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<title>
Entry
- #102700 - SEVERE COMBINED IMMUNODEFICIENCY, AUTOSOMAL RECESSIVE, T CELL-NEGATIVE, B CELL-NEGATIVE, NK CELL-NEGATIVE, DUE TO ADENOSINE DEAMINASE DEFICIENCY
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<span class="h4">#102700</span>
<br />
<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/102700"><strong>Clinical Synopsis</strong></a>
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<a href="/phenotypicSeries/PS601457"> <strong>Phenotypic Series</strong> </a>
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<a href="#text"><strong>Text</strong></a>
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<a href="#otherFeatures">Other Features</a>
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<a href="#pathogenesis">Pathogenesis</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="#inheritance">Inheritance</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="#animalModel">Animal Model</a>
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<a href="#references"><strong>References</strong></a>
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<a href="#contributors"><strong>Contributors</strong></a>
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<div><a href="https://clinicaltrials.gov/search?cond=SEVERE COMBINED IMMUNODEFICIENCY, AUTOSOMAL RECESSIVE, T CELL-NEGATIVE, B CELL-NEGATIVE, NK CELL-NEGATIVE, DUE TO ADENOSINE DEAMINASE DEFICIENCY" 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/gtr/all/tests/?term=102700[mim]" class="mim-tip-hint" title="Genetic Testing Registry." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'GTR', 'domain': 'ncbi.nlm.nih.gov'})">GTR</a></div>
<div><a href="https://www.acmg.net/PDFLibrary/SCID.pdf" class="mim-tip-hint" title="Information and resources for newborn screening and genetics." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Newborn Screening', 'domain': 'www.acmg.net'})">Newborn Screening</a></div>
<div><a href="https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=277" 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>
</div>
</div>
</div>
<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
<div class="panel-heading mim-panel-heading" role="tab" id="mimAnimalModels">
<span class="panel-title">
<span class="small">
<a href="#mimAnimalModelsLinksFold" id="mimAnimalModelsLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
<div style="display: table-row">
<div id="mimAnimalModelsLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">&#9658;</div>
&nbsp;
<div style="display: table-cell;">Animal Models</div>
</div>
</a>
</span>
</span>
</div>
<div id="mimAnimalModelsLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
<div class="panel-body small mim-panel-body">
<div><a href="https://www.alliancegenome.org/disease/DOID:5810" 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/102700" 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:5810" 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:102700" 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> 22406001<br />
<strong>ICD10CM:</strong> D81.31<br />
<strong>ORPHA:</strong> 277<br />
<strong>DO:</strong> 5810<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>
102700
</span>
</span>
</div>
</div>
<div>
<a id="preferredTitle" class="mim-anchor"></a>
<h3>
<span class="mim-font">
SEVERE COMBINED IMMUNODEFICIENCY, AUTOSOMAL RECESSIVE, T CELL-NEGATIVE, B CELL-NEGATIVE, NK CELL-NEGATIVE, DUE TO ADENOSINE DEAMINASE DEFICIENCY
</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">
SCID DUE TO ADA DEFICIENCY<br />
ADA-SCID<br />
SCID DUE TO ADA DEFICIENCY, EARLY-ONSET
</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">
SCID DUE TO ADA DEFICIENCY, DELAYED ONSET, INCLUDED
</span>
</div>
<div>
<span class="h4 mim-font">
SCID DUE TO ADA DEFICIENCY, LATE-ONSET, INCLUDED<br />
ADENOSINE DEAMINASE DEFICIENCY, PARTIAL, INCLUDED<br />
PARTIAL ADA DEFICIENCY, 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/20/314?start=-3&limit=10&highlight=314">
20q13.12
</a>
</span>
</td>
<td>
<span class="mim-font">
Adenosine deaminase deficiency, partial
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/102700"> 102700 </a>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>, <abbr class="mim-tip-hint" title="Somatic mosaicism">SMo</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">
ADA
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/608958"> 608958 </a>
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/20/314?start=-3&limit=10&highlight=314">
20q13.12
</a>
</span>
</td>
<td>
<span class="mim-font">
Severe combined immunodeficiency due to ADA deficiency
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/102700"> 102700 </a>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>, <abbr class="mim-tip-hint" title="Somatic mosaicism">SMo</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">
ADA
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/608958"> 608958 </a>
</span>
</td>
</tr>
</tbody>
</table>
</div>
</div>
<div>
<div class="btn-group ">
<a href="/clinicalSynopsis/102700" 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">
<a href="/phenotypicSeries/PS601457" class="btn btn-info" role="button"> Phenotypic Series </a>
<button type="button" id="mimPhenotypicSeriesToggle" class="btn btn-info dropdown-toggle mimSingletonFoldToggle" data-toggle="collapse" href="#mimPhenotypicSeriesFold" onclick="ga('send', 'event', 'Unfurl', 'PhenotypicSeries', '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/102700" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Linear'})"> Linear </a></li>
<li><a href="/graph/radial/102700" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Radial'})"> Radial </a></li>
</ul>
</div>
<span class="glyphicon glyphicon-question-sign mim-tip-hint" title="OMIM PheneGene graphics depict relationships between phenotypes, groups of related phenotypes (Phenotypic Series), and genes.<br /><a href='/static/omim/pdf/OMIM_Graphics.pdf' target='_blank'>A quick reference overview and guide (PDF)</a>"></span>
<div>
<p />
</div>
<div id="mimClinicalSynopsisFold" class="well well-sm collapse mimSingletonToggleFold">
<div class="small" style="margin: 5px">
<div>
<div>
<span class="h5 mim-font">
<strong> INHERITANCE </strong>
</span>
</div>
<div style="margin-left: 2em;">
<div>
<span class="mim-font">
- Autosomal recessive <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/258211005" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">258211005</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0441748&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0441748</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000007" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000007</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000007" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000007</a>]</span><br /> -
Somatic mosaicism <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C5848753&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C5848753</a>, <a href="https://bioportal.bioontology.org/search?q=C1866227&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1866227</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001442" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001442</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001442" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001442</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">
- Failure to thrive <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/432788009" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">432788009</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/54840006" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">54840006</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/783.41" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">783.41</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0015544&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0015544</a>, <a href="https://bioportal.bioontology.org/search?q=C2315100&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C2315100</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001508" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001508</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001508" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001508</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> Nasopharynx </em>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
- Sinusitis <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/36971009" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">36971009</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/J32" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">J32</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0037199&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0037199</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000246" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000246</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000246" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000246</a>]</span><br />
</span>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<em> Airways </em>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
- Asthma <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/195967001" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">195967001</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/J45.909" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">J45.909</a>, <a href="https://purl.bioontology.org/ontology/ICD10CM/J45" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">J45</a>, <a href="https://purl.bioontology.org/ontology/ICD10CM/J45.90" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">J45.90</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/493.9" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">493.9</a>, <a href="https://purl.bioontology.org/ontology/ICD9CM/493" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">493</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0004096&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0004096</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002099" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002099</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002099" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002099</a>]</span><br />
</span>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<em> Lung </em>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
- Pneumonia <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/233604007" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">233604007</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0032285&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0032285</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002090" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002090</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002090" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002090</a>]</span><br />
</span>
</div>
</div>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<strong> CHEST </strong>
</span>
</div>
<div style="margin-left: 2em;">
<div>
<div>
<span class="h5 mim-font">
<em> External Features </em>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
- Cupping and flaring of costochondral junctions <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C3150009&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C3150009</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> Liver </em>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
- Hepatomegaly <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/80515008" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">80515008</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/R16.0" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">R16.0</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/789.1" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">789.1</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0019209&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0019209</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002240" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002240</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002240" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002240</a>]</span><br />
</span>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<em> Spleen </em>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
- Splenomegaly <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/16294009" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">16294009</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/R16.1" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">R16.1</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/789.2" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">789.2</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0038002&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0038002</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001744" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001744</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001744" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001744</a>]</span><br />
</span>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<em> Gastrointestinal </em>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
- Diarrhea <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/267060006" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">267060006</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/62315008" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">62315008</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/R19.7" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">R19.7</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/787.91" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">787.91</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0011991&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0011991</a>, <a href="https://bioportal.bioontology.org/search?q=C2169706&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C2169706</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002014" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002014</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002014" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002014</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">
- Mesangial sclerosis <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/111406002" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">111406002</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0268747&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0268747</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001967" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001967</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001967" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001967</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> Spine </em>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
- Platyspondyly <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1844704&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1844704</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000926" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000926</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000926" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000926</a>]</span><br />
</span>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<em> Pelvis </em>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
- Pelvic dysplasia <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1863247&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1863247</a>]</span><br />
</span>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<em> Limbs </em>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
- Thick growth arrest lines <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1863248&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1863248</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">
- Autoimmune hemolytic anemia <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/413603009" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">413603009</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/283.0" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">283.0</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0002880&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0002880</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001890" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001890</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001890" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001890</a>]</span><br /> -
Idiopathic thrombocytopenia <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/13172003" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">13172003</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/D69.3" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">D69.3</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/287.31" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">287.31</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0920163&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0920163</a>, <a href="https://bioportal.bioontology.org/search?q=C0398650&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0398650</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001973" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001973</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001973" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001973</a>]</span><br /> -
Eosinophilia <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/386789004" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">386789004</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/D72.10" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">D72.10</a>, <a href="https://purl.bioontology.org/ontology/ICD10CM/D72.1" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">D72.1</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/288.3" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">288.3</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0014457&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0014457</a>, <a href="https://bioportal.bioontology.org/search?q=C2240374&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C2240374</a>, <a href="https://bioportal.bioontology.org/search?q=C1306759&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1306759</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001880" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001880</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001880" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001880</a>]</span><br />
</span>
</div>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<strong> IMMUNOLOGY </strong>
</span>
</div>
<div style="margin-left: 2em;">
<div>
<span class="mim-font">
- Frequent fungal, viral, and opportunistic infections <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1863242&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1863242</a>]</span><br /> -
Lymphopenia <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/48813009" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">48813009</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/D72.810" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">D72.810</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/288.51" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">288.51</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0853986&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0853986</a>, <a href="https://bioportal.bioontology.org/search?q=C0024312&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0024312</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001888" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001888</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001888" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001888</a>]</span><br /> -
Absent B cells <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1863715&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1863715</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0005365" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0005365</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0005365" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0005365</a>]</span><br /> -
Absent T cells <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1863243&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1863243</a>]</span><br /> -
Absent or reduced CD3+ cells <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1863244&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1863244</a>]</span><br /> -
Absent or small dysplastic thymus <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1863245&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1863245</a>]</span><br /> -
Absent specific antibody response <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1863246&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1863246</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0005424" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0005424</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0005424" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0005424</a>]</span><br />
</span>
</div>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<strong> NEOPLASIA </strong>
</span>
</div>
<div style="margin-left: 2em;">
<div>
<span class="mim-font">
- B-cell lymphoma <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/413616009" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">413616009</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/109979007" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">109979007</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0079731&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0079731</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0012191" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0012191</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0012191" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0012191</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">
- Reduced erythrocyte adenosine deaminase activity <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1863249&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1863249</a>]</span><br /> -
Increased IgE levels <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0236175&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0236175</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003212" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003212</a>]</span><br /> -
