adult-onset MLD: a gene mutation with isolated polyneuropathy.</strong> Neurology 55: 1036-1039, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11061266/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11061266</a>] [<a href="https://doi.org/10.1212/wnl.55.7.1036" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11061266">Felice et al. (2000)</a> reported a 22-year-old Asian Indian man with arylsulfatase deficiency (<a href="/entry/250100">250100</a>), born of consanguineous parents, who presented with acute left hand weakness. Nerve conduction studies showed demyelinating polyneuropathy. Cognitive function was normal, and no leukodystrophy was found on neuroimaging. The patient was found to be homozygous for a 1505A-C transversion in exon 5 of the ARSA gene, resulting in a thr286-to-pro substitution. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11061266" 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>.0044 METACHROMATIC LEUKODYSTROPHY, LATE INFANTILE</strong>
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ARSA, GLU253LYS
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs74315483 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs74315483;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs74315483?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs74315483" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs74315483" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000003237 OR RCV000169048 OR RCV000364541" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000003237, RCV000169048, RCV000364541" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000003237...</a>
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<p>In a patient with late infantile metachromatic leukodystrophy (<a href="/entry/250100">250100</a>), <a href="#48" class="mim-tip-reference" title="Regis, S., Corsolini, F., Stroppiano, M., Cusano, R., Filocamo, M. <strong>Contribution of arylsulfatase A mutations located on the same allele to enzyme activity reduction and metachromatic leukodystrophy severity.</strong> Hum. Genet. 110: 351-355, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11941485/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11941485</a>] [<a href="https://doi.org/10.1007/s00439-002-0701-y" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11941485">Regis et al. (2002)</a> found a glu253-to-lys (E253K) amino acid substitution due to a G-to-A transition in the ARSA gene. This mutation, which occurred with the T391S polymorphism on the same allele, was in compound heterozygosity with P426L (<a href="#0004">607574.0004</a>) and the N350S (<a href="#0002">607574.0002</a>) and *96A-G pseudodeficiency mutations on the other. <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>
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<a id="0045" class="mim-anchor"></a>
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<span class="mim-font">
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<strong>.0045 METACHROMATIC LEUKODYSTROPHY, ADULT</strong>
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ARSA, THR408ILE
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs28940895 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs28940895;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs28940895?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs28940895" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs28940895" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000003238 OR RCV001376978" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000003238, RCV001376978" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000003238...</a>
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<p><a href="#9" class="mim-tip-reference" title="Comabella, M., Waye, J. S., Raguer, N., Eng, B., Dominguez, C., Navarro, C., Borras, C., Krivit, W., Montalban, X. <strong>Late-onset metachromatic leukodystrophy clinically presenting as isolated peripheral neuropathy: compound heterozygosity for the IVS2+1G-to-A mutation and a newly identified missense mutation (thr408-to-ile) in a Spanish family.</strong> Ann. Neurol. 50: 108-112, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11456299/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11456299</a>]" pmid="11456299">Comabella et al. (2001)</a> reported a consanguineous Spanish family in which a proband and her daughter had atypical adult-onset metachromatic leukodystrophy (<a href="/entry/250100">250100</a>) presenting as isolated peripheral neuropathy. Electrophysiologic studies were consistent with a chronic acquired demyelinating polyneuropathy. Both patients were compound heterozygotes for 2 mutations in the ARSA gene: a G-A transition at IVS2 (<a href="#0003">607574.0003</a>) and a 1223C-T transition resulting in a thr408-to-ile (T408I) substitution. The mutations segregated independently; the unaffected father was a carrier for the IVS2 mutation and 2 daughters from the proband's second marriage were each carriers for one or the other of the mutations. Noting that homozygosity for the IVS2 mutation results in severe infantile disease, the authors concluded that the T408I mutation has a relatively mild effect. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11456299" 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="0046" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<strong>.0046 METACHROMATIC LEUKODYSTROPHY, LATE INFANTILE</strong>
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ARSA, CYS300PHE
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs74315484 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs74315484;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs74315484" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs74315484" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000003239 OR RCV000058989" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000003239, RCV000058989" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000003239...</a>
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<p>In a Portuguese patient with severe late infantile MLD (<a href="/entry/250100">250100</a>), Marcao et al. (<a href="#38" class="mim-tip-reference" title="Marcao, A., Amaral, O., Pinto, E., Pinto, R., Sa Miranda, M. C. <strong>Metachromatic leucodystrophy in Portugal--finding of four new molecular lesions: C300F, P425T, g.1190-1191insC, and g.2408delC.</strong> Hum. Mutat. 13: 337-338, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10220151/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10220151</a>] [<a href="https://doi.org/10.1002/(sici)1098-1004(1999)13:4<337::aid-humu14>3.0.co;2-9" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10220151">1999</a>, <a href="#40" class="mim-tip-reference" title="Marcao, A., Simonis, H., Schestag, F., Sa Miranda, M. C., Gieselmann, V. <strong>Biochemical characterization of two (C300F, P425T) arylsulfatase A missense mutations.</strong> Am. J. Med. Genet. 116A: 238-242, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12503099/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12503099</a>] [<a href="https://doi.org/10.1002/ajmg.a.10822" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12503099">2003</a>) identified a homozygous missense mutation in the ARSA gene, resulting in a cys300-to-phe (C300F) substitution. Transfection experiments with C300F cDNA demonstrated a reduction of ARSA enzyme activity to less than 1% of wildtype, and resulted in more rapid enzyme degradation in lysosomes. Using sedimentation analysis of the mutated protein, <a href="#39" class="mim-tip-reference" title="Marcao, A., Azevedo, J. E., Gieselmann, V., Sa Miranda, M. C. <strong>Oligomerization capacity of two arylsulfatase A mutants: C300F and P425T.</strong> Biochem. Biophys. Res. Commun. 306: 293-297, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12788103/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12788103</a>] [<a href="https://doi.org/10.1016/s0006-291x(03)00969-0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12788103">Marcao et al. (2003)</a> showed that the C300F mutation strongly interfered with the octamerization process of ARSA at low pH, which may be related to the reduced lysosomal half-life of the enzyme. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=12503099+10220151+12788103" 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>.0047 METACHROMATIC LEUKODYSTROPHY, JUVENILE</strong>
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ARSA, PRO425THR
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs74315485 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs74315485;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs74315485" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs74315485" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000003240" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000003240" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000003240</a>
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<p>In a patient with juvenile MLD (<a href="/entry/250100">250100</a>), Marcao et al. (<a href="#38" class="mim-tip-reference" title="Marcao, A., Amaral, O., Pinto, E., Pinto, R., Sa Miranda, M. C. <strong>Metachromatic leucodystrophy in Portugal--finding of four new molecular lesions: C300F, P425T, g.1190-1191insC, and g.2408delC.</strong> Hum. Mutat. 13: 337-338, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10220151/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10220151</a>] [<a href="https://doi.org/10.1002/(sici)1098-1004(1999)13:4<337::aid-humu14>3.0.co;2-9" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10220151">1999</a>, <a href="#40" class="mim-tip-reference" title="Marcao, A., Simonis, H., Schestag, F., Sa Miranda, M. C., Gieselmann, V. <strong>Biochemical characterization of two (C300F, P425T) arylsulfatase A missense mutations.</strong> Am. J. Med. Genet. 116A: 238-242, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12503099/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12503099</a>] [<a href="https://doi.org/10.1002/ajmg.a.10822" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12503099">2003</a>) identified compound heterozygosity for a P426L (<a href="#0004">607574.0004</a>) and a pro425-to-thr (P425T) mutation in the ARSA gene. Transfection experiments with P425T cDNA demonstrated residual ARSA enzyme activity of about 10% of normal, and resulted in more rapid enzyme degradation in lysosomes. Using sedimentation analysis of the mutated protein, <a href="#39" class="mim-tip-reference" title="Marcao, A., Azevedo, J. E., Gieselmann, V., Sa Miranda, M. C. <strong>Oligomerization capacity of two arylsulfatase A mutants: C300F and P425T.</strong> Biochem. Biophys. Res. Commun. 306: 293-297, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12788103/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12788103</a>] [<a href="https://doi.org/10.1016/s0006-291x(03)00969-0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12788103">Marcao et al. (2003)</a> showed that the P425L mutation resulted in a modest reduction of the octamerization capacity of ARSA at low pH, which may be related to the reduced lysosomal half-life of the enzyme. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=12503099+10220151+12788103" 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 href="#Bruns1978" class="mim-tip-reference" title="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> Cytogenet. Cell Genet. 22: 182-185, 1978.">Bruns et al. (1978)</a>; <a href="#Francke1981" class="mim-tip-reference" title="Francke, U., Tetri, P., Taggart, R. T., Oliver, N. <strong>Conserved autosomal syntenic group on mouse (MMU) chromosome 15 and human (HSA) chromosome 22: assignment of a gene for arylsulfatase A to MMU 15 and regional mapping of DIA1, ARSA, and ACO2 on HSA22.</strong> Cytogenet. Cell Genet. 31: 58-69, 1981.">Francke et al. (1981)</a>; <a href="#Waheed1983" class="mim-tip-reference" title="Waheed, A., Steckel, F., Hasilik, A., von Figura, K. <strong>Two allelic forms of human arylsulfatase A with different numbers of asparagine-linked oligosaccharides.</strong> Am. J. Hum. Genet. 35: 228-233, 1983.">Waheed et al. (1983)</a>
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[<a href="https://doi.org/10.1093/hmg/2.12.2117" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1007/BF00230227" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1002/humu.1380060210" target="_blank">Full Text</a>]
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7815433/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7815433</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7815433" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9888390/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9888390</a>, <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'})">related citations</a>]
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[<a href="https://doi.org/10.1002/(SICI)1098-1004(1999)13:1<61::AID-HUMU7>3.0.CO;2-H" 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.
