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- #301500 - FABRY DISEASE
- OMIM
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<span class="h4">#301500</span>
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<strong>Table of Contents</strong>
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<a href="#title"><strong>Title</strong></a>
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<a href="#phenotypeMap"><strong>Phenotype-Gene Relationships</strong></a>
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<a href="/clinicalSynopsis/301500"><strong>Clinical Synopsis</strong></a>
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<a href="#text"><strong>Text</strong></a>
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<a href="#clinicalFeatures">Clinical Features</a>
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<a href="#otherFeatures">Other Features</a>
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<a href="#biochemicalFeatures">Biochemical Features</a>
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<a href="#diagnosis">Diagnosis</a>
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<a href="#clinicalManagement">Clinical Management</a>
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<a href="#molecularGenetics">Molecular Genetics</a>
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<a href="#genotypePhenotypeCorrelations">Genotype/Phenotype Correlations</a>
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<a href="#populationGenetics">Population Genetics</a>
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<a href="#nomenclature">Nomenclature</a>
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<a href="#seeAlso"><strong>See Also</strong></a>
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<a href="#references"><strong>References</strong></a>
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<a href="#contributors"><strong>Contributors</strong></a>
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<a href="#creationDate"><strong>Creation Date</strong></a>
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<div><a href="https://clinicaltrials.gov/search?cond=FABRY DISEASE" class="mim-tip-hint" title="A registry of federally and privately supported clinical trials conducted in the United States and around the world." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Clinical Trials', 'domain': 'clinicaltrials.gov'})">Clinical Trials</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/books/NBK1292/" class="mim-tip-hint" title="Expert-authored, peer-reviewed descriptions of inherited disorders including the uses of genetic testing in diagnosis, management, and genetic counseling." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Gene Reviews', 'domain': 'ncbi.nlm.nih.gov'})">Gene Reviews</a></div>
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<div><a href="https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=324" class="mim-tip-hint" title="European reference portal for information on rare diseases and orphan drugs." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'OrphaNet', 'domain': 'orpha.net'})">OrphaNet</a></div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
<div class="panel-heading mim-panel-heading" role="tab" id="mimAnimalModels">
<span class="panel-title">
<span class="small">
<a href="#mimAnimalModelsLinksFold" id="mimAnimalModelsLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
<div style="display: table-row">
<div id="mimAnimalModelsLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">&#9658;</div>
&nbsp;
<div style="display: table-cell;">Animal Models</div>
</div>
</a>
</span>
</span>
</div>
<div id="mimAnimalModelsLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
<div class="panel-body small mim-panel-body">
<div><a href="https://www.alliancegenome.org/disease/DOID:14499" class="mim-tip-hint" title="Search Across Species; explore model organism and human comparative genomics." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Alliance Genome', 'domain': 'alliancegenome.org'})">Alliance Genome</a></div>
<div><a href="http://www.informatics.jax.org/disease/301500" class="mim-tip-hint" title="Phenotypes, alleles, and disease models from Mouse Genome Informatics." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MGI Mouse Phenotype', 'domain': 'informatics.jax.org'})">MGI Mouse Phenotype</a></div>
<div><a href="https://wormbase.org/resources/disease/DOID:14499" class="mim-tip-hint" title="Database of the biology and genome of Caenorhabditis elegans and related nematodes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Wormbase Disease Ontology', 'domain': 'wormbase.org'})">Wormbase Disease Ontology</a></div>
</div>
</div>
</div>
<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
<div class="panel-heading mim-panel-heading" role="tab" id="mimCellLines">
<span class="panel-title">
<span class="small">
<a href="#mimCellLinesLinksFold" id="mimCellLinesLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
<div style="display: table-row">
<div id="mimCellLinesLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">&#9658;</div>
&nbsp;
<div style="display: table-cell;">Cell Lines</div>
</div>
</a>
</span>
</span>
</div>
<div id="mimCellLinesLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
<div class="panel-body small mim-panel-body">
<div><a href="https://catalog.coriell.org/Search?q=OmimNum:301500" class="definition" title="Coriell Cell Repositories; cell cultures and DNA derived from cell cultures." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'CCR', 'domain': 'ccr.coriell.org'})">Coriell</a></div>
</div>
</div>
</div>
</div>
</div>
</div>
<span>
<span class="mim-tip-bottom" qtip_title="<strong>Looking for this gene or this phenotype in other resources?</strong>" qtip_text="Select a related resource from the dropdown menu and click for a targeted link to information directly relevant.">
&nbsp;
</span>
</span>
</div>
<div class="col-lg-8 col-lg-pull-2 col-md-8 col-md-pull-2 col-sm-8 col-sm-pull-2 col-xs-12">
<div>
<a id="title" class="mim-anchor"></a>
<div>
<a id="number" class="mim-anchor"></a>
<div class="text-right">
<a href="#" class="mim-tip-icd" qtip_title="<strong>ICD+</strong>" qtip_text="
<strong>SNOMEDCT:</strong> 124464003, 16652001<br />
<strong>ICD10CM:</strong> E75.21<br />
<strong>ORPHA:</strong> 324<br />
<strong>DO:</strong> 14499<br />
">ICD+</a>
</div>
<div>
<span class="h3">
<span class="mim-font mim-tip-hint" title="Phenotype description, molecular basis known">
<span class="text-danger"><strong>#</strong></span>
301500
</span>
</span>
</div>
</div>
<div>
<a id="preferredTitle" class="mim-anchor"></a>
<h3>
<span class="mim-font">
FABRY DISEASE
</span>
</h3>
</div>
<div>
<br />
</div>
<div>
<a id="alternativeTitles" class="mim-anchor"></a>
<div>
<p>
<span class="mim-font">
<em>Alternative titles; symbols</em>
</span>
</p>
</div>
<div>
<h4>
<span class="mim-font">
ANGIOKERATOMA CORPORIS DIFFUSUM<br />
ANDERSON-FABRY DISEASE<br />
HEREDITARY DYSTOPIC LIPIDOSIS<br />
ALPHA-GALACTOSIDASE A DEFICIENCY<br />
GLA DEFICIENCY<br />
CERAMIDE TRIHEXOSIDASE DEFICIENCY
</span>
</h4>
</div>
</div>
<div>
<br />
</div>
<div>
<a id="includedTitles" class="mim-anchor"></a>
<div>
<p>
<span class="mim-font">
Other entities represented in this entry:
</span>
</p>
</div>
<div>
<span class="h3 mim-font">
FABRY DISEASE, CARDIAC VARIANT, INCLUDED
</span>
</div>
</div>
<div>
<br />
</div>
</div>
<div>
<a id="phenotypeMap" class="mim-anchor"></a>
<h4>
<span class="mim-font">
<strong>Phenotype-Gene Relationships</strong>
</span>
</h4>
<div>
<table class="table table-bordered table-condensed table-hover small mim-table-padding">
<thead>
<tr class="active">
<th>
Location
</th>
<th>
Phenotype
</th>
<th>
Phenotype <br /> MIM number
</th>
<th>
Inheritance
</th>
<th>
Phenotype <br /> mapping key
</th>
<th>
Gene/Locus
</th>
<th>
Gene/Locus <br /> MIM number
</th>
</tr>
</thead>
<tbody>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/X/502?start=-3&limit=10&highlight=502">
Xq22.1
</a>
</span>
</td>
<td>
<span class="mim-font">
Fabry disease, cardiac variant
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/301500"> 301500 </a>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="X-linked">XL</abbr>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
</span>
</td>
<td>
<span class="mim-font">
GLA
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/300644"> 300644 </a>
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/X/502?start=-3&limit=10&highlight=502">
Xq22.1
</a>
</span>
</td>
<td>
<span class="mim-font">
Fabry disease
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/301500"> 301500 </a>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="X-linked">XL</abbr>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
</span>
</td>
<td>
<span class="mim-font">
GLA
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/300644"> 300644 </a>
</span>
</td>
</tr>
</tbody>
</table>
</div>
</div>
<div>
<div class="btn-group ">
<a href="/clinicalSynopsis/301500" class="btn btn-warning" role="button"> Clinical Synopsis </a>
<button type="button" id="mimPhenotypicSeriesToggle" class="btn btn-warning dropdown-toggle mimSingletonFoldToggle" data-toggle="collapse" href="#mimClinicalSynopsisFold" onclick="ga('send', 'event', 'Unfurl', 'ClinicalSynopsis', 'omim.org')">
<span class="caret"></span>
<span class="sr-only">Toggle Dropdown</span>
</button>
</div>
&nbsp;
<div class="btn-group">
<button type="button" class="btn btn-success dropdown-toggle" data-toggle="dropdown" aria-haspopup="true" aria-expanded="false">
PheneGene Graphics <span class="caret"></span>
</button>
<ul class="dropdown-menu" style="width: 17em;">
<li><a href="/graph/linear/301500" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Linear'})"> Linear </a></li>
<li><a href="/graph/radial/301500" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Radial'})"> Radial </a></li>
</ul>
</div>
<span class="glyphicon glyphicon-question-sign mim-tip-hint" title="OMIM PheneGene graphics depict relationships between phenotypes, groups of related phenotypes (Phenotypic Series), and genes.<br /><a href='/static/omim/pdf/OMIM_Graphics.pdf' target='_blank'>A quick reference overview and guide (PDF)</a>"></span>
<div>
<p />
</div>
<div id="mimClinicalSynopsisFold" class="well well-sm collapse mimSingletonToggleFold">
<div class="small" style="margin: 5px">
<div>
<div>
<span class="h5 mim-font">
<strong> INHERITANCE </strong>
</span>
</div>
<div style="margin-left: 2em;">
<div>
<span class="mim-font">
- X-linked <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/263934009" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">263934009</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0241764&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0241764</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001417" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001417</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001417" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001417</a>]</span><br />
</span>
</div>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<strong> GROWTH </strong>
</span>
</div>
<div style="margin-left: 2em;">
<div>
<div>
<span class="h5 mim-font">
<em> Other </em>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
- Retarded growth <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/59576002" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">59576002</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/444896005" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">444896005</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0151686&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0151686</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001510" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001510</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001510" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001510</a>]</span><br /> -
Delayed puberty <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/400003000" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">400003000</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/123526007" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">123526007</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/E30.0" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">E30.0</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0034012&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0034012</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000823" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000823</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000823" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000823</a>]</span><br />
</span>
</div>
</div>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<strong> HEAD & NECK </strong>
</span>
</div>
<div style="margin-left: 2em;">
<div>
<div>
<span class="h5 mim-font">
<em> Eyes </em>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
- Corneal and lenticular opacities <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C2748998&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C2748998</a>]</span><br /> -
Whorl-like corneal dystrophy in carrier females <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C2748999&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C2748999</a>]</span><br />
</span>
</div>
</div>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<strong> CARDIOVASCULAR </strong>
</span>
</div>
<div style="margin-left: 2em;">
<div>
<div>
<span class="h5 mim-font">
<em> Heart </em>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
- Angina <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/194828000" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">194828000</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/225566008" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">225566008</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/I20.9" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">I20.9</a>, <a href="https://purl.bioontology.org/ontology/ICD10CM/I20" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">I20</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/413" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">413</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C2024883&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C2024883</a>, <a href="https://bioportal.bioontology.org/search?q=C0002962&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0002962</a>, <a href="https://bioportal.bioontology.org/search?q=C2926611&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C2926611</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001681" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001681</a>]</span><br /> -
Electrocardiographic changes <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0855329&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0855329</a>]</span><br /> -
Left ventricular wall hypertrophy <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/55827005" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">55827005</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0149721&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0149721</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001712" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001712</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001712" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001712</a>]</span><br /> -
Ventricular septal hypertrophy <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/111027004" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">111027004</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0344955&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0344955</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0005144" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0005144</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0005144" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0005144</a>]</span><br /> -
Hypertension <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/38341003" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">38341003</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/I10" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">I10</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/401-405.99" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">401-405.99</a>, <a href="https://purl.bioontology.org/ontology/ICD9CM/997.91" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">997.91</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0020538&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0020538</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000822" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000822</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000822" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000822</a>]</span><br /> -
Myocardial infarction <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/22298006" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">22298006</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/I22" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">I22</a>, <a href="https://purl.bioontology.org/ontology/ICD10CM/I21" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">I21</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C2926063&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C2926063</a>, <a href="https://bioportal.bioontology.org/search?q=C0027051&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0027051</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001658" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001658</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001658" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001658</a>]</span><br /> -
Valvular disease (mitral) <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/11851006" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">11851006</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/424.0" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">424.0</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0026265&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0026265</a>]</span><br /> -
Congestive heart failure <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/42343007" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">42343007</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/I50.9" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">I50.9</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/428.0" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">428.0</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0018802&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0018802</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001635" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001635</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001635" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001635</a>]</span><br />
</span>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<em> Vascular </em>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
- Vessel ectasia <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C4746987&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C4746987</a>]</span><br />
</span>
</div>
</div>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<strong> RESPIRATORY </strong>
</span>
</div>
<div style="margin-left: 2em;">
<div>
<div>
<span class="h5 mim-font">
<em> Lung </em>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
- Mild obstructive lung disease <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1845017&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1845017</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0006536" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0006536</a>]</span><br />
</span>
</div>
</div>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<strong> ABDOMEN </strong>
</span>
</div>
<div style="margin-left: 2em;">
<div>
<div>
<span class="h5 mim-font">
<em> Gastrointestinal </em>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
- Abdominal pain <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/21522001" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">21522001</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/R10.9" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">R10.9</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/789.00" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">789.00</a>, <a href="https://purl.bioontology.org/ontology/ICD9CM/789.0" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">789.0</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0000737&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0000737</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002027" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002027</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002027" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002027</a>]</span><br /> -
Episodic diarrhea <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0239181&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0239181</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002254" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002254</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002254" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002254</a>]</span><br /> -
Nausea <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/422587007" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">422587007</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/R11.0" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">R11.0</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0027497&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0027497</a>, <a href="https://bioportal.bioontology.org/search?q=C4255480&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C4255480</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002018" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002018</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002018" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002018</a>]</span><br /> -
Vomiting <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/422400008" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">422400008</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/300359004" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">300359004</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/249497008" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">249497008</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/R11.1" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">R11.1</a>, <a href="https://purl.bioontology.org/ontology/ICD10CM/R11.10" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">R11.10</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0042963&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0042963</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002013" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002013</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002013" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002013</a>]</span><br /> -
Tenesmus <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/302770003" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">302770003</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0232726&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0232726</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0012702" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0012702</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0012702" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0012702</a>]</span><br />
</span>
</div>
</div>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<strong> GENITOURINARY </strong>
</span>
</div>
<div style="margin-left: 2em;">
<div>
<div>
<span class="h5 mim-font">
<em> Kidneys </em>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
- Renal failure <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/42399005" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">42399005</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/N19" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">N19</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/586" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">586</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0035078&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0035078</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000083" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000083</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000083" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000083</a>]</span><br /> -
Isosthenuria <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/102829006" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">102829006</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0235627&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0235627</a>]</span><br /> -
Renal biopsy shows glomerular sclerosis <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C2748996&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C2748996</a>]</span><br /> -
Vacuolization of glomerular and tubular epithelial cells <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C2748997&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C2748997</a>]</span><br />
</span>
</div>
</div>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<strong> SKELETAL </strong>
</span>
</div>
<div style="margin-left: 2em;">
<div>
<div>
<span class="h5 mim-font">
<em> Hands </em>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
- Limited extension of terminal joints <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1845012&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1845012</a>]</span><br />
</span>
</div>
</div>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<strong> SKIN, NAILS, & HAIR </strong>
</span>
</div>
<div style="margin-left: 2em;">
<div>
<div>
<span class="h5 mim-font">
<em> Skin </em>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
- Hypohidrosis <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/45004005" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">45004005</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/L74.4" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">L74.4</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0020620&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0020620</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000966" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000966</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000966" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000966</a>]</span><br /> -
Angiokeratoma <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/26810009" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">26810009</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0002985&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0002985</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001014" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001014</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001014" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001014</a>]</span><br />
</span>
</div>
</div>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<strong> MUSCLE, SOFT TISSUES </strong>
</span>
</div>
<div style="margin-left: 2em;">
<div>
<span class="mim-font">
- Muscle cramps <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/45352006" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">45352006</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/55300003" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">55300003</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/M62.83" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">M62.83</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/728.85" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">728.85</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0037763&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0037763</a>, <a href="https://bioportal.bioontology.org/search?q=C0026821&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0026821</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003394" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003394</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003394" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003394</a>]</span><br /> -
Fasciculations <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/82470000" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">82470000</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/R25.3" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">R25.3</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0015644&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0015644</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002380" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002380</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002380" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002380</a>]</span><br /> -
Lymphedema <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/30213001" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">30213001</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/234097001" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">234097001</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0024236&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0024236</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001004" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001004</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001004" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001004</a>]</span><br />
</span>
</div>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<strong> NEUROLOGIC </strong>
</span>
</div>
<div style="margin-left: 2em;">
<div>
<div>
<span class="h5 mim-font">
<em> Central Nervous System </em>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
- Transient ischemic attacks <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/266257000" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">266257000</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/G45.9" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">G45.9</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0007787&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0007787</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002326" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002326</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002326" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002326</a>]</span><br /> -
Strokes <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/230690007" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">230690007</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/I63.9" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">I63.9</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0038454&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0038454</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001297" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001297</a>]</span><br /> -
Seizures <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/91175000" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">91175000</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0036572&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0036572</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001250" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001250</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001250" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001250</a>]</span><br /> -
Autonomic dysfunction <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/15241006" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">15241006</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/G90.9" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">G90.9</a>, <a href="https://purl.bioontology.org/ontology/ICD10CM/G90" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">G90</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/337" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">337</a>, <a href="https://purl.bioontology.org/ontology/ICD9CM/337.9" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">337.9</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1145628&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1145628</a>, <a href="https://bioportal.bioontology.org/search?q=C0013363&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0013363</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0012332" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0012332</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0012332" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0012332</a>]</span><br />
</span>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<em> Peripheral Nervous System </em>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
- Acroparesthesias, episodic <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C2748994&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C2748994</a>]</span> <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/79256006" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">79256006</a>]</span><br /> -
Pain and paresthesia in the extremities, episodic <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C2748995&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C2748995</a>]</span><br /> -
Painful crises precipitated by exercise, fatigue, or stress <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1845024&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1845024</a>]</span><br />
</span>
</div>
</div>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<strong> HEMATOLOGY </strong>
</span>
</div>
<div style="margin-left: 2em;">
<div>
<span class="mim-font">
- Anemia <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/271737000" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">271737000</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/D64.9" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">D64.9</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/285.9" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">285.9</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0002871&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0002871</a>, <a href="https://bioportal.bioontology.org/search?q=C1000483&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1000483</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001903" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001903</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001903" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001903</a>]</span><br /> -
Bone marrow contains lipid-laden macrophages <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1845014&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1845014</a>]</span><br />
</span>
</div>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<strong> LABORATORY ABNORMALITIES </strong>
</span>
</div>
<div style="margin-left: 2em;">
<div>
<span class="mim-font">
- Proteinuria <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/29738008" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">29738008</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/231860006" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">231860006</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/R80.9" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">R80.9</a>, <a href="https://purl.bioontology.org/ontology/ICD10CM/R80" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">R80</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/791.0" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">791.0</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1279888&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1279888</a>, <a href="https://bioportal.bioontology.org/search?q=C0033687&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0033687</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000093" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000093</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000093" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000093</a>]</span><br /> -
Alpha-galactosidase A deficiency in plasma, leukocytes, or fibroblasts <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1845013&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1845013</a>]</span><br /> -
Increased level of globotriaosylceramide (GB3) in plasma and urinary sediment <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1845015&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1845015</a>]</span><br /> -
Intracellular glycosphingolipid deposition in all tissues of the body <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C2749000&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C2749000</a>]</span><br /> -
Increased plasma globotriaosylsphingosine (lyso-GB3) <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C2749001&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C2749001</a>]</span><br />
</span>
</div>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<strong> MISCELLANEOUS </strong>
</span>
</div>
<div style="margin-left: 2em;">
<div>
<span class="mim-font">
- Onset usually in childhood or adolescence<br /> -
Death secondary to renal failure, cardiac or cerebrovascular disease<br /> -
Atypical affected males, 'cardiac variants' <a href="/entry/301500#0005">301500.0005</a> exist<br /> -
Female carriers experience significant clinical manifestations<br /> -
Occurs in at least 1 in 55,000 male births (that figure may not include milder variants)<br />
</span>
</div>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<strong> MOLECULAR BASIS </strong>
</span>
</div>
<div style="margin-left: 2em;">
<div>
<span class="mim-font">
- Caused by mutation in alpha-galactosidase A gene (GLA, <a href="/entry/300644#0001">300644.0001</a>)<br />
</span>
</div>
</div>
</div>
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<a href="#mimClinicalSynopsisFold" data-toggle="collapse">&#9650;&nbsp;Close</a>
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<p>A number sign (#) is used with this entry because Fabry disease is caused by mutations in the GLA gene (<a href="/entry/300644">300644</a>), encoding alpha-galactosidase A, on chromosome Xq22. A cardiac variant of Fabry disease is also caused by mutation in the GLA gene.</p>
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<strong>Description</strong>