Low or absent IgA levels <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1863250&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1863250</a>]</span><br /> -
Low or absent IgM levels <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1863251&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1863251</a>]</span><br /> -
Absent IgG2 subclass <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1863252&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1863252</a>]</span><br /> -
CD4+/CD8+ ratio often reversed <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1863253&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1863253</a>]</span><br /> -
Elevated serum levels of adenosine <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1863254&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1863254</a>]</span><br /> -
Elevated serum levels of 2-prime deoxyadenosine <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1863255&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1863255</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">
- Late onset combined immunodeficiency with allelic variant <a href="/entry/102700#0020">102700.0020</a><br /> -
85-90% with manifestations in first months of life<br /> -
10-15% with primarily defects of cellular immunity, not manifesting until >2yrs of age<br /> -
Recurrent bacterial, viral, and fungal infections <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1855778&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1855778</a>]</span><br /> -
Treatment with polyethylene glycol-modified bovine ADA, bone marrow transplantation, and/or gene therapy<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 the adenosine deaminase gene (ADA, <a href="/entry/608958#0001">608958.0001</a>)<br />
</span>
</div>
</div>
</div>
<div class="text-right">
<a href="#mimClinicalSynopsisFold" data-toggle="collapse">&#9650;&nbsp;Close</a>
</div>
</div>
</div>
<div id="mimPhenotypicSeriesFold" class="well well-sm collapse mimSingletonToggleFold">
<div class="small">
<div class="row">
<div class="col-lg-12 col-md-12 col-sm-12 col-xs-12">
<h5>
Severe combined immunodeficiency (select examples)
- <a href="/phenotypicSeries/PS601457">PS601457</a>
- 19 Entries
</h5>
</div>
</div>
<div class="row" style="margin-left: 0.125em; margin-right: 0.125em;">
<table class="table table-bordered table-condensed table-hover mim-table-padding">
<thead>
<tr>
<th class="col-lg-1 col-md-1 col-sm-1 col-xs-1 text-nowrap">
<strong>Location</strong>
</th>
<th class="col-lg-5 col-md-5 col-sm-5 col-xs-6 text-nowrap">
<strong>Phenotype</strong>
</th>
<th class="col-lg-1 col-md-1 col-sm-1 col-xs-1 text-nowrap">
<strong>Inheritance</strong>
</th>
<th class="col-lg-1 col-md-1 col-sm-1 col-xs-1 text-nowrap">
<strong>Phenotype<br />mapping key</strong>
</th>
<th class="col-lg-1 col-md-1 col-sm-1 col-xs-1 text-nowrap">
<strong>Phenotype<br />MIM number</strong>
</th>
<th class="col-lg-1 col-md-1 col-sm-1 col-xs-1 text-nowrap">
<strong>Gene/Locus</strong>
</th>
<th class="col-lg-1 col-md-1 col-sm-1 col-xs-1 text-nowrap">
<strong>Gene/Locus<br />MIM number</strong>
</th>
</tr>
</thead>
<tbody>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/1/411?start=-3&limit=10&highlight=411"> 1p35.1 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/267500"> Reticular dysgenesis </a>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/267500"> 267500 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/103020"> AK2 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/103020"> 103020 </a>
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/1/1541?start=-3&limit=10&highlight=1541"> 1q31.3-q32.1 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/619924"> Immunodeficiency 105, severe combined </a>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/619924"> 619924 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/151460"> PTPRC </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/151460"> 151460 </a>
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/2/1028?start=-3&limit=10&highlight=1028"> 2q35 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/611291"> Immunodeficiency 124, severe combined </a>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/611291"> 611291 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/611290"> NHEJ1 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/611290"> 611290 </a>
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/5/106?start=-3&limit=10&highlight=106"> 5p13.2 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/608971"> Immunodeficiency 104, severe combined </a>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/608971"> 608971 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/146661"> IL7R </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/146661"> 146661 </a>
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/10/70?start=-3&limit=10&highlight=70"> 10p13 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/603554"> Omenn syndrome </a>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/603554"> 603554 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/605988"> DCLRE1C </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/605988"> 605988 </a>
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/10/70?start=-3&limit=10&highlight=70"> 10p13 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/602450"> Severe combined immunodeficiency, Athabascan type </a>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/602450"> 602450 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/605988"> DCLRE1C </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/605988"> 605988 </a>
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/11/316?start=-3&limit=10&highlight=316"> 11p12 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/601457"> Severe combined immunodeficiency, B cell-negative </a>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/601457"> 601457 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/179615"> RAG1 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/179615"> 179615 </a>
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/11/316?start=-3&limit=10&highlight=316"> 11p12 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/603554"> Omenn syndrome </a>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/603554"> 603554 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/179615"> RAG1 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/179615"> 179615 </a>
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/11/317?start=-3&limit=10&highlight=317"> 11p12 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/601457"> Severe combined immunodeficiency, B cell-negative </a>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/601457"> 601457 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/179616"> RAG2 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/179616"> 179616 </a>
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/11/317?start=-3&limit=10&highlight=317"> 11p12 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/603554"> Omenn syndrome </a>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/603554"> 603554 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/179616"> RAG2 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/179616"> 179616 </a>
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/11/981?start=-3&limit=10&highlight=981"> 11q23.3 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/615615"> Immunodeficiency 18, SCID variant </a>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/615615"> 615615 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/186830"> CD3E </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/186830"> 186830 </a>
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/11/981?start=-3&limit=10&highlight=981"> 11q23.3 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/615615"> Immunodeficiency 18 </a>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/615615"> 615615 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/186830"> CD3E </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/186830"> 186830 </a>
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/11/982?start=-3&limit=10&highlight=982"> 11q23.3 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/615617"> Immunodeficiency 19, severe combined </a>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/615617"> 615617 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/186790"> CD3D </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/186790"> 186790 </a>
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/14/515?start=-3&limit=10&highlight=515"> 14q32.2 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/617237"> Immunodeficiency 49, severe combined </a>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</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">
<a href="/entry/617237"> 617237 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/606558"> BCL11B </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/606558"> 606558 </a>
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/16/187?start=-3&limit=10&highlight=187"> 16p13.13 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/209920"> MHC class II deficiency 1 </a>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/209920"> 209920 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/600005"> CIITA </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/600005"> 600005 </a>
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/19/447?start=-3&limit=10&highlight=447"> 19p13.11 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/600802"> Severe combined immunodeficiency, autosomal recessive, T-negative/B-positive type </a>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/600802"> 600802 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/600173"> JAK3 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/600173"> 600173 </a>
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/20/314?start=-3&limit=10&highlight=314"> 20q13.12 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/102700"> Adenosine deaminase deficiency, partial </a>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>, <abbr class="mim-tip-hint" title="Somatic mosaicism">SMo</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">
<a href="/entry/102700"> 102700 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/608958"> ADA </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/608958"> 608958 </a>
</span>
</td>
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<a href="/geneMap/20/314?start=-3&limit=10&highlight=314"> 20q13.12 </a>
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<a href="/entry/102700"> Severe combined immunodeficiency due to ADA deficiency </a>
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<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>, <abbr class="mim-tip-hint" title="Somatic mosaicism">SMo</abbr>
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<a href="/entry/102700"> 102700 </a>
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<a href="/entry/608958"> ADA </a>
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<a href="/entry/608958"> 608958 </a>
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<a href="/geneMap/X/403?start=-3&limit=10&highlight=403"> Xq13.1 </a>
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<a href="/entry/300400"> Severe combined immunodeficiency, X-linked </a>
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<abbr class="mim-tip-hint" title="X-linked recessive">XLR</abbr>
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<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
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<a href="/entry/300400"> 300400 </a>
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<a href="/entry/308380"> IL2RG </a>
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<a href="/entry/308380"> 308380 </a>
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<p>A number sign (#) is used with this entry because T cell-negative (T-), B cell-negative (B-), natural killer cell-negative (NK-) severe combined immunodeficiency (SCID) is caused by homozygous or compound heterozygous mutation in the adenosine deaminase gene (ADA; <a href="/entry/608958">608958</a>) on chromosome 20q13.</p><p>For a general phenotypic description and a discussion of genetic heterogeneity of autosomal recessive SCID, see <a href="/entry/601457">601457</a>.</p>
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<p>Severe combined immunodeficiency (SCID) resulting from inherited ADA deficiency causes a variable phenotypic spectrum, the most severe being SCID presenting in infancy and usually resulting in early death. Ten to 15% of patients have a 'delayed' clinical onset by age 6 to 24 months, and a smaller percentage of patients have 'later' onset, diagnosed from ages 4 years to adulthood, showing less severe infections and gradual immunologic deterioration. Finally, 'partial' ADA deficiency occurs in a subset of immunocompetent individuals who show decreased enzyme activity in erythrocytes, but retain substantial enzyme activity ranging from 5 to 80% of normal in leukocytes and other nucleated cells (summary by <a href="#9" class="mim-tip-reference" title="Arredondo-Vega, F. X., Santisteban, I., Kelly, S., Schlossman, C. M., Umetsu, D. T., Hershfield, M. S. &lt;strong&gt;Correct splicing despite mutation of the invariant first nucleotide of a 5-prime splice site: a possible basis for disparate clinical phenotypes in siblings with adenosine deaminase deficiency.&lt;/strong&gt; Am. J. Hum. Genet. 54: 820-830, 1994.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/8178821/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;8178821&lt;/a&gt;]" pmid="8178821">Arredondo-Vega et al., 1994</a>). ADA deficiency accounts for approximately 15% of all SCID cases and one-third of cases of autosomal recessive SCID (<a href="#39" class="mim-tip-reference" title="Hershfield, M. S. &lt;strong&gt;Genotype is an important determinant of phenotype in adenosine deaminase deficiency.&lt;/strong&gt; Curr. Opin. Immun. 15: 571-577, 2003.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/14499267/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;14499267&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/s0952-7915(03)00104-3&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="14499267">Hershfield, 2003</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=8178821+14499267" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><strong><em>Early-Onset SCID</em></strong></p><p>
<a href="#33" class="mim-tip-reference" title="Giblett, E. R., Anderson, J. E., Cohen, F., Pollara, B., Meuwissen, H. J. &lt;strong&gt;Adenosine-deaminase deficiency in two patients with severely impaired cellular immunity.&lt;/strong&gt; Lancet 300: 1067-1069, 1972. Note: Originally Volume II.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/4117384/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;4117384&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/s0140-6736(72)92345-8&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="4117384">Giblett et al. (1972)</a> reported 2 unrelated girls with impaired cellular immunity and absence of red cell adenosine deaminase activity. One child, aged 22 months, had recurrent respiratory infections, candidiasis, and marked lymphopenia from birth. The other, aged 3.5 years, was allegedly normal in the first 2 years of life. Mild upper respiratory infections began at age 24 months and progressed to severe pulmonary insufficiency and hepatosplenomegaly by age 30 months. The parents of the first child were related and the second child had a sister who died as a result of a major immunologic defect (<a href="#52" class="mim-tip-reference" title="Hong, R., Gatti, R., Rathbun, J. C., Good, R. A. &lt;strong&gt;Thymic hypoplasia and thyroid dysfunction.&lt;/strong&gt; New Eng. J. Med. 282: 470-474, 1970.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/5413970/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;5413970&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1056/NEJM197002262820903&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="5413970">Hong et al., 1970</a>). The finding that both pairs of parents had an intermediate level of red cell ADA supported recessive inheritance; the parents of the first child had about a 50% level of normal, whereas the parents of the second child had about a 66% level. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=4117384+5413970" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#75" class="mim-tip-reference" title="Parkman, R., Gelfand, E. W., Rosen, F. S., Sanderson, A., Hirschhorn, R. &lt;strong&gt;Severe combined immunodeficiency and adenosine deaminase deficiency.&lt;/strong&gt; New Eng. J. Med. 292: 714-719, 1975.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/1089883/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;1089883&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1056/NEJM197504032921402&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="1089883">Parkman et al. (1975)</a> reported 3 affected infants from 2 families with SCID due to ADA deficiency inherited in an autosomal recessive pattern. None of the infants had detectable erythrocyte ADA activity. Two infants had successful bone marrow transplantation with restoration of normal cellular and humoral immunity, but erythrocytic ADA deficiency persisted. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1089883" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>Reporting on a workshop on SCID due to ADA deficiency, <a href="#68" class="mim-tip-reference" title="Meuwissen, H. J., Pollara, B., Pickering, R. J. &lt;strong&gt;Combined immunodeficiency disease associated with adenosine deaminase deficiency (report on a workshop held in Albany, New York, October 1, 1973).&lt;/strong&gt; J. Pediat. 86: 169-181, 1975.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/1089440/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;1089440&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/s0022-3476(75)80463-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="1089440">Meuwissen et al. (1975)</a> noted that the phenotype is transmitted as an autosomal recessive disorder. Some patients had characteristic skeletal abnormalities, and all had thymic involution with Hassall's corpuscles and differentiated germinal epithelium. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1089440" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#39" class="mim-tip-reference" title="Hershfield, M. S. &lt;strong&gt;Genotype is an important determinant of phenotype in adenosine deaminase deficiency.&lt;/strong&gt; Curr. Opin. Immun. 15: 571-577, 2003.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/14499267/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;14499267&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/s0952-7915(03)00104-3&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="14499267">Hershfield (2003)</a> stated that red cell 2-prime-deoxyadenosine triphosphate (dATP; dAXP), a substrate of adenosine deaminase, is elevated by 30-fold to greater than 1,500-fold in SCID patients. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14499267" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>Delayed or Late-Onset SCID</em></strong></p><p>
<a href="#81" class="mim-tip-reference" title="Santisteban, I., Arredondo-Vega, F. X., Kelly, S., Mary, A., Fischer, A., Hummell, D. S., Lawton, A., Sorensen, R. U., Stiehm, E. R., Uribe, L., Weinberg, K., Hershfield, M. S. &lt;strong&gt;Novel splicing, missense, and deletion mutations in seven adenosine deaminase-deficient patients with late/delayed onset of combined immunodeficiency disease: contribution of genotype to phenotype.&lt;/strong&gt; J. Clin. Invest. 92: 2291-2302, 1993.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/8227344/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;8227344&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1172/JCI116833&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="8227344">Santisteban et al. (1993)</a> reported 7 patients with 'delayed' or 'late' onset of SCID due to ADA deficiency. Three of these patients had onset of symptoms at ages 9, 12, and 12 months, respectively, although diagnosis of ADA deficiency was not made until ages 14 months, 2, and 3 years, respectively. Four patients were relatively asymptomatic until ages 2 to 5 years, when recurrent respiratory infections became prominent. ADA activity in cultured T cells and deoxyadenosine nucleotide levels in red cells in all 7 patients were intermediate between typical early-onset SCID patients and immunocompetent individuals with partial ADA deficiency. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8227344" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="Umetsu, D. T., Schlossman, C. M., Ochs, H. D., Hershfield, M. S. &lt;strong&gt;Heterogeneity of phenotype in two siblings with adenosine deaminase deficiency.&lt;/strong&gt; J. Allergy Clin. Immun. 93: 543-550, 1994.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/8120281/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;8120281&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/0091-6749(94)90365-4&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="8120281">Umetsu et al. (1994)</a> reported 2 sisters with SCID due to ADA deficiency. The second-born child presented first with serious infections and failure to thrive at age 4 months; the diagnosis of SCID was made at age 9 months when the child was hospitalized for Pseudomonas sepsis and Pneumocystis pneumonia. Her healthy 39-month-old sister was then tested and found to be ADA deficient. She had an unremarkable history, including normal development and uncomplicated varicella zoster at age 6 months. Although she was lymphopenic, antibody production, delayed hypersensitivity, and in vitro T-cell function were intact. She became more lymphopenic over a period of 6 to 7 months and developed persistent upper respiratory infections. Both sisters were treated by enzyme replacement with polyethylene glycol (PEG)-ADA. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8120281" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="Shovlin, C. L., Hughes, J. M. B., Simmonds, H. A., Fairbanks, L., Deacock, S., Lechler, R., Roberts, I., Webster, A. D. B. &lt;strong&gt;Adult presentation of adenosine deaminase deficiency. (Letter)&lt;/strong&gt; Lancet 341: 1471, 1993.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/8099155/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;8099155&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/0140-6736(93)90910-9&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="8099155">Shovlin et al. (1993)</a> described adult onset of ADA deficiency in 2 sisters who presented with recurrent infections together with laboratory phenotypes similar to those of advanced HIV disease, including severe CD4 lymphopenia. Both were HIV-negative. A 34-year-old woman reported asthma and recurrent chest infections from childhood. As an adult, she had widespread viral warts, recurrent oral and vaginal candidosis, and reported 2 episodes of dermatomal zoster. Her 35-year-old sister was well until age 17 when she developed idiopathic thrombocytopenic purpura necessitating splenectomy, azathioprine for 7 years, and prednisolone until the time of report. By age 20 she had asthma, recurrent chest infections, vaginal and oral candidosis, widespread viral warts, and recurrent dermatomal zoster. Both sisters had clinical and radiologic evidence of extensive lung damage. Medical records showed lymphopenia in both sisters from ages 20 and 17 years, respectively. These were the oldest patients ever described with a new diagnosis of primary ADA deficiency. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8099155" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="Ozsahin, H., Arredondo-Vega, F. X., Santisteban, I., Fuhrer, H., Tuchschmid, P., Jochum, W., Aguzzi, A., Lederman, H. M., Fleischman, A., Winkelstein, J. A., Seger, R. A., Hershfield, M. S. &lt;strong&gt;Adenosine deaminase deficiency in adults.&lt;/strong&gt; Blood 89: 2849-2855, 1997.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/9108404/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;9108404&lt;/a&gt;]" pmid="9108404">Ozsahin et al. (1997)</a> reported metabolic, immunologic, and genetic findings in 2 ADA-deficient adults with distinct phenotypes. A 39-year-old woman had combined immunodeficiency with frequent infections, lymphopenia, and recurrent hepatitis as a child, but did relatively well in her second and third decades. She later developed chronic sinopulmonary infections, including tuberculosis, and hepatobiliary disease, and died of viral leukoencephalopathy at 40 years of age. The second patient was a healthy 28-year-old man with normal immune function who was identified after his niece died of SCID. Both adult patients lacked erythrocyte ADA activity, but had only modestly elevated deoxyadenosine nucleotides. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9108404" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#39" class="mim-tip-reference" title="Hershfield, M. S. &lt;strong&gt;Genotype is an important determinant of phenotype in adenosine deaminase deficiency.&lt;/strong&gt; Curr. Opin. Immun. 15: 571-577, 2003.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/14499267/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;14499267&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/s0952-7915(03)00104-3&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="14499267">Hershfield (2003)</a> stated that red cell dATP (dAXP) is elevated by 30- to 300-fold in delayed or late-onset patients. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14499267" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>Partial ADA Deficiency</em></strong></p><p>