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<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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[<a href="https://doi.org/10.1136/jmg.32.10.787" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1073/pnas.76.4.1957" target="_blank">Full Text</a>]
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9090526/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9090526</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9090526" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1002/(SICI)1098-1004(1997)9:3<234::AID-HUMU4>3.0.CO;2-7" target="_blank">Full Text</a>]
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11061266/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11061266</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11061266" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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<strong>Conserved autosomal syntenic group on mouse (MMU) chromosome 15 and human (HSA) chromosome 22: assignment of a gene for arylsulfatase A to MMU 15 and regional mapping of DIA1, ARSA, and ACO2 on HSA22.</strong>
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[<a href="https://doi.org/10.1159/000131626" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1159/000131527" target="_blank">Full Text</a>]
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<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 href="https://doi.org/10.1002/humu.1380040402" target="_blank">Full Text</a>]
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<strong>An assay for the rapid detection of the arylsulfatase A pseudodeficiency allele facilitates diagnosis and genetic counseling for metachromatic leukodystrophy.</strong>
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[<a href="https://doi.org/10.1007/BF00202403" target="_blank">Full Text</a>]
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<strong>Molecular genetic characterization of two metachromatic leukodystrophy patients who carry the T799G mutation and show different phenotypes; description of a novel null-type mutation.</strong>
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[<a href="https://doi.org/10.1007/s004390050721" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1093/hmg/7.8.1215" target="_blank">Full Text</a>]
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<strong>An arylsulfatase A (ARSA) missense mutation (T274M) causing late-infantile metachromatic leukodystrophy.</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8104633/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8104633</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8104633" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1002/humu.1380020405" target="_blank">Full Text</a>]
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<strong>Mutations in the arylsulfatase A gene of Japanese patients with metachromatic leukodystrophy.</strong>
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[<a href="https://doi.org/10.1089/dna.1993.12.493" target="_blank">Full Text</a>]
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<a id="Hasegawa1994" class="mim-anchor"></a>
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<strong>Single exon mutation in arylsulfatase A gene has two effects: loss of enzyme activity and aberrant splicing.</strong>
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[<a href="https://doi.org/10.1007/BF00201666" target="_blank">Full Text</a>]
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<strong>Multiple mutations are responsible for the high frequency of metachromatic leukodystrophy in a small geographic area.</strong>
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<strong>An adult-type metachromatic leukodystrophy caused by substitution of serine for glycine-122 in arylsulfatase A.</strong>
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[<a href="https://doi.org/10.1007/BF00216449" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1007/BF00277684" target="_blank">Full Text</a>]
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<strong>Genotype-phenotype relationship in various degrees of arylsulfatase A deficiency.</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1673113/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1673113</a>, <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'})">related citations</a>]
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[<a href="https://doi.org/10.1007/BF00194634" target="_blank">Full Text</a>]
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Kappler, J., Sommerlade, H. J., von Figura, K., Gieselmann, V.
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<strong>Complex arylsulfatase A alleles causing metachromatic leukodystrophy.</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7981715/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7981715</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7981715" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1002/humu.1380040205" target="_blank">Full Text</a>]
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<a id="Kappler1992" class="mim-anchor"></a>
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<strong>Late-onset metachromatic leukodystrophy: molecular pathology in two siblings.</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1353340/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1353340</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1353340" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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<a id="49" class="mim-anchor"></a>
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<a id="Ricketts1998" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
|
|
Ricketts, M. H., Poretz, R. D., Manowitz, P.
|
|
<strong>The R496H mutation of arylsulfatase A does not cause metachromatic leukodystrophy.</strong>
|
|
Hum. Mutat. 12: 238-239, 1998.
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|
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|
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9744473/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9744473</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9744473" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1002/(SICI)1098-1004(1998)12:4<238::AID-HUMU3>3.0.CO;2-B" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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<li>
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<a id="50" class="mim-anchor"></a>
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<a id="Shen1993" class="mim-anchor"></a>
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<div class="">
|
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<p class="mim-text-font">
|
|
Shen, N., Li, Z.-G., Waye, J. S., Francis, G., Chang, P. L.
|
|
<strong>Complications in the genotypic molecular diagnosis of pseudo arylsulfatase A deficiency.</strong>
|
|
Am. J. Med. Genet. 45: 631-637, 1993.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8456837/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8456837</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8456837" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1002/ajmg.1320450523" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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<li>
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<a id="51" class="mim-anchor"></a>
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<a id="Stein1989" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Stein, C., Gieselmann, V., Kreysing, J., Schmidt, B., Pohlmann, R., Waheed, A., Meyer, H. E., O'Brien, J. S., von Figura, K.
|
|
<strong>Cloning and expression of human arylsulfatase A.</strong>
|
|
J. Biol. Chem. 264: 1252-1259, 1989.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2562955/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2562955</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2562955" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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</p>
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</div>
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</li>
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<li>
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<a id="52" class="mim-anchor"></a>
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<a id="Waheed1983" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Waheed, A., Steckel, F., Hasilik, A., von Figura, K.
|
|
<strong>Two allelic forms of human arylsulfatase A with different numbers of asparagine-linked oligosaccharides.</strong>
|
|
Am. J. Hum. Genet. 35: 228-233, 1983.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/6132551/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">6132551</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=6132551" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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</p>
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</div>
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</li>
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<li>
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<a id="53" class="mim-anchor"></a>
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<a id="Zlotogora1994" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Zlotogora, J., Gieselman, V., von Figura, K., Zeigler, M., Bach, G.
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<strong>Late infantile metachromatic leukodystrophy in Israel.</strong>
|
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Biomed. Pharmacother. 48: 347-350, 1994.