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<p>Fabry disease is an X-linked inborn error of glycosphingolipid catabolism resulting from deficient or absent activity of the lysosomal enzyme alpha-galactosidase A. This enzymatic defect leads to the systemic accumulation of globotriaoslyceramide (Gb3) and related glycosphingolipids in the plasma and cellular lysosomes of vessels, nerves, tissues, and organs throughout the body (<a href="#89" class="mim-tip-reference" title="Nance, C. S., Klein, C. J., Banikazemi, M., Dikman, S. H., Phelps, R. G., McArthur, J. C., Rodriguez, M., Desnick, R. J. &lt;strong&gt;Later-onset Fabry disease: an adult variant presenting with the cramp-fasciculation syndrome.&lt;/strong&gt; Arch. Neurol. 63: 453-457, 2006.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/16533976/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;16533976&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1001/archneur.63.3.453&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="16533976">Nance et al., 2006</a>). The disorder is a systemic disease, manifest as progressive renal failure, cardiac disease, cerebrovascular disease, small-fiber peripheral neuropathy, and skin lesions, among other abnormalities (<a href="#119" class="mim-tip-reference" title="Schiffmann, R. &lt;strong&gt;Fabry disease.&lt;/strong&gt; Pharm. Ther. 122: 65-77, 2009.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/19318041/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;19318041&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/j.pharmthera.2009.01.003&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="19318041">Schiffmann, 2009</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=19318041+16533976" 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>An atypical variant of Fabry disease has been reported in which cardiac disease, specifically left ventricular hypertrophy, with or without renal failure, develops in the sixth decade of life. These patients have residual GLA activity (<a href="#88" class="mim-tip-reference" title="Nakao, S., Takenaka, T., Maeda, M., Kodama, C., Tanaka, A., Tahara, M., Yoshida, A., Kuriyama, M., Hayashibe, H., Sakuraba, H., Tanaka, H. &lt;strong&gt;An atypical variant of Fabry&#x27;s disease in men with left ventricular hypertrophy.&lt;/strong&gt; New Eng. J. Med. 333: 288-293, 1995.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/7596372/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;7596372&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1056/NEJM199508033330504&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="7596372">Nakao et al., 1995</a>; <a href="#87" class="mim-tip-reference" title="Nakao, S., Kodama, C., Takenaka, T., Tanaka, A., Yasumoto, Y., Yoshida, A., Kanzaki, T., Enriquez, A. L. D., Eng, C. M., Tanaka, H., Tei, C., Desnick, R. J. &lt;strong&gt;Fabry disease: detection of undiagnosed hemodialysis patients and identification of a &#x27;renal variant&#x27; phenotype.&lt;/strong&gt; Kidney Int. 64: 801-807, 2003.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/12911529/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;12911529&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1046/j.1523-1755.2003.00160.x&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="12911529">Nakao et al., 2003</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=12911529+7596372" 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>Although Fabry disease was previously considered to be an X-linked recessive disorder, <a href="#140" class="mim-tip-reference" title="Wang, R. Y., Lelis, A., Mirocha, J., Wilcox, W. R. &lt;strong&gt;Heterozygous Fabry women are not just carriers, but have a significant burden of disease and impaired quality of life.&lt;/strong&gt; Genet. Med. 9: 34-45, 2007.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/17224688/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;17224688&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1097/gim.0b013e31802d8321&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="17224688">Wang et al. (2007)</a> found that heterozygous women with Fabry disease experience significant life-threatening conditions requiring medical treatment and intervention. Thus, heterozygous Fabry women should not be called carriers, as this term underestimates the seriousness of the disease in these patients. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17224688" 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="Clarke, J. T. R. &lt;strong&gt;Narrative review: Fabry disease.&lt;/strong&gt; Ann. Intern. Med. 146: 425-433, 2007.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/17371887/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;17371887&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.7326/0003-4819-146-6-200703200-00007&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="17371887">Clarke (2007)</a> and <a href="#119" class="mim-tip-reference" title="Schiffmann, R. &lt;strong&gt;Fabry disease.&lt;/strong&gt; Pharm. Ther. 122: 65-77, 2009.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/19318041/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;19318041&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/j.pharmthera.2009.01.003&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="19318041">Schiffmann (2009)</a> provided detailed reviews of Fabry disease. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=19318041+17371887" 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 his first paper on this subject, <a href="#34" class="mim-tip-reference" title="Fabry, J. &lt;strong&gt;Ein Beitrag Zur Kenntnis der Purpura haemorrhagica nodularis (Purpura papulosa hemorrhagica Hebrae).&lt;/strong&gt; Arch. Derm. Syph. 43: 187-200, 1898."None>Fabry (1898)</a> called the skin lesions 'purpura papulosa haemorrhagica Hebrae,' suggesting that they had previously been described by Hebra, the famous Austrian dermatologist. Affected individuals had painful crises in the extremities, thought to result from lipid changes in ganglion cells of the autonomic nervous system. Attacks of pain in the abdomen may have been misdiagnosed as appendicitis or other surgical emergencies. Vascular lesions of lipid nature occurred at other sites such as the ocular fundi and kidney. Renal failure was the usual cause of death.</p><p><a href="#54" class="mim-tip-reference" title="Hamburger, J., Dormont, J., De Montera, H., Hinglais, N. &lt;strong&gt;Sur une singuliere malformation familiale de l&#x27;epithelium renal.&lt;/strong&gt; Schweiz. Med. Wschr. 94: 871-876, 1964.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/14238342/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;14238342&lt;/a&gt;]" pmid="14238342">Hamburger et al. (1964)</a> described a familial nephropathy, manifested clinically by proteinuria and renal insufficiency. Renal biopsy showed that the epithelial cells of the glomerular tufts and to a lesser extent the tubular epithelial cells, glomerular endocapillary cells and arteriolar muscular cells were severely deformed with a large amount of cytoplasmic inclusion material appearing lipoid in nature. The mother's father died of uremia. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14238342" 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>Skin lesion may be lacking even in patients with severe visceral manifestations (<a href="#65" class="mim-tip-reference" title="Johnston, A. W. &lt;strong&gt;Fabry&#x27;s disease without skin lesions. (Letter)&lt;/strong&gt; Lancet 289: 1277 only, 1967. Note: Originally Volume 1."None>Johnston, 1967</a>). Furthermore, identical angiokeratoma skin lesions occur in other lysosomal disorders: (see, e.g., <a href="#97" class="mim-tip-reference" title="Patel, V., Watanabe, I., Zeman, W. &lt;strong&gt;Deficiency of alpha-L-fucosidase.&lt;/strong&gt; Science 176: 426-428, 1972.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/5026163/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;5026163&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1126/science.176.4033.426&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="5026163">Patel et al., 1972</a> and <a href="#75" class="mim-tip-reference" title="Loonen, M. C. B., van de Lugt, L., Franke, C. L. &lt;strong&gt;Angiokeratoma corporis diffusum and lysosomal enzyme deficiency. (Letter)&lt;/strong&gt; Lancet 304: 785 only, 1974. Note: Originally Volume 2.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/4143049/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;4143049&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/s0140-6736(74)90984-2&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="4143049">Loonen et al., 1974</a>). <a href="#39" class="mim-tip-reference" title="Flynn, D. M., Lake, B. D., Boothby, C. B., Young, E. P. &lt;strong&gt;Gut lesions in Fabry&#x27;s disease without a rash.&lt;/strong&gt; Arch. Dis. Child. 47: 26-33, 1972.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/5018655/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;5018655&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1136/adc.47.251.26&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="5018655">Flynn et al. (1972)</a> described a family without skin lesions. One affected male had severe enteropathy. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=4143049+5018655+5026163" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#40" class="mim-tip-reference" title="Franceschetti, A. T., Philippart, M., Franceschetti, A. &lt;strong&gt;A study of Fabry&#x27;s disease. I. Clinical examination of a family with cornea verticillata.&lt;/strong&gt; Dermatologica 138: 209-221, 1969.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/5771636/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;5771636&lt;/a&gt;]" pmid="5771636">Franceschetti et al. (1969)</a> reexamined a family with 'cornea verticillata' reported by <a href="#51" class="mim-tip-reference" title="Gruber, M. &lt;strong&gt;Cornea verticillata. (Eine einfach-dominante Variante der Hornhaut des menschlichen Auges).&lt;/strong&gt; Ophthalmologica 111: 120-129, 1946.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/20275792/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;20275792&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1159/000300313&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="20275792">Gruber (1946)</a> and showed that Fabry disease was responsible for the corneal change. The extent of involvement of the cornea was about the same in males and females, thus allowing affected females to be identified. The corneal condition was formerly called Fleischer vortex dystrophy, or whorl-like corneal dystrophy. <a href="#128" class="mim-tip-reference" title="Stark, W. J. &lt;strong&gt;Personal Communication.&lt;/strong&gt; Baltimore, Md. 11/16/1999."None>Stark (1999)</a> noted that the antimalarial drug atabrine and the antiarrhythmic drug amiodarone can also cause these changes. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=5771636+20275792" 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="#81" class="mim-tip-reference" title="Mastropasqua, L., Nubile, M., Lanzini, M., Carpineto, P., Toto, L., Ciancaglini, M. &lt;strong&gt;Corneal and conjunctival manifestations in Fabry disease: in vivo confocal microscopy study.&lt;/strong&gt; Am. J. Ophthal. 141: 709-718, 2006.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/16564807/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;16564807&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/j.ajo.2005.11.053&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="16564807">Mastropasqua et al. (2006)</a> found that although Fabry disease-related corneal verticillata attributable to glycosphingolipid accumulation was considered to be primarily a corneal disease, in vivo confocal microscopy demonstrated structural alterations throughout the entire ocular surface epithelia. Different types of corneal epithelial lesions were observed in hemizygous and heterozygous patients. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16564807" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In a period of a few months at a Montreal hospital, <a href="#21" class="mim-tip-reference" title="Clarke, J. T., Knaack, J., Crawhall, J. C., Wolfe, L. S. &lt;strong&gt;Ceramide trihexosidosis (Fabry&#x27;s disease) without skin lesions.&lt;/strong&gt; New Eng. J. Med. 284: 233-235, 1971.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/5539345/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;5539345&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1056/NEJM197102042840503&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="5539345">Clarke et al. (1971)</a> saw 2 men with Fabry disease with clear corneas and without skin lesions, suggesting that it may be a more frequent cause of proteinuria or renal failure than realized. <a href="#109" class="mim-tip-reference" title="Romeo, G., Childs, B., Migeon, B. R. &lt;strong&gt;Genetic heterogeneity of alpha-galactosidase in Fabry&#x27;s disease.&lt;/strong&gt; FEBS Lett. 27: 161-166, 1972.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/11946830/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;11946830&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/0014-5793(72)80432-0&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="11946830">Romeo et al. (1972)</a> studied one of Clarke's cases and concluded that enzymatically there were differences from the classic cases. A difference from the usual form of Fabry disease is suggested by the fact that leukocyte alpha-galactosidase deficiency was only partial rather than complete (<a href="#69" class="mim-tip-reference" title="Kint, J. A. &lt;strong&gt;Fabry&#x27;s disease: alpha-galactosidase deficiency.&lt;/strong&gt; Science 167: 1268-1269, 1970.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/5411915/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;5411915&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1126/science.167.3922.1268&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="5411915">Kint, 1970</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=5539345+11946830+5411915" 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="#53" class="mim-tip-reference" title="Halsted, C. H., Rowe, J. W. &lt;strong&gt;Occurrence of celiac sprue in a patient with Fabry&#x27;s disease.&lt;/strong&gt; Ann. Intern. Med. 83: 524-525, 1975.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/810052/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;810052&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.7326/0003-4819-83-4-524&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="810052">Halsted and Rowe (1975)</a> described a 59-year-old man with Fabry disease. In addition to his unusually advanced age, he had celiac sprue (<a href="/entry/212750">212750</a>), which may have been related to the presence of the HLA-8 antigen. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=810052" 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="#113" class="mim-tip-reference" title="Roudebush, C. P., Foerster, J. M., Bing, O. H. L. &lt;strong&gt;The abbreviated PR interval of Fabry&#x27;s disease.&lt;/strong&gt; New Eng. J. Med. 289: 357-358, 1973.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/4268777/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;4268777&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1056/NEJM197308162890709&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="4268777">Roudebush et al. (1973)</a> may have reported the first cases of 'abbreviated PR interval' in Fabry disease, which may be related to to the development of tachyarrhythmias and sudden death (<a href="#27" class="mim-tip-reference" title="Efthimiou, J., McLelland, J., Betteridge, D. J. &lt;strong&gt;Short PR intervals and tachyarrhythmias in Fabry&#x27;s disease.&lt;/strong&gt; Postgrad. Med. J. 62: 285-287, 1986.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/3086855/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;3086855&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1136/pgmj.62.726.285&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="3086855">Efthimiou et al., 1986</a>). <a href="#114" class="mim-tip-reference" title="Sakuraba, H., Yanagawa, Y., Igarashi, T., Suzuki, Y., Suzuki, T., Watanabe, K., Ieki, K., Shimoda, K., Yamanaka, T. &lt;strong&gt;Cardiovascular manifestations in Fabry&#x27;s disease: a high incidence of mitral valve prolapse in hemizygotes and heterozygotes.&lt;/strong&gt; Clin. Genet. 29: 276-283, 1986.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/3087663/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;3087663&lt;/a&gt;]" pmid="3087663">Sakuraba et al. (1986)</a> reported a high incidence of mitral valve prolapse in male Fabry patients as well as female patients. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=3086855+3087663+4268777" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#71" class="mim-tip-reference" title="Ko, Y.-H., Kim, H.-J., Roh, Y.-S., Park, C.-K., Kwon, C.-K., Park, M.-H. &lt;strong&gt;Atypical Fabry&#x27;s disease: an oligosymptomatic variant.&lt;/strong&gt; Arch. Path. Lab. Med. 120: 86-89, 1996.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/8554452/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;8554452&lt;/a&gt;]" pmid="8554452">Ko et al. (1996)</a> described an 'oligosymptomatic' variant of Fabry disease. A renal biopsy performed for evaluation of trace proteinuria revealed histologic and ultrastructural findings compatible with Fabry disease in a 34-year-old man with no history of renal disease in other family members. Biopsy of a few initially unrecognized, scattered, dark-pinkish scrotal papules showed typical angiokeratoma. Alpha-galactosidase was markedly decreased in urine and plasma. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8554452" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#77" class="mim-tip-reference" title="MacDermot, K. D., Holmes, A., Miners, A. H. &lt;strong&gt;Anderson-Fabry disease: clinical manifestations and impact of disease in a cohort of 98 hemizygous males.&lt;/strong&gt; J. Med. Genet. 38: 750-760, 2001.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/11694547/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;11694547&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1136/jmg.38.11.750&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="11694547">MacDermot et al. (2001)</a> studied 98 males with Fabry disease. Mean age at diagnosis was 21.9 years, and the median survival was 50 years. Neuropathic pain was present in 93 individuals (77%), with a mean pain score of 5 (scale from 0 to 10). Cerebrovascular complications were present in 24.2% of individuals studied and renal failure in 30%. High frequency sensorineural deafness was confirmed in 78% of audiograms. Attendance at school, sports, and social activities were significantly affected by Fabry disease and only 46 patients (56.6%) were employed. Psychosexual function was affected by the presence of genital angiokeratoma, genital pain, and impotence. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11694547" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#15" class="mim-tip-reference" title="Branton, M. H., Schiffmann, R., Sabnis, S. G., Murray, G. J., Quirk, J. M., Altarescu, G., Goldfarb, L., Brady, R. O., Balow, J. E., Austin, H. A., III, Kopp, J. B. &lt;strong&gt;Natural history of Fabry renal disease: influence of alpha-galactosidase A activity and genetic mutations on clinical course.&lt;/strong&gt; Medicine 81: 122-138, 2002.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/11889412/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;11889412&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1097/00005792-200203000-00003&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="11889412">Branton et al. (2002)</a> reviewed the medical records of 105 male patients with Fabry disease. Diagnosis of Fabry disease occurred later in patients without a known family history. Fifty percent of patients developed proteinuria by age 35 years and chronic renal insufficiency by age 42. Detectable residual alpha-galactosidase A activity was associated with a slower progression of Fabry renal disease, and with lower scores for renal histologic damage and renal content of globotriaosylceramide. Conservative mutations in the GLA gene were also associated with a slower progression in Fabry renal disease. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11889412" 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="#120" class="mim-tip-reference" title="Senechal, M., Germain, D. P. &lt;strong&gt;Fabry disease: a functional and anatomical study of cardiac manifestations in 20 hemizygous male patients.&lt;/strong&gt; Clin. Genet. 63: 46-52, 2003.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/12519371/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;12519371&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1034/j.1399-0004.2003.630107.x&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="12519371">Senechal and Germain (2003)</a> reviewed the functional and anatomical cardiac manifestations in 20 hemizygous male patients with Fabry disease. Left ventricular hypertrophy and/or concentric remodeling were found in 60% of cases; structural changes in mitral and aortic valves in 25% and 10%, respectively; and short PR interval in 40%. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12519371" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#108" class="mim-tip-reference" title="Rolfs, A., Bottcher, T., Zschiesche, M., Morris, P., Winchester, B., Bauer, P., Walter, U., Mix, E., Lohr, M., Harzer, K., Strauss, U., Pahnke, J., Grossmann, A., Benecke, R. &lt;strong&gt;Prevalence of Fabry disease in patients with cryptogenic stroke: a prospective study.&lt;/strong&gt; Lancet 366: 1794-1796, 2005. Note: Erratum: Lancet 368: 2210 only, 2006.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/16298216/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;16298216&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/S0140-6736(05)67635-0&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="16298216">Rolfs et al. (2005)</a> found that 21 (4.9%) of 342 males and 7 (2.4%) of 289 females with cryptogenic stroke had biologically significant mutations in the GLA gene. The mean age at onset of symptomatic cerebrovascular disease was 38.4 and 40.3 years in the men and women, respectively. Approximately 30% had classic manifestations of Fabry disease. Due to the high frequency of Fabry disease (4%, 28 of 721) in this cohort of stroke patients with cryptogenic stroke aged between 18 and 55 years, <a href="#108" class="mim-tip-reference" title="Rolfs, A., Bottcher, T., Zschiesche, M., Morris, P., Winchester, B., Bauer, P., Walter, U., Mix, E., Lohr, M., Harzer, K., Strauss, U., Pahnke, J., Grossmann, A., Benecke, R. &lt;strong&gt;Prevalence of Fabry disease in patients with cryptogenic stroke: a prospective study.&lt;/strong&gt; Lancet 366: 1794-1796, 2005. Note: Erratum: Lancet 368: 2210 only, 2006.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/16298216/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;16298216&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/S0140-6736(05)67635-0&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="16298216">Rolfs et al. (2005)</a> suggested that Fabry disease should be considered in young patients with unexplained stroke. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16298216" 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="#89" class="mim-tip-reference" title="Nance, C. S., Klein, C. J., Banikazemi, M., Dikman, S. H., Phelps, R. G., McArthur, J. C., Rodriguez, M., Desnick, R. J. &lt;strong&gt;Later-onset Fabry disease: an adult variant presenting with the cramp-fasciculation syndrome.&lt;/strong&gt; Arch. Neurol. 63: 453-457, 2006.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/16533976/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;16533976&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1001/archneur.63.3.453&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="16533976">Nance et al. (2006)</a> reported a 34-year-old man who presented with chronic exercise-induced pain, cramps, and fasciculations of the legs and feet. His mother was similarly affected. Alpha-glucosidase activity was 8.8% and 13.4% of normal, respectively. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16533976" 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="#83" class="mim-tip-reference" title="Moore, D. F., Kaneski, C. R., Askari, H., Schiffmann, R. &lt;strong&gt;The cerebral vasculopathy of Fabry disease.&lt;/strong&gt; J. Neurol. Sci. 257: 258-263, 2007.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/17362993/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;17362993&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/j.jns.2007.01.053&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="17362993">Moore et al. (2007)</a> provided a review of the cerebral vasculopathy in Fabry disease. Patients presented more commonly with radiologic findings consistent with small-vessel disease rather than large-vessel disease, although both may occur. The posterior circulation was more commonly affected. The pathomechanism is believed to result from a combination of abnormalities of the vessel wall, blood components, such as pro- and anti-coagulants, and abnormal hemodynamics or blood flow. <a href="#119" class="mim-tip-reference" title="Schiffmann, R. &lt;strong&gt;Fabry disease.&lt;/strong&gt; Pharm. Ther. 122: 65-77, 2009.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/19318041/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;19318041&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/j.pharmthera.2009.01.003&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="19318041">Schiffmann (2009)</a> noted that patients with Fabry disease have a 20-fold increased risk of ischemic stroke and transient ischemic attacks compared to the general population. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=19318041+17362993" 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>To evaluate life expectancy and cause of death among patients with Fabry disease, <a href="#137" class="mim-tip-reference" title="Waldek, S., Patel, M. R., Bankiazemi, M., Lemay, R., Lee, P. &lt;strong&gt;Life expectancy and cause of death in males and females with Fabry disease: findings from the Fabry Registry.&lt;/strong&gt; Genet. Med. 11: 790-796, 2009.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/19745746/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;19745746&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1097/GIM.0b013e3181bb05bb&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="19745746">Waldek et al. (2009)</a> examined data from 2,848 patients in the Fabry Registry. Life expectancy at birth was compared with that of the United States general population. As of August 2008, 75 of 1,422 males and 12 of 1,426 females in the Fabry Registry were reported to have died. The 87 deceased patients were diagnosed at a much older age than other patients in the Fabry Registry: median age at diagnosis was 40 versus 24 years in males and 55 versus 33 years in females. Life expectancy of males with Fabry disease was 58.2 years, compared with 74.7 years in the general population of the United States. The life expectancy of females with Fabry disease was 75.4 years, compared with 80.0 years in the United States general population. The most common cause of death among both genders was cardiovascular disease. Most (57%) patients who died of cardiovascular disease had previously received renal replacement therapy. <a href="#137" class="mim-tip-reference" title="Waldek, S., Patel, M. R., Bankiazemi, M., Lemay, R., Lee, P. &lt;strong&gt;Life expectancy and cause of death in males and females with Fabry disease: findings from the Fabry Registry.&lt;/strong&gt; Genet. Med. 11: 790-796, 2009.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/19745746/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;19745746&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1097/GIM.0b013e3181bb05bb&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="19745746">Waldek et al. (2009)</a> concluded that most deceased Fabry Registry patients exhibited serious cardiac and renal dysfunction, and that late diagnosis may have contributed to the early deaths of these patients. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19745746" 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="#82" class="mim-tip-reference" title="Mehta, A., Clarke, J. T. R., Giugliani, R., Elliott, P., Linhart, A., Beck, M., Sunder-Plassmann, G. &lt;strong&gt;Natural course of Fabry disease: changing pattern of causes of death in FOS - Fabry Outcome Survey.&lt;/strong&gt; J. Med. Genet. 46: 548-552, 2009.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/19473999/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;19473999&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1136/jmg.2008.065904&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="19473999">Mehta et al. (2009)</a> reported the clinical outcomes of 1,453 Fabry patients (699 males and 754 females) from 19 countries participating in the Fabry Outcome Survey (FOS). The most frequently reported signs and symptoms were neurologic, affecting 75% of males and 61% of females. Renal failure was present in 134 males and 21 females: 89 males and 5 females had end-stage renal disease at a mean age of 32.3 and 23.3 years, respectively. Cardiac manifestations were recorded in 422 male and 376 female patients: 284 males and 180 females had left ventricular hypertrophy with onset at a mean age of 28.7 and 34.1 years, respectively. Cerebrovascular events occurred with approximately the same frequency in males and females (25% and 21%, respectively). Stroke was reported in 39 females and 63 males at mean ages of 51.4 and 39.2 years, respectively. Forty-two patients had died, including 35 males and 7 females at a mean age of 51.8 and 64.4 years, respectively. The primary cause of death in both male and female patients was cardiac disease, reported in 34% and 57%, respectively. This was in contrast to the principal causes of death among 181 affected relatives of Fabry patients who died before 2001: the most common causes of death were due to renal failure in males (42%) and cerebrovascular disease in females (25%). Overall, the data suggested that renal disease as a cause of death in patients with Fabry disease is decreasing while cardiac disease is increasing. This pattern probably reflects improvements in the management of renal disease in patients with Fabry disease. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19473999" 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="#134" class="mim-tip-reference" title="Testai, F. D., Gorelick, P. B. &lt;strong&gt;Inherited metabolic disorders and stroke part 1: Fabry disease and mitochondrial myopathy, encephalopathy, lactic acidosis, and strokelike episodes.&lt;/strong&gt; Arch. Neurol. 67: 19-24, 2010.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/20065125/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;20065125&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1001/archneurol.2009.309&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="20065125">Testai and Gorelick (2010)</a> reviewed the pathophysiology of stroke in patients with Fabry disease. Population studies had estimated that Fabry disease is responsible for 1.2% of cryptogenic strokes in patients younger than 55 years, and women are more likely to be affected than men (27% vs 12%). Stroke may result from both cardiac (hypertrophy, arrhythmia) or vascular (stenosis, vessel occlusion, vessel dilation) factors. The posterior circulation is most commonly affected. Brain imaging may show progressive white matter lesions. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20065125" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Cardiac Variant of Fabry Disease</em></strong></p><p>
The observations of <a href="#91" class="mim-tip-reference" title="Ogawa, K., Sugamata, K., Funamoto, N., Abe, T., Sato, T., Nagashima, K., Ohkawa, S. &lt;strong&gt;Restricted accumulation of globotriaosylceramide in the hearts of atypical cases of Fabry&#x27;s disease.&lt;/strong&gt; Hum. Path. 21: 1067-1073, 1990.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/2120125/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;2120125&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/0046-8177(90)90258-7&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="2120125">Ogawa et al. (1990)</a>, <a href="#28" class="mim-tip-reference" title="Elleder, M., Bradova, V., Smid, F., Budesinsky, M., Harzer, K., Kustermann-Kuhn, B., Ledvinova, J., Belohlavek, (NI), Kral, V., Dorazilova, V. &lt;strong&gt;Cardiocyte storage and hypertrophy as a sole manifestation of Fabry&#x27;s disease: report on a case simulating hypertrophic non-obstructive cardiomyopathy.&lt;/strong&gt; Virchows Arch. A Pathol. Anat. Histopathol. 417: 449-455, 1990.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/2173254/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;2173254&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1007/BF01606034&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="2173254">Elleder et al. (1990)</a>, <a href="#86" class="mim-tip-reference" title="Nagao, Y., Nakashima, H., Fukuhara, Y., Shimmoto, M., Oshima, A., Ikari, Y., Mori, Y., Sakuraba, H., Suzuki, Y. &lt;strong&gt;Hypertrophic cardiomyopathy in late-onset variant of Fabry disease with high residual activity of alpha-galactosidase A.&lt;/strong&gt; Clin. Genet. 39: 233-237, 1991.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/1645238/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;1645238&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1111/j.1399-0004.1991.tb03018.x&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="1645238">Nagao et al. (1991)</a>, and <a href="#136" class="mim-tip-reference" title="von Scheidt, W., Eng, C. M., Fitzmaurice, T. F., Erdmann, E., Hubner, G., Olsen, E. G. J., Christomanou, H., Kandolf, R., Bishop, D. F., Desnick, R. J. &lt;strong&gt;An atypical variant of Fabry&#x27;s disease with manifestations confined to the myocardium.&lt;/strong&gt; New Eng. J. Med. 324: 395-399, 1991.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/1846223/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;1846223&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1056/NEJM199102073240607&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="1846223">von Scheidt et al. (1991)</a> indicated that manifestations of Fabry disease can be limited to the heart. These authors suggested that Fabry disease should be considered in patients who have cardiac symptoms, such as angina, exercise intolerance, and electrocardiographic changes, but normal coronary arteries, heart size, and hemodynamic findings. Cases of Fabry disease limited to the cardiac manifestation may be identified by ultrastructural examination of endomyocardial biopsy specimens or, less invasively, by determining the plasma GLA activity in male patients with unexplained cardiac symptoms. The oldest of the patients reported with this form of the disease was a Japanese patient who died at the age of 71 years (<a href="#91" class="mim-tip-reference" title="Ogawa, K., Sugamata, K., Funamoto, N., Abe, T., Sato, T., Nagashima, K., Ohkawa, S. &lt;strong&gt;Restricted accumulation of globotriaosylceramide in the hearts of atypical cases of Fabry&#x27;s disease.&lt;/strong&gt; Hum. Path. 21: 1067-1073, 1990.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/2120125/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;2120125&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/0046-8177(90)90258-7&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="2120125">Ogawa et al., 1990</a>). <a href="#86" class="mim-tip-reference" title="Nagao, Y., Nakashima, H., Fukuhara, Y., Shimmoto, M., Oshima, A., Ikari, Y., Mori, Y., Sakuraba, H., Suzuki, Y. &lt;strong&gt;Hypertrophic cardiomyopathy in late-onset variant of Fabry disease with high residual activity of alpha-galactosidase A.&lt;/strong&gt; Clin. Genet. 39: 233-237, 1991.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/1645238/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;1645238&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1111/j.1399-0004.1991.tb03018.x&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="1645238">Nagao et al. (1991)</a> reported 2 unrelated males who developed hypertrophic cardiomyopathy after the age of 50 as their first manifestation of Fabry disease. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=1645238+2120125+1846223+2173254" 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="#136" class="mim-tip-reference" title="von Scheidt, W., Eng, C. M., Fitzmaurice, T. F., Erdmann, E., Hubner, G., Olsen, E. G. J., Christomanou, H., Kandolf, R., Bishop, D. F., Desnick, R. J. &lt;strong&gt;An atypical variant of Fabry&#x27;s disease with manifestations confined to the myocardium.&lt;/strong&gt; New Eng. J. Med. 324: 395-399, 1991.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/1846223/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;1846223&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1056/NEJM199102073240607&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="1846223">Von Scheidt et al. (1991)</a> reported a 54-year-old man with the cardiac variant of Fabry disease confirmed by genetic analysis (M296V; <a href="/entry/300644#0005">300644.0005</a>). The patient had 'crescendo angina,' relieved by nitroglycerin, as well as electrocardiographic changes, but normal cardiac chamber size and normal systolic and diastolic function by echocardiogram. Cardiac catheterization showed no stenoses of the extramural coronary arteries. Diagnosis of Fabry disease was made by endomyocardial biopsy. Light-microscopic examination showed that approximately half the myocytes contained a centrally stored foamy material that stained metachromatically. By electron microscopy, typical myelin-figure-like concentric lamellar inclusions in lysosomes were observed. Most remarkably, the endothelial cells of the myocardial capillaries were not involved and no changes were observed in specimens of skeletal muscle, liver, rectum, and skin, including small blood vessels and nerves. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1846223" 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="#88" class="mim-tip-reference" title="Nakao, S., Takenaka, T., Maeda, M., Kodama, C., Tanaka, A., Tahara, M., Yoshida, A., Kuriyama, M., Hayashibe, H., Sakuraba, H., Tanaka, H. &lt;strong&gt;An atypical variant of Fabry&#x27;s disease in men with left ventricular hypertrophy.&lt;/strong&gt; New Eng. J. Med. 333: 288-293, 1995.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/7596372/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;7596372&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1056/NEJM199508033330504&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="7596372">Nakao et al. (1995)</a> found that 7 of 230 unrelated Japanese men with left ventricular hypertrophy had the atypical variant of Fabry disease. These 7 unrelated men, ranging in age from 55 to 72 years, did not have angiokeratoma, acroparesthesias, hypohidrosis, or corneal opacities. Endomyocardial biopsy revealed marked sarcoplasmic vacuolization in all 5 patients examined. Electron microscopy, performed on tissues from 4 of these patients, revealed typical lysosomal inclusions with a concentric lamellar configuration. Two patients had novel missense mutations in the GLA gene (<a href="/entry/300644#0051">300644.0051</a>; <a href="/entry/300644#0052">300644.0052</a>). The remaining 5 patients had no mutations in the coding region of the GLA gene; however, in addition to low plasma alpha-galactosidase activity, GLA mRNA was markedly lower than normal. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7596372" 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="#29" class="mim-tip-reference" title="Elleder, M., Christomanou, H., Kustermann-Kuhn, B., Harzer, K. &lt;strong&gt;Leptomeningeal lipid storage patterns in Fabry disease.&lt;/strong&gt; Acta Neuropath. 88: 579-582, 1994.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/7879606/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;7879606&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1007/BF00296496&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="7879606">Elleder et al. (1994)</a> demonstrated storage material in the external arachnoidal epithelium of the leptomeninges in a case of cardiocyte-restricted Fabry disease. The patient, a 65-year-old male with Fabry disease who died from bile duct carcinoma, showed only cardiac symptoms and signs premortem. This pattern contrasted with the generalized leptomeningeal storage seen in typical Fabry disease. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7879606" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Female Fabry Patients</em></strong></p><p>