<a href="#58" class="mim-tip-reference" title="Jenkins, T. &lt;strong&gt;Red-blood-cell adenosine deaminase deficiency in a &#x27;healthy&#x27; ! Kung individual. (Letter)&lt;/strong&gt; Lancet 302: 736 only, 1973. Note: Originally Volume 2.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/4125820/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;4125820&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/s0140-6736(73)92568-3&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="4125820">Jenkins (1973)</a> and <a href="#57" class="mim-tip-reference" title="Jenkins, T., Rabson, A. R., Nurse, G. T., Lane, A. B., Hopkinson, D. A. &lt;strong&gt;Deficiency of adenosine deaminase not associated with severe combined immunodeficiency.&lt;/strong&gt; J. Pediat. 89: 732-736, 1976.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/978319/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;978319&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/s0022-3476(76)80792-5&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="978319">Jenkins et al. (1976)</a> reported a South African Kalahari San ('Bushman') patient with 'partial' ADA deficiency not associated with immunodeficiency. ADA activity was 2 to 3%, 10 to 12%, and 10 to 30% of normal in red blood cells, white blood cells, and fibroblasts, respectively. Multiple tests showed that the child had normal humoral and cellular immunity. A sib had similar ADA levels and the parents had intermediate levels. In a study of 36 South African populations comprising more than 3,000 individuals, <a href="#57" class="mim-tip-reference" title="Jenkins, T., Rabson, A. R., Nurse, G. T., Lane, A. B., Hopkinson, D. A. &lt;strong&gt;Deficiency of adenosine deaminase not associated with severe combined immunodeficiency.&lt;/strong&gt; J. Pediat. 89: 732-736, 1976.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/978319/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;978319&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/s0022-3476(76)80792-5&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="978319">Jenkins et al. (1976)</a> found that many members of the Kung Bushman population had red cell ADA deficiency not associated with immunodeficiency. The authors concluded that the phenotype was due to a polymorphic allele, designated ADA-8, with a frequency of approximately 0.11 in the Kung population. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=4125820+978319" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#34" class="mim-tip-reference" title="Hart, S. L., Lane, A. B., Jenkins, T. &lt;strong&gt;Partial adenosine deaminase deficiency: another family from southern Africa.&lt;/strong&gt; Hum. Genet. 74: 307-312, 1986.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/3781559/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;3781559&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1007/BF00282554&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="3781559">Hart et al. (1986)</a> reported a second Bantu-speaking Xhosa man from South Africa with partial ADA deficiency similar to the type previously reported by <a href="#57" class="mim-tip-reference" title="Jenkins, T., Rabson, A. R., Nurse, G. T., Lane, A. B., Hopkinson, D. A. &lt;strong&gt;Deficiency of adenosine deaminase not associated with severe combined immunodeficiency.&lt;/strong&gt; J. Pediat. 89: 732-736, 1976.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/978319/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;978319&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/s0022-3476(76)80792-5&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="978319">Jenkins et al. (1976)</a>. Erythrocyte ADA levels were decreased at 6 to 9% of normal, whereas white cell ADA was approximately 30% of normal, and the enzyme showed decreased stability in vitro. Levels of dATP were 2- to 3-fold above normal in red blood cells. Electrophoretic studies suggested compound heterozygosity. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=3781559+978319" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="Hirschhorn, R., Roegner, V., Jenkins, T., Seaman, C., Piomelli, S., Borkowsky, W. &lt;strong&gt;Erythrocyte adenosine deaminase deficiency without immunodeficiency: evidence for an unstable mutant enzyme.&lt;/strong&gt; J. Clin. Invest. 64: 1130-1139, 1979.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/479373/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;479373&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1172/JCI109552&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="479373">Hirschhorn et al. (1979)</a> reported a patient with ADA deficiency without immunodeficiency in whom the mutant ADA enzyme was unstable. <a href="#25" class="mim-tip-reference" title="Daddona, P. E., Mitchell, B. S., Meuwissen, H. J., Davidson, B. L., Wilson, J. M., Koller, C. A. &lt;strong&gt;Adenosine deaminase deficiency with normal immune function: an acidic enzyme mutation.&lt;/strong&gt; J. Clin. Invest. 72: 483-492, 1983.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/6603477/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;6603477&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1172/jci110996&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="6603477">Daddona et al. (1983)</a> reported another patient with partial ADA deficiency and normal immune function. ADA activity and protein were undetectable in red blood cells, 0.9% of normal in lymphocytes, 4% in lymphoblasts, and 14% in fibroblasts. The ADA protein was abnormally acidic. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=6603477+479373" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="#43" class="mim-tip-reference" title="Hirschhorn, R., Martiniuk, F., Roegner-Maniscalco, V., Ellenbogen, A., Perignon, J.-L., Jenkins, T. &lt;strong&gt;Genetic heterogeneity in partial adenosine deaminase deficiency.&lt;/strong&gt; J. Clin. Invest. 71: 1887-1892, 1983.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/6863546/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;6863546&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1172/jci110944&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="6863546">Hirschhorn et al. (1983)</a> reported 4 unrelated children with partial ADA deficiency who lacked ADA in their erythrocytes but retained variable amounts of activity in their lymphoid cells. None had significant immunologic deficiency. Electrophoretic mobility studies showed different forms of the enzyme: one form was acidic, had very low activity, and was heat-stable; a second was basic, had low activity, and was heat-labile; a third was heat-labile and retained relatively normal activity; and a fourth had decreased activity without qualitative abnormalities. <a href="#43" class="mim-tip-reference" title="Hirschhorn, R., Martiniuk, F., Roegner-Maniscalco, V., Ellenbogen, A., Perignon, J.-L., Jenkins, T. &lt;strong&gt;Genetic heterogeneity in partial adenosine deaminase deficiency.&lt;/strong&gt; J. Clin. Invest. 71: 1887-1892, 1983.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/6863546/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;6863546&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1172/jci110944&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="6863546">Hirschhorn et al. (1983)</a> concluded that 3 of the individuals had mutations at the structural locus for ADA, and that the fourth may have had a mutation at a regulatory locus. Noting that 2 of the partially deficient families were of African descent and a third came from the Mediterranean basin, <a href="#43" class="mim-tip-reference" title="Hirschhorn, R., Martiniuk, F., Roegner-Maniscalco, V., Ellenbogen, A., Perignon, J.-L., Jenkins, T. &lt;strong&gt;Genetic heterogeneity in partial adenosine deaminase deficiency.&lt;/strong&gt; J. Clin. Invest. 71: 1887-1892, 1983.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/6863546/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;6863546&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1172/jci110944&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="6863546">Hirschhorn et al. (1983)</a> suggested that partial ADA deficiency may confer an advantage against intraerythrocytic parasites, such as malaria or babesiosis, which require exogenous purines derived from the host to survive. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=6863546" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="Hirschhorn, R., Ellenbogen, A. &lt;strong&gt;Genetic heterogeneity in adenosine deaminase (ADA) deficiency: five different mutations in five new patients with partial ADA deficiency.&lt;/strong&gt; Am. J. Hum. Genet. 38: 13-25, 1986.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/3946419/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;3946419&lt;/a&gt;]" pmid="3946419">Hirschhorn and Ellenbogen (1986)</a> reported 5 unrelated patients with partial ADA deficiency identified through a New York state neonatal screening program. None of them had immunologic abnormalities. Three patients were shown to be genetic compounds by the presence of 2 electrophoretically distinguishable allozymes or by family studies that demonstrated a null allele in addition to an electrophoretically abnormal enzyme. All 5 of the children were either black or of West Indian descent, suggesting a clustering of the partial ADA deficiency phenotype in this ethnic group. The genetically distinct enzymes excluded a founder effect, and the authors again concluded a selective advantage for partial ADA deficiency. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=3946419" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#39" class="mim-tip-reference" title="Hershfield, M. S. &lt;strong&gt;Genotype is an important determinant of phenotype in adenosine deaminase deficiency.&lt;/strong&gt; Curr. Opin. Immun. 15: 571-577, 2003.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/14499267/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;14499267&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/s0952-7915(03)00104-3&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="14499267">Hershfield (2003)</a> stated that red cell dATP (dAXP) is elevated by zero to approximately 30-fold in patients with partial ADA deficiency. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14499267" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="#77" class="mim-tip-reference" title="Ratech, H., Greco, M. A., Gallo, G., Rimoin, D. L., Kamino, H., Hirschhorn, R. &lt;strong&gt;Pathologic findings in adenosine-deaminase-deficient severe combined immunodeficiency. I. Kidney, adrenal, and chondro-osseous tissue alterations.&lt;/strong&gt; Am. J. Path. 120: 157-169, 1985.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/4014441/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;4014441&lt;/a&gt;]" pmid="4014441">Ratech et al. (1985)</a> reported postmortem findings in 8 patients with SCID due to ADA deficiency. Seven patients had renal mesangial sclerosis, and 6 had adrenal cortical sclerosis. Tissue from vertebrae and costochondral junctions in 4 patients showed short growth plates with few proliferating and some hypertrophic chondrocytes. Two patients who had received bone marrow or enzyme infusions had milder changes. The authors concluded that disordered nucleoside metabolism due to absent ADA activity results in multisystem pathologic changes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=4014441" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#13" class="mim-tip-reference" title="Bollinger, M. E., Arredondo-Vega, F. X., Santisteban, I., Schwarz, K., Hershfield, M. S., Lederman, H. M. &lt;strong&gt;Hepatic dysfunction as a complication of adenosine deaminase deficiency.&lt;/strong&gt; New Eng. J. Med. 334: 1367-1371, 1996.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/8614422/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;8614422&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1056/NEJM199605233342104&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="8614422">Bollinger et al. (1996)</a> described a human neonate with ADA deficiency, confirmed by genetic analysis, who developed prolonged hyperbilirubinemia with hepatitis that resolved after the institution of ADA replacement therapy. Percutaneous liver biopsy showed early giant-cell transformation, with enlarged foamy hepatocytes and portal and lobular eosinophilic infiltrates. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8614422" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="Hirschhorn, R., Papageorgiou, P. S., Kesarwala, H. H., Taft, L. T. &lt;strong&gt;Amelioration of neurologic abnormalities after &#x27;enzyme replacement&#x27; in adenosine deaminase deficiency.&lt;/strong&gt; New Eng. J. Med. 303: 377-380, 1980.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/6156414/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;6156414&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1056/NEJM198008143030706&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="6156414">Hirschhorn et al. (1980)</a> referred to neurologic abnormalities that had been reported in 2 of 23 ADA-deficient patients and reported a third who showed improvement of these features with enzyme replacement by red cell infusion. Neurologic abnormalities included movement disorders, nystagmus, and sensorineural deafness. <a href="#79" class="mim-tip-reference" title="Rogers, M. H., Lwin, R., Fairbanks, L., Gerritsen, B., Gaspar, H. B. &lt;strong&gt;Cognitive and behavioral abnormalities in adenosine deaminase deficient severe combined immunodeficiency.&lt;/strong&gt; J. Pediat. 139: 44-50, 2001.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/11445793/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;11445793&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1067/mpd.2001.115023&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="11445793">Rogers et al. (2001)</a> evaluated the cognitive, behavioral, and neurodevelopmental function in 11 case-matched pairs of patients with ADA-SCID and non-ADA-deficient SCID, all of whom had undergone bone marrow transplantation. Cognitive ability was not significantly different between the 2 groups, but patients with ADA-SCID had a significant inverse correlation between dATP levels at diagnosis and IQ. Behavioral assessment showed that patients with ADA-SCID functioned in the pathologic range on all domains, whereas mean scores for the control group were within normal limits. Behavioral impairment in patients with ADA-SCID also showed a significant positive correlation with age. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=6156414+11445793" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
</span>
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<div>
<a id="mapping" class="mim-anchor"></a>
<h4 href="#mimMappingFold" id="mimMappingToggle" class="mimTriangleToggle" style="cursor: pointer;" data-toggle="collapse">
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<span class="mim-font">
<strong>Mapping</strong>
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<span class="mim-text-font">
<p><a href="#62" class="mim-tip-reference" title="Koch, G., Shows, T. B. &lt;strong&gt;Somatic cell genetics of adenosine deaminase expression and severe combined immunodeficiency disease in humans.&lt;/strong&gt; Proc. Nat. Acad. Sci. 77: 4211-4215, 1980.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/6933468/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;6933468&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1073/pnas.77.7.4211&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="6933468">Koch and Shows (1980)</a> showed that ADA deficiency in SCID segregated with chromosome 20 in interspecific somatic cell hybrids, suggesting that a structural gene mutation at the ADA locus was the primary cause of ADA-deficient SCID. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=6933468" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div>
<a id="pathogenesis" class="mim-anchor"></a>
<h4 href="#mimPathogenesisFold" id="mimPathogenesisToggle" class="mimTriangleToggle" style="cursor: pointer;" data-toggle="collapse">
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<span class="mim-font">
<strong>Pathogenesis</strong>
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</h4>
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<div id="mimPathogenesisFold" class="collapse in mimTextToggleFold">