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[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>]
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[<a href="https://doi.org/10.1016/0753-3322(94)90049-3" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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</ol>
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<div>
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<br />
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</div>
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</div>
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</div>
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<div>
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<a id="contributors" class="mim-anchor"></a>
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<div class="row">
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
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<span class="mim-text-font">
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<a href="#mimCollapseContributors" role="button" data-toggle="collapse"> Contributors: </a>
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</span>
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</div>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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George E. Tiller - updated : 5/19/2008
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</span>
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</div>
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</div>
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<div class="row collapse" id="mimCollapseContributors">
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<div class="col-lg-offset-2 col-md-offset-4 col-sm-offset-4 col-xs-offset-2 col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Cassandra L. Kniffin - updated : 7/31/2007<br>Cassandra L. Kniffin - updated : 6/24/2003
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</span>
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</div>
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</div>
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</div>
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<div>
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<a id="creationDate" class="mim-anchor"></a>
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<div class="row">
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
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<span class="text-nowrap mim-text-font">
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Creation Date:
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</span>
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</div>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Cassandra L. Kniffin : 2/24/2003
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</span>
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</div>
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</div>
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</div>
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<div>
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<a id="editHistory" class="mim-anchor"></a>
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<div class="row">
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
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<span class="text-nowrap mim-text-font">
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<a href="#mimCollapseEditHistory" role="button" data-toggle="collapse"> Edit History: </a>
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</span>
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</div>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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carol : 01/07/2025
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</span>
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</div>
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</div>
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<div class="row collapse" id="mimCollapseEditHistory">
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<div class="col-lg-offset-2 col-md-offset-2 col-sm-offset-4 col-xs-offset-4 col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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carol : 03/17/2022<br>alopez : 11/07/2018<br>carol : 10/11/2016<br>carol : 02/26/2015<br>carol : 3/13/2013<br>carol : 9/3/2009<br>wwang : 5/21/2008<br>terry : 5/19/2008<br>carol : 10/23/2007<br>wwang : 8/23/2007<br>ckniffin : 7/31/2007<br>terry : 11/16/2006<br>carol : 8/8/2003<br>carol : 8/1/2003<br>carol : 7/9/2003<br>carol : 7/9/2003<br>ckniffin : 6/24/2003<br>ckniffin : 6/24/2003<br>carol : 2/28/2003<br>ckniffin : 2/27/2003<br>ckniffin : 2/27/2003
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</span>
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</div>
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</div>
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</div>
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</div>
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</div>
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</div>
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<div class="container visible-print-block">
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<div class="row">
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<div class="col-md-8 col-md-offset-1">
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<div>
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<div>
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<h3>
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<span class="mim-font">
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<strong>*</strong> 607574
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</span>
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</h3>
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</div>
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<div>
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<h3>
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<span class="mim-font">
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ARYLSULFATASE A; ARSA
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</span>
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</h3>
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</div>
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<div>
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<br />
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</div>
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<div>
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<div >
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<p>
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<span class="mim-font">
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<em>Alternative titles; symbols</em>
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</span>
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</p>
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</div>
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<div>
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<h4>
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<span class="mim-font">
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CEREBROSIDE-SULFATASE<br />
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CEREBROSIDE 3-SULFATASE
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</span>
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</h4>
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</div>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<p>
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<span class="mim-text-font">
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<strong><em>HGNC Approved Gene Symbol: ARSA</em></strong>
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</span>
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</p>
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</div>
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<div>
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<p>
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<span class="mim-text-font">
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<strong>SNOMEDCT:</strong> 24326000, 396338004, 40802007, 44359008, 47683004;
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<strong>ICD10CM:</strong> E75.25, E75.29;
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</span>
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</p>
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</div>
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<div>
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<br />
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</div>
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<div>
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<p>
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<span class="mim-text-font">
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<strong>
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<em>
|
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Cytogenetic location: 22q13.33
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Genomic coordinates <span class="small">(GRCh38)</span> : 22:50,622,754-50,628,152 </span>
|
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</em>
|
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</strong>
|
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<span class="small">(from NCBI)</span>
|
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</span>
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</p>
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</div>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
|
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<strong>Gene-Phenotype Relationships</strong>
|
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</span>
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</h4>
|
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<div>
|
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<table class="table table-bordered table-condensed small mim-table-padding">
|
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<thead>
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<tr class="active">
|
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<th>
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Location
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</th>
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<th>
|
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Phenotype
|
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</th>
|
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<th>
|
|
Phenotype <br /> MIM number
|
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</th>
|
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<th>
|
|
Inheritance
|
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</th>
|
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<th>
|
|
Phenotype <br /> mapping key
|
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</th>
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</tr>
|
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</thead>
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<tbody>
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<tr>
|
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<td rowspan="1">
|
|
<span class="mim-font">
|
|
22q13.33
|
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</span>
|
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</td>