<a href="#110" class="mim-tip-reference" title="Romeo, G., Migeon, B. R. &lt;strong&gt;Genetic inactivation of the alpha-galactosidase locus in carriers of Fabry&#x27;s disease.&lt;/strong&gt; Science 170: 180-181, 1970.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/5466114/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;5466114&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1126/science.170.3954.180&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="5466114">Romeo and Migeon (1970)</a> reported genetic inactivation of the alpha-galactosidase locus in females patients with Fabry disease, consistent with lyonization. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=5466114" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#10" class="mim-tip-reference" title="Bird, T. D., Lagunoff, D. &lt;strong&gt;Neurological manifestations of Fabry disease in female carriers.&lt;/strong&gt; Ann. Neurol. 4: 537-540, 1978.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/217299/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;217299&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ana.410040610&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="217299">Bird and Lagunoff (1978)</a> reported 2 adult sisters with Fabry disease. They both had episodic and permanent neurologic deficits, including vertigo, tinnitus, long tract motor signs, and bladder incontinence. <a href="#16" class="mim-tip-reference" title="Broadbent, J. C., Edwards, W. D., Gordon, H., Hartzler, G. O., Krawisz, J. E. &lt;strong&gt;Fabry cardiomyopathy in the female confirmed by endomyocardial biopsy.&lt;/strong&gt; Mayo Clin. Proc. 56: 623-628, 1981.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/6268901/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;6268901&lt;/a&gt;]" pmid="6268901">Broadbent et al. (1981)</a> reported a 58-year-old female patient who had cardiac enlargement and developed heart failure. Endomyocardial biopsy showed cellular changes consistent with Fabry disease. The authors postulated unfavorable lyonization of the mutant X chromosome in cardiac tissue. <a href="#107" class="mim-tip-reference" title="Rodriguez, F. H., Jr., Hoffmann, E. O., Ordinario, A. T., Baliga, M. &lt;strong&gt;Fabry&#x27;s disease in a heterozygous woman.&lt;/strong&gt; Arch. Path. Lab. Med. 109: 89-91, 1985.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/2982342/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;2982342&lt;/a&gt;]" pmid="2982342">Rodriguez et al. (1985)</a> reported a 42-year-old woman with Fabry disease who had persistent proteinuria. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=6268901+217299+2982342" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#85" class="mim-tip-reference" title="Mutoh, T., Senda, Y., Sugimura, K., Koike, Y., Matsuoka, Y., Sobue, I., Takahashi, A., Naoi, M. &lt;strong&gt;Severe orthostatic hypotension in a female carrier of Fabry&#x27;s disease.&lt;/strong&gt; Arch. Neurol. 45: 468-472, 1988.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/3128256/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;3128256&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1001/archneur.1988.00520280122030&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="3128256">Mutoh et al. (1988)</a> described an unusual degree of autonomic dysfunction, manifested by severe orthostatic hypotension, in a 21-year-old female patient. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=3128256" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#56" class="mim-tip-reference" title="Hasholt, L., Sorensen, S. A., Wandall, A., Andersen, E. B., Arlien-Soborg, P. &lt;strong&gt;A Fabry&#x27;s disease heterozygote with a new mutation: biochemical, ultrastructural, and clinical investigations.&lt;/strong&gt; J. Med. Genet. 27: 303-306, 1990.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/2161929/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;2161929&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1136/jmg.27.5.303&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="2161929">Hasholt et al. (1990)</a> described a girl in whom Fabry disease was suspected at the age of 18 years because of corneal opacities and tortuous retinal vessels. She had had attacks of high fever, arthralgia, and abdominal pain. Studies indicated that she suffered from a new mutation for Fabry disease; she was heterozygous. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2161929" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#59" class="mim-tip-reference" title="Hillsley, R. E., Hernandez, E., Steenbergen, C., Bashore, T. M., Harrison, J. K. &lt;strong&gt;Inherited restrictive cardiomyopathy in a 74-year-old woman: a case of Fabry&#x27;s disease.&lt;/strong&gt; Am. Heart J. 129: 199-202, 1995.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/7817917/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;7817917&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/0002-8703(95)90062-4&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="7817917">Hillsley et al. (1995)</a> described a 74-year-old woman with restrictive cardiomyopathy complicating conventional coronary artery disease that had been treated with angioplasty and with coronary artery bypass grafting. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7817917" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#76" class="mim-tip-reference" title="MacDermot, K. D., Holmes, A., Miners, A. H. &lt;strong&gt;Anderson-Fabry disease: clinical manifestations and impact of disease in a cohort of 60 obligate carrier females. (Letter)&lt;/strong&gt; J. Med. Genet. 38: 769-807, 2001.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/11732485/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;11732485&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1136/jmg.38.11.769&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="11732485">MacDermot et al. (2001)</a> reported clinical manifestations and impact of disease in 60 females with Fabry disease. The median cumulative survival was 70 years, representing an approximate reduction of 15 years from the general population. Six of 32 women had renal failure, 9 of 32 (28%) died of cerebrovascular complications, and 42 (70%) had experienced neuropathic pain. Twenty (30%) female patients had some serious or debilitating manifestation of Fabry disease. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11732485" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#142" class="mim-tip-reference" title="Whybra, C., Kampmann, C., Willers, I., Davies, J., Winchester, B., Kriegsmann, J., Bruhl, K., Gal, A., Bunge, S., Beck, M. &lt;strong&gt;Anderson-Fabry disease: clinical manifestations of disease in female heterozygotes.&lt;/strong&gt; J. Inherit. Metab. Dis. 24: 715-724, 2001.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/11804208/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;11804208&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1023/a:1012993305223&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="11804208">Whybra et al. (2001)</a> performed a comprehensive clinical evaluation on 20 females with Fabry disease. In addition to skin manifestations, various other clinical manifestations of the disease were present, including acroparesthesia, kidney dysfunction, cerebrovascular disease, and gastrointestinal and heart problems. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11804208" 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="#103" class="mim-tip-reference" title="Pruss, H., Bohner, G., Zschenderlein, R. &lt;strong&gt;Paroxysmal vertigo as the presenting symptom of Fabry disease.&lt;/strong&gt; Neurology 66: 249 only, 2006.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/16434665/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;16434665&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1212/01.wnl.0000195280.30895.21&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="16434665">Pruss et al. (2006)</a> reported a 50-year-old woman who presented with a 10-year history of paroxysmal rotational vertigo without hearing loss or tinnitus. Brain MRI revealed megadolichobasilar artery and white matter lesions. Due to a positive family history of Fabry disease, molecular analysis was performed, and a mutation was found in the GLA gene. She displayed cornea verticillata but neither angiokeratoma nor acroparesthesia. <a href="#103" class="mim-tip-reference" title="Pruss, H., Bohner, G., Zschenderlein, R. &lt;strong&gt;Paroxysmal vertigo as the presenting symptom of Fabry disease.&lt;/strong&gt; Neurology 66: 249 only, 2006.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/16434665/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;16434665&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1212/01.wnl.0000195280.30895.21&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="16434665">Pruss et al. (2006)</a> postulated that the vertigo resulted from megadolichobasilar compression of the vestibulocochlear nerve. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16434665" 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="#68" class="mim-tip-reference" title="Kim, W., Pyeritz, R. E., Bernhardt, B. A., Casey, M., Litt, H. I. &lt;strong&gt;Pulmonary manifestations of Fabry disease and positive response to enzyme replacement therapy.&lt;/strong&gt; Am. J. Med. Genet. 143A: 377-381, 2007.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/17256799/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;17256799&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ajmg.a.31600&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="17256799">Kim et al. (2007)</a> reported a 38-year-old woman with Fabry disease who had acroparesthesias and anhidrosis since adolescence. She later developed gastrointestinal bloating and interstitial lung disease with progressive dyspnea requiring supplemental oxygen at all times. High-resolution CT scans showed regions of both abnormally dense and lucent lung parenchyma, reflecting a combination of ground-glass opacity and air trapping, most conspicuous in the upper lobes. There was also evidence of pulmonary hypertension. Skin examination showed cutaneous angiokeratomas and digital clubbing. Treatment with enzyme replacement therapy resulted in significant pulmonary and gastrointestinal improvement within several months. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17256799" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In a review of the medical records of 44 heterozygous female patients with Fabry disease, <a href="#140" class="mim-tip-reference" title="Wang, R. Y., Lelis, A., Mirocha, J., Wilcox, W. R. &lt;strong&gt;Heterozygous Fabry women are not just carriers, but have a significant burden of disease and impaired quality of life.&lt;/strong&gt; Genet. Med. 9: 34-45, 2007.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/17224688/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;17224688&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1097/gim.0b013e31802d8321&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="17224688">Wang et al. (2007)</a> concluded that female Fabry patients experience significant multisystemic disease and reduced quality of life. Acroparesthesias were the first reported symptom in 76%; most reported the first symptoms during the first 2 decades of life. Clinical features and findings included fatigue, exercise intolerance, stroke, obstructive pulmonary disease, angina, renal disease, gastrointestinal complaints, and decreased vibration sense. Eleven patients were treated with enzyme replacement therapy. <a href="#140" class="mim-tip-reference" title="Wang, R. Y., Lelis, A., Mirocha, J., Wilcox, W. R. &lt;strong&gt;Heterozygous Fabry women are not just carriers, but have a significant burden of disease and impaired quality of life.&lt;/strong&gt; Genet. Med. 9: 34-45, 2007.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/17224688/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;17224688&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1097/gim.0b013e31802d8321&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="17224688">Wang et al. (2007)</a> suggested that Fabry disease should not be considered an X-linked recessive disorder and that heterozygous Fabry women should not be called carriers because they experience significant life-threatening conditions requiring medical treatment and intervention. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17224688" 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="Cable, W. J. L., Kolodny, E. H., Adams, R. D. &lt;strong&gt;Fabry disease: impaired autonomic function.&lt;/strong&gt; Neurology 32: 498-502, 1982.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/6803189/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;6803189&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1212/wnl.32.5.498&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="6803189">Cable et al. (1982)</a> reported impaired autonomic function in 10 patients with Fabry disease. All had decreased sweating and about half had impaired pupillary constriction and decreased saliva and tear formation. Older patients showed disordered intestinal mobility. <a href="#42" class="mim-tip-reference" title="Friedman, L. S., Kirkham, S. E., Thistlethwaite, J. R., Platika, D., Kolodny, E. H., Schuffler, M. D. &lt;strong&gt;Jejunal diverticulosis with perforation as a complication of Fabry&#x27;s disease.&lt;/strong&gt; Gastroenterology 86: 558-563, 1984.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/6420224/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;6420224&lt;/a&gt;]" pmid="6420224">Friedman et al. (1984)</a> reported a patient with Fabry disease who had jejunal diverticulosis complicated by perforation and abscess formation. Microscopic examination showed glycolipid deposition in the neurons and nerve fibers of the intestinal myenteric plexus and smooth muscle. <a href="#42" class="mim-tip-reference" title="Friedman, L. S., Kirkham, S. E., Thistlethwaite, J. R., Platika, D., Kolodny, E. H., Schuffler, M. D. &lt;strong&gt;Jejunal diverticulosis with perforation as a complication of Fabry&#x27;s disease.&lt;/strong&gt; Gastroenterology 86: 558-563, 1984.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/6420224/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;6420224&lt;/a&gt;]" pmid="6420224">Friedman et al. (1984)</a> concluded that uncoordinated smooth muscle activity resulting from Fabry disease caused mucosal protrusion through the smooth muscle. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=6420224+6803189" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#112" class="mim-tip-reference" title="Rosenberg, D. M., Ferrans, V. J., Fulmer, J. D., Line, B. R., Barranger, J. A., Brady, R. O., Crystal, R. G. &lt;strong&gt;Chronic airflow obstruction in Fabry&#x27;s disease.&lt;/strong&gt; Am. J. Med. 68: 898-905, 1980.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/6247911/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;6247911&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/0002-9343(80)90224-7&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="6247911">Rosenberg et al. (1980)</a> pointed out that deposition of sphingolipid in epithelial cells of the respiratory tract leads to chronic obstruction of airflow; the effect was especially apparent in smokers. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=6247911" 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>Among 25 male patients with Fabry disease, <a href="#17" class="mim-tip-reference" title="Brown, L. K., Miller, A., Bhuptani, A., Sloane, M. F., Zimmerman, M. I., Schilero, G., Eng, C. M., Desnick, R. J. &lt;strong&gt;Pulmonary involvement in Fabry disease.&lt;/strong&gt; Am. J. Resp. Crit. Care Med. 155: 1004-1010, 1997.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/9116979/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;9116979&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1164/ajrccm.155.3.9116979&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="9116979">Brown et al. (1997)</a> reported dyspnea in 36% and cough and/or wheezing in 24%. Symptoms were similar in smokers and nonsmokers. Nine (36%) had airway obstruction on spirometry; this finding was associated with age of more than 26 years and with dyspnea or wheezing, but only weakly associated with smoking. Five of 8 patients responded to bronchodilators, but all 10 methylcholine challenges were negative. Chest radiographs showed normal lung fields in 24 patients and streaky bibasilar densities in 1. Specific GLA mutations were identified in 17 patients; all 3 patients with frameshift mutations and both subjects with an N264V mutation (<a href="/entry/300644#0021">300644.0021</a>) had obstructive impairment. <a href="#17" class="mim-tip-reference" title="Brown, L. K., Miller, A., Bhuptani, A., Sloane, M. F., Zimmerman, M. I., Schilero, G., Eng, C. M., Desnick, R. J. &lt;strong&gt;Pulmonary involvement in Fabry disease.&lt;/strong&gt; Am. J. Resp. Crit. Care Med. 155: 1004-1010, 1997.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/9116979/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;9116979&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1164/ajrccm.155.3.9116979&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="9116979">Brown et al. (1997)</a> concluded that airway obstruction occurs commonly in patients with Fabry disease regardless of smoking history, and that it increases with age. The presence of obstruction may be associated with certain mutations and most likely results from fixed narrowing of the airways by accumulated glycosphingolipid. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9116979" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#45" class="mim-tip-reference" title="Germain, D. P., Avan, P., Chassaing, A., Bonfils, P. &lt;strong&gt;Patients affected with Fabry disease have an increased incidence of progressive hearing loss and sudden deafness: an investigation of twenty-two hemizygous male patients.&lt;/strong&gt; BMC Med. Genet. 3: 10, 2002. Note: Electronic Article.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/12377100/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;12377100&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=12377100[PMID]&amp;report=imagesdocsum&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed Image&#x27;, &#x27;domain&#x27;: &#x27;ncbi.nlm.nih.gov&#x27;})&quot;&gt;images&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1186/1471-2350-3-10&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="12377100">Germain et al. (2002)</a> concluded that progressive hearing loss and sudden deafness are frequent findings in Fabry disease. Abnormal hearing was found in 12 (54.5%) of 22 hemizygous males aged 19 to 64 years: progressive hearing loss in 5 and sudden deafness in 7. Hearing loss on high-tone frequencies was found in 7 of the 10 remaining patients without clinical impairment, despite a young age. The incidence of hearing loss appeared significantly increased in patients with kidney failure or cardiovascular lesions, whereas there was no correlation with left ventricular hypertrophy. Tinnitus aurium was found in 6 patients (27%). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12377100" 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="#46" class="mim-tip-reference" title="Germain, D. P., Benistan, K., Boutouyrie, P., Mutschler, C. &lt;strong&gt;Osteopenia and osteoporosis: previously unrecognized manifestations of Fabry disease. (Letter)&lt;/strong&gt; Clin. Genet. 68: 93-95, 2005.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/15952993/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;15952993&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1111/j.1399-0004.2005.00457.x&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="15952993">Germain et al. (2005)</a> prospectively investigated bone involvement in 23 consecutive hemizygous male patients with Fabry disease using dual energy x-ray absorptiometry and found that 20 (87%) had either osteopenia or osteoporosis. The authors stated that this was the first study demonstrating that Fabry disease is associated with an increased risk of decreased bone mineral density. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15952993" 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="#67" class="mim-tip-reference" title="Kaneski, C. R., Moore, D. F., Ries, M., Zirzow, G. C., Schiffmann, R. &lt;strong&gt;Myeloperoxidase predicts risk of vasculopathic events in hemizygous males with Fabry disease.&lt;/strong&gt; Neurology 67: 2045-2047, 2006.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/17159117/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;17159117&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1212/01.wnl.0000247278.88077.09&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="17159117">Kaneski et al. (2006)</a> observed significantly increased serum myeloperoxidase (MPO; <a href="/entry/606989">606989</a>) levels in 73 male patients with Fabry disease compared to controls. Follow-up for a mean of 6 years showed that increased serum MPO was associated with increased risk for vascular events. Heterozygous female Fabry carriers also had increased MPO levels compared to controls, but the difference was not statistically significant. Long-term enzyme replacement therapy did not reduce MPO levels or eliminate the risk of vasculopathic events. <a href="#67" class="mim-tip-reference" title="Kaneski, C. R., Moore, D. F., Ries, M., Zirzow, G. C., Schiffmann, R. &lt;strong&gt;Myeloperoxidase predicts risk of vasculopathic events in hemizygous males with Fabry disease.&lt;/strong&gt; Neurology 67: 2045-2047, 2006.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/17159117/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;17159117&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1212/01.wnl.0000247278.88077.09&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="17159117">Kaneski et al. (2006)</a> hypothesized that the increased MPO in Fabry disease was produced by neutrophils in response to reactive oxygen species. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17159117" 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>To investigate the function and morphology of the endocrine glands in patients with Fabry disease, <a href="#35" class="mim-tip-reference" title="Faggiano, A., Pisani, A., Milone, F., Gaccione, M., Filippella, M., Santoro, A., Vallone, G., Tortora, F., Sabbatini, M., Spinelli, L., Lombardi, G., Cianciaruso, B., Colao, A. &lt;strong&gt;Endocrine dysfunction in patients with Fabry disease.&lt;/strong&gt; J. Clin. Endocr. Metab. 91: 4319-4325, 2006.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/16926253/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;16926253&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1210/jc.2006-0858&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="16926253">Faggiano et al. (2006)</a> evaluated the thyroid, gonadal, adrenal, and growth hormone/insulin-like growth factor-1 (<a href="/entry/139250">139250</a>/<a href="/entry/147440">147440</a>) axes in 18 Fabry disease patients and 18 sex- and age-matched healthy subjects. Ten of the 18 patients received enzyme replacement therapy. Fabry disease patients had higher baseline thyroid-stimulating hormone (TSH; see <a href="/entry/188540">188540</a>) levels than controls (P less than 0.01). Three subjects were diagnosed with an early stage of subclinical primary hypothyroidism associated with negative antithyroid antibodies. A history of menstrual abnormalities, miscarriage, or assisted delivery was found in 89% of women with Fabry disease. Asthenozoospermia, oligozoospermia, or both were found in all men with Fabry disease through seminal fluid analysis. Fabry disease patients had significantly higher circulating ACTH and lower cortisol levels than controls (P less than 0.05). In patients under enzyme replacement therapy, a suboptimal cortisol response to the 250-microgram ACTH test was found in 10%, and the ACTH-stimulated cortisol peak was significantly correlated to the health status profile (P less than 0.05). <a href="#35" class="mim-tip-reference" title="Faggiano, A., Pisani, A., Milone, F., Gaccione, M., Filippella, M., Santoro, A., Vallone, G., Tortora, F., Sabbatini, M., Spinelli, L., Lombardi, G., Cianciaruso, B., Colao, A. &lt;strong&gt;Endocrine dysfunction in patients with Fabry disease.&lt;/strong&gt; J. Clin. Endocr. Metab. 91: 4319-4325, 2006.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/16926253/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;16926253&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1210/jc.2006-0858&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="16926253">Faggiano et al. (2006)</a> concluded that a variety of latent endocrine dysfunctions, including life-threatening conditions (e.g., adrenal insufficiency), occur in patients with Fabry disease. Endocrine dysfunctions are also present in patients already receiving enzyme replacement therapy and are in part related to their persistent poor quality of life. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16926253" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Using a personality inventory questionnaire to evaluate the psychologic profile of 28 adult patients with Fabry disease, <a href="#25" class="mim-tip-reference" title="Crosbie, T. W., Packman, W., Packman, S. &lt;strong&gt;Psychological aspects of patients with Fabry disease.&lt;/strong&gt; J. Inherit. Metab. Dis. 32: 745-753, 2009.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/19924564/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;19924564&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1007/s10545-009-1254-1&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="19924564">Crosbie et al. (2009)</a> found that the patients had significantly higher (abnormal) scores on several scales, including hypochondriasis, depression, and hysteria, compared to the general population and compared to patients with chronic heart disease. However, the psychologic profiles were similar to patients with chronic pain. Fabry patients reported high levels of pain, difficulty tolerating extreme temperatures, feeling tired or weak, and gastrointestinal problems. Fabry patients appeared preoccupied with health problems, resulting in isolation, unhappiness, worry, despair, and emotional turmoil, indicating the serious nature of this chronic debilitating disease. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19924564" 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="#1" class="mim-tip-reference" title="Aerts, J. M., Groener, J. E., Kuiper, S., Donker-Kooperman, W. E., Strijland, A., Ottenhoff, R., van Roomen, C., Mirzaian, M., Wijburg, F. A., Linthorst, G. E., Vedder, A. C., Rombach, S. M., Cox-Brinkman, J., Somerharju, P., Boot, R. G., Hollak, C. E., Brady, R. O., Poorthuis, B. J. &lt;strong&gt;Elevated globotriaosylsphingosine is a hallmark of Fabry disease.&lt;/strong&gt; Proc. Nat. Acad. Sci. 105: 2812-2817, 2008.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/18287059/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;18287059&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=18287059[PMID]&amp;report=imagesdocsum&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed Image&#x27;, &#x27;domain&#x27;: &#x27;ncbi.nlm.nih.gov&#x27;})&quot;&gt;images&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1073/pnas.0712309105&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="18287059">Aerts et al. (2008)</a> found that patients with Fabry disease had dramatically increased plasma deacylated Gb3 (globotriaosylsphingosine, or lyso-Gb3). The authors noted that lyso-Gb3 is highly hydrophilic, which may explain why it had been overlooked for many years. Plasma measurement of several Fabry patients, including a large Dutch family, showed marked increases of plasma lyso-Gb3 in hemizygotes at a young age. Heterozygous females carriers had mild increases of lyso-Gb3. Further studies showed that Gb3 at these concentrations promoted Gb3 storage, induced proliferation of smooth muscle cells, and inhibited GLA activity. Enzyme replacement therapy resulted in reduced, but not normalized, plasma levels of lyso-Gb3. <a href="#1" class="mim-tip-reference" title="Aerts, J. M., Groener, J. E., Kuiper, S., Donker-Kooperman, W. E., Strijland, A., Ottenhoff, R., van Roomen, C., Mirzaian, M., Wijburg, F. A., Linthorst, G. E., Vedder, A. C., Rombach, S. M., Cox-Brinkman, J., Somerharju, P., Boot, R. G., Hollak, C. E., Brady, R. O., Poorthuis, B. J. &lt;strong&gt;Elevated globotriaosylsphingosine is a hallmark of Fabry disease.&lt;/strong&gt; Proc. Nat. Acad. Sci. 105: 2812-2817, 2008.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/18287059/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;18287059&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=18287059[PMID]&amp;report=imagesdocsum&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed Image&#x27;, &#x27;domain&#x27;: &#x27;ncbi.nlm.nih.gov&#x27;})&quot;&gt;images&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1073/pnas.0712309105&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="18287059">Aerts et al. (2008)</a> postulated that high levels of lyso-Gb3 may provide explanations for poorly understood phenomena in Fabry disease, including proliferation of smooth vascular endothelial cells, manifestations in heterozygous females, or extralysosomal accumulation of Gb3. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18287059" 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 73 men with Fabry disease followed before and after enzyme replacement therapy, <a href="#118" class="mim-tip-reference" title="Schiffmann, R., Ries, M., Blankenship, D., Nicholls, K., Mehta, A., Clarke, J. T. R., Steiner, R. D., Beck, M., Barshop, B. A., Rhead, W., West, M., Martin, R., Amato, D., Nair, N., Huertas, P. &lt;strong&gt;Changes in plasma and urine globotriaosylceramide levels do not predict Fabry disease progression over 1 year of agalsidase alfa.&lt;/strong&gt; Genet. Med. 15: 983-989, 2013.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/23680766/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;23680766&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1038/gim.2013.56&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="23680766">Schiffmann et al. (2013)</a> found that changes in globotriaosylceramide concentrations did not appear to be useful biomarkers for prediction of Fabry disease-related changes in estimated glomerular filtration rate or left ventricular mass index. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23680766" 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="#69" class="mim-tip-reference" title="Kint, J. A. &lt;strong&gt;Fabry&#x27;s disease: alpha-galactosidase deficiency.&lt;/strong&gt; Science 167: 1268-1269, 1970.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/5411915/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;5411915&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1126/science.167.3922.1268&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="5411915">Kint (1970)</a> showed that the activity of alpha-galactosidase is deficient in leukocytes of male patients with Fabry disease and that affected females can be identified by this method. <a href="#84" class="mim-tip-reference" title="Moser, H. W. &lt;strong&gt;Personal Communication.&lt;/strong&gt; Baltimore, Md. 12/14/1983."None>Moser (1983)</a> considered the urinary trihexoside assay, described by <a href="#18" class="mim-tip-reference" title="Cable, W. J. L., Dvorak, A. M., Osage, J. E., Kolodny, E. H. &lt;strong&gt;Fabry disease: significance of ultrastructural localization of lipid inclusions in dermal nerves.&lt;/strong&gt; Neurology 32: 347-353, 1982.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/6278363/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;6278363&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1212/wnl.32.4.347&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="6278363">Cable et al. (1982)</a>, to be the most reliable way to identify individuals with Fabry disease. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=6278363+5411915" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In a Nova Scotia kindred in which 30 males had Fabry disease and there were 50 possible females with the mutation, <a href="#70" class="mim-tip-reference" title="Kirkilionis, A. J., Riddell, D. C., Spence, M. W., Fenwick, R. G. &lt;strong&gt;Fabry disease in a large Nova Scotia kindred: carrier detection using leucocyte alpha-galactosidase activity and an NcoI polymorphism detected by an alpha-galactosidase cDNA clone.&lt;/strong&gt; J. Med. Genet. 28: 232-240, 1991.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/1677424/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;1677424&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1136/jmg.28.4.232&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="1677424">Kirkilionis et al. (1991)</a> used cDNA analysis of a polymorphic NcoI site 3-prime to the gene to identify females with the mutation. All of 17 females with the mutation examined were identified, including 6 who were not identified by enzyme assay. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1677424" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#44" class="mim-tip-reference" title="Germain, D., Biasotto, M., Tosi, M., Meo, T., Kahn, A., Poenaru, L. &lt;strong&gt;Fluorescence-assisted mismatch analysis (FAMA) for exhaustive screening of the alpha-galactosidase A gene and detection of carriers in Fabry disease.&lt;/strong&gt; Hum. Genet. 98: 719-726, 1996.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/8931708/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;8931708&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1007/s004390050292&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="8931708">Germain et al. (1996)</a> used the fluorescence-assisted mismatch analysis (FAMA) method to screen the GLA gene rapidly in patients with Fabry disease. Mutations were identified in affected members of 9 unrelated kindreds. Among the 7 previously undescribed sequence changes, 3 were obviously pathogenic because they led to premature protein termination. The other 4, a splice site mutation and 3 missense mutations, were the only changes found upon complete scanning of the gene and its promoter. The authors claimed that FAMA detected female heterozygotes more dependably than direct sequencing, and thus provided a valuable diagnostic test in connection with genetic counseling since heterozygotes can be asymptomatic and their enzymatic values within the normal range. <a href="#48" class="mim-tip-reference" title="Germain, D. P., Poenaru, L. &lt;strong&gt;Fabry disease: identification of novel alpha-galactosidase A mutations and molecular carrier detection by use of fluorescent chemical cleavage of mismatches.&lt;/strong&gt; Biochem. Biophys. Res. Commun. 257: 708-713, 1999.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/10208848/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;10208848&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1006/bbrc.1999.0310&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="10208848">Germain and Poenaru (1999)</a> reported further experience in the use of the fluorescent chemical cleavage of mismatches in the detection of mutations and identification of heterozygotes. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=10208848+8931708" 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="#123" class="mim-tip-reference" title="Spada, M., Pagliardini, S., Yasuda, M., Tukel, T., Thiagarajan, G., Sakuraba, H., Ponzone, A., Desnick, R. J. &lt;strong&gt;High incidence of later-onset Fabry disease revealed by newborn screening.&lt;/strong&gt; Am. J. Hum. Genet. 79: 31-40, 2006.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/16773563/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;16773563&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=16773563[PMID]&amp;report=imagesdocsum&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed Image&#x27;, &#x27;domain&#x27;: &#x27;ncbi.nlm.nih.gov&#x27;})&quot;&gt;images&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1086/504601&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="16773563">Spada et al. (2006)</a> reported the screening of 37,104 consecutive newborn males for Fabry disease by determination of the alpha-Gal A activity in dried blood spots. Twelve neonates, or 1 in approximately 3,100 males, had deficiency of enzyme activity and GLA mutations. Molecular modeling studies and in vitro studies of mutant enzyme activity yielded a ratio of 11:1 of patients with the later-onset:classic phenotypes. The higher incidence of the later-onset phenotype in patients raised ethical issues related to when screening should be performed, in the neonatal period or at early maturity, perhaps in conjunction with screening for other treatable adult-onset disorders. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16773563" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Using structural brain MRI and brain MR angiography to evaluate 25 patients with Fabry disease, <a href="#38" class="mim-tip-reference" title="Fellgiebel, A., Keller, I., Marin, D., Muller, M. J., Schermuly, I., Yakushev, I., Albrecht, J., Bellhauser, H., Kinateder, M., Beck, M., Stoeter, P. &lt;strong&gt;Diagnostic utility of different MRI and MR angiography measures in Fabry disease.&lt;/strong&gt; Neurology 72: 63-68, 2009.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/19122032/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;19122032&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1212/01.wnl.0000338566.54190.8a&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="19122032">Fellgiebel et al. (2009)</a> found that patients with the disorder had significantly enlarged diameters of several cerebral arteries, including the basilar, middle cerebral, posterior cerebral, and carotid compared to controls. A total of 87% of individuals with Fabry disease could be correctly classified as affected using basilar artery diameters alone (sensitivity of 95%; specificity of 83%). The difference in basilar artery diameter was clearly superior to white matter lesion load in distinguishing between patients and controls. <a href="#38" class="mim-tip-reference" title="Fellgiebel, A., Keller, I., Marin, D., Muller, M. J., Schermuly, I., Yakushev, I., Albrecht, J., Bellhauser, H., Kinateder, M., Beck, M., Stoeter, P. &lt;strong&gt;Diagnostic utility of different MRI and MR angiography measures in Fabry disease.&lt;/strong&gt; Neurology 72: 63-68, 2009.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/19122032/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;19122032&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1212/01.wnl.0000338566.54190.8a&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="19122032">Fellgiebel et al. (2009)</a> concluded that basilar artery diameters as measured by MR angiography could be used for early detection and monitoring of brain involvement in patients with Fabry disease. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19122032" 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="#6" class="mim-tip-reference" title="Balendran, S., Oliva, P., Sansen, S., Mechtler, T. P., Streubel, B., Cobos, P. N., Lukacs, Z., Kasper, D. C. &lt;strong&gt;Diagnostic strategy for females suspected of Fabry disease.&lt;/strong&gt; Clin. Genet. 97: 655-660, 2020.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/31860127/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;31860127&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1111/cge.13694&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="31860127">Balendran et al. (2020)</a> measured alpha-Gal A enzyme activity and lyso-GL-3 levels in dried blood spots from 11,948 females suspected of having Fabry disease, and performed GLA gene sequencing by Sanger sequencing when one or both biochemical tests were abnormal. The authors additionally performed GLA sequencing in 389 of the patients with normal alpha-Gal A enzyme activity and normal lyso-GL-3 levels. They found that low alpha-Gal A enzyme activity and elevated lyso-GL-3 had a 97% positive predictive value for a diagnosis of Fabry disease, normal alpha-Gal A enzyme activity and elevated lyso-GL-3 had a 39% positive predictive value for the diagnosis, and low alpha-Gal A enzyme activity and normal lyso-GL-3 had a 6% positive predictive value for the diagnosis. None of the females with completely normal biochemical testing had pathogenic mutations in GLA. <a href="#6" class="mim-tip-reference" title="Balendran, S., Oliva, P., Sansen, S., Mechtler, T. P., Streubel, B., Cobos, P. N., Lukacs, Z., Kasper, D. C. &lt;strong&gt;Diagnostic strategy for females suspected of Fabry disease.&lt;/strong&gt; Clin. Genet. 97: 655-660, 2020.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/31860127/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;31860127&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1111/cge.13694&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="31860127">Balendran et al. (2020)</a> concluded that complementary diagnostic testing of alpha-Gal A activity and lyso-GL-3 improves the diagnostic value for the detection of Fabry disease in females. They therefore recommended that in females with any positive or borderline biochemical test (alpha-Gal A enzyme activity and/or lyso-GL-3), GLA gene sequencing should be performed, and that if both are normal, sequencing is not necessary. The authors noted that in males who have low alpha-Gal A enzyme activity, lyso-GL-3 testing is optional, and gene sequencing should be performed. They also noted that biochemical testing cannot be used as a standalone diagnostic test in families with an index patient or in young symptomatic individuals in whom lyso-GL-3 may be low; genetic testing is always needed in these cases. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=31860127" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>Clinical Management</strong>
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<span class="mim-text-font">
<p><a href="#32" class="mim-tip-reference" title="Eng, C. M., Germain, D. P., Banikazemi, M., Warnock, D. G., Wanner, C., Hopkin, R. J., Bultas, J., Lee, P., Sims, K., Brodie, S. E., Pastores, G. M., Strotmann, J. M., Wilcox, W. R. &lt;strong&gt;Fabry disease: guidelines for the evaluation and management of the multi-organ system involvement.&lt;/strong&gt; Genet. Med. 8: 539-548, 2006.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/16980809/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;16980809&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1097/01.gim.0000237866.70357.c6&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="16980809">Eng et al. (2006)</a> published guidelines for the evaluation and management of multiorgan system involvement in patients with Fabry disease. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16980809" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#139" class="mim-tip-reference" title="Wang, R. Y., Bodamer, O. A., Watson, M. S., Wilcox, W. R. &lt;strong&gt;Lysosomal storage diseases: diagnostic confirmation and management of presymptomatic individuals.&lt;/strong&gt; Genet. Med. 13: 457-484, 2011.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/21502868/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;21502868&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1097/GIM.0b013e318211a7e1&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="21502868">Wang et al. (2011)</a> described the ACMG standards and guidelines for the diagnostic confirmation and management of presymptomatic individuals with lysosomal storage diseases. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21502868" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#141" class="mim-tip-reference" title="Wanner, C., Arad, M., Baron, R., Burlina, A., Elliott, P. M., Feldt-Rasmussen, U., Fomin, V. V., Germain, D. P., Hughes, D. A., Jovanovic, A., Kantola, I., Linhart, A., and 13 others. &lt;strong&gt;European expert consensus statement on therapeutic goals in Fabry disease.&lt;/strong&gt; Molec. Genet. Metab. 124: 189-203, 2018.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/30017653/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;30017653&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/j.ymgme.2018.06.004&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="30017653">Wanner et al. (2018)</a> reported a European expert consensus statement on therapeutic goals in Fabry disease. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30017653" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Renal Transplantation</em></strong></p><p>