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<p><a href="#70" class="mim-tip-reference" title="Mitchell, B. S., Mejias, E., Daddona, P. E., Kelley, W. N. &lt;strong&gt;Purinogenic immunodeficiency disease: selective toxicity of deoxyribonucleosides for T-cells.&lt;/strong&gt; Proc. Nat. Acad. Sci. 75: 5011-5014, 1978.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/311004/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;311004&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1073/pnas.75.10.5011&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="311004">Mitchell et al. (1978)</a> found that deoxyadenosine and deoxyguanosine were particularly toxic to T cells but not to B cells. Addition of deoxycytidine or dipyridamole prevented deoxyribonucleoside toxicity. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=311004" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#16" class="mim-tip-reference" title="Boss, G. R., Thompson, L. F., O&#x27;Connor, R. D., Ziering, R. W., Seegmiller, J. E. &lt;strong&gt;Ecto-5-prime-nucleotidase deficiency: association with adenosine deaminase deficiency and nonassociation with deoxyadenosine toxicity.&lt;/strong&gt; Clin. Immun. Immunopath. 19: 1-7, 1981.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/6260402/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;6260402&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/0090-1229(81)90042-8&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="6260402">Boss et al. (1981)</a> concluded that ecto-5-prime-nucleotidase deficiency is secondary to the primary defect of ADA. In cells from a patient with ADA-deficient SCID, <a href="#35" class="mim-tip-reference" title="Herbschleb-Voogt, E., Scholten, J.-W., Meera Khan, P. &lt;strong&gt;Basic defect in the expression of adenosine deaminase in ADA SCID disease. II. Deficiency of ADA-CRM detected in heterozygote human-Chinese hamster cell hybrids.&lt;/strong&gt; Hum. Genet. 63: 121-125, 1983.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/6840756/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;6840756&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1007/BF00291530&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="6840756">Herbschleb-Voogt et al. (1983)</a> found a deficiency of ADA activity and a comparable deficiency of ADA-specific cross-reacting material, indicating a decrease of the enzyme. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=6260402+6840756" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="#21" class="mim-tip-reference" title="Cohen, A., Hirschhorn, R., Horowitz, S. D., Rubinstein, A., Polmar, S. H., Hong, R., Martin, D. W., Jr. &lt;strong&gt;Deoxyadenosine triphosphate as a potentially toxic metabolite in adenosine deaminase deficiency.&lt;/strong&gt; Proc. Nat. Acad. Sci. 75: 472-476, 1978.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/272665/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;272665&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1073/pnas.75.1.472&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="272665">Cohen et al. (1978)</a> observed greater than 50-fold elevations of 2-prime-deoxyadenosine triphosphate (dATP) in the erythrocytes of 3 SCID ADA-deficient patients, but not in the erythrocytes of an immunocompetent ADA-deficient patient or 2 unrelated immunodeficient patients with normal ADA. In vivo infusion of normal erythrocytes containing normal ADA activity in 2 SCID ADA-deficient patients resulted in a dramatic decrease in dATP and some clinical response. <a href="#21" class="mim-tip-reference" title="Cohen, A., Hirschhorn, R., Horowitz, S. D., Rubinstein, A., Polmar, S. H., Hong, R., Martin, D. W., Jr. &lt;strong&gt;Deoxyadenosine triphosphate as a potentially toxic metabolite in adenosine deaminase deficiency.&lt;/strong&gt; Proc. Nat. Acad. Sci. 75: 472-476, 1978.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/272665/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;272665&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1073/pnas.75.1.472&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="272665">Cohen et al. (1978)</a> concluded that deoxyadenosine is the toxic substrate in ADA deficiency, and that the toxic effect is mediated by dATP inhibition of ribonucleotide reductase (see, e.g., <a href="/entry/180410">180410</a>), which is responsible for the reduction of all the purine and pyrimidine ribonucleotides to their respective 2-prime-deoxyribonucleotides, the necessary precursors for DNA synthesis. Immunodeficiency is the consequence of the particular sensitivity of immature lymphoid cells to the toxic effects of ADA substrates. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=272665" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="#91" class="mim-tip-reference" title="Van de Wiele, C. J., Vaughn, J. G., Blackburn, M. R., Ledent, C. A., Jacobson, M., Jiang, H., Thompson, L. F. &lt;strong&gt;Adenosine kinase inhibition promotes survival of fetal adenosine deaminase-deficient thymocytes by blocking dATP accumulation.&lt;/strong&gt; J. Clin. Invest. 110: 395-402, 2002.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/12163459/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;12163459&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=12163459[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/10.1172/JCI15683&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="12163459">Van de Wiele et al. (2002)</a> noted that most immature thymocytes undergo apoptosis as a result of lymphocyte selection in the thymus. Degradation of cell DNA and RNA by ADA generates adenosine and deoxyadenosine. Accumulation of these metabolites and their derivatives in ADA deficiency is lymphotoxic, resulting in reduced production of T cells. In addition, dATP inhibits ribonucleotide reductase, which is necessary for DNA synthesis, and dATP and adenosine inhibit S-adenosylhomocysteine hydrolase (SAHH; <a href="/entry/180960">180960</a>), which is necessary for methylation reactions that are required for cell viability. In cell cultures (fetal thymic organ culture, FTOC) from a mouse model of ADA deficiency, <a href="#91" class="mim-tip-reference" title="Van de Wiele, C. J., Vaughn, J. G., Blackburn, M. R., Ledent, C. A., Jacobson, M., Jiang, H., Thompson, L. F. &lt;strong&gt;Adenosine kinase inhibition promotes survival of fetal adenosine deaminase-deficient thymocytes by blocking dATP accumulation.&lt;/strong&gt; J. Clin. Invest. 110: 395-402, 2002.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/12163459/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;12163459&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=12163459[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/10.1172/JCI15683&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="12163459">van de Wiele et al. (2002)</a> found that inhibition of adenosine kinase (<a href="/entry/102750">102750</a>) resulted in an increase in T-cell recovery, indicating that toxicity in ADA deficiency is due to a phosphorylated form of an ADA substrate and not adenosine or deoxyadenosine. Further studies suggested that inhibition of SAH or ribonucleotide reductase was not sufficient to cause toxicity. <a href="#91" class="mim-tip-reference" title="Van de Wiele, C. J., Vaughn, J. G., Blackburn, M. R., Ledent, C. A., Jacobson, M., Jiang, H., Thompson, L. F. &lt;strong&gt;Adenosine kinase inhibition promotes survival of fetal adenosine deaminase-deficient thymocytes by blocking dATP accumulation.&lt;/strong&gt; J. Clin. Invest. 110: 395-402, 2002.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/12163459/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;12163459&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=12163459[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/10.1172/JCI15683&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="12163459">Van de Wiele et al. (2002)</a> concluded that the mechanism of dATP toxicity involves dATP-induced cytochrome c release from mitochondria, which initiates the apoptotic cascade. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12163459" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="Apasov, S. G., Blackburn, M. R., Kellems, R. E., Smith, P. T., Sitkovsky, M. V. &lt;strong&gt;Adenosine deaminase deficiency increases thymic apoptosis and causes defective T cell receptor signaling.&lt;/strong&gt; J. Clin. Invest. 108: 131-141, 2001.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/11435465/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;11435465&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=11435465[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/10.1172/JCI10360&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="11435465">Apasov et al. (2001)</a> found that Ada -/- mice had a pronounced decrease in the size and lymphocyte content of spleen, lymph nodes, and thymus at 3 weeks of age compared to wildtype mice. There was increased apoptosis of immature T cells in the thymi of mutant mice, but not in the peripheral lymphoid organs, indicating specific effects on developing T cells. In addition, mature CD4- and CD8-positive T cells from Ada -/- mice showed decreased T cell receptor (TCR; see <a href="/entry/186880">186880</a>)-triggered activation in vivo and in vitro as a result of increased exogenous adenosine, to a lesser extent than in mature T cells of wildtype mice, indicating that adenosine can affect normal T cell activation. The nucleoside 2-prime-deoxyadenosine was directly cytotoxic to lymphocytes. <a href="#6" class="mim-tip-reference" title="Apasov, S. G., Blackburn, M. R., Kellems, R. E., Smith, P. T., Sitkovsky, M. V. &lt;strong&gt;Adenosine deaminase deficiency increases thymic apoptosis and causes defective T cell receptor signaling.&lt;/strong&gt; J. Clin. Invest. 108: 131-141, 2001.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/11435465/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;11435465&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=11435465[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/10.1172/JCI10360&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="11435465">Apasov et al. (2001)</a> concluded that T-cell depletion in ADA-deficient SCID results from at least 2 mechanisms: intracellular toxicity of adenosine, dATP, and 2-prime-deoxyadenosine, and inhibition of T-cell signaling by elevated levels of adenosine. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11435465" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div>
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</div>
<div>
<a id="diagnosis" class="mim-anchor"></a>
<h4 href="#mimDiagnosisFold" id="mimDiagnosisToggle" class="mimTriangleToggle" style="cursor: pointer;" data-toggle="collapse">
<span id="mimDiagnosisToggleTriangle" class="small mimTextToggleTriangle">&#9660;</span>
<span class="mim-font">
<strong>Diagnosis</strong>
</span>
</h4>
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<div id="mimDiagnosisFold" class="collapse in mimTextToggleFold">
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<p><strong><em>Prenatal Diagnosis</em></strong></p><p>
<a href="#40" class="mim-tip-reference" title="Hirschhorn, R., Beratis, N., Rosen, F. S., Parkman, R., Stern, R., Polmar, S. &lt;strong&gt;Adenosine-deaminase deficiency in a child diagnosed prenatally.&lt;/strong&gt; Lancet 302: 73-75, 1975. Note: Originally Volume 1.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/46025/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;46025&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/s0140-6736(75)91075-2&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="46025">Hirschhorn et al. (1975)</a> diagnosed ADA deficiency in a fetus by finding less than 1.5% ADA activity in cultured amniotic fluid cells. An older sib had died from SCID due to ADA deficiency. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=46025" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="#2" class="mim-tip-reference" title="Aitken, D. A., Kleijer, W. J., Niermeijer, M. F., Herbschleb-Voogt, E., Galjaard, H. &lt;strong&gt;Prenatal detection of a probable heterozygote for ADA deficiency and severe combined immunodeficiency disease using a microradioassay.&lt;/strong&gt; Clin. Genet. 17: 293-298, 1980.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/7371221/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;7371221&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1111/j.1399-0004.1980.tb00150.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="7371221">Aitken et al. (1980)</a> used a microradioassay to evaluate ADA activity in cultured amniotic fluid cells in a pregnancy at risk for ADA deficiency and SCID. A low-normal level of activity consistent with the heterozygous state was found in the fetus, which was confirmed after birth. In 2 subsequent pregnancies of a mother of a child with SCID due to ADA deficiency, <a href="#100" class="mim-tip-reference" title="Ziegler, J. B., Van Der Weyden, M. B., Lee, C. H., Daniel, A. &lt;strong&gt;Prenatal diagnosis for adenosine deaminase deficiency.&lt;/strong&gt; J. Med. Genet. 18: 154-156, 1981.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/7241535/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;7241535&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1136/jmg.18.2.154&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="7241535">Ziegler et al. (1981)</a> assayed ADA activity in amniotic fluid fibroblasts and diagnosed a normal fetus and a homozygous ADA-deficient fetus, respectively. The diagnoses were confirmed after birth and in abortus tissue. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=7371221+7241535" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div>
<a id="clinicalManagement" class="mim-anchor"></a>
<h4 href="#mimClinicalManagementFold" id="mimClinicalManagementToggle" class="mimTriangleToggle" style="cursor: pointer;" data-toggle="collapse">
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<strong>Clinical Management</strong>
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<p><strong><em>Enzyme Replacement Therapy</em></strong></p><p>
<a href="#76" class="mim-tip-reference" title="Polmar, S. H., Stern, R. C., Schwartz, A. L., Wetzler, E. M., Chase, P. A., Hirschhorn, R. &lt;strong&gt;Enzyme replacement therapy for adenosine deaminase deficiency and severe combined immunodeficiency.&lt;/strong&gt; New Eng. J. Med. 295: 1337-1343, 1976.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/980079/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;980079&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1056/NEJM197612092952402&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="980079">Polmar et al. (1976)</a> reported successful treatment of a child with SCID due to ADA deficiency by 'enzyme replacement therapy' using frozen irradiated red blood cells with normal ADA activity. After treatment, a thymic shadow appeared radiographically, lymphocytic responses were demonstrated in vitro, and there was immunoglobulin synthesis. With infusions at 4-week intervals, the child remained free of infection for 17 months. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=980079" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#99" class="mim-tip-reference" title="Ziegler, J. B., Lee, C. H., Van Der Weyden, M. B., Bagnara, A. S., Beveridge, J. &lt;strong&gt;Severe combined immunodeficiency and adenosine deaminase deficiency: failure of enzyme replacement therapy.&lt;/strong&gt; Arch. Dis. Child. 55: 452-457, 1980.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/7436484/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;7436484&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1136/adc.55.6.452&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="7436484">Ziegler et al. (1980)</a> reported a patient with SCID due to ADA deficiency who was treated with ADA-positive red cell infusions. Although there was some resolution of interstitial pneumonitis and skeletal abnormalities, there was no evidence of immunologic reconstitution, and the patient died at age 17 months. The authors noted that severe cases of SCID due to ADA deficiency may not respond to exogenous enzyme therapy. <a href="#65" class="mim-tip-reference" title="Markert, M. L., Hershfield, M. S., Schiff, R. I., Buckley, R. H. &lt;strong&gt;Adenosine deaminase and purine nucleoside phosphorylase deficiencies: evaluation of therapeutic interventions in eight patients.&lt;/strong&gt; J. Clin. Immun. 7: 389-399, 1987.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/3116034/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;3116034&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1007/BF00917017&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="3116034">Markert et al. (1987)</a> reported 5 ADA-deficient patients who showed no lasting benefit from red blood cell transfusions. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=3116034+7436484" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="Hershfield, M. S., Buckley, R. H., Greenberg, M. L., Melton, A. L., Schiff, R., Hatem, C., Kurtzberg, J., Markert, M. L., Kobayashi, R. H., Kobayashi, A. L., Abuchowski, A. &lt;strong&gt;Treatment of adenosine deaminase deficiency with polyethylene glycol-modified adenosine deaminase.&lt;/strong&gt; New Eng. J. Med. 316: 589-596, 1987.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/3807953/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;3807953&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1056/NEJM198703053161005&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="3807953">Hershfield et al. (1987)</a> reported successful treatment of 2 SCID ADA-deficient patients with polyethylene glycol-modified bovine intestinal ADA (PEG-ADA). The modified enzyme was rapidly absorbed after intramuscular injection and had a half-life in plasma of 48 to 72 hours. Weekly doses maintained plasma ADA activity at 2 to 3 times the level of red cell ADA in normal subjects, resulting in a decrease in toxic deoxyadenosine nucleotides to less than 0.5% of total adenine nucleotides. The activity of S-adenosylhomocysteine hydrolase, which is inactivated by deoxyadenosine, increased to normal in red cells and nucleated marrow cells. Neither toxic effects nor hypersensitivity reactions were observed. In vitro tests of cellular immune function of each patient showed marked improvement, together with an increase in T lymphocytes. Covalent attachment of polyethylene glycol to ADA blocked access to vulnerable sites on the surface of the protein, inhibiting clearance from the circulation, attack by degrading enzymes, binding of antibodies, and processing by antigen-presenting cells. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=3807953" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#64" class="mim-tip-reference" title="Levy, Y., Hershfield, M. S., Fernandez-Mejia, C., Polmar, S. H., Scudiery, D., Berger, M., Sorensen, R. U. &lt;strong&gt;Adenosine deaminase deficiency with late onset of recurrent infections: response to treatment with polyethylene glycol-modified adenosine deaminase.&lt;/strong&gt; J. Pediat. 113: 312-317, 1988.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/3260944/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;3260944&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/s0022-3476(88)80271-3&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="3260944">Levy et al. (1988)</a> reported a child who developed symptoms of SCID due to ADA deficiency at age 3 years. She had 0.6% and 1% of normal ADA activity in erythrocytes and mononuclear cells, respectively. Weekly treatment with PEG-modified ADA was well tolerated and her T lymphocyte numbers and response to mitogens became normal. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=3260944" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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, <a href="#38" class="mim-tip-reference" title="Hershfield, M. S. &lt;strong&gt;PEG-ADA: an alternative to haploidentical bone marrow transplantation and an adjunct to gene therapy for adenosine deaminase deficiency.&lt;/strong&gt; Hum. Mutat. 5: 107-112, 1995.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/7749407/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;7749407&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/humu.1380050202&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="7749407">Hershfield (1995)</a> noted that PEG-ADA works in the plasma by degrading adenosine (Ado) and deoxyadenosine (dAdo), followed by rapid equilibration with intracellular concentrations via a plasma membrane nucleoside transporter. After approximately 2 months of treatment, lymphocyte counts increase and show a proliferative response to mitogens in vitro, a thymic shadow may appear, and patients often develop persistent antibody titers. Although immune function is not normal, serious opportunistic infections usually resolve. Development of anti-ADA antibodies rarely occurs. <a href="#38" class="mim-tip-reference" title="Hershfield, M. S. &lt;strong&gt;PEG-ADA: an alternative to haploidentical bone marrow transplantation and an adjunct to gene therapy for adenosine deaminase deficiency.&lt;/strong&gt; Hum. Mutat. 5: 107-112, 1995.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/7749407/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;7749407&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/humu.1380050202&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="7749407">Hershfield (1995)</a> noted that PEG-ADA treatment is indicated for patients who lack an HLA-identical bone marrow donor, but are at too high a risk for HLA-haploidentical marrow transplantation. Mortality with PEG-ADA is lower than that with haploidentical bone marrow transplantation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7749407" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>Bone Marrow Transplantation</em></strong></p><p>
<a href="#15" class="mim-tip-reference" title="Bortin, M. M., Rimm, A. A. (eds.). &lt;strong&gt;Severe combined immunodeficiency disease: characterization of the disease and results of transplantation.&lt;/strong&gt; JAMA 238: 591-600, 1977.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/18618/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;18618&lt;/a&gt;]" pmid="18618">Bortin and Rimm (1977)</a> reported on the characteristics and results of treatment in 69 patients with SCID due to various causes; 4 of 25 (16%) patients tested had ADA deficiency. The highest 6-month survival rate occurred in those who had undergone bone marrow transplant (BMT) from HLA genotypically identical donors. In surveying 18 of 80 SCID patients who survived bone marrow transplantation, <a href="#61" class="mim-tip-reference" title="Kenny, A. B., Hitzig, W. H. &lt;strong&gt;Bone marrow transplantation for severe combined immunodeficiency disease: reported from 1968-1977.&lt;/strong&gt; Europ. J. Pediat. 131: 155-176, 1979.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/38963/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;38963&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1007/BF00538940&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="38963">Kenny and Hitzig (1979)</a> found that 3 of the 18 patients had ADA deficiency. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=18618+38963" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#17" class="mim-tip-reference" title="Buckley, R. H., Schiff, S. E., Schiff, R. I., Markert, M. L., Williams, L. W., Roberts, J. L., Myers, L. A., Ward, F. E. &lt;strong&gt;Hematopoietic stem-cell transplantation for the treatment of severe combined immunodeficiency.&lt;/strong&gt; New Eng. J. Med. 340: 508-516, 1999.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/10021471/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;10021471&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1056/NEJM199902183400703&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="10021471">Buckley et al. (1999)</a> reported survival of 11 of 13 ADA-deficient patients who underwent bone marrow transplantation. Seven of 9 children who underwent haploidentical BMT were alive 1.6 to 15.6 years after transplantation, with hematopoietic chimerism demonstrable in 6. T-cell numbers and function improved approximately 3 to 4 months after transplantation; B-cell numbers and function improved to a lesser degree. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10021471" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="inheritance" class="mim-anchor"></a>
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<strong>Inheritance</strong>
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<p>The transmission pattern of SCID due to ADA deficiency in the patients reported by <a href="#89" class="mim-tip-reference" title="Valerio, D., Dekker, B. M. M., Duyvesteyn, M. G. C., van der Voorn, L., Berkvens, T. M., van Ormondt, H., van der Eb, A. J. &lt;strong&gt;One adenosine deaminase allele in a patient with severe combined immunodeficiency contains a point mutation abolishing enzyme activity.&lt;/strong&gt; EMBO J. 5: 113-119, 1986.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/3007108/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;3007108&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/j.1460-2075.1986.tb04184.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="3007108">Valerio et al. (1986)</a> and <a href="#5" class="mim-tip-reference" title="Akeson, A. L., Wiginton, D. A., States, J. C., Perme, C. M., Dusing, M. R., Hutton, J. J. &lt;strong&gt;Mutations in the human adenosine deaminase gene that affect protein structure and RNA splicing.&lt;/strong&gt; Proc. Nat. Acad. Sci. 84: 5947-5951, 1987.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/3475710/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;3475710&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1073/pnas.84.16.5947&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="3475710">Akeson et al. (1987)</a> was consistent with autosomal recessive inheritance. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=3475710+3007108" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="molecularGenetics" class="mim-anchor"></a>