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<td>
|
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<span class="mim-font">
|
|
Metachromatic leukodystrophy
|
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</span>
|
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</td>
|
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<td>
|
|
<span class="mim-font">
|
|
250100
|
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</span>
|
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</td>
|
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<td>
|
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<span class="mim-font">
|
|
Autosomal recessive
|
|
</span>
|
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</td>
|
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<td>
|
|
<span class="mim-font">
|
|
3
|
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</span>
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</td>
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</tr>
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</tbody>
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</table>
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</div>
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</div>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
|
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<strong>TEXT</strong>
|
|
</span>
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</h4>
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<div>
|
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<h4>
|
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<span class="mim-font">
|
|
<strong>Description</strong>
|
|
</span>
|
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</h4>
|
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</div>
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<span class="mim-text-font">
|
|
<p>The ARSA gene encodes the lysosomal enzyme arylsulfatase A (EC 3.1.6.8).</p>
|
|
</span>
|
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<div>
|
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<br />
|
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</div>
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<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>Cloning and Expression</strong>
|
|
</span>
|
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</h4>
|
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</div>
|
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<span class="mim-text-font">
|
|
<p>Stein et al. (1989) cloned and sequenced a full-length cDNA for human arylsulfatase A. The predicted amino acid sequence comprised 507 residues, including a putative signal peptide of 18 residues. The sequence contains 3 potential N-glycosylation sites. The cDNA hybridized to 2.0- and 3.9-kb species in RNA from human fibroblasts and human liver. </p><p>Kreysing et al. (1990) found that 3 different mRNA species of 2.1, 3.7, and 4.8 kb are transcribed from the gene and probably arise from the use of different polyadenylation signals. </p>
|
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</span>
|
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<div>
|
|
<br />
|
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</div>
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<div>
|
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<h4>
|
|
<span class="mim-font">
|
|
<strong>Biochemical Features</strong>
|
|
</span>
|
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</h4>
|
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</div>
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<span class="mim-text-font">
|
|
<p>Lukatela et al. (1998) determined the crystal structure of ARSA at 2.1 angstrom resolution. The core of the enzyme consists of 2 beta-pleated sheets, linked by several hydrogen bonds and 1 disulfide bridge. The large central beta-pleated sheet is associated with several helices on each side, resembling bacterial alkaline phosphatase. The quaternary structure of ARSA is highly pH dependent and oscillates between 2 states: at neutral pH, it is predominantly dimeric, and at lysosomal acid pH, it is predominantly a homo-octamer, composed of 4 dimers arranged in a ring-like structure. The dimer-octamer equilibrium is regulated by deprotonation-protonation of glu424. </p>
|
|
</span>
|
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<div>
|
|
<br />
|
|
</div>
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<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>Gene Structure</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
<span class="mim-text-font">
|
|
<p>Kreysing et al. (1990) determined that the ARSA gene contains 8 exons. </p>
|
|
</span>
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
|
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|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>Mapping</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
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<span class="mim-text-font">
|
|
<p>By somatic cell hybridization methods, DeLuca et al. (1979) assigned arylsulfatases A and B (611542) to chromosome 22 and 5, respectively. Using somatic cell hybrids, Hors-Cayla et al. (1979) confirmed the assignment of human ARSA to chromosome 22. From study of human-rodent hybrid clones, Geurts van Kessel et al. (1980) concluded that arylsulfatase A is located distal to 22q13. </p><p>In an infant with deletion of 22q13.31-qter, Narahara et al. (1992) found partial deficiency of ARSA, indicating that the ARSA locus was in the deleted region. </p>
|
|
</span>
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
|
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|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>Molecular Genetics</strong>
|
|
</span>
|
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</h4>
|
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</div>
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<span class="mim-text-font">
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<p>In fibroblasts of 2 patients with metachromatic leukodystrophy (MLD; 250100), Stein et al. (1989) detected ARSA RNA species of similar size. One was a form in which synthesis of ARSA polypeptides was not detectable, and the second was a form in which catalytically active enzyme was synthesized but was unstable in lysosomes. </p><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>Kappler et al. (1994) found that a patient with late infantile MLD was a genetic compound for 2 alleles, each of which carried 2 deleterious mutations. One allele carried 2 missense mutations; the other allele bore a splice donor site mutation and a missense mutation, both of which had previously been described but on different alleles. When ARSA cDNAs carrying these mutations, separately or in combination, were transfected into baby hamster kidney cells, expression of arylsulfatase A activity could not be detected. Among the lysosomal storage disorders, a single allele with 2 disease-causing mutations had been described for the GLA gene in Fabry disease (301500.0011) and in the complex glucocerebrosidase alleles associated with Gaucher disease (230800.0009). </p><p>Barth et al. (1995) found 7 novel mutations in ARSA associated with MLD that they had detected by chemical mismatch analysis. Coulter-Mackie et al. (1995) described a child with MLD who had inherited a common splicing mutation, termed the 'I' allele, from the father and had a ring chromosome 22 from which the arylsulfatase A gene was deleted. </p><p>Draghia et al. (1997) described 10 novel and 5 previously described mutations in 21 MLD patients (14 late infantile and 7 juvenile cases), confirming the heterogeneity of mutations causing MLD. One of the 10 novel mutations was an R496H missense change. </p><p>Gomez-Lira et al. (1998) described mutations in the ARSA gene in 2 Italian patients with metachromatic leukodystrophy, one with juvenile onset and the other with adult onset. Both carried the ile179-to-ser mutation (607574.0008) in compound heterozygosity with distinct null mutations. The patient with juvenile onset also had a previously described splice site mutation, 459+1G-A (607574.0003), and the patient with adult onset had a previously undescribed mutation, pro135 to leu (607574.0042). </p><p><strong><em>Pseudoarylsulfatase A Deficiency Alleles</em></strong></p><p>
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Gieselmann et al. (1989) found that the pseudoarylsulfatase A deficiency (250100) allele had 2 A-to-G transitions: one, an asn350-to-ser mutation in exon 6, causing the loss of an N-glycosylation site (607574.0002), and the other occurring in exon 8 at the 3-prime end of the gene, causing the loss of a polyadenylation signal (607574.0001). Gieselmann (1991) found that these 2 mutations could be detected simultaneously with a rapid 3-prime-mismatch polymerase chain reaction. Shen et al. (1993) found another complication: a pseudodeficiency allele in which only 1 of the 2 A-to-G mutations was present. </p><p>Although the ARSA pseudodeficiency allele contains 2 sequence alterations, a polyadenylation defect (607574.0001) and an amino acid substitution, N350S (607574.0002), the reduction in arylsulfatase activity had previously been attributed to the polyadenylation defect which reduces the amount of ARSA mRNA and hence arylsulfatase A protein by approximately 90%. Harvey et al. (1998) performed ribonuclease protection assay analysis of ARSA mRNA transcripts and investigated the activity and lysosomal localization of protein expressed by an ARSA expression construct containing the N350S variant. They concluded that both the N350S and the polyadenylation defect play roles in biochemically defining the pseudodeficiency phenotype. The combined effect of the reduction in ARSA mRNA due to the polyadenylation defect and the lowering of ARSA activity and aberrant targeting of the expressed N350S ARSA protein to the lysosome was estimated to reduce ARSA activity in the pseudodeficiency homozygote to approximately 8% of normal. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Genotype/Phenotype Correlations</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<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. The late infantile patient inherited from his mother the frequent IVS2DS+1G-A mutation (607574.0003), and from his father a novel, single basepair microdeletion of guanine at nucleotide 7 in exon 1 (7delG). The 2 clinically unaffected sibs carried the maternal mutation IVS2DS+1G-A and, on their paternal allele, a novel C-to-T transition at nucleotide 2435 in exon 8, resulting in an ala464-to-val amino acid substitution. The father's genotype thus was 7delG/A464V. The A464V mutation was not found in 18 unrelated MLD patients and 50 controls. A464V, although clearly modifying ARSA and GS levels, apparently has little significance for clinical manifestation of MLD, mimicking the frequent ARSA pseudodeficiency allele (607574.0001). 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 similar to A464V may exist which, together with 0-type mutations such as IVS2DS+1G-A, 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 who 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 spasticity 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>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Population Genetics</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Ricketts et al. (1998) demonstrated that the ARSA polymorphism R496H has a relatively high frequency in an African American population, i.e., a frequency of 0.09 in 61 subjects tested. One normal 21-year-old subject was homozygous for the R496H mutation without evidence of MLD. The ARSA enzyme activity in subjects with or without R496H was found to be normal. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Animal Model</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<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. The 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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</span>