<a href="#23" class="mim-tip-reference" title="Clement, M., McGonigle, R. J. S., Monkhouse, P. M., Keogh, A. M., Marten, R. H., Bewick, M., Parsons, V. &lt;strong&gt;Renal transplantation in Anderson-Fabry disease.&lt;/strong&gt; J. Roy. Soc. Med. 75: 557-560, 1982.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/6283080/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;6283080&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1177/014107688207500716&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="6283080">Clement et al. (1982)</a> reported that successful renal transplantation in Fabry disease not only corrected the anemia but also produced a marked improvement in other clinical manifestations of the disease. <a href="#7" class="mim-tip-reference" title="Bannwart, F. &lt;strong&gt;Morbus Fabry: Licht- und Elektronenmikroskopischer Herzbefund 12 Jahre nach erfolgreicher Nierentransplantation.&lt;/strong&gt; Schweiz. Med. Wschr. 112: 1742-1747, 1982.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/6294821/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;6294821&lt;/a&gt;]" pmid="6294821">Bannwart (1982)</a> described a postmortem examination 12 years after transplantation; no histologic recurrence of Fabry disease in the kidney graft was found by light or electron microscopy. In contrast, <a href="#37" class="mim-tip-reference" title="Faraggiana, T., Churg, J., Grishman, E., Strauss, L., Prado, A., Bishop, D. F., Schuchman, E., Desnick, R. J. &lt;strong&gt;Light and electron-microscopic histochemistry of Fabry&#x27;s disease.&lt;/strong&gt; Am. J. Path. 103: 247-262, 1981.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/6786101/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;6786101&lt;/a&gt;]" pmid="6786101">Faraggiana et al. (1981)</a> examined the kidney of a patient who died 6 months following transplantation and found widespread recurrence of the disease in the graft. In that case, there was evidence of a circulating inhibitor of galactosidase A activity. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=6283080+6294821+6786101" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#41" class="mim-tip-reference" title="Friedlaender, M. M., Kopolovic, J., Rubinger, D., Silver, J., Drukker, A., Ben-Gershon, Z., Durst, A. L., Popovtzer, M. M. &lt;strong&gt;Renal biopsy in Fabry&#x27;s disease eight years after successful renal transplantation.&lt;/strong&gt; Clin. Nephrol. 27: 206-211, 1987.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/3107860/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;3107860&lt;/a&gt;]" pmid="3107860">Friedlaender et al. (1987)</a> presented renal biopsy data on a patient with Fabry disease before and 8 years after successful renal transplantation. The graft maintained normal function and graft histology showed no abnormalities. The patient had been able to return to work and his severe symptoms of acroparesthesia had been cured. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=3107860" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Enzyme Replacement Therapy</em></strong></p><p>
<a href="#80" class="mim-tip-reference" title="Mapes, C. A., Anderson, R. L., Sweeley, C. C., Desnick, R. J., Krivit, W. &lt;strong&gt;Enzyme replacement in Fabry&#x27;s disease, an inborn error of metabolism.&lt;/strong&gt; Science 169: 987-989, 1970.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/4914726/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;4914726&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1126/science.169.3949.987&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="4914726">Mapes et al. (1970)</a> reported one of the first enzyme replacement strategies in Fabry disease. Two patients demonstrated a decline in the plasma level of galactosylgalactosylglucosylceramide when normal plasma was infused to provide active enzyme. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=4914726" 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="Fan, J.-Q., Ishii, S., Asano, N., Suzuki, Y. &lt;strong&gt;Accelerated transport and maturation of lysosomal alpha-galactosidase A in Fabry lymphoblasts by an enzyme inhibitor.&lt;/strong&gt; Nature Med. 5: 112-115, 1999.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/9883849/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;9883849&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1038/4801&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="9883849">Fan et al. (1999)</a> proposed a molecular therapeutic strategy for Fabry disease in which competitive inhibitors are administered as 'chemical chaperones' at subinhibitory intracellular concentrations to enhance residual enzyme activity in Fabry disease. Some mutant alpha-Gal A enzymes have shown kinetic properties similar to those of wildtype, but are significantly less stable, especially in conditions of neutral pH. The biosynthetic processing was delayed in cultured fibroblasts of a Fabry disease patient (<a href="#74" class="mim-tip-reference" title="Lemansky, P., Bishop, D. F., Desnick, R. J., Hasilik, A., von Figura, K. &lt;strong&gt;Synthesis and processing of alpha-galactosidase A in human fibroblasts: evidence for different mutations in Fabry disease.&lt;/strong&gt; J. Biol. Chem. 262: 2062-2065, 1987.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/3029062/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;3029062&lt;/a&gt;]" pmid="3029062">Lemansky et al., 1987</a>), and the mutant protein formed an aggregate in endoplasmic reticulum (<a href="#62" class="mim-tip-reference" title="Ishii, S., Kase, R., Okumiya, T., Sakuraba, H., Suzuki, Y. &lt;strong&gt;Aggregation of the inactive form of human alpha-galactosidase in the endoplasmic reticulum.&lt;/strong&gt; Biochem. Biophys. Res. Commun. 220: 812-815, 1996.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/8607847/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;8607847&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1006/bbrc.1996.0486&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="8607847">Ishii et al., 1996</a>), indicating that the enzyme deficiency in some mutants is mainly caused by abortive exit from the endoplasmic reticulum, leading to excessive degradation of the enzyme. <a href="#36" class="mim-tip-reference" title="Fan, J.-Q., Ishii, S., Asano, N., Suzuki, Y. &lt;strong&gt;Accelerated transport and maturation of lysosomal alpha-galactosidase A in Fabry lymphoblasts by an enzyme inhibitor.&lt;/strong&gt; Nature Med. 5: 112-115, 1999.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/9883849/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;9883849&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1038/4801&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="9883849">Fan et al. (1999)</a> and <a href="#3" class="mim-tip-reference" title="Asano, N., Ishii, S., Kizu, H., Ikeda, K., Yasuda, K., Kato, A., Martin, O. R., Fan, J.-Q. &lt;strong&gt;In vitro inhibition and intracellular enhancement of lysosomal alpha-galactosidase A activity in Fabry lymphoblasts by 1-deoxygalactonojirimycin and its derivatives.&lt;/strong&gt; Europ. J. Biochem. 267: 4179-4186, 2000.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/10866822/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;10866822&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1046/j.1432-1327.2000.01457.x&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="10866822">Asano et al. (2000)</a> reported that 1-deoxygalactonojirimycin (DGJ), a potent competitive inhibitor of alpha-Gal A, effectively enhanced enzyme activity in Fabry disease lymphoblasts when administered in concentrations lower than those usually required for intracellular inhibition of the enzyme. DGJ seemed to accelerate transport and maturation of the mutant enzyme. Oral administration of DGJ to transgenic mice overexpressing a mutant alpha-Gal A substantially elevated enzyme activity in some organs. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=8607847+10866822+3029062+9883849" 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="#117" class="mim-tip-reference" title="Schiffmann, R., Murray, G. J., Treco, D., Daniel, P., Sellos-Moura, M., Myers, M., Quirk, J. M., Zirzow, G. C., Borowski, M., Loveday, K., Anderson, T., Gillespie, F., Oliver, K. L., Jeffries, N. O., Doo, E., Liang, T. J., Kreps, C., Gunter, K., Frei, K., Crutchfield, K., Selden, R. F., Brady, R. O. &lt;strong&gt;Infusion of alpha-galactosidase A reduces tissue globotriaosylceramide storage in patients with Fabry disease.&lt;/strong&gt; Proc. Nat. Acad. Sci. 97: 365-370, 2000.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/10618424/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;10618424&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=10618424[PMID]&amp;report=imagesdocsum&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed Image&#x27;, &#x27;domain&#x27;: &#x27;ncbi.nlm.nih.gov&#x27;})&quot;&gt;images&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1073/pnas.97.1.365&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="10618424">Schiffmann et al. (2000)</a> studied the safety and pharmacokinetics of intravenously administered alpha-galactosidase A produced by transfection of human skin fibroblasts in patients with Fabry disease. Infusions were well tolerated in all patients. Immunohistochemical staining of liver tissue approximately 2 days after enzyme infusion identified alpha-galactosidase A in several cell types, suggesting diffuse uptake via the mannose 6-phosphate receptor (M6PR; <a href="/entry/154540">154540</a>). The tissue half-life in the liver was greater than 24 hours. The degree of substrate reduction as potentially clinically significant was observed from studies of glycosphingolipid globotriaosylceramide (also referred to as ceramidetrihexoside) levels in the patients after a single dose of alpha-galactosidase A. <a href="#14" class="mim-tip-reference" title="Brady, R. O., Schiffmann, R. &lt;strong&gt;Clinical features of and recent advances in therapy for Fabry disease.&lt;/strong&gt; JAMA 284: 2771-2775, 2000. Note: Erratum: JAMA 285: 169 only, 2001.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/11105184/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;11105184&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1001/jama.284.21.2771&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="11105184">Brady and Schiffmann (2000)</a> reviewed the clinical features of Fabry disease and recent advances in its therapy. They stated that their double-blind, placebo-controlled trial of intravenous infusions of alpha-galactosidase A in patients with Fabry disease demonstrated the safety and efficacy of this treatment. <a href="#30" class="mim-tip-reference" title="Eng, C. M., Banikazemi, M., Gordon, R. E., Goldman, M., Phelps, R., Kim, L., Gass, A., Winston, J., Dikman, S., Fallon, J. T., Brodie, S., Stacy, C. B., Mehta, D., Parsons, R., Norton, K., O&#x27;Callaghan, M., Desnick, R. J. &lt;strong&gt;A phase 1/2 clinical trial of enzyme replacement in Fabry disease: pharmacokinetic, substrate clearance, and safety studies.&lt;/strong&gt; Am. J. Hum. Genet. 68: 711-722, 2001.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/11179018/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;11179018&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=11179018[PMID]&amp;report=imagesdocsum&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed Image&#x27;, &#x27;domain&#x27;: &#x27;ncbi.nlm.nih.gov&#x27;})&quot;&gt;images&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1086/318809&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="11179018">Eng et al. (2001)</a> reported the results of a clinical trial of enzyme replacement in Fabry disease indicating overall safety and subjective and objective evidence of improvement. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=10618424+11179018+11105184" 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>Two differently produced enzyme preparations have independently been examined in clinical investigations for the treatment of Fabry disease: one produced by Chinese hamster ovary (CHO) cells with classic recombinant technology (agalsidase-beta, Fabrazyme), and the other produced by cultured human skin fibroblasts with an activated promoter of the alpha-Gal A gene (agalsidase-alpha, Replagal). With both preparations, promising lipid substrate reductions in tissue biopsies have been observed (<a href="#30" class="mim-tip-reference" title="Eng, C. M., Banikazemi, M., Gordon, R. E., Goldman, M., Phelps, R., Kim, L., Gass, A., Winston, J., Dikman, S., Fallon, J. T., Brodie, S., Stacy, C. B., Mehta, D., Parsons, R., Norton, K., O&#x27;Callaghan, M., Desnick, R. J. &lt;strong&gt;A phase 1/2 clinical trial of enzyme replacement in Fabry disease: pharmacokinetic, substrate clearance, and safety studies.&lt;/strong&gt; Am. J. Hum. Genet. 68: 711-722, 2001.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/11179018/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;11179018&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=11179018[PMID]&amp;report=imagesdocsum&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed Image&#x27;, &#x27;domain&#x27;: &#x27;ncbi.nlm.nih.gov&#x27;})&quot;&gt;images&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1086/318809&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="11179018">Eng et al., 2001</a>; <a href="#96" class="mim-tip-reference" title="Pastores, G. M., Thadhani, R. &lt;strong&gt;Enzyme-replacement therapy for Anderson-Fabry disease. (Commentary)&lt;/strong&gt; Lancet 358: 601-603, 2001.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/11530143/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;11530143&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/S0140-6736(01)05816-0&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="11530143">Pastores and Thadhani, 2001</a>; <a href="#116" class="mim-tip-reference" title="Schiffmann, R., Kopp, J. B., Austin, H. A., III, Sabnis, S., Moore, D. F., Weibel, T., Balow, J. E., Brady, R. O. &lt;strong&gt;Enzyme replacement therapy in Fabry disease: a randomized controlled trial.&lt;/strong&gt; JAMA 285: 2743-2749, 2001.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/11386930/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;11386930&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1001/jama.285.21.2743&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="11386930">Schiffmann et al., 2001</a>). Although it had been suggested that alpha-Gal A mRNA undergoes editing, which might result in coproduction of an edited protein with a phe396-to-tyr conversion that might have a relevant physiologic function (<a href="#90" class="mim-tip-reference" title="Novo, F. J., Kruszewski, A., MacDermot, K. D., Goldspink, G., Gorecki, D. C. &lt;strong&gt;Editing of human alpha-galactosidase RNA resulting in a pyrimidine to purine conversion.&lt;/strong&gt; Nucleic Acids Res. 23: 2636-2640, 1995.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/7503918/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;7503918&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1093/nar/23.14.2636&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="7503918">Novo et al., 1995</a>), <a href="#12" class="mim-tip-reference" title="Blom, D., Speijer, D., Linthorst, G. E., Donker-Koopman, W. G., Strijland, A., Aerts, J. M. F. G. &lt;strong&gt;Recombinant enzyme therapy for Fabry disease: absence of editing of human alpha-galactosidase A mRNA.&lt;/strong&gt; Am. J. Hum. Genet. 72: 23-31, 2003.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/12471562/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;12471562&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=12471562[PMID]&amp;report=imagesdocsum&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed Image&#x27;, &#x27;domain&#x27;: &#x27;ncbi.nlm.nih.gov&#x27;})&quot;&gt;images&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1086/345309&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="12471562">Blom et al. (2003)</a> found no indication for the existence of editing at the protein or RNA levels in either recombinant GLA enzyme. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=12471562+11179018+11530143+7503918+11386930" 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="#138" class="mim-tip-reference" title="Waldek, S. &lt;strong&gt;PR interval and the response to enzyme-replacement therapy for Fabry&#x27;s disease. (Letter)&lt;/strong&gt; New Eng. J. Med. 348: 1186-1187, 2003.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/12646684/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;12646684&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1056/NEJM200303203481224&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="12646684">Waldek (2003)</a> suggested that duration of the PR interval may be a useful marker of both the severity of cardiac disease and the response to treatment in patients with Fabry disease. In a patient who had a favorable response to enzyme replacement therapy, the PR interval and cardiac globotriaosylceramide level were restored to normal values, with an improvement in cardiac function shown by the increase in the left ventricular ejection fraction. The rapid increase in the PR interval coincided with a dramatic decline in the cardiac glycosphingolipid level. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12646684" 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="#143" class="mim-tip-reference" title="Wilcox, W. R., Banikazemi, M., Guffon, N., Waldek, S., Lee, P., Linthorst, G. E., Desnick, R. J., Germain, D. P. &lt;strong&gt;Long-term safety and efficacy of enzyme replacement therapy for Fabry disease.&lt;/strong&gt; Am. J. Hum. Genet. 75: 65-74, 2004.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/15154115/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;15154115&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=15154115[PMID]&amp;report=imagesdocsum&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed Image&#x27;, &#x27;domain&#x27;: &#x27;ncbi.nlm.nih.gov&#x27;})&quot;&gt;images&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1086/422366&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="15154115">Wilcox et al. (2004)</a> reported that enzyme replacement therapy for 30 to 36 months with agalsidase-beta resulted in continuously decreased plasma globotriaosylceramide levels, sustained endothelial Gb3 clearance, stable kidney function, and a favorable safety profile. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15154115" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Using clinical, electrocardiographic, and echocardiographic evaluation, <a href="#127" class="mim-tip-reference" title="Spinelli, L., Pisani, A., Sabbatini, M., Petretta, M., Andreucci, M. V., Procaccini, D., Lo Surdo, N., Federico, S., Cianciaruso, B. &lt;strong&gt;Enzyme replacement therapy with agalsidase beta improves cardiac performance in Fabry&#x27;s disease.&lt;/strong&gt; Clin. Genet. 66: 158-165, 2004.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/15253767/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;15253767&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1111/j.1399-0004.2004.00284.x&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="15253767">Spinelli et al. (2004)</a> studied 9 patients with Fabry cardiomyopathy before and after 6 and 12 months of treatment with agalsidase-beta. At 12 months, interventricular septal thickness and left ventricular mass had decreased significantly (p less than 0.01 for both), as had the difference in duration between the pulmonary vein flow velocity wave and the mitral wave at atrial systole (p less than 0.01). <a href="#127" class="mim-tip-reference" title="Spinelli, L., Pisani, A., Sabbatini, M., Petretta, M., Andreucci, M. V., Procaccini, D., Lo Surdo, N., Federico, S., Cianciaruso, B. &lt;strong&gt;Enzyme replacement therapy with agalsidase beta improves cardiac performance in Fabry&#x27;s disease.&lt;/strong&gt; Clin. Genet. 66: 158-165, 2004.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/15253767/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;15253767&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1111/j.1399-0004.2004.00284.x&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="15253767">Spinelli et al. (2004)</a> suggested that enzyme replacement therapy in patients with Fabry cardiomyopathy is able to reduce the left ventricular mass and ameliorate its stiffness. (<a href="#101" class="mim-tip-reference" title="Pisani, A. &lt;strong&gt;Personal Communication.&lt;/strong&gt; Naples, Italy 4/19/2005."None>Pisani (2005)</a> stated that the p values were incorrect in the abstract but correct in the figures of the article of <a href="#127" class="mim-tip-reference" title="Spinelli, L., Pisani, A., Sabbatini, M., Petretta, M., Andreucci, M. V., Procaccini, D., Lo Surdo, N., Federico, S., Cianciaruso, B. &lt;strong&gt;Enzyme replacement therapy with agalsidase beta improves cardiac performance in Fabry&#x27;s disease.&lt;/strong&gt; Clin. Genet. 66: 158-165, 2004.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/15253767/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;15253767&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1111/j.1399-0004.2004.00284.x&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="15253767">Spinelli et al. (2004)</a>.) <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15253767" 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="#131" class="mim-tip-reference" title="Tajima, Y., Kawashima, I., Tsukimura, T., Sugawara, K., Kuroda, M., Suzuki, T., Togawa, T., Chiba, Y., Jigami, Y., Ohno, K., Fukushige, T., Kanekura, T., Itoh, K., Ohashi, T., Sakuraba, H. &lt;strong&gt;Use of a modified alpha-N-acetylgalactosaminidase in the development of enzyme replacement therapy for Fabry disease.&lt;/strong&gt; Am. J. Hum. Genet. 85: 569-580, 2009.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/19853240/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;19853240&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=19853240[PMID]&amp;report=imagesdocsum&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed Image&#x27;, &#x27;domain&#x27;: &#x27;ncbi.nlm.nih.gov&#x27;})&quot;&gt;images&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/j.ajhg.2009.09.016&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="19853240">Tajima et al. (2009)</a> designed and produced a modified alpha-N-acetylgalactosaminidase (NAGA; <a href="/entry/104170">104170</a>) with alpha-galactosidase A (GLA)-like substrate specificity in Chinese hamster ovary cells. The enzyme acquired the ability to catalyze the degradation of 4-methylumbelliferyl-alpha-D-galactopyranoside, an artificial substrate of GLA, but not for a NAGA substrate. It showed stability in plasma and had mannose 6-phosphate residues for incorporation into cells. There was no immunologic crossreactivity between the modified NAGA and GLA, and the modified NAGA did not react to serum from a patient with Fabry disease treated with a recombinant GLA. In cultured fibroblasts from a patient with Fabry disease, the modified enzyme cleaved accumulated globotriaosylceramide (Gb3). Intravenous injection into Fabry mice prevented Gb3 storage in the liver, kidneys, and heart, and improved pathologic changes in these organs. <a href="#131" class="mim-tip-reference" title="Tajima, Y., Kawashima, I., Tsukimura, T., Sugawara, K., Kuroda, M., Suzuki, T., Togawa, T., Chiba, Y., Jigami, Y., Ohno, K., Fukushige, T., Kanekura, T., Itoh, K., Ohashi, T., Sakuraba, H. &lt;strong&gt;Use of a modified alpha-N-acetylgalactosaminidase in the development of enzyme replacement therapy for Fabry disease.&lt;/strong&gt; Am. J. Hum. Genet. 85: 569-580, 2009.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/19853240/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;19853240&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=19853240[PMID]&amp;report=imagesdocsum&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed Image&#x27;, &#x27;domain&#x27;: &#x27;ncbi.nlm.nih.gov&#x27;})&quot;&gt;images&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/j.ajhg.2009.09.016&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="19853240">Tajima et al. (2009)</a> concluded that this modified NAGA could be a highly promising safe enzyme for treatment of Fabry disease. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19853240" 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="#49" class="mim-tip-reference" title="Germain, D. P., Weidemann, F., Abiose, A., Patel, M. R., Cizmarik, M., Cole, J. A., Beitner-Johnson, D., Benistan, K., Cabrera, G., Charrow, J., Kantola, I., Linhart, A., Nicholls, K., Niemann, M., Scott, C. R., Sims, K., Waldek, S., Warnock, D. G., Strotmann, J. &lt;strong&gt;Analysis of left ventricular mass in untreated men and in men treated with agalsidase-beta: data from the Fabry Registry.&lt;/strong&gt; Genet. Med. 15: 958-965, 2013.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/23703683/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;23703683&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1038/gim.2013.53&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="23703683">Germain et al. (2013)</a> evaluated the progression of left ventricular hypertrophy in untreated men with Fabry disease and compared them with treated men. They analyzed longitudinal Fabry Registry data from 115 men treated with 1 mg/kg agalsidase-beta for 2 weeks and 48 untreated men. Measurements included baseline left ventricular mass and at least 1 additional left ventricular mass assessment over at least 2 years. Patients were grouped into quartiles, based on left ventricular mass slopes. Multivariate logistic regression analyses identified factors associated with left ventricular hypertrophy progression. For men in whom treatment was initiated at the age of 18 to less than 30 years (n = 31), mean left ventricular mass slope was -3.6 g/year, compared with +9.5 g/year in untreated men of that age (n = 15) (p less than 0.0001). Untreated men had a 3.4-fold higher risk of having faster increases in left ventricular mass compared with treated men (odds ratio 3.43; 95% confidence interval 1.05-11.22; p = 0.0415). A baseline age of 40 or more years was also associated with left ventricular hypertrophy progression (odds ratio 5.03; 95% confidence interval 1.03-24.49; p = 0.0457) compared with men younger than 30 years. <a href="#49" class="mim-tip-reference" title="Germain, D. P., Weidemann, F., Abiose, A., Patel, M. R., Cizmarik, M., Cole, J. A., Beitner-Johnson, D., Benistan, K., Cabrera, G., Charrow, J., Kantola, I., Linhart, A., Nicholls, K., Niemann, M., Scott, C. R., Sims, K., Waldek, S., Warnock, D. G., Strotmann, J. &lt;strong&gt;Analysis of left ventricular mass in untreated men and in men treated with agalsidase-beta: data from the Fabry Registry.&lt;/strong&gt; Genet. Med. 15: 958-965, 2013.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/23703683/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;23703683&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1038/gim.2013.53&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="23703683">Germain et al. (2013)</a> concluded that agalsidase-beta treatment for 2 or more years may improve or stabilize left ventricular mass in men with Fabry disease. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23703683" 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="Germain, D. P., Charrow, J., Desnick, R. J., Guffon, N., Kempf, J., Lachmann, R. H., Lemay, R., Linthorst, G. E., Packman, S., Scott, C. R., Waldek, S., Warnock, D. G., Weinreb, N. J., Wilcox, W. R. &lt;strong&gt;Ten-year outcome of enzyme replacement therapy with agalsidase beta in patients with Fabry disease.&lt;/strong&gt; J. Med. Genet. 52: 353-358, 2015.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/25795794/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;25795794&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=25795794[PMID]&amp;report=imagesdocsum&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed Image&#x27;, &#x27;domain&#x27;: &#x27;ncbi.nlm.nih.gov&#x27;})&quot;&gt;images&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1136/jmedgenet-2014-102797&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="25795794">Germain et al. (2015)</a> reported a 10-year follow-up of 52 Fabry patients treated with agalsidase. The mean age of patients at treatment initiation was 30 years; 11 patients were over age 40. Twenty patients had high renal involvement and 32 had low renal involvement at the onset of treatment. Most patients (81%) did not have any severe clinical events during the interval, and 94% were alive at the end of the study. Ten patients reported a total of 16 adverse events, most frequently stroke, followed by a severe renal event (dialysis, transplant) and cardiac events. Renal disease progressed in almost all patients despite treatment but was slower and less severe in those treated at a younger age and those who had low kidney involvement at the outset. The mean left ventricular posterior wall thickness and interventricular septum thickness remained unchanged and normal among treated patients. The findings indicated that treatment with agalsidase is effective in Fabry disease, and that early treatment is most beneficial. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25795794" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Gene Therapy</em></strong></p><p>
<a href="#105" class="mim-tip-reference" title="Qin, G., Takenaka, T., Telsch, K., Kelley, L., Howard, T., Levade, T., Deans, R., Howard, B. H., Malech, H. L., Brady, R. O., Medin, J. A. &lt;strong&gt;Preselective gene therapy for Fabry disease.&lt;/strong&gt; Proc. Nat. Acad. Sci. 98: 3428-3433, 2001.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/11248095/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;11248095&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=11248095[PMID]&amp;report=imagesdocsum&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed Image&#x27;, &#x27;domain&#x27;: &#x27;ncbi.nlm.nih.gov&#x27;})&quot;&gt;images&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1073/pnas.061020598&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="11248095">Qin et al. (2001)</a> used a novel bicistronic retroviral vector that engineers expression of both the therapeutic GLA gene and the human IL2R-alpha chain gene (CD25; <a href="/entry/147730">147730</a>) as a selectable marker. Coexpression of IL2R-alpha allowed selective immunoenrichment, preselection, of a variety of transduced human and murine cells, resulting in enhanced intracellular and secreted activities of the alpha-Gal A enzyme. The results suggested that a CD25-based preselection strategy may enhance the clinical utility of ex vivo hematopoietic stem/progenitor cell gene therapy in Fabry disease and other disorders. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11248095" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Migalastat Therapy</em></strong></p><p>
<a href="#60" class="mim-tip-reference" title="Hughes, D. A., Nicholls, K., Shankar, S. P., Sunder-Plassmann, G., Koeller, D., Nedd, K., Vockley, G., Hamazaki, T., Lachmann, R., Ohashi, T., Olivotto, I., Sakai, N., and 26 others. &lt;strong&gt;Oral pharmacological chaperone migalastat compared with enzyme replacement therapy in Fabry disease: 18-month results from the randomised phase III ATTRACT study.&lt;/strong&gt; J. Med. Genet. 54: 288-296, 2017. Note: Erratum: J. Med. Genet. 55: 429 only, 2018.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/27834756/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;27834756&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1136/jmedgenet-2016-104178&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="27834756">Hughes et al. (2017)</a> performed an 18-month randomized active-controlled study to access the effects of migalastat on renal function in patients with Fabry disease previously treated with enzyme replacement therapy (ERT). Effects on heart, disease substrate, patient-reported outcomes, and safety were also assessed. Fifty-seven adults (56% female) receiving ERT (88% with multiorgan disease) were randomized (1.5:1), based on a preliminary cell-based assay of responsiveness to migalastat, to receive 18 months open-label migalastat or remain on ERT. Migalastat and ERT had similar effects on renal function. Left ventricular mass index decreased significantly with migalastat treatment (-6.6 g/m(2), range -11.0 to -2.2); there was no significant change with ERT. Predefined renal, cardiac, or cerebrovascular events occurred in 29% and 44% of patients in the migalastat and ERT groups, respectively. Plasma globotriaosylsphingosine remained low and stable following the switch from ERT to migalastat. Patient-reported outcomes were comparable between groups. Migalastat was generally safe and well tolerated. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27834756" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="mapping" class="mim-anchor"></a>
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<p><a href="#95" class="mim-tip-reference" title="Opitz, J. M., Stiles, F. C., Wise, D., Race, R. R., Sanger, R., Von Gemmingen, G. R., Kierland, R. R., Cross, E. G., DeGroot, W. P. &lt;strong&gt;The genetics of angiokeratoma corporis diffusum (Fabry&#x27;s disease) and its linkage relations with the Xg locus.&lt;/strong&gt; Am. J. Hum. Genet. 17: 325-342, 1965.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/17948499/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;17948499&lt;/a&gt;]" pmid="17948499">Opitz et al. (1965)</a> reported linkage between Fabry disease and the X chromosome. <a href="#63" class="mim-tip-reference" title="Johnston, A. W., Frost, P., Spaeth, G. L., Renwick, J. H. &lt;strong&gt;Linkage relationships of the angiokeratoma (Fabry) locus.&lt;/strong&gt; Ann. Hum. Genet. 32: 369-374, 1969.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/5307232/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;5307232&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1111/j.1469-1809.1969.tb00088.x&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="5307232">Johnston et al. (1969)</a> estimated the recombination fraction of Fabry versus Xg (<a href="/entry/314700">314700</a>) to be 0.24 (95% probability limits, 8-49.8%) and of angiokeratoma versus deutan (<a href="/entry/303800">303800</a>) to be 0.17 (95% probability limits, 1-50%). <a href="#64" class="mim-tip-reference" title="Johnston, A. W., Sanger, R. &lt;strong&gt;Linkage relationship of the loci for Anderson-Fabry disease and the Xg blood groups.&lt;/strong&gt; Ann. Hum. Genet. 45: 155-157, 1981.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/6274251/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;6274251&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1111/j.1469-1809.1981.tb00317.x&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="6274251">Johnston and Sanger (1981)</a> reanalyzed all data on Xg and Fabry linkage and obtained negative lod scores at all recombination rates. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=17948499+6274251+5307232" 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="#78" class="mim-tip-reference" title="MacDermot, K. D., Morgan, S. H., Cheshire, J. K., Wilson, T. M. &lt;strong&gt;Anderson Fabry disease, a close linkage with highly polymorphic DNA markers DXS17, DXS87, and DXS88.&lt;/strong&gt; Hum. Genet. 77: 263-266, 1987.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/2890570/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;2890570&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1007/BF00284482&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="2890570">MacDermot et al. (1987)</a> found close linkage between Fabry disease and 3 DNA markers on the X chromosome: DXS87, DXS88, and DXS17, which gave maximum lod scores of 6.4, 6.4, and 5.8, respectively, at theta = 0.00. DXYS1 was not linked. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2890570" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="molecularGenetics" class="mim-anchor"></a>