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<strong>Molecular Genetics</strong>
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<p><strong><em>Severe Combined Immunodeficiency due to ADA Deficiency</em></strong></p><p>
In a patient with SCID due to ADA deficiency who was originally reported by <a href="#40" class="mim-tip-reference" title="Hirschhorn, R., Beratis, N., Rosen, F. S., Parkman, R., Stern, R., Polmar, S. &lt;strong&gt;Adenosine-deaminase deficiency in a child diagnosed prenatally.&lt;/strong&gt; Lancet 302: 73-75, 1975. Note: Originally Volume 1.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/46025/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;46025&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/s0140-6736(75)91075-2&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="46025">Hirschhorn et al. (1975)</a>, <a href="#89" class="mim-tip-reference" title="Valerio, D., Dekker, B. M. M., Duyvesteyn, M. G. C., van der Voorn, L., Berkvens, T. M., van Ormondt, H., van der Eb, A. J. &lt;strong&gt;One adenosine deaminase allele in a patient with severe combined immunodeficiency contains a point mutation abolishing enzyme activity.&lt;/strong&gt; EMBO J. 5: 113-119, 1986.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/3007108/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;3007108&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/j.1460-2075.1986.tb04184.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="3007108">Valerio et al. (1986)</a> identified compound heterozygosity for 2 mutations in the ADA gene (<a href="/entry/608958#0001">608958.0001</a>; <a href="/entry/608958#0005">608958.0005</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=46025+3007108" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#5" class="mim-tip-reference" title="Akeson, A. L., Wiginton, D. A., States, J. C., Perme, C. M., Dusing, M. R., Hutton, J. J. &lt;strong&gt;Mutations in the human adenosine deaminase gene that affect protein structure and RNA splicing.&lt;/strong&gt; Proc. Nat. Acad. Sci. 84: 5947-5951, 1987.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/3475710/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;3475710&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1073/pnas.84.16.5947&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="3475710">Akeson et al. (1987)</a> reported several biallelic mutations in the ADA gene in patients with ADA-deficient SCID (see, e.g., <a href="/entry/608958#0004">608958.0004</a>; <a href="/entry/608958#0006">608958.0006</a>; <a href="/entry/608958#0017">608958.0017</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=3475710" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In 2 sisters with SCID due to ADA deficiency reported by <a href="#88" class="mim-tip-reference" title="Umetsu, D. T., Schlossman, C. M., Ochs, H. D., Hershfield, M. S. &lt;strong&gt;Heterogeneity of phenotype in two siblings with adenosine deaminase deficiency.&lt;/strong&gt; J. Allergy Clin. Immun. 93: 543-550, 1994.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/8120281/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;8120281&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/0091-6749(94)90365-4&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="8120281">Umetsu et al. (1994)</a>, <a href="#9" class="mim-tip-reference" title="Arredondo-Vega, F. X., Santisteban, I., Kelly, S., Schlossman, C. M., Umetsu, D. T., Hershfield, M. S. &lt;strong&gt;Correct splicing despite mutation of the invariant first nucleotide of a 5-prime splice site: a possible basis for disparate clinical phenotypes in siblings with adenosine deaminase deficiency.&lt;/strong&gt; Am. J. Hum. Genet. 54: 820-830, 1994.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/8178821/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;8178821&lt;/a&gt;]" pmid="8178821">Arredondo-Vega et al. (1994)</a> identified compound heterozygosity for 2 splice site mutations in the ADA gene (<a href="/entry/608598#0022">608598.0022</a>; <a href="/entry/608598#0023">608598.0023</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=8178821+8120281" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>Delayed or Late-Onset SCID</em></strong></p><p>
In 7 patients with delayed or late onset of SCID due to ADA deficiency, <a href="#81" class="mim-tip-reference" title="Santisteban, I., Arredondo-Vega, F. X., Kelly, S., Mary, A., Fischer, A., Hummell, D. S., Lawton, A., Sorensen, R. U., Stiehm, E. R., Uribe, L., Weinberg, K., Hershfield, M. S. &lt;strong&gt;Novel splicing, missense, and deletion mutations in seven adenosine deaminase-deficient patients with late/delayed onset of combined immunodeficiency disease: contribution of genotype to phenotype.&lt;/strong&gt; J. Clin. Invest. 92: 2291-2302, 1993.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/8227344/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;8227344&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1172/JCI116833&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="8227344">Santisteban et al. (1993)</a> identified mutations in the ADA gene (see, e.g., <a href="/entry/608958#0020">608958.0020</a> and <a href="/entry/608958#0032">608958.0032</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8227344" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>Partial ADA Deficiency</em></strong></p><p>
In patients with partial ADA deficiency, Hirschhorn et al. (<a href="#46" class="mim-tip-reference" title="Hirschhorn, R., Tzall, S., Ellenbogen, A., Orkin, S. H. &lt;strong&gt;Identification of a point mutation resulting in a heat-labile adenosine deaminase (ADA) in two unrelated children with partial ADA deficiency.&lt;/strong&gt; J. Clin. Invest. 83: 497-501, 1989.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/2783588/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;2783588&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1172/JCI113909&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="2783588">1989</a>, <a href="#47" class="mim-tip-reference" title="Hirschhorn, R., Tzall, S., Ellenbogen, A. &lt;strong&gt;Hot spot mutations in adenosine deaminase deficiency.&lt;/strong&gt; Proc. Nat. Acad. Sci. 87: 6171-6175, 1990.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/2166947/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;2166947&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1073/pnas.87.16.6171&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="2166947">1990</a>) identified several biallelic mutations in the ADA gene (<a href="/entry/608958#0009">608958.0009</a>-<a href="/entry/608958#0015">608958.0015</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=2166947+2783588" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#49" class="mim-tip-reference" title="Hirschhorn, R., Yang, D. R., Israni, A., Huie, M. L., Ownby, D. R. &lt;strong&gt;Somatic mosaicism for a newly identified splice-site mutation in a patient with adenosine deaminase-deficient immunodeficiency and spontaneous clinical recovery.&lt;/strong&gt; Am. J. Hum. Genet. 55: 59-68, 1994.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/8023852/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;8023852&lt;/a&gt;]" pmid="8023852">Hirschhorn et al. (1994)</a> reported a patient diagnosed with SCID due to ADA deficiency at age 2.5 years because of life-threatening pneumonia, recurrent infections, failure of normal growth, and lymphopenia. However, he retained significant cellular immune function. His condition improved dramatically in the absence of specific therapy, and he was a healthy adolescent at age 16 years with no medical problems at age 20 years. A fibroblast cell line and a B-cell line, established at the time of diagnosis, lacked ADA activity. Genetic analysis identified compound heterozygosity for a splice site mutation (<a href="/entry/608958#0024">608958.0024</a>) and a missense mutation (<a href="/entry/608958#0003">608958.0003</a>). All clones isolated from the B-cell mRNA carried the missense mutation, indicating that the allele with the splice site mutation produced unstable mRNA. In striking contrast, a B-cell line established at age 16 expressed 50% of normal ADA; 50% of ADA mRNA had normal sequence, and 50% had the missense mutation. Genomic DNA contained the missense mutation, but not the splice site mutation. Genomic DNA from peripheral blood cells obtained at 16 years of age indicated in vivo somatic mosaicism; less than half the DNA carried the splice site mutation (P less than 0.002, vs original B-cell line). Consistent with the mosaicism, erythrocyte content of the toxic metabolite deoxy-ATP was only minimally elevated. <a href="#49" class="mim-tip-reference" title="Hirschhorn, R., Yang, D. R., Israni, A., Huie, M. L., Ownby, D. R. &lt;strong&gt;Somatic mosaicism for a newly identified splice-site mutation in a patient with adenosine deaminase-deficient immunodeficiency and spontaneous clinical recovery.&lt;/strong&gt; Am. J. Hum. Genet. 55: 59-68, 1994.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/8023852/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;8023852&lt;/a&gt;]" pmid="8023852">Hirschhorn et al. (1994)</a> postulated that somatic mosaicism could have arisen by somatic mutation or by reversion at the site of mutation. Selection in vivo for ADA normal hematopoietic cells likely played a role in the return to normal health in the absence of therapy. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8023852" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#51" class="mim-tip-reference" title="Hirschhorn, R., Yang, D. R., Puck, J. M., Huie, M. L., Jiang, C.-K., Kurlandsky, L. E. &lt;strong&gt;Spontaneous in vivo reversion to normal of an inherited mutation in a patient with adenosine deaminase deficiency.&lt;/strong&gt; Nature Genet. 13: 290-295, 1996.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/8673127/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;8673127&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1038/ng0796-290&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="8673127">Hirschhorn et al. (1996)</a> reported a patient who presented during the first years of life with recurrent infections and lymphopenia. A prior sib died before age 3 years of SCID affecting both T and B cells. At age 5 years, the proband lacked ADA activity in erythrocytes, but concentrations of deoxy-ATP in red blood cells were only mildly elevated compared to concentrations found in severe SCID patients. Mononuclear cells had 15% of normal ADA activity. Both the mother and father had 50% and 20 to 25% normal activity in erythrocytes and lymphocytes, respectively. Between the ages of 8 and 12 years, the proband was clinically healthy, with normal growth and development, although he had persistent hyper-IgE, decreased numbers of CD4+ T cells and B cells, and increased numbers of CD8+ T cells. Genetic analysis identified compound heterozygosity for 2 mutations in the ADA gene: a splice site mutation (<a href="/entry/608958#0026">608958.0026</a>), inherited from the father, and an R156H mutation (<a href="/entry/608958#0032">608958.0032</a>) inherited from the mother. Peripheral blood from the proband at age 11 years showed the splice site and R156H mutations in 50% and 34%, respectively, of cells, whereas 17% of cells did not carry either mutation. Cell lines established showed virtual absence of the maternally derived R156H mutation, indicating in vivo reversion of the mutation to normal. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8673127" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 similar moderation of phenotype had been observed involving a revertant mutation in the IL2RG gene (<a href="/entry/308380">308380</a>) in X-linked SCID (<a href="/entry/300400">300400</a>) (<a href="#87" class="mim-tip-reference" title="Stephan, V., Wahn, V., Le Deist, F., Dirksen, U., Broker, B., Muller-Fleckenstein, I., Horneff, G., Schroten, H., Fischer, A., de Saint Basile, G. &lt;strong&gt;Atypical X-linked severe combined immunodeficiency due to possible spontaneous reversion of the genetic defect in T cells.&lt;/strong&gt; New Eng. J. Med. 335: 1563-1567, 1996.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/8900089/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;8900089&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1056/NEJM199611213352104&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="8900089">Stephan et al., 1996</a>). Revertant cells have also been identified in patients with Fanconi anemia (see <a href="/entry/227650">227650</a> and <a href="/entry/227645">227645</a>), Bloom syndrome (<a href="/entry/210900">210900</a>), Wiskott-Aldrich syndrome (<a href="/entry/301000">301000</a>), and epidermolysis bullosa (<a href="/entry/226650">226650</a>) due to mutations in the COL17A1 gene (<a href="/entry/113811">113811</a>). In addition to back mutation, allele function has been restored by mitotic recombination or gene conversion, which can eliminate the original mutation, and by 'second-site' events that restore reading frame or led to an amino acid substitution better tolerated than the original. In Bloom syndrome, intragenic recombination or gene conversion are the usual mechanisms, consistent with reversion being much more common in heteroallelic than in homoallelic patients (<a href="#31" class="mim-tip-reference" title="Ellis, N. A., Lennon, D. J., Proytcheva, M., Alhadeff, B., Henderson, E. E., German, J. &lt;strong&gt;Somatic intragenic recombination within the mutated locus BLM can correct the high SCE phenotype of Bloom syndrome cells.&lt;/strong&gt; Am. J. Hum. Genet. 57: 1019-1027, 1995. Note: Erratum: Am. J. Hum. Genet. 58: 254 only, 1996.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/7485150/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;7485150&lt;/a&gt;]" pmid="7485150">Ellis et al., 1995</a>). <a href="#10" class="mim-tip-reference" title="Arredondo-Vega, F. X., Santisteban, I., Richard, E., Bali, P., Koleilat, M., Loubser, M., Al-Ghonaium, A., Al-Helali, M., Hershfield, M. S. &lt;strong&gt;Adenosine deaminase deficiency with mosaicism for a &#x27;second-site suppressor&#x27; of a splicing mutation: decline in revertant T lymphocytes during enzyme replacement therapy.&lt;/strong&gt; Blood 99: 1005-1013, 2002.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/11807006/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;11807006&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1182/blood.v99.3.1005&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="11807006">Arredondo-Vega et al. (2002)</a> reported 1 member of a Saudi Arabian family with delayed onset of SCID due to a homozygous splice site mutation in the ADA gene (<a href="/entry/608958#0030">608958.0030</a>) who also carried an acquired second distinct splice site mutation (<a href="/entry/608958#0031">608958.0031</a>) that suppressed the defect of the first mutation. The patient had a milder phenotype than his sister who did not carry the second mutation. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=7485150+8900089+11807006" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="#8" class="mim-tip-reference" title="Arredondo-Vega, F. X., Santisteban, I., Daniels, S., Toutain, S., Hershfield, M. S. &lt;strong&gt;Adenosine deaminase deficiency: genotype-phenotype correlations based on expressed activity of 29 mutant alleles.&lt;/strong&gt; Am. J. Hum. Genet. 63: 1049-1059, 1998.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/9758612/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;9758612&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1086/302054&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="9758612">Arredondo-Vega et al. (1998)</a> noted that the phenotype of ADA deficiency is strongly associated with the sum of ADA activity provided by both alleles. Many mutations are private and patients are often heteroallelic, precluding definite genotype/phenotype correlations. Functional expression analysis of 29 different missense mutations expressed in an ADA-deleted E. coli strain showed that alleles from immunodeficient patients expressed 0.001 to 0.6% ADA activity compared to wildtype. Alleles found only in healthy individuals with partial deficiency showed 1 to 28% of normal activity. In all, the activity levels spanned 5 orders of magnitude. The authors found that 1 to 1.5% residual ADA activity was consistent with sustaining immune function. There was a strong inverse correlation between red cell dAXP concentration and the sum of ADA activity expressed by both alleles, establishing a direct link between the effects of genotype on residual ADA activity, metabolism, and clinical expression. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9758612" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="Abbott, C. M., Skidmore, C. J., Searle, A. G., Peters, J. &lt;strong&gt;Deficiency of adenosine deaminase in the wasted mouse.&lt;/strong&gt; Proc. Nat. Acad. Sci. 83: 693-695, 1986.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/3456164/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;3456164&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1073/pnas.83.3.693&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="3456164">Abbott et al. (1986)</a> presented evidence that 'wasted' (wst) in mice is caused by a mutation in the structural gene for ADA. As occurs in humans with ADA deficiency, wasted mice are immunodeficient, develop neurologic abnormalities, and die soon after weaning. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=3456164" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>Unlike humans, mice that express no adenosine deaminase die perinatally of severe hepatocellular degeneration (<a href="#69" class="mim-tip-reference" title="Migchielsen, A. A. J., Breuer, M. L., van Roon, M. A., te Riele, H., Zurcher, C., Ossendorp, F., Toutain, S., Hershfield, M. S., Berns, A., Valerio, D. &lt;strong&gt;Adenosine-deaminase-deficient mice die perinatally and exhibit liver-cell degeneration, atelectasis and small intestinal cell death.&lt;/strong&gt; Nature Genet. 10: 279-287, 1995.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/7670465/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;7670465&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1038/ng0795-279&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="7670465">Migchielsen et al., 1995</a>; <a href="#93" class="mim-tip-reference" title="Wakamiya, M., Blackburn, M. R., Jurecic, R., McArthur, M. J., Geske, R. S., Cartwright, J., Jr., Mitani, K., Vaishnav, S., Belmont, J. W., Kellems, R. E., Finegold, M. J., Montgomery, Jr., C. A., Bradley, A., Caskey, C. T. &lt;strong&gt;Disruption of the adenosine deaminase gene causes hepatocellular impairment and perinatal lethality in mice.&lt;/strong&gt; Proc. Nat. Acad. Sci. 92: 3673-3677, 1995.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/7731963/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;7731963&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1073/pnas.92.9.3673&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="7731963">Wakamiya et al., 1995</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=7670465+7731963" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="#11" class="mim-tip-reference" title="Blackburn, M. R., Datta, S. K., Kellems, R. E. &lt;strong&gt;Adenosine deaminase-deficient mice generated using a two-stage genetic engineering strategy exhibit a combined immunodeficiency.&lt;/strong&gt; J. Biol. Chem. 273: 5093-5100, 1998.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/9478961/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;9478961&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1074/jbc.273.9.5093&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="9478961">Blackburn et al. (1998)</a> reported the use of a 2-stage genetic engineering strategy to generate ADA-deficient mice that retained many features associated with ADA deficiency in humans, including a combined immunodeficiency. Severe T- and B-cell lymphopenia was accompanied by a pronounced accumulation of 2-deoxyadenosine and dATP in the thymus and spleen, and a marked inhibition of S-adenosylhomocysteine hydrolase in the same organs. Accumulation of adenosine was widespread among all tissues examined. ADA-deficient mice also exhibited severe pulmonary insufficiency, bone abnormalities, and kidney pathology. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9478961" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="seeAlso" class="mim-anchor"></a>
<h4 href="#mimSeeAlsoFold" id="mimSeeAlsoToggle" class="mimTriangleToggle" style="cursor: pointer;" data-toggle="collapse">
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</h4>
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<span class="mim-text-font">
<a href="#Aiuti2009" class="mim-tip-reference" title="Aiuti, A., Cattaneo, F., Galimberti, S., Benninghoff, U., Cassani, B., Callegaro, L., Scaramuzza, S., Andolfi, G., Mirolo, M., Brigida, I., Tabucchi, A., Carlucci, F., and 18 others. &lt;strong&gt;Gene therapy for immunodeficiency due to adenosine deaminase deficiency.&lt;/strong&gt; New Eng. J. Med. 360: 447-458, 2009.">Aiuti et al. (2009)</a>; <a href="#Aiuti2002" class="mim-tip-reference" title="Aiuti, A., Slavin, S., Aker, M., Ficara, F., Deola, S., Mortellaro, A., Morecki, S., Andolfi, G., Tabucchi, A., Carlucci, F., Marinello, E., Cattaneo, F., Vai, S., Servida, P., Miniero, R., Roncarolo, M. G., Bordignon, C. &lt;strong&gt;Correction of ADA-SCID by stem cell gene therapy combined with nonmyeloablative conditioning.&lt;/strong&gt; Science 296: 2410-2413, 2002.">Aiuti et al. (2002)</a>; <a href="#Arredondo-Vega1990" class="mim-tip-reference" title="Arredondo-Vega, F. X., Kurtzberg, J., Chaffee, S., Santisteban, I., Reisner, E., Povey, M. S., Hershfield, M. S. &lt;strong&gt;Paradoxical expression of adenosine deaminase in T cells cultured from a patient with adenosine deaminase deficiency and combined immunodeficiency.&lt;/strong&gt; J. Clin. Invest. 86: 444-452, 1990.">Arredondo-Vega et al.