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<div>
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<br />
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</div>
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>ALLELIC VARIANTS</strong>
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</span>
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<strong>47 Selected Examples):</strong>
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</span>
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</h4>
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<div>
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<p />
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0001 ARYLSULFATASE A PSEUDODEFICIENCY</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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ARSA, MUTATION IN POLYADENYLATION SIGNAL
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<br />
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SNP: rs6151429,
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gnomAD: rs6151429,
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ClinVar: RCV000003190, RCV000020309, RCV000180167, RCV000246300
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In an individual homozygous for the ARSA pseudodeficiency (250100) allele, Gieselmann et al. (1989) found 2 A-to-G transitions: one changed asn350 to serine, leading to loss of an N-glycosylation site (607574.0002). This loss explained the smaller size of ARSA in ARSA pseudodeficient fibroblasts. Introduction of ser350 into normal ARSA cDNA did not affect the rate of synthesis, stability, or catalytic properties of ARSA in stably transfected baby hamster kidney cells, however. The other A-to-G transition changed the first polyadenylation signal downstream of the stop codon from AATAAC to AGTAAC. The latter change caused a severe deficiency of a 2.1-kb RNA species. The deficiency of the 2.1-kb RNA species explained the diminished synthesis of ARSA in pseudodeficiency fibroblasts. The same change was found in 4 unrelated individuals with pseudodeficiency. In those who are homozygous for the pseudodeficiency allele or carry it in heterozygous state with a normal allele, enough arylsulfatase A is synthesized to prevent clinically apparent disease. In combination with other mutant alleles, it may cause metachromatic leukodystrophy. Nelson et al. (1991) likewise found the A-to-G change at nucleotide 1620 in the first polyadenylation signal of the ARSA gene resulting in loss of its major mRNA species and a greatly reduced level of enzyme activity. This change was found to be closely linked to another A-to-G transition at nucleotide 1049 which changed asparagine-350 to serine but did not affect ARSA activity. The findings of Nelson et al. (1991) supported the conclusion of Gieselmann et al. (1989) that the change in nucleotide 1620 is always associated with that at nucleotide 1049. Barth et al. (1994) stated that the 2 mutations do not always occur together and that at least the N350S mutation may be found alone. The carrier frequency of the ARSA pseudodeficiency mutation in Australia was estimated to be about 20%. Li et al. (1992) described a polymerase chain reaction (PCR)-based method for genotypically identifying pseudodeficiency. </p><p>Barth et al. (1994) used PCR and restriction endonuclease digestion to determine the frequency of A-to-G transitions at bases 1049 (N350S) and 1620 in healthy persons from England. Mutations were found in 24 of 77 screened persons. Two were homozygous for both mutations, 16 were heterozygous for both, 5 were heterozygous for the N350S mutation alone, and 1 was homozygous for the N350S mutation. Study of the 16 persons heterozygous for both mutations showed that in 15 persons both mutations were located on the same chromosome, and in 1 person the mutations were located on different chromosomes. Persons homozygous for both mutations had the lowest activities of ARSA. </p><p>Harvey et al. (1998) presented evidence that the combined effect of reduction in ARSA mRNA due to the polyadenylation defect and the lowering of ARSA activity and aberrant targeting of the expressed N350S ARSA protein (607574.0002) to the lysosome was estimated to reduce ARSA activity in pseudodeficiency homozygotes to approximately 8% of normal. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0002 ARSA POLYMORPHISM</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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ARSA, ASN350SER
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<br />
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SNP: rs2071421,
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gnomAD: rs2071421,
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ClinVar: RCV000020310, RCV000078931, RCV000249834, RCV001357207
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In a homozygote for ARSA deficiency (250100), Gieselmann et al. (1989) demonstrated that an A-to-G transition in the polyadenylation signal downstream of the stop codon, from AATAAC to AGTAAC, was responsible for the severe deficiency of a 2.1-kb RNA species and the diminished synthesis of ARSA (607574.0001). A second mutation, asn350-to-serine, resulting from an A-to-G transition, appeared to be responsible for the small size of ARSA produced by pseudodeficiency fibroblasts because it led to loss of an N-glycosylation site. It was not, however, responsible for the defective synthesis of enzyme. The asn350-to-ser mutation is a polymorphism that does not affect the activity or stability of the enzyme, whereas the other mutation causes the loss of about 90% of ARSA mRNA, which explains the loss of 90% of ARSA crossreacting material and enzyme activity. </p><p>The 'pseudodeficiency' allele, found in a frequency of approximately 10% in many populations, is associated with 2 A-to-G transitions in cis in the ARSA gene causing the simultaneous loss of an N-glycosylation and a polyadenylation signal. To understand the evolutionary relationship between such common and tightly linked mutations, Ott et al. (1997) studied 400 individuals in the African, European, Indian, and East Asian populations and found none carrying the polyadenylation mutation alone. However, the N-glycosylation mutation could occur independently. Its frequency varies from 0.01 in Indians and 0.06 in Europeans to 0.21 in East Asians and 0.32 in Africans. The frequencies of both mutations occurring together range from almost nonexistent in the Africans and East Asians, to 0.075 in Europeans and 0.125 in Indians. These frequencies were significantly different among populations. Haplotype analysis among homozygous pseudodeficiency individuals and 8 multigeneration families with 6 polymorphism-identifying restriction enzymes showed that, of the 5 haplotypes found in the general population, only 1 was linked to the double mutations. Alleles among the 4 populations with only the N-glycosylation mutation also supported linkage to the same haplotype except in some Europeans, whose alleles were discordant. These results were considered consistent with the hypothesis that the N-glycosylation mutation may be a recurrent event among Europeans but first occurred in an ancestral allele before the emergence of modern Homo sapiens from Africa approximately 100,000 to 200,000 years ago. Subsequently, the polyadenylation mutation occurred in this ancient allele with the N-glycosylation mutation, an event that likely took place after the divergence between the European and East Asian lineages. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0003 METACHROMATIC LEUKODYSTROPHY, JUVENILE</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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ARYLSULFATASE A, ALLELE I, INCLUDED<br />
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METACHROMATIC LEUKODYSTROPHY, ADULT, INCLUDED
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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ARSA, IVS2DS, G-A, +1
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<br />
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SNP: rs80338815,
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gnomAD: rs80338815,
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ClinVar: RCV000003192, RCV000003194, RCV000020319, RCV000335617, RCV001251910, RCV001267384, RCV001778645, RCV002251862, RCV003934795
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In a patient with juvenile-onset metachromatic leukodystrophy (250100), Polten et al. (1991) found 2 different metachromatic leukodystrophy alleles. One, designated allele I, differed in 3 positions from the published sequence for the ARSA gene. Two of the substitutions represented functionally silent changes; only the loss of a splice donor site in allele I was considered to be relevant to metachromatic leukodystrophy. Specifically, a G-to-A transition destroyed the splice donor site of exon 2 by changing the classic exon-intron boundary consensus sequence from AGgt to AGat. In all 6 instances of homozygosity for allele I, Polten et al. (1991) reported that the clinical picture was that of the late infantile form of metachromatic leukodystrophy. Heinisch et al. (1995) found this mutation in homozygous state in 3 separate Arab families living in the Jerusalem area. </p><p>Draghia et al. (1997), who referred to this mutation as 459+1G-A, cited reports stating that it, and the P426L mutation (607574.0004), have the highest frequency in MLD, each accounting for 25% of mutant alleles among Caucasian patients (Polten et al., 1991; Barth et al., 1993). The remaining 50% of alleles are very heterogeneous, most of them being found in only 1 or 2 patients (Gieselmann et al., 1994). </p><p>Comabella et al. (2001) reported a consanguineous Spanish family in which a proband and her daughter had atypical adult-onset metachromatic leukodystrophy presenting as isolated peripheral neuropathy. Electrophysiologic studies were consistent with a chronic acquired demyelinating polyneuropathy. Both patients were compound heterozygotes for this mutation and a 1223C-T transition resulting in a thr408-to-ile (T408I; 607574.0045) substitution in the ARSA gene. The mutations segregated independently; the unaffected father was a carrier for this mutation and 2 daughters from the proband's second marriage were each carriers for one or the other of the mutations. Noting that homozygosity for this mutation results in severe infantile disease, the authors concluded that the T408I mutation has a relatively mild effect. </p><p>In an Italian patient with juvenile-onset metachromatic leukodystrophy, Gomez-Lira et al. (1998) identified compound heterozygosity for the 459+1G-A and the I179S (607574.0008) mutations in the ARSA gene. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0004 METACHROMATIC LEUKODYSTROPHY, JUVENILE</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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ARYLSULFATASE A, ALLELE A, INCLUDED<br />
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METACHROMATIC LEUKODYSTROPHY, ADULT, INCLUDED
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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ARSA, PRO426LEU