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<p><a href="#110" class="mim-tip-reference" title="Romeo, G., Migeon, B. R. &lt;strong&gt;Genetic inactivation of the alpha-galactosidase locus in carriers of Fabry&#x27;s disease.&lt;/strong&gt; Science 170: 180-181, 1970.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/5466114/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;5466114&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1126/science.170.3954.180&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="5466114">Romeo and Migeon (1970)</a> presented evidence for a structural change in the GLA enzyme in patients with Fabry disease. The disease-associated enzymes showed slower heat inactivation and different K(m) values compared to normal. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=5466114" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>By Southern blot analysis, <a href="#9" class="mim-tip-reference" title="Bernstein, H. S., Bishop, D. F., Astrin, K. H., Kornreich, R., Eng, C. M., Sakuraba, H., Desnick, R. J. &lt;strong&gt;Fabry disease: six gene rearrangements and an exonic point mutation in the alpha-galactosidase gene.&lt;/strong&gt; J. Clin. Invest. 83: 1390-1399, 1989.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/2539398/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;2539398&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1172/JCI114027&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="2539398">Bernstein et al. (1989)</a> found that 6 of 130 unrelated males with Fabry disease had GLA gene rearrangements. Five partial gene deletions were detected, ranging in size from 0.4 to more than 5.5 kb. Four of the 5 deletions had breakpoints in exon 2, a region containing multiple Alu repeat sequences. <a href="#72" class="mim-tip-reference" title="Kornreich, R., Bishop, D. F., Desnick, R. J. &lt;strong&gt;Alpha-galactosidase A gene rearrangements causing Fabry disease: identification of short direct repeats at breakpoints in an Alu-rich gene.&lt;/strong&gt; J. Biol. Chem. 265: 9319-9326, 1990.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/2160973/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;2160973&lt;/a&gt;]" pmid="2160973">Kornreich et al. (1990)</a> assessed the gene arrangements identified by <a href="#9" class="mim-tip-reference" title="Bernstein, H. S., Bishop, D. F., Astrin, K. H., Kornreich, R., Eng, C. M., Sakuraba, H., Desnick, R. J. &lt;strong&gt;Fabry disease: six gene rearrangements and an exonic point mutation in the alpha-galactosidase gene.&lt;/strong&gt; J. Clin. Invest. 83: 1390-1399, 1989.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/2539398/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;2539398&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1172/JCI114027&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="2539398">Bernstein et al. (1989)</a> to determine the possible role of Alu repetitive elements and short direct and/or inverted repeats in the generation of these germinal mutations. Although the GLA gene contains 12 Alu repetitive elements (representing about 30% of the 12-kb gene), only 1 deletion resulted from an Alu-Alu recombination. The remaining 5 rearrangements involved illegitimate recombinational events between short direct repeats of 2 to 6 bp at the deletion or duplication breakpoints. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=2160973+2539398" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In a patient with Fabry disease, <a href="#9" class="mim-tip-reference" title="Bernstein, H. S., Bishop, D. F., Astrin, K. H., Kornreich, R., Eng, C. M., Sakuraba, H., Desnick, R. J. &lt;strong&gt;Fabry disease: six gene rearrangements and an exonic point mutation in the alpha-galactosidase gene.&lt;/strong&gt; J. Clin. Invest. 83: 1390-1399, 1989.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/2539398/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;2539398&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1172/JCI114027&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="2539398">Bernstein et al. (1989)</a> identified a mutation in the GLA gene (<a href="/entry/300644#0001">300644.0001</a>). The substitution altered the enzyme's kinetic properties and stability. <a href="#33" class="mim-tip-reference" title="Eng, C. M., Resnick-Silverman, L. A., Niehaus, D. J., Astrin, K. H., Desnick, R. J. &lt;strong&gt;Nature and frequency of mutations in the alpha-galactosidase A gene that cause Fabry disease.&lt;/strong&gt; Am. J. Hum. Genet. 53: 1186-1197, 1993.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/7504405/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;7504405&lt;/a&gt;]" pmid="7504405">Eng et al. (1993)</a> identified 18 different mutations in the GLA gene (see, e.g., <a href="/entry/300644#0012">300644.0012</a>; <a href="/entry/300644#0013">300644.0013</a>; <a href="/entry/300644#0018">300644.0018</a>-<a href="/entry/300644#0022">300644.0022</a>) in patients with Fabry disease. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=7504405+2539398" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#26" class="mim-tip-reference" title="Davies, J. P., Winchester, B. G., Malcolm, S. &lt;strong&gt;Mutation analysis in patients with the typical form of Anderson-Fabry disease.&lt;/strong&gt; Hum. Molec. Genet. 2: 1051-1053, 1993.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/8395937/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;8395937&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1093/hmg/2.7.1051&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="8395937">Davies et al. (1993)</a> found 7 mutations in the GLA gene in 9 unrelated families with the classic form of Fabry disease. <a href="#31" class="mim-tip-reference" title="Eng, C. M., Desnick, R. J. &lt;strong&gt;Molecular basis of Fabry disease: mutations and polymorphisms in the human alpha-galactosidase A gene.&lt;/strong&gt; Hum. Mutat. 3: 103-111, 1994.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/7911050/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;7911050&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/humu.1380030204&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="7911050">Eng and Desnick (1994)</a> reviewed and tabulated 15 GLA gene rearrangements, 3 GLA mRNA processing defects, and 31 GLA point mutations causing Fabry disease. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=7911050+8395937" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>By SSCP analysis followed by sequencing of the GLA gene, <a href="#11" class="mim-tip-reference" title="Blanch, L. C., Meaney, C., Morris, C. P. &lt;strong&gt;A sensitive mutation screening strategy for Fabry disease: detection of nine mutations in the alpha-galactosidase A gene.&lt;/strong&gt; Hum. Mutat. 8: 38-43, 1996.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/8807334/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;8807334&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/(SICI)1098-1004(1996)8:1&lt;38::AID-HUMU5&gt;3.0.CO;2-L&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="8807334">Blanch et al. (1996)</a> identified pathogenic mutations in 9 patients with classic severe Fabry disease. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8807334" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In a 45-year-old man with Fabry disease who had only renal manifestations, including moderate proteinuria, <a href="#115" class="mim-tip-reference" title="Sawada, K., Mizoguchi, K., Hishida, A., Kaneko, E., Koide, Y., Nishimura, K., Kimura, M. &lt;strong&gt;Point mutation in the alpha-galactosidase A gene of atypical Fabry disease with only nephropathy.&lt;/strong&gt; Clin. Nephrol. 45: 289-294, 1996.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/8738659/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;8738659&lt;/a&gt;]" pmid="8738659">Sawada et al. (1996)</a> identified a mutation in the GLA gene (<a href="/entry/300644#0003">300644.0003</a>). The mutation was inherited from his mother. The patient was unique in that he demonstrated only renal manifestations. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8738659" 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="#135" class="mim-tip-reference" title="Verovnik, F., Benko, D., Vujkovac, B., Linthorst, G. E. &lt;strong&gt;Remarkable variability in renal disease in a large Slovenian family with Fabry disease.&lt;/strong&gt; Europ. J. Hum. Genet. 12: 678-681, 2004.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/15162124/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;15162124&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1038/sj.ejhg.5201184&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="15162124">Verovnik et al. (2004)</a> reported the first Slovenian family with Fabry disease in which 7 males, including a set of twins, and 10 females had a GLA mutation (N272S; <a href="/entry/300644#0062">300644.0062</a>). Affected members of the family demonstrated remarkable phenotypic heterogeneity. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15162124" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Modifier Genes</em></strong></p><p>
Endothelial nitric oxide synthase (NOS3; <a href="/entry/163729">163729</a>) plays a key role in the regulation of normal function of the vessel wall. <a href="#58" class="mim-tip-reference" title="Heltianu, C., Costache, G., Azibi, K., Poenaru, L., Simionescu, M. &lt;strong&gt;Endothelial nitric oxide synthase gene polymorphisms in Fabry&#x27;s disease.&lt;/strong&gt; Clin. Genet. 61: 423-429, 2002.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/12121349/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;12121349&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1034/j.1399-0004.2002.610605.x&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="12121349">Heltianu et al. (2002)</a> found a relatively high frequency of 2 polymorphic variants of NOS3 in males with Fabry disease and suggested that in addition to mutations in the alpha-galactosidase A gene, variation in NOS3 may be significant in determining the phenotype. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12121349" 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>Among 32 children and 78 adults with Fabry disease, <a href="#4" class="mim-tip-reference" title="Auray-Blais, C., Cyr, D., Ntwari, A., West, M. L., Cox-Brinkman, J., Bichet, D. G., Germain, D. P., Laframboise, R., Melancon, S. B., Stockley, T., Clarke, J. T. R., Drouin, R. &lt;strong&gt;Urinary globotriaosylceramide excretion correlates with the genotype in children and adults with Fabry disease.&lt;/strong&gt; Molec. Genet. Metab. 93: 331-340, 2008.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/18023222/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;18023222&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/j.ymgme.2007.10.001&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="18023222">Auray-Blais et al. (2008)</a> identified 35 different mutations in the GLA gene, including missense (76.4%), nonsense (16.4%), frameshift (3.6%), and splice site defects (3.6%). Forty-one of the patients were being treated with enzyme replacement therapy. Although there was a wide range within each mutation group, a significant correlation existed between genotype and urinary Gb3/creatinine excretion among untreated patients, with missense mutations resulting in lower levels in general. There were also correlations between urinary Gb3/creatinine excretion and sex and between urinary Gb3/creatinine excretion and treatment. There was no correlation with age. <a href="#4" class="mim-tip-reference" title="Auray-Blais, C., Cyr, D., Ntwari, A., West, M. L., Cox-Brinkman, J., Bichet, D. G., Germain, D. P., Laframboise, R., Melancon, S. B., Stockley, T., Clarke, J. T. R., Drouin, R. &lt;strong&gt;Urinary globotriaosylceramide excretion correlates with the genotype in children and adults with Fabry disease.&lt;/strong&gt; Molec. Genet. Metab. 93: 331-340, 2008.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/18023222/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;18023222&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/j.ymgme.2007.10.001&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="18023222">Auray-Blais et al. (2008)</a> developed and utilized a multiplex liquid chromatography-tandem mass spectrometry methodology that allowed for simultaneous analysis of urinary Gb3 and creatinine eluted from the same filter paper sample. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18023222" 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="#94" class="mim-tip-reference" title="Oliveira, J. P., Nowak, A., Barbey, F., Torres, M., Nunes, J. P., Teixeira-e-Costa, F., Carvalho, F., Sampaio, S., Tavares, I., Pereira, O., Soares, A. L., Carmona, C, Cardoso, M.-T., Jurca-Simina, I. E., Spada, M., Ferreira, S., Germain, D. P. &lt;strong&gt;Fabry disease caused by the GLA p.Phe113Leu (p.F113L) variant: natural history in males.&lt;/strong&gt; Europ. J. Med. Genet. 63: 103703, 2020. Note: Electronic Article.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/31200018/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;31200018&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/j.ejmg.2019.103703&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="31200018">Oliveira et al. (2020)</a> reported 11 symptomatic Portuguese males from 10 families with Fabry disease who had a hemizygous F113L (<a href="/entry/300644#0063">300644.0063</a>) mutation in the GLA gene. All of the patients had a late-onset form of the disorder, manifesting with a cardiac phenotype invariably including cardiomyopathy/hypertrophic cardiomyopathy, and often including other features such as conduction defects, arrhythmias, and myocardial ischemia. Some patients also had cerebrovascular or kidney involvement, although the association with the GLA mutation was confounded by the presence of other risk factors (e.g., hypertension, diabetes, obesity). None of the patients had acroparesthesias, sweating problems, heat intolerance, or multiple angiokeratomas. Seven of 8 patients tested had normal corneas. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=31200018" 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>The incidence of Fabry disease has been estimated at 1 in 55,000 male births. However, this figure is almost certainly a substantial underestimate of the true frequency, particularly of milder variants of the disease (<a href="#22" class="mim-tip-reference" title="Clarke, J. T. R. &lt;strong&gt;Narrative review: Fabry disease.&lt;/strong&gt; Ann. Intern. Med. 146: 425-433, 2007.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/17371887/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;17371887&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.7326/0003-4819-146-6-200703200-00007&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="17371887">Clarke, 2007</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17371887" 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>Based on a newborn screening study, <a href="#123" class="mim-tip-reference" title="Spada, M., Pagliardini, S., Yasuda, M., Tukel, T., Thiagarajan, G., Sakuraba, H., Ponzone, A., Desnick, R. J. &lt;strong&gt;High incidence of later-onset Fabry disease revealed by newborn screening.&lt;/strong&gt; Am. J. Hum. Genet. 79: 31-40, 2006.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/16773563/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;16773563&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=16773563[PMID]&amp;report=imagesdocsum&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed Image&#x27;, &#x27;domain&#x27;: &#x27;ncbi.nlm.nih.gov&#x27;})&quot;&gt;images&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1086/504601&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="16773563">Spada et al. (2006)</a> estimated that the incidence of Fabry disease may be 1 in 3,100 to 4,600 individuals. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16773563" 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="#94" class="mim-tip-reference" title="Oliveira, J. P., Nowak, A., Barbey, F., Torres, M., Nunes, J. P., Teixeira-e-Costa, F., Carvalho, F., Sampaio, S., Tavares, I., Pereira, O., Soares, A. L., Carmona, C, Cardoso, M.-T., Jurca-Simina, I. E., Spada, M., Ferreira, S., Germain, D. P. &lt;strong&gt;Fabry disease caused by the GLA p.Phe113Leu (p.F113L) variant: natural history in males.&lt;/strong&gt; Europ. J. Med. Genet. 63: 103703, 2020. Note: Electronic Article.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/31200018/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;31200018&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/j.ejmg.2019.103703&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="31200018">Oliveira et al. (2020)</a> reported 13 males with Fabry disease, including 11 symptomatic Portuguese males from 10 families and 2 Italian males identified by newborn screening, who had a hemizygous F113L (<a href="/entry/300644#0063">300644.0063</a>) mutation in the GLA gene. Microsatellite analysis showed that all of the alleles were on the same GLA haplotype, suggesting inheritance from a common ancestor. <a href="#94" class="mim-tip-reference" title="Oliveira, J. P., Nowak, A., Barbey, F., Torres, M., Nunes, J. P., Teixeira-e-Costa, F., Carvalho, F., Sampaio, S., Tavares, I., Pereira, O., Soares, A. L., Carmona, C, Cardoso, M.-T., Jurca-Simina, I. E., Spada, M., Ferreira, S., Germain, D. P. &lt;strong&gt;Fabry disease caused by the GLA p.Phe113Leu (p.F113L) variant: natural history in males.&lt;/strong&gt; Europ. J. Med. Genet. 63: 103703, 2020. Note: Electronic Article.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/31200018/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;31200018&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/j.ejmg.2019.103703&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="31200018">Oliveira et al. (2020)</a> stated that due to the late-onset presentation associated with this mutation, it is not expected to reduce the reproductive fitness of affected individuals. <a href="#94" class="mim-tip-reference" title="Oliveira, J. P., Nowak, A., Barbey, F., Torres, M., Nunes, J. P., Teixeira-e-Costa, F., Carvalho, F., Sampaio, S., Tavares, I., Pereira, O., Soares, A. L., Carmona, C, Cardoso, M.-T., Jurca-Simina, I. E., Spada, M., Ferreira, S., Germain, D. P. &lt;strong&gt;Fabry disease caused by the GLA p.Phe113Leu (p.F113L) variant: natural history in males.&lt;/strong&gt; Europ. J. Med. Genet. 63: 103703, 2020. Note: Electronic Article.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/31200018/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;31200018&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/j.ejmg.2019.103703&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="31200018">Oliveira et al. (2020)</a> stated that the F113L mutation is the most frequent mutation identified in Portuguese individuals with Fabry disease. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=31200018" 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="#73" class="mim-tip-reference" title="Koto, Y., Sakai, N., Lee, Y., Kakee, N., Matsuda, J., Tsuboi, K., Shimozawa, N., Okuyama, T., Nakamura, K., Narita, A., kobayashi, H., Uehara, R., Nakamura, Y., Kato, K., Eto, Y. &lt;strong&gt;Prevalence of patients with lysosomal storage disorders and peroxisomal disorders: a nationwide survey in Japan.&lt;/strong&gt; Molec. Genet. Metab. 133: 277-288, 2021.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/34090759/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;34090759&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/j.ymgme.2021.05.004&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="34090759">Koto et al. (2021)</a> surveyed hospitals in Japan for information about patients with lysosomal storage diseases (LSDs) treated between 2013-2016 and 2018-2019. Fabry disease was the most common LSD, with 339 patients identified, of whom 31% had the classic form, 8.6% had the late-onset form, and 46.6% were heterozygous females; for 13.9%, there was no additional information. When these data were extrapolated across Japan, <a href="#73" class="mim-tip-reference" title="Koto, Y., Sakai, N., Lee, Y., Kakee, N., Matsuda, J., Tsuboi, K., Shimozawa, N., Okuyama, T., Nakamura, K., Narita, A., kobayashi, H., Uehara, R., Nakamura, Y., Kato, K., Eto, Y. &lt;strong&gt;Prevalence of patients with lysosomal storage disorders and peroxisomal disorders: a nationwide survey in Japan.&lt;/strong&gt; Molec. Genet. Metab. 133: 277-288, 2021.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/34090759/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;34090759&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/j.ymgme.2021.05.004&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="34090759">Koto et al. (2021)</a> estimated that there were 1,658 patients with Fabry disease, including 770 heterozygous females. They calculated a birth prevalence of Fabry disease in Japan of 1.25 per 100,000, which was lower than the previously estimated birth prevalence of 14.7 per 100,000 based on newborn screening. <a href="#73" class="mim-tip-reference" title="Koto, Y., Sakai, N., Lee, Y., Kakee, N., Matsuda, J., Tsuboi, K., Shimozawa, N., Okuyama, T., Nakamura, K., Narita, A., kobayashi, H., Uehara, R., Nakamura, Y., Kato, K., Eto, Y. &lt;strong&gt;Prevalence of patients with lysosomal storage disorders and peroxisomal disorders: a nationwide survey in Japan.&lt;/strong&gt; Molec. Genet. Metab. 133: 277-288, 2021.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/34090759/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;34090759&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/j.ymgme.2021.05.004&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="34090759">Koto et al. (2021)</a> suggested that the discrepancy may be due to underdiagnosis of late-onset Fabry disease patients and heterozygous females. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=34090759" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>Skin lesions of vascular nature are the basis of the name 'angiokeratoma.' Since angiokeratoma occurs with some other lysosomal diseases and may be missing in Fabry disease, the use of the eponym 'Fabry disease' is preferred, even though it ignores the important contribution of <a href="#2" class="mim-tip-reference" title="Anderson, W. &lt;strong&gt;A case of &#x27;angeio-keratoma&#x27;.&lt;/strong&gt; Brit. J. Derm. 10: 113-117, 1898."None>Anderson (1898)</a>. Fabry, of Dortmund, Germany, wrote about the disorder first in 1898 and again in 1930.</p>
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<p><a href="#98" class="mim-tip-reference" title="Peltier, A., Herbeuval, E., Baondeau, M. T., Belleville, F., Nabet, P. &lt;strong&gt;Pseudo-clinical Fabry&#x27;s disease without alpha-galactosidase deficiency.&lt;/strong&gt; Biomedicine 26: 194-201, 1977.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/407951/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;407951&lt;/a&gt;]" pmid="407951">Peltier et al. (1977)</a> reported male twins with Fabry disease but normal alpha-galactosidase and normality of several other lysosomal enzymes including alpha-fucosidase. The authors referred to this as 'pseudo-clinical Fabry disease.' <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=407951" 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="#92" class="mim-tip-reference" title="Ohshima, T., Murray, G. J., Swaim, W. D., Longenecker, G., Quirk, J. M., Cardarelli, C. O., Sugimoto, Y., Pastan, I., Gottesman, M. M., Brady, R. O., Kulkarni, A. B. &lt;strong&gt;Alpha-galactosidase A deficient mice: a model of Fabry disease.&lt;/strong&gt; Proc. Nat. Acad. Sci. 94: 2540-2544, 1997.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/9122231/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;9122231&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=9122231[PMID]&amp;report=imagesdocsum&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed Image&#x27;, &#x27;domain&#x27;: &#x27;ncbi.nlm.nih.gov&#x27;})&quot;&gt;images&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1073/pnas.94.6.2540&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="9122231">Ohshima et al. (1997)</a> generated Gla-deficient mice by gene targeting. The knockout mice displayed a complete lack of alpha-galactosidase A activity but appeared clinically normal at 10 weeks of age. Ultrastructural analysis revealed concentric lamellar inclusions in the kidneys, and confocal microscopy using a fluorescent-labeled lectin specific for alpha-D-galactosyl residues showed accumulation of substrate in the kidneys as well as in cultured fibroblasts. Lipid analysis revealed a marked accumulation of ceramide trihexaside in the liver and the kidneys. The deficiency of enzyme activity and the accumulation of material containing terminal alpha-galactosyl residues in cultured embryonic fibroblasts derived from the knockout mice were corrected by transducing these cells with human GLA cDNA. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9122231" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#93" class="mim-tip-reference" title="Ohshima, T., Schiffmann, R., Murray, G. J., Kopp, J., Quirk, J. M., Stahl, S., Chan, C.-C., Zerfas, P., Tao-Cheng, J.-H., Ward, J. M., Brady, R. O., Kulkarni, A. B. &lt;strong&gt;Aging accentuates and bone marrow transplantation ameliorates metabolic defects in Fabry disease mice.&lt;/strong&gt; Proc. Nat. Acad. Sci. 96: 6423-6427, 1999.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/10339603/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;10339603&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=10339603[PMID]&amp;report=imagesdocsum&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed Image&#x27;, &#x27;domain&#x27;: &#x27;ncbi.nlm.nih.gov&#x27;})&quot;&gt;images&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1073/pnas.96.11.6423&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="10339603">Ohshima et al. (1999)</a> characterized the progression of Fabry disease with aging in Gla-deficient mice and explored the effects of bone marrow transplantation on the phenotype. Histopathologic analysis of the deficient mice showed subclinical lesions in the Kupffer cells in the liver and macrophages in the skin with no gross lesions in the endothelial cells. Accumulation of globotriaosylceramide (Gb3) and pathologic lesions in the affected organs increased with age. Treatment with bone marrow transplantation from wildtype mice resulted in the clearance of accumulated Gb3 in the liver, spleen, and heart with concomitant elevation of Gla activity. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10339603" 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>Overexpression of alpha-galactosidase A by transduced cells results in secretion of this enzyme. Secreted enzyme is available for uptake by nontransduced cells, presumably by receptor-mediated endocytosis. Correction of bystander cells may occur locally or systemically after circulation of the enzyme in the blood. <a href="#133" class="mim-tip-reference" title="Takenaka, T., Murray, G. J., Qin, G., Quirk, J. M., Ohshima, T., Qasba, P., Clark, K., Kulkarni, A. B., Brady, R. O., Medin, J. A. &lt;strong&gt;Long-term enzyme correction and lipid reduction in multiple organs of primary and secondary transplanted Fabry mice receiving transduced bone marrow cells.&lt;/strong&gt; Proc. Nat. Acad. Sci. 97: 7515-7520, 2000.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/10840053/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;10840053&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1073/pnas.120177997&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="10840053">Takenaka et al. (2000)</a> reported studies on long-term genetic correction in an alpha-Gal A-deficient mouse model of Fabry disease. Enzyme-deficient bone marrow mononuclear cells (BMMCs) were transduced with a retrovirus encoding alpha-Gal A and transplanted into sublethally and lethally irradiated enzyme-deficient mice. Primary recipient animals were followed for up to 26 weeks. BMMCs were then transplanted into secondary recipients. Increased enzyme activity and decreased storage of globotriaosylceramide storage were observed in all recipient groups in all organs and tissues except the brain. These effects occurred even with a low percentage of transduced cells. The findings indicate that genetic correction of bone marrow cells derived from patients with Fabry disease may be useful. <a href="#105" class="mim-tip-reference" title="Qin, G., Takenaka, T., Telsch, K., Kelley, L., Howard, T., Levade, T., Deans, R., Howard, B. H., Malech, H. L., Brady, R. O., Medin, J. A. &lt;strong&gt;Preselective gene therapy for Fabry disease.&lt;/strong&gt; Proc. Nat. Acad. Sci. 98: 3428-3433, 2001.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/11248095/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;11248095&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=11248095[PMID]&amp;report=imagesdocsum&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed Image&#x27;, &#x27;domain&#x27;: &#x27;ncbi.nlm.nih.gov&#x27;})&quot;&gt;images&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1073/pnas.061020598&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="11248095">Qin et al. (2001)</a> reported marked improvement in the efficiency of the gene therapy approach for Fabry disease described by <a href="#133" class="mim-tip-reference" title="Takenaka, T., Murray, G. J., Qin, G., Quirk, J. M., Ohshima, T., Qasba, P., Clark, K., Kulkarni, A. B., Brady, R. O., Medin, J. A. &lt;strong&gt;Long-term enzyme correction and lipid reduction in multiple organs of primary and secondary transplanted Fabry mice receiving transduced bone marrow cells.&lt;/strong&gt; Proc. Nat. Acad. Sci. 97: 7515-7520, 2000.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/10840053/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;10840053&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1073/pnas.120177997&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="10840053">Takenaka et al. (2000)</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=11248095+10840053" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#61" class="mim-tip-reference" title="Ioannou, Y. A., Zeidner, K. M., Gordon, R. E., Desnick, R. J. &lt;strong&gt;Fabry disease: preclinical studies demonstrate the effectiveness of alpha-galactosidase A replacement in enzyme-deficient mice.&lt;/strong&gt; Am. J. Hum. Genet. 68: 14-25, 2001.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/11115376/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;11115376&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=11115376[PMID]&amp;report=imagesdocsum&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed Image&#x27;, &#x27;domain&#x27;: &#x27;ncbi.nlm.nih.gov&#x27;})&quot;&gt;images&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1086/316953&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="11115376">Ioannou et al. (2001)</a> demonstrated a dose-dependent clearance of tissue and plasma globotriaosylceramide in alpha-Gal A-deficient mice treated with recombinant human GLA. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11115376" 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="#102" class="mim-tip-reference" title="Prigozy, T. I., Naidenko, O., Qasba, P., Elewaut, D., Brossay, L., Khurana, A., Natori, T., Koezuka, Y., Kulkarni, A., Kronenberg, M. &lt;strong&gt;Glycolipid antigen processing for presentation by CD1d molecules.&lt;/strong&gt; Science 291: 664-667, 2001.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/11158680/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;11158680&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1126/science.291.5504.664&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="11158680">Prigozy et al. (2001)</a> found that splenic antigen-presenting cells from Gla-deficient mice could present alpha-galactosylceramide (alpha-GalCer) or 6-prime-linked alpha-GalGalCer, but not 2-prime-linked alpha-GalGalCer, to NK T-cell lines; these glycolipids are all presented by CD1D (<a href="/entry/188410">188410</a>) molecules. The authors also noted that Gla-deficient mice had a selective decrease in the number of splenic NK T cells and in their ability to respond to alpha-GalCer. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11158680" 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="#66" class="mim-tip-reference" title="Jung, S.-C., Han, I. P., Limaye, A., Xu, R., Gelderman, M. P., Zerfas, P., Tirumalai, K., Murray, G. J., During, M. J., Brady, R. O., Qasba, P. &lt;strong&gt;Adeno-associated viral vector-mediated gene transfer results in long-term enzymatic and functional correction in multiple organs of Fabry mice.&lt;/strong&gt; Proc. Nat. Acad. Sci. 98: 2676-2681, 2001.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/11226298/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;11226298&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=11226298[PMID]&amp;report=imagesdocsum&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed Image&#x27;, &#x27;domain&#x27;: &#x27;ncbi.nlm.nih.gov&#x27;})&quot;&gt;images&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1073/pnas.051634498&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="11226298">Jung et al. (2001)</a> constructed a recombinant adeno-associated virus (AAV) vector encoding the human GLA enzyme and injected it into the hepatic portal vein of Fabry mice. Two weeks postinjection, enzyme activity in the livers of the injected mice was 20 to 35% of that in normal mice. The transduced animals continued to show higher enzyme levels in liver and other tissues compared with the untouched Fabry controls as long as 6 months after treatment. In parallel to the elevated enzyme levels, significant reductions occurred in globotriaosylceramide levels to near normal at 2 and 5 weeks posttreatment. The lower Gb3 levels continued in liver, spleen, and heart up to 25 weeks with no significant immune response to the virus or the enzyme. There were no signs of liver toxicity. <a href="#66" class="mim-tip-reference" title="Jung, S.-C., Han, I. P., Limaye, A., Xu, R., Gelderman, M. P., Zerfas, P., Tirumalai, K., Murray, G. J., During, M. J., Brady, R. O., Qasba, P. &lt;strong&gt;Adeno-associated viral vector-mediated gene transfer results in long-term enzymatic and functional correction in multiple organs of Fabry mice.&lt;/strong&gt; Proc. Nat. Acad. Sci. 98: 2676-2681, 2001.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/11226298/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;11226298&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=11226298[PMID]&amp;report=imagesdocsum&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed Image&#x27;, &#x27;domain&#x27;: &#x27;ncbi.nlm.nih.gov&#x27;})&quot;&gt;images&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1073/pnas.051634498&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="11226298">Jung et al. (2001)</a> suggested that an AAV-mediated gene transfer may be useful for the treatment of Fabry disease and possibly other metabolic disorders. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11226298" 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="#132" class="mim-tip-reference" title="Takahashi, H., Hirai, Y., Migita, M., Seino, Y., Fukuda, Y., Sakuraba, H., Kase, R., Kobayashi, T., Hashimoto, Y., Shimada, T. &lt;strong&gt;Long-term systemic therapy of Fabry disease in a knockout mouse by adeno-associated virus-mediated muscle-directed gene transfer.&lt;/strong&gt; Proc. Nat. Acad. Sci. 99: 13777-13782, 2002.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/12370426/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;12370426&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=12370426[PMID]&amp;report=imagesdocsum&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed Image&#x27;, &#x27;domain&#x27;: &#x27;ncbi.nlm.nih.gov&#x27;})&quot;&gt;images&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1073/pnas.222221899&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="12370426">Takahashi et al. (2002)</a> used the AAV vector containing the alpha-Gal A gene in the treatment of Fabry disease in knockout mice. The vector containing the gene was injected into the quadriceps muscle. Elevated enzyme activity in plasma persisted for up to at least 30 weeks without development of antibodies. Enzyme activity in various organs of treated Fabry mice remained 5 to 20% of those observed in normal mice. Accumulated globotriaosylceramide in these organs was completely cleared by 25 weeks after vector injection. Echocardiographic examination of treated mice demonstrated structural improvement of cardiac hypertrophy 25 weeks after the treatment. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12370426" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<h4 href="#mimSeeAlsoFold" id="mimSeeAlsoToggle" class="mimTriangleToggle" style="cursor: pointer;" data-toggle="collapse">
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<strong>See Also:</strong>
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<a href="#Bach1982" class="mim-tip-reference" title="Bach, G., Rosenmann, E., Karni, A., Cohen, T. &lt;strong&gt;Pseudodeficiency of alpha-galactosidase A.&lt;/strong&gt; Clin. Genet. 21: 59-64, 1982.">Bach et al. (1982)</a>; <a href="#Beaudet1978" class="mim-tip-reference" title="Beaudet, A. L., Caskey, C. T. &lt;strong&gt;Detection of Fabry&#x27;s disease heterozygotes by hair root analysis.&lt;/strong&gt; Clin. Genet. 13: 251-258, 1978.">Beaudet and Caskey (1978)</a>; <a href="#Brady1967" class="mim-tip-reference" title="Brady, R. O., Gal, A. E., Bradley, R. M., Martensson, E., Warshaw, A. L., Laster, L. &lt;strong&gt;Enzymatic defect in Fabry&#x27;s disease: ceramidetrihexosidase deficiency.&lt;/strong&gt; New Eng. J. Med. 276: 1163-1167, 1967.">Brady et al. (1967)</a>; <a href="#Cable1982" class="mim-tip-reference" title="Cable, W. J. L., McCluer, R. H., Kolodny, E. H., Ullman, M. D. &lt;strong&gt;Fabry disease: detection of heterozygotes by examination of glycolipids in urinary sediment.&lt;/strong&gt; Neurology 32: 1139-1145, 1982.">Cable et al. (1982)</a>; <a href="#Colucci1982" class="mim-tip-reference" title="Colucci, W. S., Lorell, B. H., Schoen, F. J., Warhol, M. J., Grossman, W. &lt;strong&gt;Hypertrophic obstructive cardiomyopathy due to Fabry&#x27;s disease.&lt;/strong&gt; New Eng. J. Med. 307: 926-931, 1982.">Colucci et al. (1982)</a>; <a href="#Frost1966" class="mim-tip-reference" title="Frost, P., Tanaka, Y., Spaeth, G. L. &lt;strong&gt;Fabry&#x27;s disease--glycolipid lipidoses. Histochemical and electron microscopic studies of two cases.&lt;/strong&gt; Am. J. Med. 40: 618-627, 1966.">Frost et al. (1966)</a>; <a href="#Germain2001" class="mim-tip-reference" title="Germain, D. P. &lt;strong&gt;Co-occurrence and contribution of Fabry disease and Klippel-Trenaunay-Weber syndrome to a patient with atypical skin lesions.&lt;/strong&gt; Clin. Genet. 60: 63-67, 2001.">Germain (2001)</a>; <a href="#Gruber1946" class="mim-tip-reference" title="Gruber, M. &lt;strong&gt;Cornea verticillata. II. Mitteilung.&lt;/strong&gt; Ophthalmologica 112: 88-91, 1946.">Gruber (1946)</a>; <a href="#Hamers1979" class="mim-tip-reference" title="Hamers, M. N., Wise, D., Ejiofor, A., Strijland, A., Robinson, D., Tager, J. M. &lt;strong&gt;Relationship between biochemical and clinical features in an English Anderson-Fabry family.&lt;/strong&gt; Acta Med. Scand. 206: 5-10, 1979.">Hamers et al. (1979)</a>; <a href="#Hasholt1986" class="mim-tip-reference" title="Hasholt, L., Sorensen, S. A. &lt;strong&gt;Lysosomal alpha-galactosidase in endothelial cell cultures established from a Fabry hemizygous and normal umbilical veins.&lt;/strong&gt; Hum. Genet. 72: 72-76, 1986.">Hasholt and
Sorensen (1986)</a>; <a href="#Maisey1980" class="mim-tip-reference" title="Maisey, D. N., Cosh, J. A. &lt;strong&gt;Basilar artery aneurysm and Anderson-Fabry disease.&lt;/strong&gt; J. Neurol. Neurosurg. Psychiat. 43: 85-87, 1980.">Maisey and Cosh (1980)</a>; <a href="#Philippart1969" class="mim-tip-reference" title="Philippart, M., Sarlieve, L., Manacorda, A. &lt;strong&gt;Urinary glycolipids in Fabry&#x27;s disease. Their examination in the detection of atypical variants and the pre-symptomatic state.&lt;/strong&gt; Pediatrics 43: 201-206, 1969.">Philippart et al. (1969)</a>; <a href="#Pierides1976" class="mim-tip-reference" title="Pierides, A. M., Holti, G., Crombie, A. L., Roberts, D. F., Gardiner, S. E., Colling, A., Anderson, J. &lt;strong&gt;Study on a family with Anderson-Fabry&#x27;s disease and associated familial spastic paraplegia.&lt;/strong&gt; J. Med. Genet. 13: 455-461, 1976.">Pierides et al. (1976)</a>; <a href="#Pyeritz1980" class="mim-tip-reference" title="Pyeritz, R. E., Ullman, M. D., Moser, A. B., Braine, H. G., Moser, H. W. &lt;strong&gt;Plasma exchange removes glycosphingolipid in Fabry disease.&lt;/strong&gt; Am. J. Med. Genet. 7: 301-308, 1980.">Pyeritz et al. (1980)</a>; <a href="#Rahman1961" class="mim-tip-reference" title="Rahman, A. N., Simeone, F. A., Hackel, D. B., Hall, P. W., III, Hirsch, E. Z., Harris, J. W. &lt;strong&gt;Angiokeratoma corporis diffusum universale (hereditary dystopic lipidosis).&lt;/strong&gt; Trans. Assoc. Am. Phys. 74: 366-377, 1961.">Rahman et al. (1961)</a>; <a href="#Ropers1977" class="mim-tip-reference" title="Ropers, H.-H., Wienker, T., Grimm, T., Schroetter, K., Bender, K. &lt;strong&gt;Evidence for preferential X-chromosome inactivation in a family with Fabry&#x27;s disease.&lt;/strong&gt; Am. J. Hum. Genet. 29: 361-370, 1977.">Ropers et al. (1977)</a>; <a href="#Sheth1981" class="mim-tip-reference" title="Sheth, K. J., Good, T. A., Murphy, J. V. &lt;strong&gt;Heterozygote detection in Fabry disease utilizing multiple enzyme activities.&lt;/strong&gt; Am. J. Med. Genet. 10: 141-146, 1981.">Sheth et al. (1981)</a>; <a href="#Sorensen1980" class="mim-tip-reference" title="Sorensen, S. A., Hasholt, L. &lt;strong&gt;Alpha-galactosidase isozymes in normal individuals, and in Fabry homozygotes and heterozygotes.&lt;/strong&gt; Ann. Hum. Genet. 43: 313-321, 1980.">Sorensen and Hasholt
(1980)</a>; <a href="#Spada2002" class="mim-tip-reference" title="Spada, M., Pagliardini, S. &lt;strong&gt;Screening for Fabry disease in end-stage nephropathies. (Abstract)&lt;/strong&gt; J. Inherit. Metab. Dis. 25 (Suppl. 1): 113 only, 2002.">Spada and Pagliardini (2002)</a>; <a href="#Spence1978" class="mim-tip-reference" title="Spence, M. W., Clarke, J. T. R., D&#x27;Entremont, D. M., Sapp, G. A., Smith, E. R., Goldbloom, A. L., Davar, G. &lt;strong&gt;Angiokeratoma corporis diffusum (Anderson-Fabry disease) in a single family in Nova Scotia.&lt;/strong&gt; J. Med. Genet. 15: 428-434, 1978.">Spence et al. (1978)</a>; <a href="#Spence1976" class="mim-tip-reference" title="Spence, M. W., MacKinnon, K. E., Burgess, J. K., d&#x27;Entremont, D. M., Belitsky, P., Lannon, S. G., MacDonald, A. S. &lt;strong&gt;Failure to correct the metabolic defect by renal allotransplantation in Fabry&#x27;s disease.&lt;/strong&gt; Ann. Intern. Med. 84: 13-16, 1976.">Spence et
al. (1976)</a>; <a href="#Sweeley1963" class="mim-tip-reference" title="Sweeley, C. C., Klionsky, B. &lt;strong&gt;Fabry&#x27;s disease: classification as a sphingolipidosis and partial characterization of a novel glycolipid.&lt;/strong&gt; J. Biol. Chem. 238: 3148-3150, 1963.">Sweeley and Klionsky (1963)</a>; <a href="#Tagliavini1982" class="mim-tip-reference" title="Tagliavini, F., Pietrini, V., Gemignani, F., Lechi, A., Pallini, R., Federico, A. &lt;strong&gt;Anderson-Fabry&#x27;s disease: neuropathological and neurochemical investigation.&lt;/strong&gt; Acta Neuropath. 56: 93-98, 1982.">Tagliavini et al. (1982)</a>; <a href="#Wise1962" class="mim-tip-reference" title="Wise, D., Wallace, H. J., Jellinek, E. H. &lt;strong&gt;Angiokeratoma corporis diffusum: a clinical study of eight affected families.&lt;/strong&gt; Quart. J. Med. 31: 177-206, 1962.">Wise et al. (1962)</a>
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<a id="references"class="mim-anchor"></a>
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<a id="Aerts2008" class="mim-anchor"></a>
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Aerts, J. M., Groener, J. E., Kuiper, S., Donker-Kooperman, W. E., Strijland, A., Ottenhoff, R., van Roomen, C., Mirzaian, M., Wijburg, F. A., Linthorst, G. E., Vedder, A. C., Rombach, S. M., Cox-Brinkman, J., Somerharju, P., Boot, R. G., Hollak, C. E., Brady, R. O., Poorthuis, B. J.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18287059/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18287059</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18287059[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18287059" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1073/pnas.0712309105" target="_blank">Full Text</a>]
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Anderson, W.
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Asano, N., Ishii, S., Kizu, H., Ikeda, K., Yasuda, K., Kato, A., Martin, O. R., Fan, J.-Q.