(1990)</a>; <a href="#Blaese1995" class="mim-tip-reference" title="Blaese, R. M., Culver, K. W., Miller, A. D., Carter, C. S., Fleisher, T., Clerici, M., Shearer, G., Chang, L., Chiang, Y., Tolstoshev, P., Greenblatt, J. J., Rosenberg, S. A., Klein, H., Berger, M., Mullen, C. A., Ramsey, W. J., Muul, L., Morgan, R. A., Anderson, W. F. &lt;strong&gt;T lymphocyte-directed gene therapy for ADA-SCID: initial trial results after 4 years.&lt;/strong&gt; Science 270: 475-480, 1995.">Blaese et al. (1995)</a>; <a href="#Bordignon1995" class="mim-tip-reference" title="Bordignon, C., Notarangelo, L. D., Nobili, N., Ferrari, G., Casorati, G., Panina, P., Mazzolari, E., Maggioni, D., Rossi, C., Servida, P., Ugazio, A. G., Mavilio, F. &lt;strong&gt;Gene therapy in peripheral blood lymphocytes and bone marrow for ADA: immunodeficient patients.&lt;/strong&gt; Science 270: 470-475, 1995.">Bordignon et al. (1995)</a>; <a href="#Chen1979" class="mim-tip-reference" title="Chen, S.-H., Ochs, H. D., Scott, C. R., Giblett, E. R. &lt;strong&gt;Adenosine deaminase and nucleoside phosphorylase activity in patients with immunodeficiency syndromes.&lt;/strong&gt; Clin. Immun. Immunopath. 13: 156-160, 1979.">Chen et al.
(1979)</a>; <a href="#Chen1978" class="mim-tip-reference" title="Chen, S.-H., Ochs, H. D., Scott, C. R. &lt;strong&gt;Adenosine deaminase deficiency: disappearance of adenine deoxynucleotides from a patient&#x27;s erythrocytes after successful marrow transplantation.&lt;/strong&gt; J. Clin. Invest. 62: 1386-1389, 1978.">Chen et al. (1978)</a>; <a href="#Chen1974" class="mim-tip-reference" title="Chen, S.-H., Scott, C. R., Giblett, E. R. &lt;strong&gt;Adenosine deaminase: demonstration of a &#x27;silent&#x27; gene associated with combined immunodeficiency disease.&lt;/strong&gt; Am. J. Hum. Genet. 26: 103-107, 1974.">Chen et al. (1974)</a>; <a href="#Cook1970" class="mim-tip-reference" title="Cook, P. J. L., Hopkinson, D. A., Robson, E. B. &lt;strong&gt;The linkage relationships of adenosine deaminase.&lt;/strong&gt; Ann. Hum. Genet. 34: 187-188, 1970.">Cook et al. (1970)</a>; <a href="#Culver1996" class="mim-tip-reference" title="Culver, K. W. &lt;strong&gt;Gene Therapy: A Primer for Physicians.&lt;/strong&gt; Larchmont, New York: Mary Ann Liebert, Inc. 1996.">Culver (1996)</a>; <a href="#Daddona1979" class="mim-tip-reference" title="Daddona, P. E., Kelley, W. N. &lt;strong&gt;Human adenosine deaminase: stoichiometry of the adenosine deaminase-binding protein complex.&lt;/strong&gt; Biochim. Biophys. Acta 580: 302-311, 1979.">Daddona and Kelley (1979)</a>; <a href="#Detter1970" class="mim-tip-reference" title="Detter, J. C., Stamatoyannopoulos, G., Giblett, E. R., Motulsky, A. G. &lt;strong&gt;Adenosine deaminase: racial distribution and report of a new phenotype.&lt;/strong&gt; J. Med. Genet. 7: 356-357, 1970.">Detter et al. (1970)</a>; <a href="#Dissing1972" class="mim-tip-reference" title="Dissing, J., Knudsen, B. &lt;strong&gt;Adenosine-deaminase deficiency and combined immunodeficiency syndrome. (Letter)&lt;/strong&gt; Lancet 300: 1316 only, 1972. Note: Originally Volume II.">Dissing and Knudsen (1972)</a>; <a href="#Dissing1969" class="mim-tip-reference" title="Dissing, J., Knudsen, J. B. &lt;strong&gt;A new red cell adenosine deaminase phenotype in man.&lt;/strong&gt; Hum. Hered. 19: 375-377, 1969.">Dissing and Knudsen (1969)</a>; <a href="#Dyminski1979" class="mim-tip-reference" title="Dyminski, J. W., Daoud, A., Lampkin, B. C., Limouze, S., Donofrio, J., Coleman, M. S., Hutton, J. J. &lt;strong&gt;Immunological and biochemical profiles in response to transfusion therapy in adenosine deaminase-deficient patient with severe combined immunodeficiency disease.&lt;/strong&gt; Clin. Immun. Immunopath. 14: 307-326, 1979.">Dyminski et
al. (1979)</a>; <a href="#Egashira1998" class="mim-tip-reference" title="Egashira, M., Ariga, T., Kawamura, N., Miyoshi, O., Niikawa, N., Sakiyama, Y. &lt;strong&gt;Visible integration of the adenosine deaminase (ADA) gene into the recipient genome after gene therapy.&lt;/strong&gt; Am. J. Med. Genet. 75: 314-317, 1998.">Egashira et al. (1998)</a>; <a href="#Ferrari1991" class="mim-tip-reference" title="Ferrari, G., Rossini, S., Giavazzi, R., Maggioni, D., Nobili, N., Soldati, M., Ungers, G., Mavilio, F., Gilboa, E., Bordignon, C. &lt;strong&gt;An in vivo model of somatic cell gene therapy for human severe combined immunodeficiency.&lt;/strong&gt; Science 251: 1363-1366, 1991.">Ferrari et al. (1991)</a>; <a href="#Hershfield1978" class="mim-tip-reference" title="Hershfield, M. S., Krodich, N. M. &lt;strong&gt;S-adenosylhomocysteine hydrolase is an adenosine-binding protein: a target for adenosine toxicity.&lt;/strong&gt; Science 202: 757-760, 1978.">Hershfield
and Krodich (1978)</a>; <a href="#Hirschhorn1974" class="mim-tip-reference" title="Hirschhorn, R., Levytska, V., Parkman, R. &lt;strong&gt;A mutant form of adenosine deaminase in severe combined immunodeficiency. (Abstract)&lt;/strong&gt; J. Clin. Invest. 53: 33A, 1974.">Hirschhorn et al. (1974)</a>; <a href="#Hirschhorn1979" class="mim-tip-reference" title="Hirschhorn, R., Vawter, G. F., Kirkpatrick, J. A., Jr., Rosen, F. S. &lt;strong&gt;Adenosine deaminase deficiency: frequency and comparative pathology in autosomally recessive severe combined immunodeficiency.&lt;/strong&gt; Clin. Immun. Immunopath. 14: 107-120, 1979.">Hirschhorn et al.
(1979)</a>; <a href="#Hirschhorn1994" class="mim-tip-reference" title="Hirschhorn, R., Yang, D. R., Israni, A. &lt;strong&gt;An asp8-to-asn substitution results in the adenosine deaminase (ADA) genetic polymorphism (ADA 2 allozyme): occurrence on different chromosomal backgrounds and apparent intragenic crossover.&lt;/strong&gt; Ann. Hum. Genet. 58: 1-9, 1994.">Hirschhorn et al. (1994)</a>; <a href="#Honig1984" class="mim-tip-reference" title="Honig, J., Martiniuk, F., D&#x27;Eustachio, P., Zamfirescu, C., Desnick, R., Hirschhorn, K., Hirschhorn, L. R., Hirschhorn, R. &lt;strong&gt;Confirmation of the regional localization of the genes for human acid alpha-glucosidase (GAA) and adenosine deaminase (ADA) by somatic cell hybridization.&lt;/strong&gt; Ann. Hum. Genet. 48: 49-56, 1984.">Honig et al. (1984)</a>; <a href="#Hopkinson1969" class="mim-tip-reference" title="Hopkinson, D. A., Cook, P. J. L., Harris, H. &lt;strong&gt;Further data on the adenosine deaminase (ADA) polymorphism and a report of a new phenotype.&lt;/strong&gt; Ann. Hum. Genet. 32: 361-368, 1969.">Hopkinson et
al. (1969)</a>; <a href="#Hutton1981" class="mim-tip-reference" title="Hutton, J. J., Wiginton, D. A., Coleman, M. S., Fuller, S. A., Limouze, S., Lampkin, B. C. &lt;strong&gt;Biochemical and functional abnormalities in lymphocytes from an adenosine deaminase-deficient patient during enzyme replacement therapy.&lt;/strong&gt; J. Clin. Invest. 68: 413-421, 1981.">Hutton et al. (1981)</a>; <a href="#Jenkins1979" class="mim-tip-reference" title="Jenkins, T., Lane, A. B., Nurse, G. T., Hopkinson, D. A. &lt;strong&gt;Red cell adenosine deaminase (ADA) polymorphism in southern Africa, with special reference to ADA deficiency among the !Kung.&lt;/strong&gt; Ann. Hum. Genet. 42: 425-433, 1979.">Jenkins et al. (1979)</a>; <a href="#Kaitila1976" class="mim-tip-reference" title="Kaitila, I., Rimoin, D. L., Cederbaum, S. D., Stiehm, E. R., Lechman, R. S. &lt;strong&gt;Chondroosseous histopathology in adenosine deaminase deficient combined immunodeficiency disease.&lt;/strong&gt; Birth Defects Orig. Art. Ser. 12: 115-121, 1976.">Kaitila et
al. (1976)</a>; <a href="#Kellems1985" class="mim-tip-reference" title="Kellems, R. E., Yeung, C.-Y., Ingolia, D. E. &lt;strong&gt;Adenosine deaminase deficiency and severe combined immunodeficiencies.&lt;/strong&gt; Trends Genet. 1: 278-283, 1985.">Kellems et al. (1985)</a>; <a href="#Kredich1977" class="mim-tip-reference" title="Kredich, N. M., Martin, D. W., Jr. &lt;strong&gt;Role of 5-adenosylhomocysteine in adenosine-mediated toxicity in cultured mouse T-lymphoma cells.&lt;/strong&gt; Cell 12: 931-938, 1977.">Kredich and Martin (1977)</a>; <a href="#Markert1987" class="mim-tip-reference" title="Markert, M. L., Hershfield, M. S., Wiginton, D. A., States, J. C., Ward, F. E., Bigner, S. H., Buckley, R. H., Kaufman, R. E., Hutton, J. J. &lt;strong&gt;Identification of a deletion in the adenosine deaminase gene in a child with severe combined immunodeficiency.&lt;/strong&gt; J. Immun. 138: 3203-3206, 1987.">Markert
et al. (1987)</a>; <a href="#Markert1988" class="mim-tip-reference" title="Markert, M. L., Hutton, J. J., Wiginton, D. A., States, J. C., Kaufman, R. E. &lt;strong&gt;Adenosine deaminase (ADA) deficiency due to deletion of the ADA gene promoter and first exon by homologous recombination between two Alu elements.&lt;/strong&gt; J. Clin. Invest. 81: 1323-1327, 1988.">Markert et al. (1988)</a>; <a href="#Moen1987" class="mim-tip-reference" title="Moen, R. C., Horowitz, S. D., Sondel, P. M., Borcherding, W. R., Trigg, M. E., Billing, R., Hong, R. &lt;strong&gt;Immunologic reconstitution after haploidentical bone marrow transplantation for immune deficiency disorders: treatment of bone marrow cells with monoclonal antibody CT-2 and complement.&lt;/strong&gt; Blood 70: 664-669, 1987.">Moen et al. (1987)</a>; <a href="#Onodera1998" class="mim-tip-reference" title="Onodera, M., Ariga, T., Kawamura, N., Kobayashi, I., Ohtsu, M., Yamada, M., Tame, A., Furuta, H., Okano, M., Matsumoto, S., Kotani, H., McGarrity, G. J., Blaese, R. M., Sakiyama, Y. &lt;strong&gt;Successful peripheral T-lymphocyte-directed gene transfer for a patient with severe combined immune deficiency caused by adenosine deaminase deficiency.&lt;/strong&gt; Blood 91: 30-36, 1998.">Onodera et
al. (1998)</a>; <a href="#Palmer1987" class="mim-tip-reference" title="Palmer, T. D., Hock, R. A., Osborne, W. R. A., Miller, A. D. &lt;strong&gt;Efficient retrovirus-mediated transfer and expression of a human adenosine deaminase gene in diploid skin fibroblasts from an adenosine deaminase-deficient human.&lt;/strong&gt; Proc. Nat. Acad. Sci. 84: 1055-1059, 1987.">Palmer et al. (1987)</a>; <a href="#Ritter1971" class="mim-tip-reference" title="Ritter, H., Wendt, G. G., Tariverdian, G., Zelch, J., Rube, M., Kirchberg, G. &lt;strong&gt;Genetics and linkage analysis of adenosine deaminase.&lt;/strong&gt; Humangenetik 14: 69-71, 1971.">Ritter et al. (1971)</a>; <a href="#Rubinstein1979" class="mim-tip-reference" title="Rubinstein, A., Hirschhorn, R., Sicklick, M., Murphy, R. A. &lt;strong&gt;In vivo and in vitro effects of thymosin and adenosine deaminase on adenosine-deaminase-deficient lymphocytes.&lt;/strong&gt; New Eng. J. Med. 300: 387-392, 1979.">Rubinstein et
al. (1979)</a>; <a href="#Schmalstieg1983" class="mim-tip-reference" title="Schmalstieg, F. C., Mills, G. C., Tsuda, H., Goldman, A. S. &lt;strong&gt;Severe combined immunodeficiency in a child with a healthy adenosine deaminase deficient mother.&lt;/strong&gt; Pediat. Res. 17: 935-940, 1983.">Schmalstieg et al. (1983)</a>; <a href="#Schrader1978" class="mim-tip-reference" title="Schrader, W. P., Pollara, B., Meuwissen, H. J. &lt;strong&gt;Characterization of the residual adenosine deaminating activity in the spleen of a patient with combined immunodeficiency disease and adenosine deaminase deficiency.&lt;/strong&gt; Proc. Nat. Acad. Sci. 75: 446-450, 1978.">Schrader et al. (1978)</a>; <a href="#Scott1974" class="mim-tip-reference" title="Scott, C. R., Chen, S.-H., Giblett, E. R. &lt;strong&gt;Deletion of the carrier state in combined immunodeficiency disease associated with deaminase deficiency.&lt;/strong&gt; J. Clin. Invest. 53: 1194-1196, 1974.">Scott
et al. (1974)</a>; <a href="#Shovlin1994" class="mim-tip-reference" title="Shovlin, C. L., Simmonds, H. A., Fairbanks, L. D., Deacock, S. J., Hughes, J. M. B., Lechler, R. I., Webster, A. D. B., Sun, X.-M., Webb, J. C., Soutar, A. K. &lt;strong&gt;Adult onset immunodeficiency caused by inherited adenosine deaminase deficiency.&lt;/strong&gt; J. Immun. 153: 2331-2339, 1994.">Shovlin et al. (1994)</a>; <a href="#Valerio1984" class="mim-tip-reference" title="Valerio, D., Duyvesteyn, M. G. C., van Ormondt, H., Meera Khan, P., van der Eb, A. J. &lt;strong&gt;Adenosine deaminase (ADA) deficiency in cells derived from humans with severe combined immunodeficiency is due to an aberration of the ADA protein.&lt;/strong&gt; Nucleic Acids Res. 12: 1015-1024, 1984.">Valerio et al. (1984)</a>; <a href="#Van1974" class="mim-tip-reference" title="Van der Weyden, M. B., Kelley, W. N. &lt;strong&gt;Adenosine deaminase deficiency in severe combined immunodeficiency: evidence for a posttranslational defect. (Abstract)&lt;/strong&gt; J. Clin. Invest. 53: 81A-82A, 1974.">Van der
Weyden and Kelley (1974)</a>; <a href="#Weitkamp1971" class="mim-tip-reference" title="Weitkamp, L. R. &lt;strong&gt;Further data on the genetic linkage relations of the adenosine deaminase locus.&lt;/strong&gt; Hum. Hered. 21: 351-356, 1971.">Weitkamp (1971)</a>; <a href="#Weitkamp1972" class="mim-tip-reference" title="Weitkamp, L. R. &lt;strong&gt;Genetic linkage relationships of the ADA and 6-PGD loci in &#x27;Humangenetik.&#x27; (Letter)&lt;/strong&gt; Humangenetik 15: 359-360, 1972.">Weitkamp (1972)</a>; <a href="#Wiginton1982" class="mim-tip-reference" title="Wiginton, D. A., Hutton, J. J. &lt;strong&gt;Immunoreactive protein in adenosine deaminase deficient human lymphoblast cell lines.&lt;/strong&gt; J. Biol. Chem. 257: 3211-3217, 1982.">Wiginton
and Hutton (1982)</a>; <a href="#Yokoyama1979" class="mim-tip-reference" title="Yokoyama, S., Hayashi, T., Yoshimura, Y., Irimada, K., Saito, T., Akiba, T., Tsuchiya, S. &lt;strong&gt;Severe combined immunodeficiency disease with adenosine deaminase deficiency.&lt;/strong&gt; Tohoku J. Exp. Med. 129: 197-202, 1979.">Yokoyama et al. (1979)</a>; <a href="#Yount1974" class="mim-tip-reference" title="Yount, J., Nichols, P., Ochs, H. D., Hammar, S. P., Scott, C. R., Chen, S.-H., Giblett, E. R., Wedgwood, R. J. &lt;strong&gt;Absence of erythrocyte adenosine deaminase associated with severe combined immunodeficiency.&lt;/strong&gt; J. Pediat. 84: 173-177, 1974.">Yount et al. (1974)</a>
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Abbott, C. M., Skidmore, C. J., Searle, A. G., Peters, J.