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<br />
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SNP: rs28940893,
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gnomAD: rs28940893,
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ClinVar: RCV000003195, RCV000003196, RCV000003197, RCV000020314, RCV000392246, RCV001251909, RCV004755702, RCV004797751
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In a patient with juvenile-onset metachromatic leukodystrophy (250100), Polten et al. (1991) found compound heterozygosity for 2 mutations in the ARSA gene: a splice site mutation, referred to as 'allele I' (607574.0003) and a C-to-T transition, resulting in a pro426-to-leu (P426L) substitution, referred to as 'allele A.' To test the functional consequence of this mutation, Polten et al. (1991) introduced it into arylsulfatase A cDNA by site-directed mutagenesis, and the mutated cDNA was transiently expressed in baby-hamster kidney cells after transfection. Only a small increase in the activity of arylsulfatase A was observed in the transfected cells (3%; range, 2-5). Polten et al. (1991) determined the frequency of alleles I and A by allele-specific oligonucleotide hybridization. Of 68 patients studied, 50 carried at least 1 of the 2 alleles. In 23 patients, they found homozygosity for one or the other allele or compound heterozygosity for the 2. Neither allele was found in 18 of the 68 patients. In total, 37 I alleles and 36 A alleles were found. In 8 instances of homozygosity for allele A, Polten et al. (1991) found that in 5 it was associated with the adult form and in 3 with the juvenile form of the disease. Compound heterozygosity for allele A and allele I resulted in the juvenile form of metachromatic leukodystrophy in 7 of 7 instances. Heterozygosity for allele I (with the other allele unknown) was usually associated with late infantile disease, and heterozygosity for allele A with later onset of the disease. </p><p>Draghia et al. (1997), cited reports stating that the P426L mutation and a splice site mutation (607574.0003) have the highest frequency in MLD, each accounting for 25% of mutant alleles among Caucasian patients (Polten et al., 1991; Barth et al., 1993). The remaining 50% of alleles are very heterogeneous, most of them being found in only 1 or 2 patients (Gieselmann et al., 1994). </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0005 METACHROMATIC LEUKODYSTROPHY, ADULT</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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ARSA, GLY99ASP
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<br />
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SNP: rs74315455,
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gnomAD: rs74315455,
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ClinVar: RCV000003198, RCV000020318, RCV000724149
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|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a Japanese patient with adult-type metachromatic leukodystrophy (250100), Kondo et al. (1991) identified a G-to-A transition in exon 2, which resulted in amino acid substitution of aspartic acid for glycine-99. In transient expression studies, COS cells transfected with the mutant cDNA carrying gly99-to-asp did not show increase of ARSA activity, thus confirming that the mutation was the cause of MLD. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0006 METACHROMATIC LEUKODYSTROPHY, LATE INFANTILE</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
ARSA, SER96PHE
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs74315456,
|
|
|
|
|
|
gnomAD: rs74315456,
|
|
|
|
|
|
ClinVar: RCV000003199, RCV000020317, RCV000723374
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a patient with the late infantile form of metachromatic leukodystrophy (250100), Gieselmann et al. (1991) found homozygosity for the mutations characteristic of the arylsulfatase A pseudodeficiency allele but, in addition, a C-to-T transition in exon 2 causing a substitution of phenylalanine for serine-96. Gieselmann et al. (1991) pointed out the necessity for care in not overlooking a mutation causing severe deficiency associated with the changes of pseudodeficiency. This can be a serious problem since homozygous pseudodeficiency is present in 1 to 2% of the population. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0007 METACHROMATIC LEUKODYSTROPHY, LATE INFANTILE</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
ARSA, 11-BP DEL, EX8
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs80338823,
|
|
|
|
|
|
|
|
ClinVar: RCV000180166, RCV000723834, RCV002265665
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>Bohne et al. (1991) demonstrated an 11-bp deletion in exon 8 of one allele of the ARSA gene in a patient with the late infantile form of MLD (250100). Although this allele produced normal amounts of mRNA, no arylsulfatase A crossreacting material could be detected in cultured fibroblasts from the patient. The 11-bp deletion was found between nucleotides 2506 and 2516. It caused a frameshift downstream of the codon for amino acid 467. The polypeptide encoded by the mutant allele should be 29 amino acids longer than wildtype ASA. The other allele, which had been inherited from the father, had a splice donor site mutation in exon 7. This allele is known also to generate no ASA polypeptide. Thus, this was another example where absence of ASA polypeptide correlated with the severe late infantile form of MLD. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0008 METACHROMATIC LEUKODYSTROPHY, JUVENILE</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
METACHROMATIC LEUKODYSTROPHY, ADULT, INCLUDED
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
ARSA, ILE179SER
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs74315457,
|
|
|
|
|
|
gnomAD: rs74315457,
|
|
|
|
|
|
ClinVar: RCV000003202, RCV000003203, RCV000020320, RCV000657846, RCV001267385
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a patient with juvenile-onset metachromatic leukodystrophy (250100), Fluharty et al. (1991) identified a T-to-G transversion at nucleotide 799, resulting in a change from isoleucine to serine in exon 3. They designated this mutation E3P799 according to the following scheme: location in the gene, e.g., E3 = exon 3 or its immediately adjacent splice-recognition sequence; type of alteration, e.g., P = point mutation leading to amino acid substitution, or S = mutation in splice recognition sequence; and number of initial nucleotide in the altered sequence, e.g., 799 = 799th nucleotide beyond start of initiation codon. </p><p>Lugowska et al. (2002) pointed out that this mutation, designated I179S in the accepted terminology, had been described in 15 of 130 MLD patients in the literature. All of them were found to have been heterozygous for this mutation. Lugowska et al. (2002) stated that, according to the Hardy-Weinberg law for 2 alleles, 1 homozygote I179S/I179S among 12 late juveniles and adults studied by them should have been found. Thus, they speculated that the residual ARSA activity in an I179S homozygote might be similar to that found in an individual homozygous for the ARSA pseudodeficiency allele (607574.0001) who does not present with clinical symptoms of classic MLD. </p><p>In 2 Italian patients with metachromatic leukodystrophy, one with adult onset and the other with juvenile onset, Gomez-Lira et al. (1998) identified compound heterozygosity for mutations in the ARSA gene. Both carried the I179S mutation (607574.0008); the patient with juvenile onset had the common 459+1G-A (607574.0003) mutation, and the patient with adult onset had a pro135-to-leu mutation (607574.0042). </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0009 METACHROMATIC LEUKODYSTROPHY, JUVENILE</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
ARSA, IVS7DS, G-A, +1
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs80338820,
|
|
|
|
|
|
gnomAD: rs80338820,
|
|
|
|
|
|
ClinVar: RCV000003204, RCV000020312, RCV000723835
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a patient with juvenile-onset metachromatic leukodystrophy (250100), Fluharty et al. (1991) found compound heterozygosity for a point mutation (see 607574.0008) and for a G-to-A transition that resulted in an altered splice-recognition sequence between exon 7 and the following intron. The mutation involved nucleotide 2195, the first nucleotide in intron 7. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0010 METACHROMATIC LEUKODYSTROPHY, LATE-ONSET</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
ARSA, ARG84GLN
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs74315458,
|
|
|
|
|
|
gnomAD: rs74315458,
|
|
|
|
|
|
ClinVar: RCV000003205, RCV000020316, RCV000723563
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>Kappler et al. (1992) described an arg84-to-gln mutation in 2 sisters with late-onset metachromatic leukodystrophy (250100). One sister developed abnormal behavior at the age of 14 years and was thought to have 'frontal lobe syndrome.' Later she developed peripheral neuropathy and dementia. At the age of 30 she was bedridden. The other sister presented similar biochemical alterations. In spite of cranial CT alterations characteristic of MLD, her clinical status was almost normal when she was 21 years old. At the age of 29 years, she was still without complaints. Both sisters showed residual ARSA activity, further validating the concept that different degrees of residual ARSA activity account for phenotypic variation in this disorder. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0011 METACHROMATIC LEUKODYSTROPHY, LATE INFANTILE</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
ARSA, GLY309SER
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs74315459,
|
|
|
|
|
|
gnomAD: rs74315459,
|
|
|
|
|
|
ClinVar: RCV000003206, RCV000666302, RCV000714802, RCV001813940, RCV002286693
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>Kreysing et al. (1993) described compound heterozygosity for 2 mutant ARSA alleles in a male patient who presented with gait disturbances at the age of 18 months suggestive of MLD (250100). Subsequently he lost acquired capabilities such as walking and sitting, developed spastic paresis, and finally became bedridden. He showed episodes of pain attacks occurring several times per hour. Electromyelography showed signs of denervation and decreased nerve conduction velocity. Sural nerve biopsy demonstrated metachromatic granules. The patient had residual ARSA activity of about 10%. Fibroblasts of the patient showed significant sulfatide degradation activity exceeding that of adult MLD patients. One of the mutant alleles was a G-to-A transition in exon 5 causing a gly309-to-ser substitution. Transient expression of this allele resulted in only 13% enzyme activity as compared with the normal. The mutant enzyme was correctly targeted to the lysosomes but was unstable. The other allele showed a deletion of C447 in exon 2, causing a frameshift and a premature stop codon at amino acid position 105 (607574.0012). The findings in this patient contrasted with previous results showing that the late infantile type of MLD is always associated with the complete absence of ARSA activity. In this case, the expression of the mutant ARSA protein may have been influenced by particular features of oligodendrocytes, such that the level of mutant enzyme is lower in these cells than in others. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0012 METACHROMATIC LEUKODYSTROPHY, LATE INFANTILE</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
ARSA, 1-BP DEL, 447C