<strong>In vitro inhibition and intracellular enhancement of lysosomal alpha-galactosidase A activity in Fabry lymphoblasts by 1-deoxygalactonojirimycin and its derivatives.</strong>
Europ. J. Biochem. 267: 4179-4186, 2000.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10866822/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10866822</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10866822" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1046/j.1432-1327.2000.01457.x" target="_blank">Full Text</a>]
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<a id="Auray-Blais2008" class="mim-anchor"></a>
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Auray-Blais, C., Cyr, D., Ntwari, A., West, M. L., Cox-Brinkman, J., Bichet, D. G., Germain, D. P., Laframboise, R., Melancon, S. B., Stockley, T., Clarke, J. T. R., Drouin, R.
<strong>Urinary globotriaosylceramide excretion correlates with the genotype in children and adults with Fabry disease.</strong>
Molec. Genet. Metab. 93: 331-340, 2008.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18023222/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18023222</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18023222" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1016/j.ymgme.2007.10.001" target="_blank">Full Text</a>]
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<a id="Bach1982" class="mim-anchor"></a>
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Bach, G., Rosenmann, E., Karni, A., Cohen, T.
<strong>Pseudodeficiency of alpha-galactosidase A.</strong>
Clin. Genet. 21: 59-64, 1982.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/6279339/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">6279339</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=6279339" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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Balendran, S., Oliva, P., Sansen, S., Mechtler, T. P., Streubel, B., Cobos, P. N., Lukacs, Z., Kasper, D. C.
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Clin. Genet. 97: 655-660, 2020.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31860127/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31860127</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=31860127" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1111/cge.13694" target="_blank">Full Text</a>]
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Bannwart, F.
<strong>Morbus Fabry: Licht- und Elektronenmikroskopischer Herzbefund 12 Jahre nach erfolgreicher Nierentransplantation.</strong>
Schweiz. Med. Wschr. 112: 1742-1747, 1982.
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<strong>Detection of Fabry's disease heterozygotes by hair root analysis.</strong>
Clin. Genet. 13: 251-258, 1978.
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[<a href="https://doi.org/10.1111/j.1399-0004.1978.tb01178.x" target="_blank">Full Text</a>]
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<strong>Fabry disease: six gene rearrangements and an exonic point mutation in the alpha-galactosidase gene.</strong>
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[<a href="https://doi.org/10.1172/JCI114027" target="_blank">Full Text</a>]
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<strong>Neurological manifestations of Fabry disease in female carriers.</strong>
Ann. Neurol. 4: 537-540, 1978.
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[<a href="https://doi.org/10.1002/ana.410040610" target="_blank">Full Text</a>]
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<strong>A sensitive mutation screening strategy for Fabry disease: detection of nine mutations in the alpha-galactosidase A gene.</strong>
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[<a href="https://doi.org/10.1002/(SICI)1098-1004(1996)8:1&lt;38::AID-HUMU5&gt;3.0.CO;2-L" target="_blank">Full Text</a>]
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Blom, D., Speijer, D., Linthorst, G. E., Donker-Koopman, W. G., Strijland, A., Aerts, J. M. F. G.
<strong>Recombinant enzyme therapy for Fabry disease: absence of editing of human alpha-galactosidase A mRNA.</strong>
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[<a href="https://doi.org/10.1086/345309" target="_blank">Full Text</a>]
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<strong>Enzymatic defect in Fabry's disease: ceramidetrihexosidase deficiency.</strong>
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[<a href="https://doi.org/10.1056/NEJM196705252762101" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1001/jama.284.21.2771" target="_blank">Full Text</a>]
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Branton, M. H., Schiffmann, R., Sabnis, S. G., Murray, G. J., Quirk, J. M., Altarescu, G., Goldfarb, L., Brady, R. O., Balow, J. E., Austin, H. A., III, Kopp, J. B.
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[<a href="https://doi.org/10.1097/00005792-200203000-00003" target="_blank">Full Text</a>]
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<strong>Fabry cardiomyopathy in the female confirmed by endomyocardial biopsy.</strong>
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<strong>Pulmonary involvement in Fabry disease.</strong>
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[<a href="https://doi.org/10.1164/ajrccm.155.3.9116979" target="_blank">Full Text</a>]
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Cable, W. J. L., Dvorak, A. M., Osage, J. E., Kolodny, E. H.
<strong>Fabry disease: significance of ultrastructural localization of lipid inclusions in dermal nerves.</strong>
Neurology 32: 347-353, 1982.
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[<a href="https://doi.org/10.1212/wnl.32.4.347" target="_blank">Full Text</a>]
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Cable, W. J. L., Kolodny, E. H., Adams, R. D.
<strong>Fabry disease: impaired autonomic function.</strong>
Neurology 32: 498-502, 1982.
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[<a href="https://doi.org/10.1212/wnl.32.5.498" target="_blank">Full Text</a>]
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<a id="Cable1982" class="mim-anchor"></a>
<div class="">
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Cable, W. J. L., McCluer, R. H., Kolodny, E. H., Ullman, M. D.
<strong>Fabry disease: detection of heterozygotes by examination of glycolipids in urinary sediment.</strong>
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[<a href="https://doi.org/10.1212/wnl.32.10.1139" target="_blank">Full Text</a>]
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<a id="Clarke1971" class="mim-anchor"></a>
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<strong>Ceramide trihexosidosis (Fabry's disease) without skin lesions.</strong>
New Eng. J. Med. 284: 233-235, 1971.
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[<a href="https://doi.org/10.1056/NEJM197102042840503" target="_blank">Full Text</a>]
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Clarke, J. T. R.
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[<a href="https://doi.org/10.7326/0003-4819-146-6-200703200-00007" target="_blank">Full Text</a>]
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Clement, M., McGonigle, R. J. S., Monkhouse, P. M., Keogh, A. M., Marten, R. H., Bewick, M., Parsons, V.
<strong>Renal transplantation in Anderson-Fabry disease.</strong>
J. Roy. Soc. Med. 75: 557-560, 1982.
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[<a href="https://doi.org/10.1177/014107688207500716" target="_blank">Full Text</a>]
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<a id="Colucci1982" class="mim-anchor"></a>
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Colucci, W. S., Lorell, B. H., Schoen, F. J., Warhol, M. J., Grossman, W.
<strong>Hypertrophic obstructive cardiomyopathy due to Fabry's disease.</strong>
New Eng. J. Med. 307: 926-931, 1982.
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[<a href="https://doi.org/10.1056/NEJM198210073071505" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1007/s10545-009-1254-1" target="_blank">Full Text</a>]
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Davies, J. P., Winchester, B. G., Malcolm, S.
<strong>Mutation analysis in patients with the typical form of Anderson-Fabry disease.</strong>
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[<a href="https://doi.org/10.1093/hmg/2.7.1051" target="_blank">Full Text</a>]
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<strong>Short PR intervals and tachyarrhythmias in Fabry's disease.</strong>
Postgrad. Med. J. 62: 285-287, 1986.
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[<a href="https://doi.org/10.1136/pgmj.62.726.285" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1007/BF01606034" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1007/BF00296496" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1086/318809" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1002/humu.1380030204" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1097/01.gim.0000237866.70357.c6" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1210/jc.2006-0858" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1038/4801" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1212/01.wnl.0000338566.54190.8a" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1136/adc.47.251.26" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1016/0002-9343(66)90123-9" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1007/s004390050292" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1186/1471-2350-3-10" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1111/j.1399-0004.2005.00457.x" target="_blank">Full Text</a>]
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Germain, D. P., Charrow, J., Desnick, R. J., Guffon, N., Kempf, J., Lachmann, R. H., Lemay, R., Linthorst, G. E., Packman, S., Scott, C. R., Waldek, S., Warnock, D. G., Weinreb, N. J., Wilcox, W. R.
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[<a href="https://doi.org/10.1136/jmedgenet-2014-102797" target="_blank">Full Text</a>]
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Germain, D. P., Poenaru, L.
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[<a href="https://doi.org/10.1006/bbrc.1999.0310" target="_blank">Full Text</a>]
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Germain, D. P., Weidemann, F., Abiose, A., Patel, M. R., Cizmarik, M., Cole, J. A., Beitner-Johnson, D., Benistan, K., Cabrera, G., Charrow, J., Kantola, I., Linhart, A., Nicholls, K., Niemann, M., Scott, C. R., Sims, K., Waldek, S., Warnock, D. G., Strotmann, J.
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[<a href="https://doi.org/10.1038/gim.2013.53" target="_blank">Full Text</a>]
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<strong>Co-occurrence and contribution of Fabry disease and Klippel-Trenaunay-Weber syndrome to a patient with atypical skin lesions.</strong>
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[<a href="https://doi.org/10.1034/j.1399-0004.2001.600110.x" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1159/000300313" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1159/000300370" target="_blank">Full Text</a>]
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<strong>Occurrence of celiac sprue in a patient with Fabry's disease.</strong>
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[<a href="https://doi.org/10.7326/0003-4819-83-4-524" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1111/j.0954-6820.1979.tb13460.x" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1136/jmg.27.5.303" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1007/BF00278821" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1034/j.1399-0004.2002.610605.x" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1016/0002-8703(95)90062-4" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1086/316953" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1111/j.1469-1809.1969.tb00088.x" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1111/j.1469-1809.1981.tb00317.x" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1073/pnas.051634498" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1002/ajmg.a.31600" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1126/science.167.3922.1268" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1136/jmg.38.11.769" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1016/S0140-6736(05)67635-0" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1016/0014-5793(72)80432-0" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1126/science.170.3954.180" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1016/0002-9343(80)90224-7" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1056/NEJM197308162890709" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1073/pnas.97.1.365" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1034/j.1399-0004.2003.630107.x" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1002/ajmg.1320100207" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1086/504601" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1136/jmg.15.6.428" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1056/NEJM199102073240607" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1016/j.ymgme.2018.06.004" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1023/a:1012993305223" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1086/422366" target="_blank">Full Text</a>]
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Hilary J. Vernon - updated : 12/15/2020<br>Ada Hamosh - updated : 05/07/2019<br>Cassandra L. Kniffin - updated : 6/9/2015<br>Ada Hamosh - updated : 1/8/2014<br>Ada Hamosh - updated : 1/8/2014<br>Ada Hamosh - updated : 10/3/2012<br>Cassandra L. Kniffin - updated : 8/20/2010<br>Cassandra L. Kniffin - updated : 8/16/2010<br>Cassandra L. Kniffin - updated : 4/7/2010<br>Ada Hamosh - updated : 3/26/2010<br>Cassandra L. Kniffin - updated : 12/16/2009<br>Cassandra L. Kniffin - updated : 10/19/2009<br>Cassandra L. Kniffin - updated : 3/13/2009<br>John A. Phillips, III - updated : 1/9/2009<br>Cassandra L. Kniffin - updated : 9/10/2008<br>Cassandra L. Kniffin - updated : 3/21/2008<br>Cassandra L. Kniffin - updated : 11/6/2007<br>Jane Kelly - updated : 10/19/2007<br>Ada Hamosh - updated : 7/25/2007<br>Cassandra L. Kniffin - updated : 3/30/2007<br>Cassandra L. Kniffin - reorganized : 3/28/2007<br>Cassandra L. Kniffin - updated : 3/23/2007<br>Victor A. McKusick - updated : 6/13/2006<br>Victor A. McKusick - updated : 6/8/2006<br>Cassandra L. Kniffin - updated : 4/6/2006<br>Cassandra L. Kniffin - updated : 9/23/2005<br>Marla J. F. O'Neill - updated : 7/5/2005<br>Marla J. F. O'Neill - updated : 4/20/2005<br>Marla J. F. O'Neill - updated : 9/30/2004<br>Victor A. McKusick - updated : 6/10/2004<br>Victor A. McKusick - updated : 7/21/2003<br>Victor A. McKusick - updated : 7/11/2003<br>Victor A. McKusick - updated : 6/25/2003<br>Victor A. McKusick - updated : 4/22/2003<br>Victor A. McKusick - updated : 4/17/2003<br>Victor A. McKusick - updated : 3/5/2003<br>Victor A. McKusick - updated : 2/10/2003<br>Victor A. McKusick - updated : 1/22/2003<br>Victor A. McKusick - updated : 11/22/2002<br>Michael J. Wright - updated : 10/22/2002<br>Victor A. McKusick - updated : 9/9/2002<br>Victor A. McKusick - updated : 7/3/2002<br>Victor A. McKusick - updated : 4/12/2002<br>Ada Hamosh - updated : 1/30/2002<br>Victor A. McKusick - updated : 9/5/2001<br>Victor A. McKusick - updated : 4/11/2001<br>Victor A. McKusick - updated : 3/16/2001<br>Victor A. McKusick - updated : 3/12/2001<br>Paul J. Converse - updated : 1/30/2001<br>Victor A. McKusick - updated : 1/26/2001<br>Victor A. McKusick - updated : 1/23/2001<br>Victor A. McKusick - updated : 8/16/2000<br>Victor A. McKusick - updated : 1/31/2000<br>Victor A. McKusick - updated : 11/22/1999<br>Victor A. McKusick - updated : 8/12/1999<br>Victor A. McKusick - updated : 7/14/1999<br>Victor A. McKusick - updated : 12/7/1998<br>Victor A. McKusick - updated : 4/29/1998<br>Victor A. McKusick - updated : 8/12/1997<br>Victor A. McKusick - updated : 4/21/1997<br>Moyra Smith - updated : 3/13/1996<br>Orest Hurko - updated : 9/24/1995
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Creation Date:
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Victor A. McKusick : 6/4/1986
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carol : 09/24/2022
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carol : 09/22/2022<br>carol : 02/24/2022<br>carol : 09/13/2021<br>carol : 09/11/2021<br>carol : 09/10/2021<br>carol : 09/09/2021<br>carol : 12/16/2020<br>carol : 12/15/2020<br>carol : 04/07/2020<br>carol : 04/06/2020<br>carol : 05/15/2019<br>alopez : 05/07/2019<br>carol : 06/23/2016<br>carol : 6/10/2015<br>mcolton : 6/9/2015<br>ckniffin : 6/9/2015<br>carol : 1/14/2015<br>alopez : 1/8/2014<br>alopez : 1/8/2014<br>terry : 4/4/2013<br>alopez : 10/3/2012<br>alopez : 10/3/2012<br>terry : 3/14/2011<br>carol : 3/10/2011<br>terry : 10/14/2010<br>carol : 9/14/2010<br>wwang : 9/7/2010<br>ckniffin : 8/20/2010<br>wwang : 8/18/2010<br>ckniffin : 8/16/2010<br>joanna : 6/16/2010<br>wwang : 4/13/2010<br>ckniffin : 4/7/2010<br>alopez : 3/26/2010<br>wwang : 1/7/2010<br>ckniffin : 12/16/2009<br>wwang : 11/12/2009<br>ckniffin : 10/19/2009<br>terry : 6/5/2009<br>terry : 4/13/2009<br>wwang : 3/25/2009<br>ckniffin : 3/13/2009<br>alopez : 1/9/2009<br>wwang : 9/11/2008<br>ckniffin : 9/10/2008<br>wwang : 4/1/2008<br>ckniffin : 3/21/2008<br>wwang : 11/12/2007<br>ckniffin : 11/6/2007<br>carol : 10/19/2007<br>carol : 7/27/2007<br>terry : 7/25/2007<br>wwang : 4/3/2007<br>ckniffin : 3/30/2007<br>carol : 3/28/2007<br>ckniffin : 3/23/2007<br>terry : 11/15/2006<br>alopez : 6/15/2006<br>terry : 6/13/2006<br>terry : 6/8/2006<br>wwang : 4/11/2006<br>ckniffin : 4/6/2006<br>wwang : 10/6/2005<br>ckniffin : 9/23/2005<br>ckniffin : 9/23/2005<br>wwang : 7/11/2005<br>terry : 7/5/2005<br>wwang : 6/15/2005<br>wwang : 4/28/2005<br>wwang : 4/26/2005<br>terry : 4/20/2005<br>ckniffin : 4/1/2005<br>terry : 2/2/2005<br>tkritzer : 9/30/2004<br>alopez : 6/11/2004<br>terry : 6/10/2004<br>alopez : 3/17/2004<br>terry : 11/11/2003<br>cwells : 11/10/2003<br>tkritzer : 7/31/2003<br>carol : 7/22/2003<br>terry : 7/21/2003<br>carol : 7/21/2003<br>terry : 7/11/2003<br>tkritzer : 7/11/2003<br>carol : 7/11/2003<br>tkritzer : 7/10/2003<br>terry : 6/25/2003<br>terry : 5/15/2003<br>tkritzer : 4/30/2003<br>cwells : 4/28/2003<br>cwells : 4/28/2003<br>terry : 4/22/2003<br>terry : 4/17/2003<br>carol : 3/19/2003<br>tkritzer : 3/10/2003<br>terry : 3/5/2003<br>tkritzer : 2/20/2003<br>terry : 2/10/2003<br>tkritzer : 1/22/2003<br>terry : 1/22/2003<br>cwells : 11/22/2002<br>terry : 11/20/2002<br>tkritzer : 10/30/2002<br>tkritzer : 10/23/2002<br>terry : 10/22/2002<br>alopez : 9/9/2002<br>cwells : 7/23/2002<br>terry : 7/8/2002<br>terry : 7/3/2002<br>alopez : 4/25/2002<br>cwells : 4/19/2002<br>terry : 4/12/2002<br>alopez : 2/4/2002<br>alopez : 2/4/2002<br>terry : 1/30/2002<br>alopez : 9/10/2001<br>terry : 9/5/2001<br>mcapotos : 4/18/2001<br>mcapotos : 4/16/2001<br>terry : 4/11/2001<br>mcapotos : 3/30/2001<br>mcapotos : 3/21/2001<br>terry : 3/16/2001<br>terry : 3/12/2001<br>mgross : 1/30/2001<br>mcapotos : 1/30/2001<br>terry : 1/26/2001<br>carol : 1/23/2001<br>terry : 1/23/2001<br>carol : 10/30/2000<br>carol : 8/29/2000<br>terry : 8/16/2000<br>mcapotos : 3/10/2000<br>mcapotos : 2/22/2000<br>terry : 1/31/2000<br>carol : 11/23/1999<br>terry : 11/22/1999<br>carol : 8/18/1999<br>terry : 8/12/1999<br>mgross : 7/19/1999<br>terry : 7/14/1999<br>dkim : 12/11/1998<br>carol : 12/10/1998<br>terry : 12/7/1998<br>dkim : 9/11/1998<br>carol : 7/16/1998<br>alopez : 5/21/1998<br>carol : 5/8/1998<br>terry : 4/29/1998<br>terry : 8/12/1997<br>alopez : 7/30/1997<br>alopez : 7/30/1997<br>mark : 7/8/1997<br>mark : 7/8/1997<br>carol : 6/23/1997<br>carol : 6/23/1997<br>mark : 4/21/1997<br>terry : 4/12/1997<br>jenny : 12/9/1996<br>terry : 11/25/1996<br>mark : 9/13/1996<br>carol : 8/22/1996<br>marlene : 8/2/1996<br>terry : 7/25/1996<br>terry : 4/15/1996<br>mark : 3/13/1996<br>terry : 3/13/1996<br>mark : 3/13/1996<br>mark : 3/11/1996<br>terry : 3/6/1996<br>mark : 10/19/1995<br>carol : 2/17/1995<br>pfoster : 9/1/1994<br>jason : 7/19/1994<br>warfield : 4/21/1994
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<strong>#</strong> 301500
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FABRY DISEASE
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<em>Alternative titles; symbols</em>
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ANGIOKERATOMA CORPORIS DIFFUSUM<br />
ANDERSON-FABRY DISEASE<br />
HEREDITARY DYSTOPIC LIPIDOSIS<br />
ALPHA-GALACTOSIDASE A DEFICIENCY<br />
GLA DEFICIENCY<br />
CERAMIDE TRIHEXOSIDASE DEFICIENCY
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Other entities represented in this entry:
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FABRY DISEASE, CARDIAC VARIANT, INCLUDED
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<strong>SNOMEDCT:</strong> 124464003, 16652001; &nbsp;
<strong>ICD10CM:</strong> E75.21; &nbsp;
<strong>ORPHA:</strong> 324; &nbsp;
<strong>DO:</strong> 14499; &nbsp;
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<strong>Phenotype-Gene Relationships</strong>
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Location
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Phenotype
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Phenotype <br /> MIM number
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Inheritance
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Phenotype <br /> mapping key
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Gene/Locus
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Gene/Locus <br /> MIM number
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Xq22.1
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Fabry disease, cardiac variant
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301500
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X-linked
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3
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GLA
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300644
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Xq22.1
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Fabry disease
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301500
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X-linked
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3
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GLA
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300644
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<strong>TEXT</strong>
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<p>A number sign (#) is used with this entry because Fabry disease is caused by mutations in the GLA gene (300644), encoding alpha-galactosidase A, on chromosome Xq22. A cardiac variant of Fabry disease is also caused by mutation in the GLA gene.</p>
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<strong>Description</strong>
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<p>Fabry disease is an X-linked inborn error of glycosphingolipid catabolism resulting from deficient or absent activity of the lysosomal enzyme alpha-galactosidase A. This enzymatic defect leads to the systemic accumulation of globotriaoslyceramide (Gb3) and related glycosphingolipids in the plasma and cellular lysosomes of vessels, nerves, tissues, and organs throughout the body (Nance et al., 2006). The disorder is a systemic disease, manifest as progressive renal failure, cardiac disease, cerebrovascular disease, small-fiber peripheral neuropathy, and skin lesions, among other abnormalities (Schiffmann, 2009). </p><p>An atypical variant of Fabry disease has been reported in which cardiac disease, specifically left ventricular hypertrophy, with or without renal failure, develops in the sixth decade of life. These patients have residual GLA activity (Nakao et al., 1995; Nakao et al., 2003). </p><p>Although Fabry disease was previously considered to be an X-linked recessive disorder, Wang et al. (2007) found that heterozygous women with Fabry disease experience significant life-threatening conditions requiring medical treatment and intervention. Thus, heterozygous Fabry women should not be called carriers, as this term underestimates the seriousness of the disease in these patients. </p><p>Clarke (2007) and Schiffmann (2009) provided detailed reviews of Fabry disease. </p>
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<strong>Clinical Features</strong>
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<p>In his first paper on this subject, Fabry (1898) called the skin lesions 'purpura papulosa haemorrhagica Hebrae,' suggesting that they had previously been described by Hebra, the famous Austrian dermatologist. Affected individuals had painful crises in the extremities, thought to result from lipid changes in ganglion cells of the autonomic nervous system. Attacks of pain in the abdomen may have been misdiagnosed as appendicitis or other surgical emergencies. Vascular lesions of lipid nature occurred at other sites such as the ocular fundi and kidney. Renal failure was the usual cause of death.</p><p>Hamburger et al. (1964) described a familial nephropathy, manifested clinically by proteinuria and renal insufficiency. Renal biopsy showed that the epithelial cells of the glomerular tufts and to a lesser extent the tubular epithelial cells, glomerular endocapillary cells and arteriolar muscular cells were severely deformed with a large amount of cytoplasmic inclusion material appearing lipoid in nature. The mother's father died of uremia. </p><p>Skin lesion may be lacking even in patients with severe visceral manifestations (Johnston, 1967). Furthermore, identical angiokeratoma skin lesions occur in other lysosomal disorders: (see, e.g., Patel et al., 1972 and Loonen et al., 1974). Flynn et al. (1972) described a family without skin lesions. One affected male had severe enteropathy. </p><p>Franceschetti et al. (1969) reexamined a family with 'cornea verticillata' reported by Gruber (1946) and showed that Fabry disease was responsible for the corneal change. The extent of involvement of the cornea was about the same in males and females, thus allowing affected females to be identified. The corneal condition was formerly called Fleischer vortex dystrophy, or whorl-like corneal dystrophy. Stark (1999) noted that the antimalarial drug atabrine and the antiarrhythmic drug amiodarone can also cause these changes. </p><p>Mastropasqua et al. (2006) found that although Fabry disease-related corneal verticillata attributable to glycosphingolipid accumulation was considered to be primarily a corneal disease, in vivo confocal microscopy demonstrated structural alterations throughout the entire ocular surface epithelia. Different types of corneal epithelial lesions were observed in hemizygous and heterozygous patients. </p><p>In a period of a few months at a Montreal hospital, Clarke et al. (1971) saw 2 men with Fabry disease with clear corneas and without skin lesions, suggesting that it may be a more frequent cause of proteinuria or renal failure than realized. Romeo et al. (1972) studied one of Clarke's cases and concluded that enzymatically there were differences from the classic cases. A difference from the usual form of Fabry disease is suggested by the fact that leukocyte alpha-galactosidase deficiency was only partial rather than complete (Kint, 1970). </p><p>Halsted and Rowe (1975) described a 59-year-old man with Fabry disease. In addition to his unusually advanced age, he had celiac sprue (212750), which may have been related to the presence of the HLA-8 antigen. </p><p>Roudebush et al. (1973) may have reported the first cases of 'abbreviated PR interval' in Fabry disease, which may be related to to the development of tachyarrhythmias and sudden death (Efthimiou et al., 1986). Sakuraba et al. (1986) reported a high incidence of mitral valve prolapse in male Fabry patients as well as female patients. </p><p>Ko et al. (1996) described an 'oligosymptomatic' variant of Fabry disease. A renal biopsy performed for evaluation of trace proteinuria revealed histologic and ultrastructural findings compatible with Fabry disease in a 34-year-old man with no history of renal disease in other family members. Biopsy of a few initially unrecognized, scattered, dark-pinkish scrotal papules showed typical angiokeratoma. Alpha-galactosidase was markedly decreased in urine and plasma. </p><p>MacDermot et al. (2001) studied 98 males with Fabry disease. Mean age at diagnosis was 21.9 years, and the median survival was 50 years. Neuropathic pain was present in 93 individuals (77%), with a mean pain score of 5 (scale from 0 to 10). Cerebrovascular complications were present in 24.2% of individuals studied and renal failure in 30%. High frequency sensorineural deafness was confirmed in 78% of audiograms. Attendance at school, sports, and social activities were significantly affected by Fabry disease and only 46 patients (56.6%) were employed. Psychosexual function was affected by the presence of genital angiokeratoma, genital pain, and impotence. </p><p>Branton et al. (2002) reviewed the medical records of 105 male patients with Fabry disease. Diagnosis of Fabry disease occurred later in patients without a known family history. Fifty percent of patients developed proteinuria by age 35 years and chronic renal insufficiency by age 42. Detectable residual alpha-galactosidase A activity was associated with a slower progression of Fabry renal disease, and with lower scores for renal histologic damage and renal content of globotriaosylceramide. Conservative mutations in the GLA gene were also associated with a slower progression in Fabry renal disease. </p><p>Senechal and Germain (2003) reviewed the functional and anatomical cardiac manifestations in 20 hemizygous male patients with Fabry disease. Left ventricular hypertrophy and/or concentric remodeling were found in 60% of cases; structural changes in mitral and aortic valves in 25% and 10%, respectively; and short PR interval in 40%. </p><p>Rolfs et al. (2005) found that 21 (4.9%) of 342 males and 7 (2.4%) of 289 females with cryptogenic stroke had biologically significant mutations in the GLA gene. The mean age at onset of symptomatic cerebrovascular disease was 38.4 and 40.3 years in the men and women, respectively. Approximately 30% had classic manifestations of Fabry disease. Due to the high frequency of Fabry disease (4%, 28 of 721) in this cohort of stroke patients with cryptogenic stroke aged between 18 and 55 years, Rolfs et al. (2005) suggested that Fabry disease should be considered in young patients with unexplained stroke. </p><p>Nance et al. (2006) reported a 34-year-old man who presented with chronic exercise-induced pain, cramps, and fasciculations of the legs and feet. His mother was similarly affected. Alpha-glucosidase activity was 8.8% and 13.4% of normal, respectively. </p><p>Moore et al. (2007) provided a review of the cerebral vasculopathy in Fabry disease. Patients presented more commonly with radiologic findings consistent with small-vessel disease rather than large-vessel disease, although both may occur. The posterior circulation was more commonly affected. The pathomechanism is believed to result from a combination of abnormalities of the vessel wall, blood components, such as pro- and anti-coagulants, and abnormal hemodynamics or blood flow. Schiffmann (2009) noted that patients with Fabry disease have a 20-fold increased risk of ischemic stroke and transient ischemic attacks compared to the general population. </p><p>To evaluate life expectancy and cause of death among patients with Fabry disease, Waldek et al. (2009) examined data from 2,848 patients in the Fabry Registry. Life expectancy at birth was compared with that of the United States general population. As of August 2008, 75 of 1,422 males and 12 of 1,426 females in the Fabry Registry were reported to have died. The 87 deceased patients were diagnosed at a much older age than other patients in the Fabry Registry: median age at diagnosis was 40 versus 24 years in males and 55 versus 33 years in females. Life expectancy of males with Fabry disease was 58.2 years, compared with 74.7 years in the general population of the United States. The life expectancy of females with Fabry disease was 75.4 years, compared with 80.0 years in the United States general population. The most common cause of death among both genders was cardiovascular disease. Most (57%) patients who died of cardiovascular disease had previously received renal replacement therapy. Waldek et al. (2009) concluded that most deceased Fabry Registry patients exhibited serious cardiac and renal dysfunction, and that late diagnosis may have contributed to the early deaths of these patients. </p><p>Mehta et al. (2009) reported the clinical outcomes of 1,453 Fabry patients (699 males and 754 females) from 19 countries participating in the Fabry Outcome Survey (FOS). The most frequently reported signs and symptoms were neurologic, affecting 75% of males and 61% of females. Renal failure was present in 134 males and 21 females: 89 males and 5 females had end-stage renal disease at a mean age of 32.3 and 23.3 years, respectively. Cardiac manifestations were recorded in 422 male and 376 female patients: 284 males and 180 females had left ventricular hypertrophy with onset at a mean age of 28.7 and 34.1 years, respectively. Cerebrovascular events occurred with approximately the same frequency in males and females (25% and 21%, respectively). Stroke was reported in 39 females and 63 males at mean ages of 51.4 and 39.2 years, respectively. Forty-two patients had died, including 35 males and 7 females at a mean age of 51.8 and 64.4 years, respectively. The primary cause of death in both male and female patients was cardiac disease, reported in 34% and 57%, respectively. This was in contrast to the principal causes of death among 181 affected relatives of Fabry patients who died before 2001: the most common causes of death were due to renal failure in males (42%) and cerebrovascular disease in females (25%). Overall, the data suggested that renal disease as a cause of death in patients with Fabry disease is decreasing while cardiac disease is increasing. This pattern probably reflects improvements in the management of renal disease in patients with Fabry disease. </p><p>Testai and Gorelick (2010) reviewed the pathophysiology of stroke in patients with Fabry disease. Population studies had estimated that Fabry disease is responsible for 1.2% of cryptogenic strokes in patients younger than 55 years, and women are more likely to be affected than men (27% vs 12%). Stroke may result from both cardiac (hypertrophy, arrhythmia) or vascular (stenosis, vessel occlusion, vessel dilation) factors. The posterior circulation is most commonly affected. Brain imaging may show progressive white matter lesions. </p><p><strong><em>Cardiac Variant of Fabry Disease</em></strong></p><p>
The observations of Ogawa et al. (1990), Elleder et al. (1990), Nagao et al. (1991), and von Scheidt et al. (1991) indicated that manifestations of Fabry disease can be limited to the heart. These authors suggested that Fabry disease should be considered in patients who have cardiac symptoms, such as angina, exercise intolerance, and electrocardiographic changes, but normal coronary arteries, heart size, and hemodynamic findings. Cases of Fabry disease limited to the cardiac manifestation may be identified by ultrastructural examination of endomyocardial biopsy specimens or, less invasively, by determining the plasma GLA activity in male patients with unexplained cardiac symptoms. The oldest of the patients reported with this form of the disease was a Japanese patient who died at the age of 71 years (Ogawa et al., 1990). Nagao et al. (1991) reported 2 unrelated males who developed hypertrophic cardiomyopathy after the age of 50 as their first manifestation of Fabry disease. </p><p>Von Scheidt et al. (1991) reported a 54-year-old man with the cardiac variant of Fabry disease confirmed by genetic analysis (M296V; 300644.0005). The patient had 'crescendo angina,' relieved by nitroglycerin, as well as electrocardiographic changes, but normal cardiac chamber size and normal systolic and diastolic function by echocardiogram. Cardiac catheterization showed no stenoses of the extramural coronary arteries. Diagnosis of Fabry disease was made by endomyocardial biopsy. Light-microscopic examination showed that approximately half the myocytes contained a centrally stored foamy material that stained metachromatically. By electron microscopy, typical myelin-figure-like concentric lamellar inclusions in lysosomes were observed. Most remarkably, the endothelial cells of the myocardial capillaries were not involved and no changes were observed in specimens of skeletal muscle, liver, rectum, and skin, including small blood vessels and nerves. </p><p>Nakao et al. (1995) found that 7 of 230 unrelated Japanese men with left ventricular hypertrophy had the atypical variant of Fabry disease. These 7 unrelated men, ranging in age from 55 to 72 years, did not have angiokeratoma, acroparesthesias, hypohidrosis, or corneal opacities. Endomyocardial biopsy revealed marked sarcoplasmic vacuolization in all 5 patients examined. Electron microscopy, performed on tissues from 4 of these patients, revealed typical lysosomal inclusions with a concentric lamellar configuration. Two patients had novel missense mutations in the GLA gene (300644.0051; 300644.0052). The remaining 5 patients had no mutations in the coding region of the GLA gene; however, in addition to low plasma alpha-galactosidase activity, GLA mRNA was markedly lower than normal. </p><p>Elleder et al. (1994) demonstrated storage material in the external arachnoidal epithelium of the leptomeninges in a case of cardiocyte-restricted Fabry disease. The patient, a 65-year-old male with Fabry disease who died from bile duct carcinoma, showed only cardiac symptoms and signs premortem. This pattern contrasted with the generalized leptomeningeal storage seen in typical Fabry disease. </p><p><strong><em>Female Fabry Patients</em></strong></p><p>
Romeo and Migeon (1970) reported genetic inactivation of the alpha-galactosidase locus in females patients with Fabry disease, consistent with lyonization. </p><p>Bird and Lagunoff (1978) reported 2 adult sisters with Fabry disease. They both had episodic and permanent neurologic deficits, including vertigo, tinnitus, long tract motor signs, and bladder incontinence. Broadbent et al. (1981) reported a 58-year-old female patient who had cardiac enlargement and developed heart failure. Endomyocardial biopsy showed cellular changes consistent with Fabry disease. The authors postulated unfavorable lyonization of the mutant X chromosome in cardiac tissue. Rodriguez et al. (1985) reported a 42-year-old woman with Fabry disease who had persistent proteinuria. </p><p>Mutoh et al. (1988) described an unusual degree of autonomic dysfunction, manifested by severe orthostatic hypotension, in a 21-year-old female patient. </p><p>Hasholt et al. (1990) described a girl in whom Fabry disease was suspected at the age of 18 years because of corneal opacities and tortuous retinal vessels. She had had attacks of high fever, arthralgia, and abdominal pain. Studies indicated that she suffered from a new mutation for Fabry disease; she was heterozygous. </p><p>Hillsley et al. (1995) described a 74-year-old woman with restrictive cardiomyopathy complicating conventional coronary artery disease that had been treated with angioplasty and with coronary artery bypass grafting. </p><p>MacDermot et al. (2001) reported clinical manifestations and impact of disease in 60 females with Fabry disease. The median cumulative survival was 70 years, representing an approximate reduction of 15 years from the general population. Six of 32 women had renal failure, 9 of 32 (28%) died of cerebrovascular complications, and 42 (70%) had experienced neuropathic pain. Twenty (30%) female patients had some serious or debilitating manifestation of Fabry disease. </p><p>Whybra et al. (2001) performed a comprehensive clinical evaluation on 20 females with Fabry disease. In addition to skin manifestations, various other clinical manifestations of the disease were present, including acroparesthesia, kidney dysfunction, cerebrovascular disease, and gastrointestinal and heart problems. </p><p>Pruss et al. (2006) reported a 50-year-old woman who presented with a 10-year history of paroxysmal rotational vertigo without hearing loss or tinnitus. Brain MRI revealed megadolichobasilar artery and white matter lesions. Due to a positive family history of Fabry disease, molecular analysis was performed, and a mutation was found in the GLA gene. She displayed cornea verticillata but neither angiokeratoma nor acroparesthesia. Pruss et al. (2006) postulated that the vertigo resulted from megadolichobasilar compression of the vestibulocochlear nerve. </p><p>Kim et al. (2007) reported a 38-year-old woman with Fabry disease who had acroparesthesias and anhidrosis since adolescence. She later developed gastrointestinal bloating and interstitial lung disease with progressive dyspnea requiring supplemental oxygen at all times. High-resolution CT scans showed regions of both abnormally dense and lucent lung parenchyma, reflecting a combination of ground-glass opacity and air trapping, most conspicuous in the upper lobes. There was also evidence of pulmonary hypertension. Skin examination showed cutaneous angiokeratomas and digital clubbing. Treatment with enzyme replacement therapy resulted in significant pulmonary and gastrointestinal improvement within several months. </p><p>In a review of the medical records of 44 heterozygous female patients with Fabry disease, Wang et al. (2007) concluded that female Fabry patients experience significant multisystemic disease and reduced quality of life. Acroparesthesias were the first reported symptom in 76%; most reported the first symptoms during the first 2 decades of life. Clinical features and findings included fatigue, exercise intolerance, stroke, obstructive pulmonary disease, angina, renal disease, gastrointestinal complaints, and decreased vibration sense. Eleven patients were treated with enzyme replacement therapy. Wang et al. (2007) suggested that Fabry disease should not be considered an X-linked recessive disorder and that heterozygous Fabry women should not be called carriers because they experience significant life-threatening conditions requiring medical treatment and intervention. </p>