<strong>Deficiency of adenosine deaminase in the wasted mouse.</strong>
Proc. Nat. Acad. Sci. 83: 693-695, 1986.
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[<a href="https://doi.org/10.1016/0005-2795(79)90143-0" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1172/jci110996" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1136/jmg.7.4.356" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1016/s0140-6736(72)92692-x" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1159/000152241" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1126/science.1848369" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1016/s0140-6736(72)92345-8" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1007/BF00282554" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1007/BF00291530" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1056/NEJM198703053161005" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1126/science.715439" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1002/humu.1380050202" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1016/s0952-7915(03)00104-3" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1016/s0140-6736(75)91075-2" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1172/jci110944" target="_blank">Full Text</a>]
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<strong>Amelioration of neurologic abnormalities after 'enzyme replacement' in adenosine deaminase deficiency.</strong>
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<strong>Erythrocyte adenosine deaminase deficiency without immunodeficiency: evidence for an unstable mutant enzyme.</strong>
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[<a href="https://doi.org/10.1172/JCI109552" target="_blank">Full Text</a>]
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Hirschhorn, R., Tzall, S., Ellenbogen, A., Orkin, S. H.
<strong>Identification of a point mutation resulting in a heat-labile adenosine deaminase (ADA) in two unrelated children with partial ADA deficiency.</strong>
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[<a href="https://doi.org/10.1172/JCI113909" target="_blank">Full Text</a>]
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Hirschhorn, R., Tzall, S., Ellenbogen, A.
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[<a href="https://doi.org/10.1073/pnas.87.16.6171" target="_blank">Full Text</a>]
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<strong>Adenosine deaminase deficiency: frequency and comparative pathology in autosomally recessive severe combined immunodeficiency.</strong>
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[<a href="https://doi.org/10.1016/0090-1229(79)90131-4" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1038/ng0796-290" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1056/NEJM197002262820903" target="_blank">Full Text</a>]
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<strong>Confirmation of the regional localization of the genes for human acid alpha-glucosidase (GAA) and adenosine deaminase (ADA) by somatic cell hybridization.</strong>
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[<a href="https://doi.org/10.1111/j.1469-1809.1984.tb00833.x" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1111/j.1469-1809.1969.tb00087.x" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1172/jci110270" target="_blank">Full Text</a>]
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Jenkins, T., Lane, A. B., Nurse, G. T., Hopkinson, D. A.
<strong>Red cell adenosine deaminase (ADA) polymorphism in southern Africa, with special reference to ADA deficiency among the !Kung.</strong>
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[<a href="https://doi.org/10.1111/j.1469-1809.1979.tb00676.x" target="_blank">Full Text</a>]
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<strong>Deficiency of adenosine deaminase not associated with severe combined immunodeficiency.</strong>
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[<a href="https://doi.org/10.1016/s0022-3476(76)80792-5" target="_blank">Full Text</a>]
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Jenkins, T.
<strong>Red-blood-cell adenosine deaminase deficiency in a 'healthy' ! Kung individual. (Letter)</strong>
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[<a href="https://doi.org/10.1016/s0140-6736(73)92568-3" target="_blank">Full Text</a>]
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<strong>Chondroosseous histopathology in adenosine deaminase deficient combined immunodeficiency disease.</strong>
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[<a href="https://doi.org/10.1007/BF00538940" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1073/pnas.77.7.4211" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1016/0092-8674(77)90157-x" target="_blank">Full Text</a>]
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Levy, Y., Hershfield, M. S., Fernandez-Mejia, C., Polmar, S. H., Scudiery, D., Berger, M., Sorensen, R. U.
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[<a href="https://doi.org/10.1016/s0022-3476(88)80271-3" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1007/BF00917017" target="_blank">Full Text</a>]
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Markert, M. L., Hershfield, M. S., Wiginton, D. A., States, J. C., Ward, F. E., Bigner, S. H., Buckley, R. H., Kaufman, R. E., Hutton, J. J.
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Markert, M. L., Hutton, J. J., Wiginton, D. A., States, J. C., Kaufman, R. E.
<strong>Adenosine deaminase (ADA) deficiency due to deletion of the ADA gene promoter and first exon by homologous recombination between two Alu elements.</strong>
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[<a href="https://doi.org/10.1172/JCI113458" target="_blank">Full Text</a>]
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Meuwissen, H. J., Pollara, B., Pickering, R. J.
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[<a href="https://doi.org/10.1016/s0022-3476(75)80463-x" target="_blank">Full Text</a>]
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Migchielsen, A. A. J., Breuer, M. L., van Roon, M. A., te Riele, H., Zurcher, C., Ossendorp, F., Toutain, S., Hershfield, M. S., Berns, A., Valerio, D.
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[<a href="https://doi.org/10.1038/ng0795-279" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1073/pnas.75.10.5011" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1073/pnas.84.4.1055" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1056/NEJM197504032921402" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1056/NEJM197612092952402" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1007/BF00273036" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1067/mpd.2001.115023" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1056/NEJM197902223000802" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1172/JCI116833" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1203/00006450-198312000-00002" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1073/pnas.75.1.446" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1172/JCI107658" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1016/0140-6736(93)90910-9" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1056/NEJM199611213352104" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1016/0091-6749(94)90365-4" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1002/j.1460-2075.1986.tb04184.x" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1093/nar/12.2.1015" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1172/JCI15683" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1073/pnas.92.9.3673" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1159/000152425" target="_blank">Full Text</a>]
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<strong>Genetic linkage relationships of the ADA and 6-PGD loci in 'Humangenetik.' (Letter)</strong>
Humangenetik 15: 359-360, 1972.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/4634454/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">4634454</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=4634454" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1007/BF00281739" target="_blank">Full Text</a>]
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Wiginton, D. A., Hutton, J. J.
<strong>Immunoreactive protein in adenosine deaminase deficient human lymphoblast cell lines.</strong>
J. Biol. Chem. 257: 3211-3217, 1982.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/6977542/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">6977542</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=6977542" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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Yokoyama, S., Hayashi, T., Yoshimura, Y., Irimada, K., Saito, T., Akiba, T., Tsuchiya, S.
<strong>Severe combined immunodeficiency disease with adenosine deaminase deficiency.</strong>
Tohoku J. Exp. Med. 129: 197-202, 1979.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/494270/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">494270</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=494270" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1620/tjem.129.197" target="_blank">Full Text</a>]
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Yount, J., Nichols, P., Ochs, H. D., Hammar, S. P., Scott, C. R., Chen, S.-H., Giblett, E. R., Wedgwood, R. J.
<strong>Absence of erythrocyte adenosine deaminase associated with severe combined immunodeficiency.</strong>
J. Pediat. 84: 173-177, 1974.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/4810724/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">4810724</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=4810724" 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/s0022-3476(74)80597-4" target="_blank">Full Text</a>]
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<a id="Ziegler1980" class="mim-anchor"></a>
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Ziegler, J. B., Lee, C. H., Van Der Weyden, M. B., Bagnara, A. S., Beveridge, J.
<strong>Severe combined immunodeficiency and adenosine deaminase deficiency: failure of enzyme replacement therapy.</strong>
Arch. Dis. Child. 55: 452-457, 1980.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7436484/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7436484</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7436484" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1136/adc.55.6.452" target="_blank">Full Text</a>]
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<a id="Ziegler1981" class="mim-anchor"></a>
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Ziegler, J. B., Van Der Weyden, M. B., Lee, C. H., Daniel, A.
<strong>Prenatal diagnosis for adenosine deaminase deficiency.</strong>
J. Med. Genet. 18: 154-156, 1981.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7241535/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7241535</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7241535" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1136/jmg.18.2.154" target="_blank">Full Text</a>]
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Cassandra L. Kniffin - updated : 2/4/2009
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Cassandra L. Kniffin - updated : 11/11/2004<br>Cassandra L. Kniffin - reorganized : 10/28/2004<br>Cassandra L. Kniffin - updated : 10/20/2004<br>Ada Hamosh - updated : 7/29/2002<br>Victor A. McKusick - updated : 3/19/2002<br>Deborah L. Stone - updated : 10/3/2001<br>Victor A. McKusick - updated : 5/11/2001<br>Ada Hamosh - updated : 7/20/2000<br>Victor A. McKusick - updated : 3/25/1998<br>Victor A. McKusick - updated : 12/19/1997<br>Ethylin Wang Jabs - updated : 7/21/1997<br>Victor A. McKusick - updated : 6/5/1997<br>Victor A. McKusick - updated : 5/16/1997<br>Iosif W. Lurie - updated : 9/26/1996
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Victor A. McKusick : 6/4/1986
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carol : 09/08/2023
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alopez : 03/20/2023<br>carol : 12/22/2022<br>carol : 03/28/2022<br>alopez : 01/29/2020<br>carol : 10/18/2017<br>alopez : 08/07/2013<br>terry : 3/14/2013<br>terry : 3/23/2011<br>terry : 3/22/2011<br>terry : 12/16/2009<br>wwang : 9/9/2009<br>terry : 6/3/2009<br>terry : 4/29/2009<br>terry : 4/8/2009<br>wwang : 2/9/2009<br>ckniffin : 2/4/2009<br>terry : 1/7/2009<br>terry : 1/7/2009<br>terry : 9/27/2005<br>tkritzer : 11/16/2004<br>ckniffin : 11/11/2004<br>ckniffin : 11/11/2004<br>carol : 10/29/2004<br>carol : 10/28/2004<br>terry : 10/28/2004<br>ckniffin : 10/20/2004<br>ckniffin : 10/20/2004<br>carol : 3/17/2004<br>alopez : 6/10/2003<br>cwells : 7/29/2002<br>alopez : 7/26/2002<br>terry : 3/19/2002<br>carol : 10/4/2001<br>carol : 10/3/2001<br>mcapotos : 5/23/2001<br>mcapotos : 5/18/2001<br>terry : 5/11/2001<br>terry : 3/20/2001<br>mcapotos : 8/1/2000<br>mcapotos : 7/26/2000<br>terry : 7/20/2000<br>carol : 12/17/1998<br>alopez : 12/2/1998<br>dkim : 7/24/1998<br>dkim : 7/24/1998<br>terry : 7/9/1998<br>carol : 5/12/1998<br>dholmes : 5/12/1998<br>dholmes : 5/12/1998<br>alopez : 3/30/1998<br>terry : 3/25/1998<br>alopez : 3/25/1998<br>terry : 3/17/1998<br>mark : 1/5/1998<br>terry : 12/19/1997<br>mark : 8/1/1997<br>mark : 8/1/1997<br>mark : 8/1/1997<br>mark : 8/1/1997<br>mark : 8/1/1997<br>jenny : 8/1/1997<br>mark : 7/31/1997<br>terry : 7/10/1997<br>terry : 7/10/1997<br>terry : 7/9/1997<br>mark : 6/14/1997<br>mark : 6/14/1997<br>alopez : 6/11/1997<br>terry : 6/5/1997<br>alopez : 5/20/1997<br>terry : 5/16/1997<br>carol : 9/26/1996<br>carol : 7/23/1996<br>carol : 6/29/1996<br>mark : 6/27/1996<br>terry : 6/25/1996<br>terry : 6/6/1996<br>terry : 6/4/1996<br>carol : 5/18/1996<br>mark : 12/12/1995<br>terry : 12/5/1995<br>carol : 11/10/1994<br>terry : 8/30/1994<br>jason : 7/26/1994<br>warfield : 4/7/1994<br>pfoster : 3/25/1994<br>mimadm : 3/13/1994
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<strong>#</strong> 102700
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<span class="mim-font">
SEVERE COMBINED IMMUNODEFICIENCY, AUTOSOMAL RECESSIVE, T CELL-NEGATIVE, B CELL-NEGATIVE, NK CELL-NEGATIVE, DUE TO ADENOSINE DEAMINASE DEFICIENCY
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<em>Alternative titles; symbols</em>
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SCID DUE TO ADA DEFICIENCY<br />
ADA-SCID<br />
SCID DUE TO ADA DEFICIENCY, EARLY-ONSET
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Other entities represented in this entry:
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SCID DUE TO ADA DEFICIENCY, DELAYED ONSET, INCLUDED
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SCID DUE TO ADA DEFICIENCY, LATE-ONSET, INCLUDED<br />
ADENOSINE DEAMINASE DEFICIENCY, PARTIAL, INCLUDED<br />
PARTIAL ADA DEFICIENCY, INCLUDED
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<strong>SNOMEDCT:</strong> 22406001; &nbsp;
<strong>ICD10CM:</strong> D81.31; &nbsp;
<strong>ORPHA:</strong> 277; &nbsp;
<strong>DO:</strong> 5810; &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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20q13.12
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Adenosine deaminase deficiency, partial
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102700
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Autosomal recessive; Somatic mosaicism
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3
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ADA
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608958
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20q13.12
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Severe combined immunodeficiency due to ADA deficiency
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102700
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Autosomal recessive; Somatic mosaicism
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3
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ADA
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<span class="mim-font">
608958
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<strong>TEXT</strong>
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<p>A number sign (#) is used with this entry because T cell-negative (T-), B cell-negative (B-), natural killer cell-negative (NK-) severe combined immunodeficiency (SCID) is caused by homozygous or compound heterozygous mutation in the adenosine deaminase gene (ADA; 608958) on chromosome 20q13.</p><p>For a general phenotypic description and a discussion of genetic heterogeneity of autosomal recessive SCID, see 601457.</p>
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<strong>Description</strong>
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<p>Severe combined immunodeficiency (SCID) resulting from inherited ADA deficiency causes a variable phenotypic spectrum, the most severe being SCID presenting in infancy and usually resulting in early death. Ten to 15% of patients have a 'delayed' clinical onset by age 6 to 24 months, and a smaller percentage of patients have 'later' onset, diagnosed from ages 4 years to adulthood, showing less severe infections and gradual immunologic deterioration. Finally, 'partial' ADA deficiency occurs in a subset of immunocompetent individuals who show decreased enzyme activity in erythrocytes, but retain substantial enzyme activity ranging from 5 to 80% of normal in leukocytes and other nucleated cells (summary by Arredondo-Vega et al., 1994). ADA deficiency accounts for approximately 15% of all SCID cases and one-third of cases of autosomal recessive SCID (Hershfield, 2003). </p>