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs786204673,
|
|
|
|
|
|
|
|
ClinVar: RCV000169476, RCV002265656, RCV004724964
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>See 607574.0011 and Kreysing et al. (1993). </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0013 METACHROMATIC LEUKODYSTROPHY, SEVERE</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
ARSA, GLY86ASP
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs74315460,
|
|
|
|
|
|
gnomAD: rs74315460,
|
|
|
|
|
|
ClinVar: RCV000003207, RCV001353057
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In Muslim Arab patients with severe metachromatic leukodystrophy (250100), Gieselmann et al. (1994) reported a G-to-A substitution of the ARSA gene changing a glycine to aspartic acid at position 86 in exon 2. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0014 METACHROMATIC LEUKODYSTROPHY, SEVERE</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
ARSA, SER96LEU
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs199476371,
|
|
|
|
|
|
|
|
ClinVar: RCV000003208, RCV000058959
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In Muslim Arab patients with severe metachromatic leukodystrophy (250100), Gieselmann et al. (1994) reported a C-to-T substitution of the ARSA gene changing a serine to a leucine at position 96 in exon 2. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0015 METACHROMATIC LEUKODYSTROPHY</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
ARSA, GLY122SER
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs74315461,
|
|
|
|
|
|
gnomAD: rs74315461,
|
|
|
|
|
|
ClinVar: RCV000003209, RCV000078945, RCV000623394, RCV003415633
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In Japanese and Caucasian patients with metachromatic leukodystrophy (250100), Honke et al. (1993) and Kappler et al. (1994) identified a G-to-A substitution of the ARSA gene changing a glycine to serine at position 122 in exon 2. The mutation changes the restriction site BalI. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0016 METACHROMATIC LEUKODYSTROPHY, SEVERE</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
ARSA, PRO136LEU
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs74315462,
|
|
|
|
|
|
gnomAD: rs74315462,
|
|
|
|
|
|
ClinVar: RCV000003210, RCV000675081
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In Jewish patients with metachromatic leukodystrophy (250100), Gieselmann et al. (1994) reported a C-to-T substitution of the ARSA gene changing a proline to leucine at position 136 in exon 2. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0017 METACHROMATIC LEUKODYSTROPHY</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
ARSA, 1-BP DEL, 297C
|
|
|
|
|
|
<br />
|
|
|
|
|
|
|
|
ClinVar: RCV000003211
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In Caucasian patients with metachromatic leukodystrophy (250100), Kreysing et al. (1993) identified a 1-bp (C) deletion at position 297 of the coding sequence in exon 2 of the ARSA gene. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0018 METACHROMATIC LEUKODYSTROPHY</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
ARSA, GLY154ASP
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs74315463,
|
|
|
|
|
|
|
|
ClinVar: RCV000003212
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In Caucasian patients with metachromatic leukodystrophy (250100), Kappler et al. (1994) identified a G-to-A substitution of the ARSA gene changing a glycine to aspartic acid at position 154 in exon 3. The mutation changes the restriction site ApaI. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0019 ARYLSULFATASE A PSEUDODEFICIENCY</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
ARSA, PRO155ARG
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs74315464,
|
|
|
|
|
|
gnomAD: rs74315464,
|
|
|
|
|
|
ClinVar: RCV000003213
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In Lebanese patients with arylsulfatase A pseudodeficiency (250100), Gieselmann et al. (1994) reported a C-to-G substitution of the ARSA gene changing a proline to arginine at position 155 in exon 3. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0020 METACHROMATIC LEUKODYSTROPHY</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
ARSA, PRO167ARG
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs74315465,
|
|
|
|
|
|
|
|
ClinVar: RCV000003214
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In Caucasian patients with metachromatic leukodystrophy (250100), Kappler et al. (1994) identified a C-to-G substitution of the ARSA gene changing a proline to arginine at position 167 in exon 3. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0021 ARYLSULFATASE A PSEUDODEFICIENCY</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
ARSA, ASP169ASN
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs74315466,
|
|
|
|
|
|
gnomAD: rs74315466,
|
|
|
|
|
|
ClinVar: RCV000003215, RCV000540770, RCV001251908, RCV002265546, RCV003480017
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In Polynesian patients with arylsulfatase A pseudodeficiency (250100), Gieselmann et al. (1994) reported a G-to-A substitution of the ARSA gene changing an aspartic acid to asparagine at position 169 in exon 3. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0022 METACHROMATIC LEUKODYSTROPHY</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
ARSA, ALA212VAL
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs74315467,
|
|
|
|
|
|
gnomAD: rs74315467,
|
|
|
|
|
|
ClinVar: RCV000003216, RCV000723836
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In Caucasian patients with metachromatic leukodystrophy (250100), Barth et al. (1993) identified a G-to-T substitution of the ARSA gene changing an alanine to valine at position 212 in exon 3. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0023 METACHROMATIC LEUKODYSTROPHY</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
ARSA, ALA224VAL
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs74315468,
|
|
|
|
|
|
gnomAD: rs74315468,
|
|
|
|
|
|
ClinVar: RCV000003217, RCV000343115
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In Caucasian patients with metachromatic leukodystrophy (250100), Barth et al. (1993) identified a C-to-T substitution of the ARSA gene changing an alanine to valine at position 224 in exon 3. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0024 METACHROMATIC LEUKODYSTROPHY</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
ARSA, PRO231THR
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs74315469,
|
|
|
|
|
|
gnomAD: rs74315469,
|
|
|
|
|
|
ClinVar: RCV000003218, RCV003387714
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a patient with metachromatic leukodystrophy (250100), Caillaud et al. (1993) identified a C-to-A substitution of the ARSA gene changing a proline to threonine at position 231 in exon 4.</p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0025 METACHROMATIC LEUKODYSTROPHY</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
ARSA, ARG244CYS
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs74315470,
|
|
|
|
|
|
gnomAD: rs74315470,
|
|
|
|
|
|
ClinVar: RCV000003219, RCV003993733
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In Caucasian patients with metachromatic leukodystrophy (250100), Gieselmann et al. (1994) reported a C-to-T substitution of the ARSA gene changing an arginine to cysteine at position 244 in exon 4. The mutation changes an SstII restriction site. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0026 METACHROMATIC LEUKODYSTROPHY, SEVERE</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
ARSA, GLY245ARG
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs74315471,
|
|
|
|
|
|
gnomAD: rs74315471,
|
|
|
|
|
|
ClinVar: RCV000003220, RCV000020321, RCV000723992
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In Japanese patients with severe metachromatic leukodystrophy (250100), Hasegawa et al. (1993) identified a G-to-A substitution of the ARSA gene changing a glycine to arginine at position 245 in exon 4. The mutation changes an SstII restriction site. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0027 METACHROMATIC LEUKODYSTROPHY, SEVERE</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
ARSA, THR274MET
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs74315472,
|
|
|
|
|
|
|
|
ClinVar: RCV000003221, RCV000169246, RCV000991546, RCV003904799
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In Lebanese patients with severe metachromatic leukodystrophy (250100), Harvey et al. (1993) identified a C-to-T change in exon 4 of the ARSA gene, resulting in a thr274-to-met (T274M) substitution. The T274M allele represented 20% of all alleles among Australian patients with metachromatic leukodystrophy, and about 85% of all alleles among Australian Lebanese affected with the disease. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0028 METACHROMATIC LEUKODYSTROPHY, SEVERE</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
ARSA, IVS4DS, G-A, +1
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs886041911,
|
|
|
|
|
|
|
|
ClinVar: RCV001192373, RCV002221160, RCV004590209
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In Caucasian patients with severe metachromatic leukodystrophy (250100), Pastor-Soler et al. (1994) identified a G-to-A transition of the ARSA gene at nucleotide 848+1 (which is the first nucleotide of the donor splice site) of intron 4, resulting in abnormal splicing. This mutation causes instability of the arylsulfatase A mRNA and was found in all alleles of Navajo Indians patients with late infantile metachromatic leucodystrophy. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0029 METACHROMATIC LEUKODYSTROPHY</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
ARSA, ARG288CYS
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs74315473,
|
|
|
|
|
|
gnomAD: rs74315473,
|
|
|
|
|
|
ClinVar: RCV000003223, RCV001642197, RCV004819990
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In Caucasian patients with metachromatic leukodystrophy (250100), Gieselmann et al. (1994) reported a C-to-T substitution of the ARSA gene changing an arginine to cysteine at position 288 in exon 5. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0030 METACHROMATIC LEUKODYSTROPHY, SEVERE</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
ARSA, SER295TYR
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs74315474,
|
|
|
|
|
|
|
|
ClinVar: RCV000003224, RCV000492011
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In Saudi Arabian patients with severe metachromatic leukodystrophy (250100), Barth et al. (1993) identified a C-to-A substitution of the ARSA gene changing a serine to tyrosine at position 295 in exon 5. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0031 ARYLSULFATASE A PSEUDODEFICIENCY</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
ARSA, IVS5DS, G-T, -1, GLY325CYS
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs148092995,
|
|
|
|
|
|
gnomAD: rs148092995,
|
|
|
|
|
|
ClinVar: RCV000003225
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In Indian patients with arylsulfatase A pseudodeficiency (250100), Gieselmann et al. (1994) reported a G-to-T substitution of the last nucleotide of ARSA exon 5, changing a glycine to cysteine at position 325 and concomitantly resulting in aberrant splicing of arylsulfatase A mRNA. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0032 METACHROMATIC LEUKODYSTROPHY, SEVERE</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
ARSA, ASP335VAL
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs74315475,
|
|
|
|
|
|
gnomAD: rs74315475,
|
|
|
|
|
|
ClinVar: RCV000003226, RCV000169024, RCV000413321, RCV000414806