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<strong>Other Features</strong>
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<p>Cable et al. (1982) reported impaired autonomic function in 10 patients with Fabry disease. All had decreased sweating and about half had impaired pupillary constriction and decreased saliva and tear formation. Older patients showed disordered intestinal mobility. Friedman et al. (1984) reported a patient with Fabry disease who had jejunal diverticulosis complicated by perforation and abscess formation. Microscopic examination showed glycolipid deposition in the neurons and nerve fibers of the intestinal myenteric plexus and smooth muscle. Friedman et al. (1984) concluded that uncoordinated smooth muscle activity resulting from Fabry disease caused mucosal protrusion through the smooth muscle. </p><p>Rosenberg et al. (1980) pointed out that deposition of sphingolipid in epithelial cells of the respiratory tract leads to chronic obstruction of airflow; the effect was especially apparent in smokers. </p><p>Among 25 male patients with Fabry disease, Brown et al. (1997) reported dyspnea in 36% and cough and/or wheezing in 24%. Symptoms were similar in smokers and nonsmokers. Nine (36%) had airway obstruction on spirometry; this finding was associated with age of more than 26 years and with dyspnea or wheezing, but only weakly associated with smoking. Five of 8 patients responded to bronchodilators, but all 10 methylcholine challenges were negative. Chest radiographs showed normal lung fields in 24 patients and streaky bibasilar densities in 1. Specific GLA mutations were identified in 17 patients; all 3 patients with frameshift mutations and both subjects with an N264V mutation (300644.0021) had obstructive impairment. Brown et al. (1997) concluded that airway obstruction occurs commonly in patients with Fabry disease regardless of smoking history, and that it increases with age. The presence of obstruction may be associated with certain mutations and most likely results from fixed narrowing of the airways by accumulated glycosphingolipid. </p><p>Germain et al. (2002) concluded that progressive hearing loss and sudden deafness are frequent findings in Fabry disease. Abnormal hearing was found in 12 (54.5%) of 22 hemizygous males aged 19 to 64 years: progressive hearing loss in 5 and sudden deafness in 7. Hearing loss on high-tone frequencies was found in 7 of the 10 remaining patients without clinical impairment, despite a young age. The incidence of hearing loss appeared significantly increased in patients with kidney failure or cardiovascular lesions, whereas there was no correlation with left ventricular hypertrophy. Tinnitus aurium was found in 6 patients (27%). </p><p>Germain et al. (2005) prospectively investigated bone involvement in 23 consecutive hemizygous male patients with Fabry disease using dual energy x-ray absorptiometry and found that 20 (87%) had either osteopenia or osteoporosis. The authors stated that this was the first study demonstrating that Fabry disease is associated with an increased risk of decreased bone mineral density. </p><p>Kaneski et al. (2006) observed significantly increased serum myeloperoxidase (MPO; 606989) levels in 73 male patients with Fabry disease compared to controls. Follow-up for a mean of 6 years showed that increased serum MPO was associated with increased risk for vascular events. Heterozygous female Fabry carriers also had increased MPO levels compared to controls, but the difference was not statistically significant. Long-term enzyme replacement therapy did not reduce MPO levels or eliminate the risk of vasculopathic events. Kaneski et al. (2006) hypothesized that the increased MPO in Fabry disease was produced by neutrophils in response to reactive oxygen species. </p><p>To investigate the function and morphology of the endocrine glands in patients with Fabry disease, Faggiano et al. (2006) evaluated the thyroid, gonadal, adrenal, and growth hormone/insulin-like growth factor-1 (139250/147440) axes in 18 Fabry disease patients and 18 sex- and age-matched healthy subjects. Ten of the 18 patients received enzyme replacement therapy. Fabry disease patients had higher baseline thyroid-stimulating hormone (TSH; see 188540) levels than controls (P less than 0.01). Three subjects were diagnosed with an early stage of subclinical primary hypothyroidism associated with negative antithyroid antibodies. A history of menstrual abnormalities, miscarriage, or assisted delivery was found in 89% of women with Fabry disease. Asthenozoospermia, oligozoospermia, or both were found in all men with Fabry disease through seminal fluid analysis. Fabry disease patients had significantly higher circulating ACTH and lower cortisol levels than controls (P less than 0.05). In patients under enzyme replacement therapy, a suboptimal cortisol response to the 250-microgram ACTH test was found in 10%, and the ACTH-stimulated cortisol peak was significantly correlated to the health status profile (P less than 0.05). Faggiano et al. (2006) concluded that a variety of latent endocrine dysfunctions, including life-threatening conditions (e.g., adrenal insufficiency), occur in patients with Fabry disease. Endocrine dysfunctions are also present in patients already receiving enzyme replacement therapy and are in part related to their persistent poor quality of life. </p><p>Using a personality inventory questionnaire to evaluate the psychologic profile of 28 adult patients with Fabry disease, Crosbie et al. (2009) found that the patients had significantly higher (abnormal) scores on several scales, including hypochondriasis, depression, and hysteria, compared to the general population and compared to patients with chronic heart disease. However, the psychologic profiles were similar to patients with chronic pain. Fabry patients reported high levels of pain, difficulty tolerating extreme temperatures, feeling tired or weak, and gastrointestinal problems. Fabry patients appeared preoccupied with health problems, resulting in isolation, unhappiness, worry, despair, and emotional turmoil, indicating the serious nature of this chronic debilitating disease. </p>
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<strong>Biochemical Features</strong>
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<p>Aerts et al. (2008) found that patients with Fabry disease had dramatically increased plasma deacylated Gb3 (globotriaosylsphingosine, or lyso-Gb3). The authors noted that lyso-Gb3 is highly hydrophilic, which may explain why it had been overlooked for many years. Plasma measurement of several Fabry patients, including a large Dutch family, showed marked increases of plasma lyso-Gb3 in hemizygotes at a young age. Heterozygous females carriers had mild increases of lyso-Gb3. Further studies showed that Gb3 at these concentrations promoted Gb3 storage, induced proliferation of smooth muscle cells, and inhibited GLA activity. Enzyme replacement therapy resulted in reduced, but not normalized, plasma levels of lyso-Gb3. Aerts et al. (2008) postulated that high levels of lyso-Gb3 may provide explanations for poorly understood phenomena in Fabry disease, including proliferation of smooth vascular endothelial cells, manifestations in heterozygous females, or extralysosomal accumulation of Gb3. </p><p>In 73 men with Fabry disease followed before and after enzyme replacement therapy, Schiffmann et al. (2013) found that changes in globotriaosylceramide concentrations did not appear to be useful biomarkers for prediction of Fabry disease-related changes in estimated glomerular filtration rate or left ventricular mass index. </p>
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<strong>Diagnosis</strong>
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<p>Kint (1970) showed that the activity of alpha-galactosidase is deficient in leukocytes of male patients with Fabry disease and that affected females can be identified by this method. Moser (1983) considered the urinary trihexoside assay, described by Cable et al. (1982), to be the most reliable way to identify individuals with Fabry disease. </p><p>In a Nova Scotia kindred in which 30 males had Fabry disease and there were 50 possible females with the mutation, Kirkilionis et al. (1991) used cDNA analysis of a polymorphic NcoI site 3-prime to the gene to identify females with the mutation. All of 17 females with the mutation examined were identified, including 6 who were not identified by enzyme assay. </p><p>Germain et al. (1996) used the fluorescence-assisted mismatch analysis (FAMA) method to screen the GLA gene rapidly in patients with Fabry disease. Mutations were identified in affected members of 9 unrelated kindreds. Among the 7 previously undescribed sequence changes, 3 were obviously pathogenic because they led to premature protein termination. The other 4, a splice site mutation and 3 missense mutations, were the only changes found upon complete scanning of the gene and its promoter. The authors claimed that FAMA detected female heterozygotes more dependably than direct sequencing, and thus provided a valuable diagnostic test in connection with genetic counseling since heterozygotes can be asymptomatic and their enzymatic values within the normal range. Germain and Poenaru (1999) reported further experience in the use of the fluorescent chemical cleavage of mismatches in the detection of mutations and identification of heterozygotes. </p><p>Spada et al. (2006) reported the screening of 37,104 consecutive newborn males for Fabry disease by determination of the alpha-Gal A activity in dried blood spots. Twelve neonates, or 1 in approximately 3,100 males, had deficiency of enzyme activity and GLA mutations. Molecular modeling studies and in vitro studies of mutant enzyme activity yielded a ratio of 11:1 of patients with the later-onset:classic phenotypes. The higher incidence of the later-onset phenotype in patients raised ethical issues related to when screening should be performed, in the neonatal period or at early maturity, perhaps in conjunction with screening for other treatable adult-onset disorders. </p><p>Using structural brain MRI and brain MR angiography to evaluate 25 patients with Fabry disease, Fellgiebel et al. (2009) found that patients with the disorder had significantly enlarged diameters of several cerebral arteries, including the basilar, middle cerebral, posterior cerebral, and carotid compared to controls. A total of 87% of individuals with Fabry disease could be correctly classified as affected using basilar artery diameters alone (sensitivity of 95%; specificity of 83%). The difference in basilar artery diameter was clearly superior to white matter lesion load in distinguishing between patients and controls. Fellgiebel et al. (2009) concluded that basilar artery diameters as measured by MR angiography could be used for early detection and monitoring of brain involvement in patients with Fabry disease. </p><p>Balendran et al. (2020) measured alpha-Gal A enzyme activity and lyso-GL-3 levels in dried blood spots from 11,948 females suspected of having Fabry disease, and performed GLA gene sequencing by Sanger sequencing when one or both biochemical tests were abnormal. The authors additionally performed GLA sequencing in 389 of the patients with normal alpha-Gal A enzyme activity and normal lyso-GL-3 levels. They found that low alpha-Gal A enzyme activity and elevated lyso-GL-3 had a 97% positive predictive value for a diagnosis of Fabry disease, normal alpha-Gal A enzyme activity and elevated lyso-GL-3 had a 39% positive predictive value for the diagnosis, and low alpha-Gal A enzyme activity and normal lyso-GL-3 had a 6% positive predictive value for the diagnosis. None of the females with completely normal biochemical testing had pathogenic mutations in GLA. Balendran et al. (2020) concluded that complementary diagnostic testing of alpha-Gal A activity and lyso-GL-3 improves the diagnostic value for the detection of Fabry disease in females. They therefore recommended that in females with any positive or borderline biochemical test (alpha-Gal A enzyme activity and/or lyso-GL-3), GLA gene sequencing should be performed, and that if both are normal, sequencing is not necessary. The authors noted that in males who have low alpha-Gal A enzyme activity, lyso-GL-3 testing is optional, and gene sequencing should be performed. They also noted that biochemical testing cannot be used as a standalone diagnostic test in families with an index patient or in young symptomatic individuals in whom lyso-GL-3 may be low; genetic testing is always needed in these cases. </p>
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<h4>
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<strong>Clinical Management</strong>
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<p>Eng et al. (2006) published guidelines for the evaluation and management of multiorgan system involvement in patients with Fabry disease. </p><p>Wang et al. (2011) described the ACMG standards and guidelines for the diagnostic confirmation and management of presymptomatic individuals with lysosomal storage diseases. </p><p>Wanner et al. (2018) reported a European expert consensus statement on therapeutic goals in Fabry disease. </p><p><strong><em>Renal Transplantation</em></strong></p><p>
Clement et al. (1982) reported that successful renal transplantation in Fabry disease not only corrected the anemia but also produced a marked improvement in other clinical manifestations of the disease. Bannwart (1982) described a postmortem examination 12 years after transplantation; no histologic recurrence of Fabry disease in the kidney graft was found by light or electron microscopy. In contrast, Faraggiana et al. (1981) examined the kidney of a patient who died 6 months following transplantation and found widespread recurrence of the disease in the graft. In that case, there was evidence of a circulating inhibitor of galactosidase A activity. </p><p>Friedlaender et al. (1987) presented renal biopsy data on a patient with Fabry disease before and 8 years after successful renal transplantation. The graft maintained normal function and graft histology showed no abnormalities. The patient had been able to return to work and his severe symptoms of acroparesthesia had been cured. </p><p><strong><em>Enzyme Replacement Therapy</em></strong></p><p>
Mapes et al. (1970) reported one of the first enzyme replacement strategies in Fabry disease. Two patients demonstrated a decline in the plasma level of galactosylgalactosylglucosylceramide when normal plasma was infused to provide active enzyme. </p><p>Fan et al. (1999) proposed a molecular therapeutic strategy for Fabry disease in which competitive inhibitors are administered as 'chemical chaperones' at subinhibitory intracellular concentrations to enhance residual enzyme activity in Fabry disease. Some mutant alpha-Gal A enzymes have shown kinetic properties similar to those of wildtype, but are significantly less stable, especially in conditions of neutral pH. The biosynthetic processing was delayed in cultured fibroblasts of a Fabry disease patient (Lemansky et al., 1987), and the mutant protein formed an aggregate in endoplasmic reticulum (Ishii et al., 1996), indicating that the enzyme deficiency in some mutants is mainly caused by abortive exit from the endoplasmic reticulum, leading to excessive degradation of the enzyme. Fan et al. (1999) and Asano et al. (2000) reported that 1-deoxygalactonojirimycin (DGJ), a potent competitive inhibitor of alpha-Gal A, effectively enhanced enzyme activity in Fabry disease lymphoblasts when administered in concentrations lower than those usually required for intracellular inhibition of the enzyme. DGJ seemed to accelerate transport and maturation of the mutant enzyme. Oral administration of DGJ to transgenic mice overexpressing a mutant alpha-Gal A substantially elevated enzyme activity in some organs. </p><p>Schiffmann et al. (2000) studied the safety and pharmacokinetics of intravenously administered alpha-galactosidase A produced by transfection of human skin fibroblasts in patients with Fabry disease. Infusions were well tolerated in all patients. Immunohistochemical staining of liver tissue approximately 2 days after enzyme infusion identified alpha-galactosidase A in several cell types, suggesting diffuse uptake via the mannose 6-phosphate receptor (M6PR; 154540). The tissue half-life in the liver was greater than 24 hours. The degree of substrate reduction as potentially clinically significant was observed from studies of glycosphingolipid globotriaosylceramide (also referred to as ceramidetrihexoside) levels in the patients after a single dose of alpha-galactosidase A. Brady and Schiffmann (2000) reviewed the clinical features of Fabry disease and recent advances in its therapy. They stated that their double-blind, placebo-controlled trial of intravenous infusions of alpha-galactosidase A in patients with Fabry disease demonstrated the safety and efficacy of this treatment. Eng et al. (2001) reported the results of a clinical trial of enzyme replacement in Fabry disease indicating overall safety and subjective and objective evidence of improvement. </p><p>Two differently produced enzyme preparations have independently been examined in clinical investigations for the treatment of Fabry disease: one produced by Chinese hamster ovary (CHO) cells with classic recombinant technology (agalsidase-beta, Fabrazyme), and the other produced by cultured human skin fibroblasts with an activated promoter of the alpha-Gal A gene (agalsidase-alpha, Replagal). With both preparations, promising lipid substrate reductions in tissue biopsies have been observed (Eng et al., 2001; Pastores and Thadhani, 2001; Schiffmann et al., 2001). Although it had been suggested that alpha-Gal A mRNA undergoes editing, which might result in coproduction of an edited protein with a phe396-to-tyr conversion that might have a relevant physiologic function (Novo et al., 1995), Blom et al. (2003) found no indication for the existence of editing at the protein or RNA levels in either recombinant GLA enzyme. </p><p>Waldek (2003) suggested that duration of the PR interval may be a useful marker of both the severity of cardiac disease and the response to treatment in patients with Fabry disease. In a patient who had a favorable response to enzyme replacement therapy, the PR interval and cardiac globotriaosylceramide level were restored to normal values, with an improvement in cardiac function shown by the increase in the left ventricular ejection fraction. The rapid increase in the PR interval coincided with a dramatic decline in the cardiac glycosphingolipid level. </p><p>Wilcox et al. (2004) reported that enzyme replacement therapy for 30 to 36 months with agalsidase-beta resulted in continuously decreased plasma globotriaosylceramide levels, sustained endothelial Gb3 clearance, stable kidney function, and a favorable safety profile. </p><p>Using clinical, electrocardiographic, and echocardiographic evaluation, Spinelli et al. (2004) studied 9 patients with Fabry cardiomyopathy before and after 6 and 12 months of treatment with agalsidase-beta. At 12 months, interventricular septal thickness and left ventricular mass had decreased significantly (p less than 0.01 for both), as had the difference in duration between the pulmonary vein flow velocity wave and the mitral wave at atrial systole (p less than 0.01). Spinelli et al. (2004) suggested that enzyme replacement therapy in patients with Fabry cardiomyopathy is able to reduce the left ventricular mass and ameliorate its stiffness. (Pisani (2005) stated that the p values were incorrect in the abstract but correct in the figures of the article of Spinelli et al. (2004).) </p><p>Tajima et al. (2009) designed and produced a modified alpha-N-acetylgalactosaminidase (NAGA; 104170) with alpha-galactosidase A (GLA)-like substrate specificity in Chinese hamster ovary cells. The enzyme acquired the ability to catalyze the degradation of 4-methylumbelliferyl-alpha-D-galactopyranoside, an artificial substrate of GLA, but not for a NAGA substrate. It showed stability in plasma and had mannose 6-phosphate residues for incorporation into cells. There was no immunologic crossreactivity between the modified NAGA and GLA, and the modified NAGA did not react to serum from a patient with Fabry disease treated with a recombinant GLA. In cultured fibroblasts from a patient with Fabry disease, the modified enzyme cleaved accumulated globotriaosylceramide (Gb3). Intravenous injection into Fabry mice prevented Gb3 storage in the liver, kidneys, and heart, and improved pathologic changes in these organs. Tajima et al. (2009) concluded that this modified NAGA could be a highly promising safe enzyme for treatment of Fabry disease. </p><p>Germain et al. (2013) evaluated the progression of left ventricular hypertrophy in untreated men with Fabry disease and compared them with treated men. They analyzed longitudinal Fabry Registry data from 115 men treated with 1 mg/kg agalsidase-beta for 2 weeks and 48 untreated men. Measurements included baseline left ventricular mass and at least 1 additional left ventricular mass assessment over at least 2 years. Patients were grouped into quartiles, based on left ventricular mass slopes. Multivariate logistic regression analyses identified factors associated with left ventricular hypertrophy progression. For men in whom treatment was initiated at the age of 18 to less than 30 years (n = 31), mean left ventricular mass slope was -3.6 g/year, compared with +9.5 g/year in untreated men of that age (n = 15) (p less than 0.0001). Untreated men had a 3.4-fold higher risk of having faster increases in left ventricular mass compared with treated men (odds ratio 3.43; 95% confidence interval 1.05-11.22; p = 0.0415). A baseline age of 40 or more years was also associated with left ventricular hypertrophy progression (odds ratio 5.03; 95% confidence interval 1.03-24.49; p = 0.0457) compared with men younger than 30 years. Germain et al. (2013) concluded that agalsidase-beta treatment for 2 or more years may improve or stabilize left ventricular mass in men with Fabry disease. </p><p>Germain et al. (2015) reported a 10-year follow-up of 52 Fabry patients treated with agalsidase. The mean age of patients at treatment initiation was 30 years; 11 patients were over age 40. Twenty patients had high renal involvement and 32 had low renal involvement at the onset of treatment. Most patients (81%) did not have any severe clinical events during the interval, and 94% were alive at the end of the study. Ten patients reported a total of 16 adverse events, most frequently stroke, followed by a severe renal event (dialysis, transplant) and cardiac events. Renal disease progressed in almost all patients despite treatment but was slower and less severe in those treated at a younger age and those who had low kidney involvement at the outset. The mean left ventricular posterior wall thickness and interventricular septum thickness remained unchanged and normal among treated patients. The findings indicated that treatment with agalsidase is effective in Fabry disease, and that early treatment is most beneficial. </p><p><strong><em>Gene Therapy</em></strong></p><p>
Qin et al. (2001) used a novel bicistronic retroviral vector that engineers expression of both the therapeutic GLA gene and the human IL2R-alpha chain gene (CD25; 147730) as a selectable marker. Coexpression of IL2R-alpha allowed selective immunoenrichment, preselection, of a variety of transduced human and murine cells, resulting in enhanced intracellular and secreted activities of the alpha-Gal A enzyme. The results suggested that a CD25-based preselection strategy may enhance the clinical utility of ex vivo hematopoietic stem/progenitor cell gene therapy in Fabry disease and other disorders. </p><p><strong><em>Migalastat Therapy</em></strong></p><p>
Hughes et al. (2017) performed an 18-month randomized active-controlled study to access the effects of migalastat on renal function in patients with Fabry disease previously treated with enzyme replacement therapy (ERT). Effects on heart, disease substrate, patient-reported outcomes, and safety were also assessed. Fifty-seven adults (56% female) receiving ERT (88% with multiorgan disease) were randomized (1.5:1), based on a preliminary cell-based assay of responsiveness to migalastat, to receive 18 months open-label migalastat or remain on ERT. Migalastat and ERT had similar effects on renal function. Left ventricular mass index decreased significantly with migalastat treatment (-6.6 g/m(2), range -11.0 to -2.2); there was no significant change with ERT. Predefined renal, cardiac, or cerebrovascular events occurred in 29% and 44% of patients in the migalastat and ERT groups, respectively. Plasma globotriaosylsphingosine remained low and stable following the switch from ERT to migalastat. Patient-reported outcomes were comparable between groups. Migalastat was generally safe and well tolerated. </p>
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<h4>
<span class="mim-font">
<strong>Mapping</strong>
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</h4>
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<p>Opitz et al. (1965) reported linkage between Fabry disease and the X chromosome. Johnston et al. (1969) estimated the recombination fraction of Fabry versus Xg (314700) to be 0.24 (95% probability limits, 8-49.8%) and of angiokeratoma versus deutan (303800) to be 0.17 (95% probability limits, 1-50%). Johnston and Sanger (1981) reanalyzed all data on Xg and Fabry linkage and obtained negative lod scores at all recombination rates. </p><p>MacDermot et al. (1987) found close linkage between Fabry disease and 3 DNA markers on the X chromosome: DXS87, DXS88, and DXS17, which gave maximum lod scores of 6.4, 6.4, and 5.8, respectively, at theta = 0.00. DXYS1 was not linked. </p>
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<h4>
<span class="mim-font">
<strong>Molecular Genetics</strong>
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</div>
<span class="mim-text-font">
<p>Romeo and Migeon (1970) presented evidence for a structural change in the GLA enzyme in patients with Fabry disease. The disease-associated enzymes showed slower heat inactivation and different K(m) values compared to normal. </p><p>By Southern blot analysis, Bernstein et al. (1989) found that 6 of 130 unrelated males with Fabry disease had GLA gene rearrangements. Five partial gene deletions were detected, ranging in size from 0.4 to more than 5.5 kb. Four of the 5 deletions had breakpoints in exon 2, a region containing multiple Alu repeat sequences. Kornreich et al. (1990) assessed the gene arrangements identified by Bernstein et al. (1989) to determine the possible role of Alu repetitive elements and short direct and/or inverted repeats in the generation of these germinal mutations. Although the GLA gene contains 12 Alu repetitive elements (representing about 30% of the 12-kb gene), only 1 deletion resulted from an Alu-Alu recombination. The remaining 5 rearrangements involved illegitimate recombinational events between short direct repeats of 2 to 6 bp at the deletion or duplication breakpoints. </p><p>In a patient with Fabry disease, Bernstein et al. (1989) identified a mutation in the GLA gene (300644.0001). The substitution altered the enzyme's kinetic properties and stability. Eng et al. (1993) identified 18 different mutations in the GLA gene (see, e.g., 300644.0012; 300644.0013; 300644.0018-300644.0022) in patients with Fabry disease. </p><p>Davies et al. (1993) found 7 mutations in the GLA gene in 9 unrelated families with the classic form of Fabry disease. Eng and Desnick (1994) reviewed and tabulated 15 GLA gene rearrangements, 3 GLA mRNA processing defects, and 31 GLA point mutations causing Fabry disease. </p><p>By SSCP analysis followed by sequencing of the GLA gene, Blanch et al. (1996) identified pathogenic mutations in 9 patients with classic severe Fabry disease. </p><p>In a 45-year-old man with Fabry disease who had only renal manifestations, including moderate proteinuria, Sawada et al. (1996) identified a mutation in the GLA gene (300644.0003). The mutation was inherited from his mother. The patient was unique in that he demonstrated only renal manifestations. </p><p>Verovnik et al. (2004) reported the first Slovenian family with Fabry disease in which 7 males, including a set of twins, and 10 females had a GLA mutation (N272S; 300644.0062). Affected members of the family demonstrated remarkable phenotypic heterogeneity. </p><p><strong><em>Modifier Genes</em></strong></p><p>
Endothelial nitric oxide synthase (NOS3; 163729) plays a key role in the regulation of normal function of the vessel wall. Heltianu et al. (2002) found a relatively high frequency of 2 polymorphic variants of NOS3 in males with Fabry disease and suggested that in addition to mutations in the alpha-galactosidase A gene, variation in NOS3 may be significant in determining the phenotype. </p>
</span>
<div>
<br />
</div>
<div>
<h4>
<span class="mim-font">
<strong>Genotype/Phenotype Correlations</strong>
</span>
</h4>
</div>
<span class="mim-text-font">
<p>Among 32 children and 78 adults with Fabry disease, Auray-Blais et al. (2008) identified 35 different mutations in the GLA gene, including missense (76.4%), nonsense (16.4%), frameshift (3.6%), and splice site defects (3.6%). Forty-one of the patients were being treated with enzyme replacement therapy. Although there was a wide range within each mutation group, a significant correlation existed between genotype and urinary Gb3/creatinine excretion among untreated patients, with missense mutations resulting in lower levels in general. There were also correlations between urinary Gb3/creatinine excretion and sex and between urinary Gb3/creatinine excretion and treatment. There was no correlation with age. Auray-Blais et al. (2008) developed and utilized a multiplex liquid chromatography-tandem mass spectrometry methodology that allowed for simultaneous analysis of urinary Gb3 and creatinine eluted from the same filter paper sample. </p><p>Oliveira et al. (2020) reported 11 symptomatic Portuguese males from 10 families with Fabry disease who had a hemizygous F113L (300644.0063) mutation in the GLA gene. All of the patients had a late-onset form of the disorder, manifesting with a cardiac phenotype invariably including cardiomyopathy/hypertrophic cardiomyopathy, and often including other features such as conduction defects, arrhythmias, and myocardial ischemia. Some patients also had cerebrovascular or kidney involvement, although the association with the GLA mutation was confounded by the presence of other risk factors (e.g., hypertension, diabetes, obesity). None of the patients had acroparesthesias, sweating problems, heat intolerance, or multiple angiokeratomas. Seven of 8 patients tested had normal corneas. </p>
</span>
<div>
<br />
</div>
<div>
<h4>
<span class="mim-font">
<strong>Population Genetics</strong>
</span>
</h4>
</div>
<span class="mim-text-font">
<p>The incidence of Fabry disease has been estimated at 1 in 55,000 male births. However, this figure is almost certainly a substantial underestimate of the true frequency, particularly of milder variants of the disease (Clarke, 2007). </p><p>Based on a newborn screening study, Spada et al. (2006) estimated that the incidence of Fabry disease may be 1 in 3,100 to 4,600 individuals. </p><p>Oliveira et al. (2020) reported 13 males with Fabry disease, including 11 symptomatic Portuguese males from 10 families and 2 Italian males identified by newborn screening, who had a hemizygous F113L (300644.0063) mutation in the GLA gene. Microsatellite analysis showed that all of the alleles were on the same GLA haplotype, suggesting inheritance from a common ancestor. Oliveira et al. (2020) stated that due to the late-onset presentation associated with this mutation, it is not expected to reduce the reproductive fitness of affected individuals. Oliveira et al. (2020) stated that the F113L mutation is the most frequent mutation identified in Portuguese individuals with Fabry disease. </p><p>Koto et al. (2021) surveyed hospitals in Japan for information about patients with lysosomal storage diseases (LSDs) treated between 2013-2016 and 2018-2019. Fabry disease was the most common LSD, with 339 patients identified, of whom 31% had the classic form, 8.6% had the late-onset form, and 46.6% were heterozygous females; for 13.9%, there was no additional information. When these data were extrapolated across Japan, Koto et al. (2021) estimated that there were 1,658 patients with Fabry disease, including 770 heterozygous females. They calculated a birth prevalence of Fabry disease in Japan of 1.25 per 100,000, which was lower than the previously estimated birth prevalence of 14.7 per 100,000 based on newborn screening. Koto et al. (2021) suggested that the discrepancy may be due to underdiagnosis of late-onset Fabry disease patients and heterozygous females. </p>
</span>
<div>
<br />
</div>
<div>
<h4>
<span class="mim-font">
<strong>Nomenclature</strong>
</span>
</h4>
</div>
<span class="mim-text-font">
<p>Skin lesions of vascular nature are the basis of the name 'angiokeratoma.' Since angiokeratoma occurs with some other lysosomal diseases and may be missing in Fabry disease, the use of the eponym 'Fabry disease' is preferred, even though it ignores the important contribution of Anderson (1898). Fabry, of Dortmund, Germany, wrote about the disorder first in 1898 and again in 1930.</p>
</span>
<div>
<br />
</div>
<div>
<h4>
<span class="mim-font">
<strong>History</strong>
</span>
</h4>
</div>
<span class="mim-text-font">
<p>Peltier et al. (1977) reported male twins with Fabry disease but normal alpha-galactosidase and normality of several other lysosomal enzymes including alpha-fucosidase. The authors referred to this as 'pseudo-clinical Fabry disease.' </p>
</span>
<div>
<br />
</div>
<div>
<h4>
<span class="mim-font">
<strong>Animal Model</strong>
</span>
</h4>
</div>
<span class="mim-text-font">
<p>Ohshima et al. (1997) generated Gla-deficient mice by gene targeting. The knockout mice displayed a complete lack of alpha-galactosidase A activity but appeared clinically normal at 10 weeks of age. Ultrastructural analysis revealed concentric lamellar inclusions in the kidneys, and confocal microscopy using a fluorescent-labeled lectin specific for alpha-D-galactosyl residues showed accumulation of substrate in the kidneys as well as in cultured fibroblasts. Lipid analysis revealed a marked accumulation of ceramide trihexaside in the liver and the kidneys. The deficiency of enzyme activity and the accumulation of material containing terminal alpha-galactosyl residues in cultured embryonic fibroblasts derived from the knockout mice were corrected by transducing these cells with human GLA cDNA. </p><p>Ohshima et al. (1999) characterized the progression of Fabry disease with aging in Gla-deficient mice and explored the effects of bone marrow transplantation on the phenotype. Histopathologic analysis of the deficient mice showed subclinical lesions in the Kupffer cells in the liver and macrophages in the skin with no gross lesions in the endothelial cells. Accumulation of globotriaosylceramide (Gb3) and pathologic lesions in the affected organs increased with age. Treatment with bone marrow transplantation from wildtype mice resulted in the clearance of accumulated Gb3 in the liver, spleen, and heart with concomitant elevation of Gla activity. </p><p>Overexpression of alpha-galactosidase A by transduced cells results in secretion of this enzyme. Secreted enzyme is available for uptake by nontransduced cells, presumably by receptor-mediated endocytosis. Correction of bystander cells may occur locally or systemically after circulation of the enzyme in the blood. Takenaka et al. (2000) reported studies on long-term genetic correction in an alpha-Gal A-deficient mouse model of Fabry disease. Enzyme-deficient bone marrow mononuclear cells (BMMCs) were transduced with a retrovirus encoding alpha-Gal A and transplanted into sublethally and lethally irradiated enzyme-deficient mice. Primary recipient animals were followed for up to 26 weeks. BMMCs were then transplanted into secondary recipients. Increased enzyme activity and decreased storage of globotriaosylceramide storage were observed in all recipient groups in all organs and tissues except the brain. These effects occurred even with a low percentage of transduced cells. The findings indicate that genetic correction of bone marrow cells derived from patients with Fabry disease may be useful. Qin et al. (2001) reported marked improvement in the efficiency of the gene therapy approach for Fabry disease described by Takenaka et al. (2000). </p><p>Ioannou et al. (2001) demonstrated a dose-dependent clearance of tissue and plasma globotriaosylceramide in alpha-Gal A-deficient mice treated with recombinant human GLA. </p><p>Prigozy et al. (2001) found that splenic antigen-presenting cells from Gla-deficient mice could present alpha-galactosylceramide (alpha-GalCer) or 6-prime-linked alpha-GalGalCer, but not 2-prime-linked alpha-GalGalCer, to NK T-cell lines; these glycolipids are all presented by CD1D (188410) molecules. The authors also noted that Gla-deficient mice had a selective decrease in the number of splenic NK T cells and in their ability to respond to alpha-GalCer. </p><p>Jung et al. (2001) constructed a recombinant adeno-associated virus (AAV) vector encoding the human GLA enzyme and injected it into the hepatic portal vein of Fabry mice. Two weeks postinjection, enzyme activity in the livers of the injected mice was 20 to 35% of that in normal mice. The transduced animals continued to show higher enzyme levels in liver and other tissues compared with the untouched Fabry controls as long as 6 months after treatment. In parallel to the elevated enzyme levels, significant reductions occurred in globotriaosylceramide levels to near normal at 2 and 5 weeks posttreatment. The lower Gb3 levels continued in liver, spleen, and heart up to 25 weeks with no significant immune response to the virus or the enzyme. There were no signs of liver toxicity. Jung et al. (2001) suggested that an AAV-mediated gene transfer may be useful for the treatment of Fabry disease and possibly other metabolic disorders. </p><p>Takahashi et al. (2002) used the AAV vector containing the alpha-Gal A gene in the treatment of Fabry disease in knockout mice. The vector containing the gene was injected into the quadriceps muscle. Elevated enzyme activity in plasma persisted for up to at least 30 weeks without development of antibodies. Enzyme activity in various organs of treated Fabry mice remained 5 to 20% of those observed in normal mice. Accumulated globotriaosylceramide in these organs was completely cleared by 25 weeks after vector injection. Echocardiographic examination of treated mice demonstrated structural improvement of cardiac hypertrophy 25 weeks after the treatment. </p>
</span>
<div>
<br />
</div>
</div>
<div>
<h4>
<span class="mim-font">
<strong>See Also:</strong>
</span>
</h4>
<span class="mim-text-font">
Bach et al. (1982); Beaudet and Caskey (1978); Brady et al. (1967);
Cable et al. (1982); Colucci et al. (1982); Frost et al. (1966);
Germain (2001); Gruber (1946); Hamers et al. (1979); Hasholt and
Sorensen (1986); Maisey and Cosh (1980); Philippart et al. (1969);
Pierides et al. (1976); Pyeritz et al. (1980); Rahman et al. (1961);
Ropers et al. (1977); Sheth et al. (1981); Sorensen and Hasholt
(1980); Spada and Pagliardini (2002); Spence et al. (1978); Spence et
al. (1976); Sweeley and Klionsky (1963); Tagliavini et al. (1982);
Wise et al. (1962)
</span>
<div>
<br />
</div>
</div>
<div>
<h4>
<span class="mim-font">
<strong>REFERENCES</strong>
</span>
</h4>
<div>
<p />
</div>
<div>
<ol>
<li>
<p class="mim-text-font">
Aerts, J. M., Groener, J. E., Kuiper, S., Donker-Kooperman, W. E., Strijland, A., Ottenhoff, R., van Roomen, C., Mirzaian, M., Wijburg, F. A., Linthorst, G. E., Vedder, A. C., Rombach, S. M., Cox-Brinkman, J., Somerharju, P., Boot, R. G., Hollak, C. E., Brady, R. O., Poorthuis, B. J.
<strong>Elevated globotriaosylsphingosine is a hallmark of Fabry disease.</strong>
Proc. Nat. Acad. Sci. 105: 2812-2817, 2008.
[PubMed: 18287059]
[Full Text: https://doi.org/10.1073/pnas.0712309105]
</p>
</li>
<li>
<p class="mim-text-font">
Anderson, W.
<strong>A case of &#x27;angeio-keratoma&#x27;.</strong>
Brit. J. Derm. 10: 113-117, 1898.
</p>
</li>
<li>
<p class="mim-text-font">
Asano, N., Ishii, S., Kizu, H., Ikeda, K., Yasuda, K., Kato, A., Martin, O. R., Fan, J.-Q.
<strong>In vitro inhibition and intracellular enhancement of lysosomal alpha-galactosidase A activity in Fabry lymphoblasts by 1-deoxygalactonojirimycin and its derivatives.</strong>
Europ. J. Biochem. 267: 4179-4186, 2000.
[PubMed: 10866822]
[Full Text: https://doi.org/10.1046/j.1432-1327.2000.01457.x]
</p>
</li>
<li>
<p class="mim-text-font">
Auray-Blais, C., Cyr, D., Ntwari, A., West, M. L., Cox-Brinkman, J., Bichet, D. G., Germain, D. P., Laframboise, R., Melancon, S. B., Stockley, T., Clarke, J. T. R., Drouin, R.
<strong>Urinary globotriaosylceramide excretion correlates with the genotype in children and adults with Fabry disease.</strong>
Molec. Genet. Metab. 93: 331-340, 2008.
[PubMed: 18023222]
[Full Text: https://doi.org/10.1016/j.ymgme.2007.10.001]
</p>
</li>
<li>
<p class="mim-text-font">
Bach, G., Rosenmann, E., Karni, A., Cohen, T.
<strong>Pseudodeficiency of alpha-galactosidase A.</strong>
Clin. Genet. 21: 59-64, 1982.
[PubMed: 6279339]
</p>
</li>
<li>
<p class="mim-text-font">
Balendran, S., Oliva, P., Sansen, S., Mechtler, T. P., Streubel, B., Cobos, P. N., Lukacs, Z., Kasper, D. C.
<strong>Diagnostic strategy for females suspected of Fabry disease.</strong>
Clin. Genet. 97: 655-660, 2020.
[PubMed: 31860127]
[Full Text: https://doi.org/10.1111/cge.13694]
</p>
</li>
<li>
<p class="mim-text-font">
Bannwart, F.
<strong>Morbus Fabry: Licht- und Elektronenmikroskopischer Herzbefund 12 Jahre nach erfolgreicher Nierentransplantation.</strong>
Schweiz. Med. Wschr. 112: 1742-1747, 1982.
[PubMed: 6294821]
</p>
</li>
<li>
<p class="mim-text-font">
Beaudet, A. L., Caskey, C. T.
<strong>Detection of Fabry&#x27;s disease heterozygotes by hair root analysis.</strong>
Clin. Genet. 13: 251-258, 1978.
[PubMed: 205381]
[Full Text: https://doi.org/10.1111/j.1399-0004.1978.tb01178.x]
</p>
</li>
<li>
<p class="mim-text-font">
Bernstein, H. S., Bishop, D. F., Astrin, K. H., Kornreich, R., Eng, C. M., Sakuraba, H., Desnick, R. J.
<strong>Fabry disease: six gene rearrangements and an exonic point mutation in the alpha-galactosidase gene.</strong>
J. Clin. Invest. 83: 1390-1399, 1989.
[PubMed: 2539398]
[Full Text: https://doi.org/10.1172/JCI114027]
</p>
</li>
<li>
<p class="mim-text-font">
Bird, T. D., Lagunoff, D.
<strong>Neurological manifestations of Fabry disease in female carriers.</strong>
Ann. Neurol. 4: 537-540, 1978.
[PubMed: 217299]
[Full Text: https://doi.org/10.1002/ana.410040610]
</p>
</li>
<li>
<p class="mim-text-font">
Blanch, L. C., Meaney, C., Morris, C. P.
<strong>A sensitive mutation screening strategy for Fabry disease: detection of nine mutations in the alpha-galactosidase A gene.</strong>
Hum. Mutat. 8: 38-43, 1996.
[PubMed: 8807334]
[Full Text: https://doi.org/10.1002/(SICI)1098-1004(1996)8:1&lt;38::AID-HUMU5&gt;3.0.CO;2-L]
</p>
</li>
<li>
<p class="mim-text-font">
Blom, D., Speijer, D., Linthorst, G. E., Donker-Koopman, W. G., Strijland, A., Aerts, J. M. F. G.
<strong>Recombinant enzyme therapy for Fabry disease: absence of editing of human alpha-galactosidase A mRNA.</strong>
Am. J. Hum. Genet. 72: 23-31, 2003.
[PubMed: 12471562]
[Full Text: https://doi.org/10.1086/345309]
</p>
</li>
<li>
<p class="mim-text-font">
Brady, R. O., Gal, A. E., Bradley, R. M., Martensson, E., Warshaw, A. L., Laster, L.
<strong>Enzymatic defect in Fabry&#x27;s disease: ceramidetrihexosidase deficiency.</strong>
New Eng. J. Med. 276: 1163-1167, 1967.
[PubMed: 6023233]
[Full Text: https://doi.org/10.1056/NEJM196705252762101]
</p>
</li>
<li>
<p class="mim-text-font">
Brady, R. O., Schiffmann, R.
<strong>Clinical features of and recent advances in therapy for Fabry disease.</strong>
JAMA 284: 2771-2775, 2000. Note: Erratum: JAMA 285: 169 only, 2001.
[PubMed: 11105184]
[Full Text: https://doi.org/10.1001/jama.284.21.2771]
</p>
</li>
<li>
<p class="mim-text-font">
Branton, M. H., Schiffmann, R., Sabnis, S. G., Murray, G. J., Quirk, J. M., Altarescu, G., Goldfarb, L., Brady, R. O., Balow, J. E., Austin, H. A., III, Kopp, J. B.
<strong>Natural history of Fabry renal disease: influence of alpha-galactosidase A activity and genetic mutations on clinical course.</strong>
Medicine 81: 122-138, 2002.
[PubMed: 11889412]
[Full Text: https://doi.org/10.1097/00005792-200203000-00003]
</p>
</li>
<li>
<p class="mim-text-font">
Broadbent, J. C., Edwards, W. D., Gordon, H., Hartzler, G. O., Krawisz, J. E.
<strong>Fabry cardiomyopathy in the female confirmed by endomyocardial biopsy.</strong>
Mayo Clin. Proc. 56: 623-628, 1981.
[PubMed: 6268901]
</p>
</li>
<li>
<p class="mim-text-font">
Brown, L. K., Miller, A., Bhuptani, A., Sloane, M. F., Zimmerman, M. I., Schilero, G., Eng, C. M., Desnick, R. J.
<strong>Pulmonary involvement in Fabry disease.</strong>
Am. J. Resp. Crit. Care Med. 155: 1004-1010, 1997.
[PubMed: 9116979]
[Full Text: https://doi.org/10.1164/ajrccm.155.3.9116979]
</p>
</li>
<li>
<p class="mim-text-font">
Cable, W. J. L., Dvorak, A. M., Osage, J. E., Kolodny, E. H.
<strong>Fabry disease: significance of ultrastructural localization of lipid inclusions in dermal nerves.</strong>
Neurology 32: 347-353, 1982.
[PubMed: 6278363]
[Full Text: https://doi.org/10.1212/wnl.32.4.347]
</p>
</li>
<li>
<p class="mim-text-font">
Cable, W. J. L., Kolodny, E. H., Adams, R. D.
<strong>Fabry disease: impaired autonomic function.</strong>
Neurology 32: 498-502, 1982.
[PubMed: 6803189]
[Full Text: https://doi.org/10.1212/wnl.32.5.498]
</p>
</li>
<li>
<p class="mim-text-font">
Cable, W. J. L., McCluer, R. H., Kolodny, E. H., Ullman, M. D.
<strong>Fabry disease: detection of heterozygotes by examination of glycolipids in urinary sediment.</strong>
Neurology 32: 1139-1145, 1982.
[PubMed: 6289188]
[Full Text: https://doi.org/10.1212/wnl.32.10.1139]
</p>
</li>
<li>
<p class="mim-text-font">
Clarke, J. T., Knaack, J., Crawhall, J. C., Wolfe, L. S.
<strong>Ceramide trihexosidosis (Fabry&#x27;s disease) without skin lesions.</strong>
New Eng. J. Med. 284: 233-235, 1971.
[PubMed: 5539345]
[Full Text: https://doi.org/10.1056/NEJM197102042840503]
</p>
</li>
<li>
<p class="mim-text-font">
Clarke, J. T. R.
<strong>Narrative review: Fabry disease.</strong>
Ann. Intern. Med. 146: 425-433, 2007.
[PubMed: 17371887]
[Full Text: https://doi.org/10.7326/0003-4819-146-6-200703200-00007]
</p>
</li>
<li>
<p class="mim-text-font">
Clement, M., McGonigle, R. J. S., Monkhouse, P. M., Keogh, A. M., Marten, R. H., Bewick, M., Parsons, V.
<strong>Renal transplantation in Anderson-Fabry disease.</strong>
J. Roy. Soc. Med. 75: 557-560, 1982.
[PubMed: 6283080]
[Full Text: https://doi.org/10.1177/014107688207500716]
</p>
</li>
<li>
<p class="mim-text-font">
Colucci, W. S., Lorell, B. H., Schoen, F. J., Warhol, M. J., Grossman, W.
<strong>Hypertrophic obstructive cardiomyopathy due to Fabry&#x27;s disease.</strong>
New Eng. J. Med. 307: 926-931, 1982.
[PubMed: 6810178]
[Full Text: https://doi.org/10.1056/NEJM198210073071505]
</p>
</li>
<li>
<p class="mim-text-font">
Crosbie, T. W., Packman, W., Packman, S.
<strong>Psychological aspects of patients with Fabry disease.</strong>
J. Inherit. Metab. Dis. 32: 745-753, 2009.
[PubMed: 19924564]
[Full Text: https://doi.org/10.1007/s10545-009-1254-1]
</p>
</li>
<li>
<p class="mim-text-font">
Davies, J. P., Winchester, B. G., Malcolm, S.
<strong>Mutation analysis in patients with the typical form of Anderson-Fabry disease.</strong>
Hum. Molec. Genet. 2: 1051-1053, 1993.
[PubMed: 8395937]
[Full Text: https://doi.org/10.1093/hmg/2.7.1051]
</p>
</li>
<li>
<p class="mim-text-font">
Efthimiou, J., McLelland, J., Betteridge, D. J.
<strong>Short PR intervals and tachyarrhythmias in Fabry&#x27;s disease.</strong>
Postgrad. Med. J. 62: 285-287, 1986.
[PubMed: 3086855]
[Full Text: https://doi.org/10.1136/pgmj.62.726.285]
</p>
</li>
<li>
<p class="mim-text-font">
Elleder, M., Bradova, V., Smid, F., Budesinsky, M., Harzer, K., Kustermann-Kuhn, B., Ledvinova, J., Belohlavek, (NI), Kral, V., Dorazilova, V.
<strong>Cardiocyte storage and hypertrophy as a sole manifestation of Fabry&#x27;s disease: report on a case simulating hypertrophic non-obstructive cardiomyopathy.</strong>
Virchows Arch. A Pathol. Anat. Histopathol. 417: 449-455, 1990.
[PubMed: 2173254]
[Full Text: https://doi.org/10.1007/BF01606034]
</p>
</li>
<li>
<p class="mim-text-font">
Elleder, M., Christomanou, H., Kustermann-Kuhn, B., Harzer, K.
<strong>Leptomeningeal lipid storage patterns in Fabry disease.</strong>
Acta Neuropath. 88: 579-582, 1994.
[PubMed: 7879606]
[Full Text: https://doi.org/10.1007/BF00296496]
</p>
</li>
<li>
<p class="mim-text-font">
Eng, C. M., Banikazemi, M., Gordon, R. E., Goldman, M., Phelps, R., Kim, L., Gass, A., Winston, J., Dikman, S., Fallon, J. T., Brodie, S., Stacy, C. B., Mehta, D., Parsons, R., Norton, K., O'Callaghan, M., Desnick, R. J.
<strong>A phase 1/2 clinical trial of enzyme replacement in Fabry disease: pharmacokinetic, substrate clearance, and safety studies.</strong>
Am. J. Hum. Genet. 68: 711-722, 2001.
[PubMed: 11179018]
[Full Text: https://doi.org/10.1086/318809]
</p>
</li>
<li>
<p class="mim-text-font">
Eng, C. M., Desnick, R. J.
<strong>Molecular basis of Fabry disease: mutations and polymorphisms in the human alpha-galactosidase A gene.</strong>
Hum. Mutat. 3: 103-111, 1994.
[PubMed: 7911050]
[Full Text: https://doi.org/10.1002/humu.1380030204]
</p>
</li>
<li>
<p class="mim-text-font">
Eng, C. M., Germain, D. P., Banikazemi, M., Warnock, D. G., Wanner, C., Hopkin, R. J., Bultas, J., Lee, P., Sims, K., Brodie, S. E., Pastores, G. M., Strotmann, J. M., Wilcox, W. R.
<strong>Fabry disease: guidelines for the evaluation and management of the multi-organ system involvement.</strong>
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<br />
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</div>
</div>
<div>
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<div class="col-lg-1 col-md-1 col-sm-2 col-xs-2">
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Contributors:
</span>
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Hilary J. Vernon - updated : 09/10/2021<br>Hilary J. Vernon - updated : 12/15/2020<br>Ada Hamosh - updated : 05/07/2019<br>Cassandra L. Kniffin - updated : 6/9/2015<br>Ada Hamosh - updated : 1/8/2014<br>Ada Hamosh - updated : 1/8/2014<br>Ada Hamosh - updated : 10/3/2012<br>Cassandra L. Kniffin - updated : 8/20/2010<br>Cassandra L. Kniffin - updated : 8/16/2010<br>Cassandra L. Kniffin - updated : 4/7/2010<br>Ada Hamosh - updated : 3/26/2010<br>Cassandra L. Kniffin - updated : 12/16/2009<br>Cassandra L. Kniffin - updated : 10/19/2009<br>Cassandra L. Kniffin - updated : 3/13/2009<br>John A. Phillips, III - updated : 1/9/2009<br>Cassandra L. Kniffin - updated : 9/10/2008<br>Cassandra L. Kniffin - updated : 3/21/2008<br>Cassandra L. Kniffin - updated : 11/6/2007<br>Jane Kelly - updated : 10/19/2007<br>Ada Hamosh - updated : 7/25/2007<br>Cassandra L. Kniffin - updated : 3/30/2007<br>Cassandra L. Kniffin - reorganized : 3/28/2007<br>Cassandra L. Kniffin - updated : 3/23/2007<br>Victor A. McKusick - updated : 6/13/2006<br>Victor A. McKusick - updated : 6/8/2006<br>Cassandra L. Kniffin - updated : 4/6/2006<br>Cassandra L. Kniffin - updated : 9/23/2005<br>Marla J. F. O&#x27;Neill - updated : 7/5/2005<br>Marla J. F. O&#x27;Neill - updated : 4/20/2005<br>Marla J. F. O&#x27;Neill - updated : 9/30/2004<br>Victor A. McKusick - updated : 6/10/2004<br>Victor A. McKusick - updated : 7/21/2003<br>Victor A. McKusick - updated : 7/11/2003<br>Victor A. McKusick - updated : 6/25/2003<br>Victor A. McKusick - updated : 4/22/2003<br>Victor A. McKusick - updated : 4/17/2003<br>Victor A. McKusick - updated : 3/5/2003<br>Victor A. McKusick - updated : 2/10/2003<br>Victor A. McKusick - updated : 1/22/2003<br>Victor A. McKusick - updated : 11/22/2002<br>Michael J. Wright - updated : 10/22/2002<br>Victor A. McKusick - updated : 9/9/2002<br>Victor A. McKusick - updated : 7/3/2002<br>Victor A. McKusick - updated : 4/12/2002<br>Ada Hamosh - updated : 1/30/2002<br>Victor A. McKusick - updated : 9/5/2001<br>Victor A. McKusick - updated : 4/11/2001<br>Victor A. McKusick - updated : 3/16/2001<br>Victor A. McKusick - updated : 3/12/2001<br>Paul J. Converse - updated : 1/30/2001<br>Victor A. McKusick - updated : 1/26/2001<br>Victor A. McKusick - updated : 1/23/2001<br>Victor A. McKusick - updated : 8/16/2000<br>Victor A. McKusick - updated : 1/31/2000<br>Victor A. McKusick - updated : 11/22/1999<br>Victor A. McKusick - updated : 8/12/1999<br>Victor A. McKusick - updated : 7/14/1999<br>Victor A. McKusick - updated : 12/7/1998<br>Victor A. McKusick - updated : 4/29/1998<br>Victor A. McKusick - updated : 8/12/1997<br>Victor A. McKusick - updated : 4/21/1997<br>Moyra Smith - updated : 3/13/1996<br>Orest Hurko - updated : 9/24/1995
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Victor A. McKusick : 6/4/1986
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carol : 09/24/2022<br>carol : 09/22/2022<br>carol : 02/24/2022<br>carol : 09/13/2021<br>carol : 09/11/2021<br>carol : 09/10/2021<br>carol : 09/09/2021<br>carol : 12/16/2020<br>carol : 12/15/2020<br>carol : 04/07/2020<br>carol : 04/06/2020<br>carol : 05/15/2019<br>alopez : 05/07/2019<br>carol : 06/23/2016<br>carol : 6/10/2015<br>mcolton : 6/9/2015<br>ckniffin : 6/9/2015<br>carol : 1/14/2015<br>alopez : 1/8/2014<br>alopez : 1/8/2014<br>terry : 4/4/2013<br>alopez : 10/3/2012<br>alopez : 10/3/2012<br>terry : 3/14/2011<br>carol : 3/10/2011<br>terry : 10/14/2010<br>carol : 9/14/2010<br>wwang : 9/7/2010<br>ckniffin : 8/20/2010<br>wwang : 8/18/2010<br>ckniffin : 8/16/2010<br>joanna : 6/16/2010<br>wwang : 4/13/2010<br>ckniffin : 4/7/2010<br>alopez : 3/26/2010<br>wwang : 1/7/2010<br>ckniffin : 12/16/2009<br>wwang : 11/12/2009<br>ckniffin : 10/19/2009<br>terry : 6/5/2009<br>terry : 4/13/2009<br>wwang : 3/25/2009<br>ckniffin : 3/13/2009<br>alopez : 1/9/2009<br>wwang : 9/11/2008<br>ckniffin : 9/10/2008<br>wwang : 4/1/2008<br>ckniffin : 3/21/2008<br>wwang : 11/12/2007<br>ckniffin : 11/6/2007<br>carol : 10/19/2007<br>carol : 7/27/2007<br>terry : 7/25/2007<br>wwang : 4/3/2007<br>ckniffin : 3/30/2007<br>carol : 3/28/2007<br>ckniffin : 3/23/2007<br>terry : 11/15/2006<br>alopez : 6/15/2006<br>terry : 6/13/2006<br>terry : 6/8/2006<br>wwang : 4/11/2006<br>ckniffin : 4/6/2006<br>wwang : 10/6/2005<br>ckniffin : 9/23/2005<br>ckniffin : 9/23/2005<br>wwang : 7/11/2005<br>terry : 7/5/2005<br>wwang : 6/15/2005<br>wwang : 4/28/2005<br>wwang : 4/26/2005<br>terry : 4/20/2005<br>ckniffin : 4/1/2005<br>terry : 2/2/2005<br>tkritzer : 9/30/2004<br>alopez : 6/11/2004<br>terry : 6/10/2004<br>alopez : 3/17/2004<br>terry : 11/11/2003<br>cwells : 11/10/2003<br>tkritzer : 7/31/2003<br>carol : 7/22/2003<br>terry : 7/21/2003<br>carol : 7/21/2003<br>terry : 7/11/2003<br>tkritzer : 7/11/2003<br>carol : 7/11/2003<br>tkritzer : 7/10/2003<br>terry : 6/25/2003<br>terry : 5/15/2003<br>tkritzer : 4/30/2003<br>cwells : 4/28/2003<br>cwells : 4/28/2003<br>terry : 4/22/2003<br>terry : 4/17/2003<br>carol : 3/19/2003<br>tkritzer : 3/10/2003<br>terry : 3/5/2003<br>tkritzer : 2/20/2003<br>terry : 2/10/2003<br>tkritzer : 1/22/2003<br>terry : 1/22/2003<br>cwells : 11/22/2002<br>terry : 11/20/2002<br>tkritzer : 10/30/2002<br>tkritzer : 10/23/2002<br>terry : 10/22/2002<br>alopez : 9/9/2002<br>cwells : 7/23/2002<br>terry : 7/8/2002<br>terry : 7/3/2002<br>alopez : 4/25/2002<br>cwells : 4/19/2002<br>terry : 4/12/2002<br>alopez : 2/4/2002<br>alopez : 2/4/2002<br>terry : 1/30/2002<br>alopez : 9/10/2001<br>terry : 9/5/2001<br>mcapotos : 4/18/2001<br>mcapotos : 4/16/2001<br>terry : 4/11/2001<br>mcapotos : 3/30/2001<br>mcapotos : 3/21/2001<br>terry : 3/16/2001<br>terry : 3/12/2001<br>mgross : 1/30/2001<br>mcapotos : 1/30/2001<br>terry : 1/26/2001<br>carol : 1/23/2001<br>terry : 1/23/2001<br>carol : 10/30/2000<br>carol : 8/29/2000<br>terry : 8/16/2000<br>mcapotos : 3/10/2000<br>mcapotos : 2/22/2000<br>terry : 1/31/2000<br>carol : 11/23/1999<br>terry : 11/22/1999<br>carol : 8/18/1999<br>terry : 8/12/1999<br>mgross : 7/19/1999<br>terry : 7/14/1999<br>dkim : 12/11/1998<br>carol : 12/10/1998<br>terry : 12/7/1998<br>dkim : 9/11/1998<br>carol : 7/16/1998<br>alopez : 5/21/1998<br>carol : 5/8/1998<br>terry : 4/29/1998<br>terry : 8/12/1997<br>alopez : 7/30/1997<br>alopez : 7/30/1997<br>mark : 7/8/1997<br>mark : 7/8/1997<br>carol : 6/23/1997<br>carol : 6/23/1997<br>mark : 4/21/1997<br>terry : 4/12/1997<br>jenny : 12/9/1996<br>terry : 11/25/1996<br>mark : 9/13/1996<br>carol : 8/22/1996<br>marlene : 8/2/1996<br>terry : 7/25/1996<br>terry : 4/15/1996<br>mark : 3/13/1996<br>terry : 3/13/1996<br>mark : 3/13/1996<br>mark : 3/11/1996<br>terry : 3/6/1996<br>mark : 10/19/1995<br>carol : 2/17/1995<br>pfoster : 9/1/1994<br>jason : 7/19/1994<br>warfield : 4/21/1994
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