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In Caucasian patients with severe metachromatic leukodystrophy (250100), Gieselmann et al. (1994) reported an A-to-T substitution of the ARSA gene changing an aspartic acid to valine at position 335 in exon 6. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0033 METACHROMATIC LEUKODYSTROPHY, SEVERE</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
ARSA, ARG370TRP
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs74315476,
|
|
|
|
|
|
gnomAD: rs74315476,
|
|
|
|
|
|
ClinVar: RCV000003227, RCV000078933, RCV000723522
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In Christian Arab patients with severe metachromatic leukodystrophy (250100), Gieselmann et al. (1994) reported a C-to-T substitution of the ARSA gene changing an arginine to tryptophan at position 370 in exon 7. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0034 METACHROMATIC LEUKODYSTROPHY, MILD</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
ARSA, ARG370GLN
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs74315477,
|
|
|
|
|
|
gnomAD: rs74315477,
|
|
|
|
|
|
ClinVar: RCV000003228, RCV000544790
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In Jewish patients with mild metachromatic leukodystrophy (250100), Gieselmann et al. (1994) reported a G-to-A substitution of the ARSA gene changing an arginine to glutamine at position 370 in exon 7. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0035 ARYLSULFATASE A PSEUDODEFICIENCY, SEVERE</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
ARSA, PRO377LEU
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs74315478,
|
|
|
|
|
|
gnomAD: rs74315478,
|
|
|
|
|
|
ClinVar: RCV000003229, RCV002512051, RCV003500499
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In Habbanite Jewish patients with severe arylsulfatase A pseudodeficiency (250100), Zlotogora et al. (1994) identified a C-to-T substitution of the ARSA gene changing a proline to leucine at position 377 in exon 7. This mutation has a high frequency among the small population of Habbanite Jews (1 in 75 live births). </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0036 ARYLSULFATASE A PSEUDODEFICIENCY, INTERMEDIATE</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
ARSA, GLU382LYS
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs74315479,
|
|
|
|
|
|
gnomAD: rs74315479,
|
|
|
|
|
|
ClinVar: RCV000003230, RCV000078936, RCV000723624
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In Caucasian patients with intermediate arylsulfatase A pseudodeficiency (250100), Barth et al. (1994) identified a G-to-A substitution of the ARSA gene changing a glutamic acid to lysine at position 382 in exon 7. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0037 METACHROMATIC LEUKODYSTROPHY</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
ARSA, ARG390TRP
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs74315480,
|
|
|
|
|
|
gnomAD: rs74315480,
|
|
|
|
|
|
ClinVar: RCV000003231, RCV000723375
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In Indian patients with metachromatic leukodystrophy (250100), Gieselmann et al. (1994) reported a C-to-T substitution of the ARSA gene changing an arginine to tryptophan at position 390 in exon 7. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0038 METACHROMATIC LEUKODYSTROPHY</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
ARSA, 3-BP DEL, PHE398DEL
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs1569077723,
|
|
|
|
|
|
|
|
ClinVar: RCV000003232
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In Polynesian patients with metachromatic leukodystrophy (250100), Gieselmann et al. (1994) reported an in frame deletion of 3 bp of the ARSA gene corresponding to codon 398 (TTC) in exon 7. The mutation causes a deletion of phenylalanine at position 398. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0039 METACHROMATIC LEUKODYSTROPHY, MILD</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
ARSA, THR409ILE
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs74315481,
|
|
|
|
|
|
gnomAD: rs74315481,
|
|
|
|
|
|
ClinVar: RCV000003233, RCV000020313
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In Japanese patients with mild metachromatic leukodystrophy (250100), Hasegawa et al. (1994) identified a C-to-T substitution of the ARSA gene changing a threonine to isoleucine at position 409 in exon 8. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0040 ARYLSULFATASE A PSEUDODEFICIENCY</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
ARSA, GLN486TER
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs74315482,
|
|
|
|
|
|
|
|
ClinVar: RCV000003234
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In Caucasian patients with arylsulfatase A pseudodeficiency (250100), Gieselmann et al. (1994) reported a C-to-A substitution at nucleotide 1456 in ARSA exon 8, resulting in a stop codon at position 486. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-text-font">
|
|
<strong>.0041 MOVED TO 607574.0008</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0042 METACHROMATIC LEUKODYSTROPHY, ADULT</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
ARSA, PRO135LEU
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs121434215,
|
|
|
|
|
|
|
|
ClinVar: RCV000003235
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In an Italian patient with adult-onset metachromatic leukodystrophy (250100), Gomez-Lira et al. (1998) identified compound heterozygosity for mutations in the ARSA gene: the previously described I179S mutation (607574.0008) and a 556T-C transition in exon 2 resulting in a leu135-to-pro substitution. In an erratum, the authors stated that this was a 553T-C transition, according to the nomenclature of Gieselmann et al. (1994), and results in a pro135-to-leu (P135L) substitution. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0043 METACHROMATIC LEUKODYSTROPHY, ADULT</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
ARSA, THR286PRO
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs28940894,
|
|
|
|
|
|
gnomAD: rs28940894,
|
|
|
|
|
|
ClinVar: RCV000003236, RCV000795605, RCV004755703
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>Felice et al. (2000) reported a 22-year-old Asian Indian man with arylsulfatase deficiency (250100), born of consanguineous parents, who presented with acute left hand weakness. Nerve conduction studies showed demyelinating polyneuropathy. Cognitive function was normal, and no leukodystrophy was found on neuroimaging. The patient was found to be homozygous for a 1505A-C transversion in exon 5 of the ARSA gene, resulting in a thr286-to-pro substitution. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0044 METACHROMATIC LEUKODYSTROPHY, LATE INFANTILE</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
ARSA, GLU253LYS
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs74315483,
|
|
|
|
|
|
gnomAD: rs74315483,
|
|
|
|
|
|
ClinVar: RCV000003237, RCV000169048, RCV000364541
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a patient with late infantile metachromatic leukodystrophy (250100), Regis et al. (2002) found a glu253-to-lys (E253K) amino acid substitution due to a G-to-A transition in the ARSA gene. This mutation, which occurred with the T391S polymorphism on the same allele, was in compound heterozygosity with P426L (607574.0004) and the N350S (607574.0002) and *96A-G pseudodeficiency mutations on the other. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0045 METACHROMATIC LEUKODYSTROPHY, ADULT</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
ARSA, THR408ILE
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs28940895,
|
|
|
|
|
|
gnomAD: rs28940895,
|
|
|
|
|
|
ClinVar: RCV000003238, RCV001376978
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>Comabella et al. (2001) reported a consanguineous Spanish family in which a proband and her daughter had atypical adult-onset metachromatic leukodystrophy (250100) presenting as isolated peripheral neuropathy. Electrophysiologic studies were consistent with a chronic acquired demyelinating polyneuropathy. Both patients were compound heterozygotes for 2 mutations in the ARSA gene: a G-A transition at IVS2 (607574.0003) and a 1223C-T transition resulting in a thr408-to-ile (T408I) substitution. The mutations segregated independently; the unaffected father was a carrier for the IVS2 mutation and 2 daughters from the proband's second marriage were each carriers for one or the other of the mutations. Noting that homozygosity for the IVS2 mutation results in severe infantile disease, the authors concluded that the T408I mutation has a relatively mild effect. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0046 METACHROMATIC LEUKODYSTROPHY, LATE INFANTILE</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
ARSA, CYS300PHE
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs74315484,
|
|
|
|
|
|
|
|
ClinVar: RCV000003239, RCV000058989
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a Portuguese patient with severe late infantile MLD (250100), Marcao et al. (1999, 2003) identified a homozygous missense mutation in the ARSA gene, resulting in a cys300-to-phe (C300F) substitution. Transfection experiments with C300F cDNA demonstrated a reduction of ARSA enzyme activity to less than 1% of wildtype, and resulted in more rapid enzyme degradation in lysosomes. Using sedimentation analysis of the mutated protein, Marcao et al. (2003) showed that the C300F mutation strongly interfered with the octamerization process of ARSA at low pH, which may be related to the reduced lysosomal half-life of the enzyme. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0047 METACHROMATIC LEUKODYSTROPHY, JUVENILE</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
ARSA, PRO425THR
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs74315485,
|
|
|
|
|
|
|
|
ClinVar: RCV000003240
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a patient with juvenile MLD (250100), Marcao et al. (1999, 2003) identified compound heterozygosity for a P426L (607574.0004) and a pro425-to-thr (P425T) mutation in the ARSA gene. Transfection experiments with P425T cDNA demonstrated residual ARSA enzyme activity of about 10% of normal, and resulted in more rapid enzyme degradation in lysosomes. Using sedimentation analysis of the mutated protein, Marcao et al. (2003) showed that the P425L mutation resulted in a modest reduction of the octamerization capacity of ARSA at low pH, which may be related to the reduced lysosomal half-life of the enzyme. </p>
|
|
</span>
|
|
</div>
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<div>
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<br />
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</div>
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</div>
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>See Also:</strong>
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</span>
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</h4>
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<span class="mim-text-font">
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Bruns et al. (1978); Francke et al. (1981); Waheed et al. (1983)
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</span>
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<div>
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<br />
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</div>
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</div>
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<div>
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<h4>
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<span class="mim-font">
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