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<strong>Clinical Features</strong>
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<p><strong><em>Early-Onset SCID</em></strong></p><p>
Giblett et al. (1972) reported 2 unrelated girls with impaired cellular immunity and absence of red cell adenosine deaminase activity. One child, aged 22 months, had recurrent respiratory infections, candidiasis, and marked lymphopenia from birth. The other, aged 3.5 years, was allegedly normal in the first 2 years of life. Mild upper respiratory infections began at age 24 months and progressed to severe pulmonary insufficiency and hepatosplenomegaly by age 30 months. The parents of the first child were related and the second child had a sister who died as a result of a major immunologic defect (Hong et al., 1970). The finding that both pairs of parents had an intermediate level of red cell ADA supported recessive inheritance; the parents of the first child had about a 50% level of normal, whereas the parents of the second child had about a 66% level. </p><p>Parkman et al. (1975) reported 3 affected infants from 2 families with SCID due to ADA deficiency inherited in an autosomal recessive pattern. None of the infants had detectable erythrocyte ADA activity. Two infants had successful bone marrow transplantation with restoration of normal cellular and humoral immunity, but erythrocytic ADA deficiency persisted. </p><p>Reporting on a workshop on SCID due to ADA deficiency, Meuwissen et al. (1975) noted that the phenotype is transmitted as an autosomal recessive disorder. Some patients had characteristic skeletal abnormalities, and all had thymic involution with Hassall's corpuscles and differentiated germinal epithelium. </p><p>Hershfield (2003) stated that red cell 2-prime-deoxyadenosine triphosphate (dATP; dAXP), a substrate of adenosine deaminase, is elevated by 30-fold to greater than 1,500-fold in SCID patients. </p><p><strong><em>Delayed or Late-Onset SCID</em></strong></p><p>
Santisteban et al. (1993) reported 7 patients with 'delayed' or 'late' onset of SCID due to ADA deficiency. Three of these patients had onset of symptoms at ages 9, 12, and 12 months, respectively, although diagnosis of ADA deficiency was not made until ages 14 months, 2, and 3 years, respectively. Four patients were relatively asymptomatic until ages 2 to 5 years, when recurrent respiratory infections became prominent. ADA activity in cultured T cells and deoxyadenosine nucleotide levels in red cells in all 7 patients were intermediate between typical early-onset SCID patients and immunocompetent individuals with partial ADA deficiency. </p><p>Umetsu et al. (1994) reported 2 sisters with SCID due to ADA deficiency. The second-born child presented first with serious infections and failure to thrive at age 4 months; the diagnosis of SCID was made at age 9 months when the child was hospitalized for Pseudomonas sepsis and Pneumocystis pneumonia. Her healthy 39-month-old sister was then tested and found to be ADA deficient. She had an unremarkable history, including normal development and uncomplicated varicella zoster at age 6 months. Although she was lymphopenic, antibody production, delayed hypersensitivity, and in vitro T-cell function were intact. She became more lymphopenic over a period of 6 to 7 months and developed persistent upper respiratory infections. Both sisters were treated by enzyme replacement with polyethylene glycol (PEG)-ADA. </p><p>Shovlin et al. (1993) described adult onset of ADA deficiency in 2 sisters who presented with recurrent infections together with laboratory phenotypes similar to those of advanced HIV disease, including severe CD4 lymphopenia. Both were HIV-negative. A 34-year-old woman reported asthma and recurrent chest infections from childhood. As an adult, she had widespread viral warts, recurrent oral and vaginal candidosis, and reported 2 episodes of dermatomal zoster. Her 35-year-old sister was well until age 17 when she developed idiopathic thrombocytopenic purpura necessitating splenectomy, azathioprine for 7 years, and prednisolone until the time of report. By age 20 she had asthma, recurrent chest infections, vaginal and oral candidosis, widespread viral warts, and recurrent dermatomal zoster. Both sisters had clinical and radiologic evidence of extensive lung damage. Medical records showed lymphopenia in both sisters from ages 20 and 17 years, respectively. These were the oldest patients ever described with a new diagnosis of primary ADA deficiency. </p><p>Ozsahin et al. (1997) reported metabolic, immunologic, and genetic findings in 2 ADA-deficient adults with distinct phenotypes. A 39-year-old woman had combined immunodeficiency with frequent infections, lymphopenia, and recurrent hepatitis as a child, but did relatively well in her second and third decades. She later developed chronic sinopulmonary infections, including tuberculosis, and hepatobiliary disease, and died of viral leukoencephalopathy at 40 years of age. The second patient was a healthy 28-year-old man with normal immune function who was identified after his niece died of SCID. Both adult patients lacked erythrocyte ADA activity, but had only modestly elevated deoxyadenosine nucleotides. </p><p>Hershfield (2003) stated that red cell dATP (dAXP) is elevated by 30- to 300-fold in delayed or late-onset patients. </p><p><strong><em>Partial ADA Deficiency</em></strong></p><p>
Jenkins (1973) and Jenkins et al. (1976) reported a South African Kalahari San ('Bushman') patient with 'partial' ADA deficiency not associated with immunodeficiency. ADA activity was 2 to 3%, 10 to 12%, and 10 to 30% of normal in red blood cells, white blood cells, and fibroblasts, respectively. Multiple tests showed that the child had normal humoral and cellular immunity. A sib had similar ADA levels and the parents had intermediate levels. In a study of 36 South African populations comprising more than 3,000 individuals, Jenkins et al. (1976) found that many members of the Kung Bushman population had red cell ADA deficiency not associated with immunodeficiency. The authors concluded that the phenotype was due to a polymorphic allele, designated ADA-8, with a frequency of approximately 0.11 in the Kung population. </p><p>Hart et al. (1986) reported a second Bantu-speaking Xhosa man from South Africa with partial ADA deficiency similar to the type previously reported by Jenkins et al. (1976). Erythrocyte ADA levels were decreased at 6 to 9% of normal, whereas white cell ADA was approximately 30% of normal, and the enzyme showed decreased stability in vitro. Levels of dATP were 2- to 3-fold above normal in red blood cells. Electrophoretic studies suggested compound heterozygosity. </p><p>Hirschhorn et al. (1979) reported a patient with ADA deficiency without immunodeficiency in whom the mutant ADA enzyme was unstable. Daddona et al. (1983) reported another patient with partial ADA deficiency and normal immune function. ADA activity and protein were undetectable in red blood cells, 0.9% of normal in lymphocytes, 4% in lymphoblasts, and 14% in fibroblasts. The ADA protein was abnormally acidic. </p><p>Hirschhorn et al. (1983) reported 4 unrelated children with partial ADA deficiency who lacked ADA in their erythrocytes but retained variable amounts of activity in their lymphoid cells. None had significant immunologic deficiency. Electrophoretic mobility studies showed different forms of the enzyme: one form was acidic, had very low activity, and was heat-stable; a second was basic, had low activity, and was heat-labile; a third was heat-labile and retained relatively normal activity; and a fourth had decreased activity without qualitative abnormalities. Hirschhorn et al. (1983) concluded that 3 of the individuals had mutations at the structural locus for ADA, and that the fourth may have had a mutation at a regulatory locus. Noting that 2 of the partially deficient families were of African descent and a third came from the Mediterranean basin, Hirschhorn et al. (1983) suggested that partial ADA deficiency may confer an advantage against intraerythrocytic parasites, such as malaria or babesiosis, which require exogenous purines derived from the host to survive. </p><p>Hirschhorn and Ellenbogen (1986) reported 5 unrelated patients with partial ADA deficiency identified through a New York state neonatal screening program. None of them had immunologic abnormalities. Three patients were shown to be genetic compounds by the presence of 2 electrophoretically distinguishable allozymes or by family studies that demonstrated a null allele in addition to an electrophoretically abnormal enzyme. All 5 of the children were either black or of West Indian descent, suggesting a clustering of the partial ADA deficiency phenotype in this ethnic group. The genetically distinct enzymes excluded a founder effect, and the authors again concluded a selective advantage for partial ADA deficiency. </p><p>Hershfield (2003) stated that red cell dATP (dAXP) is elevated by zero to approximately 30-fold in patients with partial ADA deficiency. </p>
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<h4>
<span class="mim-font">
<strong>Other Features</strong>
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</div>
<span class="mim-text-font">
<p>Ratech et al. (1985) reported postmortem findings in 8 patients with SCID due to ADA deficiency. Seven patients had renal mesangial sclerosis, and 6 had adrenal cortical sclerosis. Tissue from vertebrae and costochondral junctions in 4 patients showed short growth plates with few proliferating and some hypertrophic chondrocytes. Two patients who had received bone marrow or enzyme infusions had milder changes. The authors concluded that disordered nucleoside metabolism due to absent ADA activity results in multisystem pathologic changes. </p><p>Bollinger et al. (1996) described a human neonate with ADA deficiency, confirmed by genetic analysis, who developed prolonged hyperbilirubinemia with hepatitis that resolved after the institution of ADA replacement therapy. Percutaneous liver biopsy showed early giant-cell transformation, with enlarged foamy hepatocytes and portal and lobular eosinophilic infiltrates. </p><p>Hirschhorn et al. (1980) referred to neurologic abnormalities that had been reported in 2 of 23 ADA-deficient patients and reported a third who showed improvement of these features with enzyme replacement by red cell infusion. Neurologic abnormalities included movement disorders, nystagmus, and sensorineural deafness. Rogers et al. (2001) evaluated the cognitive, behavioral, and neurodevelopmental function in 11 case-matched pairs of patients with ADA-SCID and non-ADA-deficient SCID, all of whom had undergone bone marrow transplantation. Cognitive ability was not significantly different between the 2 groups, but patients with ADA-SCID had a significant inverse correlation between dATP levels at diagnosis and IQ. Behavioral assessment showed that patients with ADA-SCID functioned in the pathologic range on all domains, whereas mean scores for the control group were within normal limits. Behavioral impairment in patients with ADA-SCID also showed a significant positive correlation with age. </p>
</span>
<div>
<br />
</div>
<div>
<h4>
<span class="mim-font">
<strong>Mapping</strong>
</span>
</h4>
</div>
<span class="mim-text-font">
<p>Koch and Shows (1980) showed that ADA deficiency in SCID segregated with chromosome 20 in interspecific somatic cell hybrids, suggesting that a structural gene mutation at the ADA locus was the primary cause of ADA-deficient SCID. </p>
</span>
<div>
<br />
</div>
<div>
<h4>
<span class="mim-font">
<strong>Pathogenesis</strong>
</span>
</h4>
</div>
<span class="mim-text-font">
<p>Mitchell et al. (1978) found that deoxyadenosine and deoxyguanosine were particularly toxic to T cells but not to B cells. Addition of deoxycytidine or dipyridamole prevented deoxyribonucleoside toxicity. </p><p>Boss et al. (1981) concluded that ecto-5-prime-nucleotidase deficiency is secondary to the primary defect of ADA. In cells from a patient with ADA-deficient SCID, Herbschleb-Voogt et al. (1983) found a deficiency of ADA activity and a comparable deficiency of ADA-specific cross-reacting material, indicating a decrease of the enzyme. </p><p>Cohen et al. (1978) observed greater than 50-fold elevations of 2-prime-deoxyadenosine triphosphate (dATP) in the erythrocytes of 3 SCID ADA-deficient patients, but not in the erythrocytes of an immunocompetent ADA-deficient patient or 2 unrelated immunodeficient patients with normal ADA. In vivo infusion of normal erythrocytes containing normal ADA activity in 2 SCID ADA-deficient patients resulted in a dramatic decrease in dATP and some clinical response. Cohen et al. (1978) concluded that deoxyadenosine is the toxic substrate in ADA deficiency, and that the toxic effect is mediated by dATP inhibition of ribonucleotide reductase (see, e.g., 180410), which is responsible for the reduction of all the purine and pyrimidine ribonucleotides to their respective 2-prime-deoxyribonucleotides, the necessary precursors for DNA synthesis. Immunodeficiency is the consequence of the particular sensitivity of immature lymphoid cells to the toxic effects of ADA substrates. </p><p>Van de Wiele et al. (2002) noted that most immature thymocytes undergo apoptosis as a result of lymphocyte selection in the thymus. Degradation of cell DNA and RNA by ADA generates adenosine and deoxyadenosine. Accumulation of these metabolites and their derivatives in ADA deficiency is lymphotoxic, resulting in reduced production of T cells. In addition, dATP inhibits ribonucleotide reductase, which is necessary for DNA synthesis, and dATP and adenosine inhibit S-adenosylhomocysteine hydrolase (SAHH; 180960), which is necessary for methylation reactions that are required for cell viability. In cell cultures (fetal thymic organ culture, FTOC) from a mouse model of ADA deficiency, van de Wiele et al. (2002) found that inhibition of adenosine kinase (102750) resulted in an increase in T-cell recovery, indicating that toxicity in ADA deficiency is due to a phosphorylated form of an ADA substrate and not adenosine or deoxyadenosine. Further studies suggested that inhibition of SAH or ribonucleotide reductase was not sufficient to cause toxicity. Van de Wiele et al. (2002) concluded that the mechanism of dATP toxicity involves dATP-induced cytochrome c release from mitochondria, which initiates the apoptotic cascade. </p><p>Apasov et al. (2001) found that Ada -/- mice had a pronounced decrease in the size and lymphocyte content of spleen, lymph nodes, and thymus at 3 weeks of age compared to wildtype mice. There was increased apoptosis of immature T cells in the thymi of mutant mice, but not in the peripheral lymphoid organs, indicating specific effects on developing T cells. In addition, mature CD4- and CD8-positive T cells from Ada -/- mice showed decreased T cell receptor (TCR; see 186880)-triggered activation in vivo and in vitro as a result of increased exogenous adenosine, to a lesser extent than in mature T cells of wildtype mice, indicating that adenosine can affect normal T cell activation. The nucleoside 2-prime-deoxyadenosine was directly cytotoxic to lymphocytes. Apasov et al. (2001) concluded that T-cell depletion in ADA-deficient SCID results from at least 2 mechanisms: intracellular toxicity of adenosine, dATP, and 2-prime-deoxyadenosine, and inhibition of T-cell signaling by elevated levels of adenosine. </p>
</span>
<div>
<br />
</div>
<div>
<h4>
<span class="mim-font">
<strong>Diagnosis</strong>
</span>
</h4>
</div>
<span class="mim-text-font">
<p><strong><em>Prenatal Diagnosis</em></strong></p><p>
Hirschhorn et al. (1975) diagnosed ADA deficiency in a fetus by finding less than 1.5% ADA activity in cultured amniotic fluid cells. An older sib had died from SCID due to ADA deficiency. </p><p>Aitken et al. (1980) used a microradioassay to evaluate ADA activity in cultured amniotic fluid cells in a pregnancy at risk for ADA deficiency and SCID. A low-normal level of activity consistent with the heterozygous state was found in the fetus, which was confirmed after birth. In 2 subsequent pregnancies of a mother of a child with SCID due to ADA deficiency, Ziegler et al. (1981) assayed ADA activity in amniotic fluid fibroblasts and diagnosed a normal fetus and a homozygous ADA-deficient fetus, respectively. The diagnoses were confirmed after birth and in abortus tissue. </p>
</span>
<div>
<br />
</div>
<div>
<h4>
<span class="mim-font">
<strong>Clinical Management</strong>
</span>
</h4>
</div>
<span class="mim-text-font">
<p><strong><em>Enzyme Replacement Therapy</em></strong></p><p>
Polmar et al. (1976) reported successful treatment of a child with SCID due to ADA deficiency by 'enzyme replacement therapy' using frozen irradiated red blood cells with normal ADA activity. After treatment, a thymic shadow appeared radiographically, lymphocytic responses were demonstrated in vitro, and there was immunoglobulin synthesis. With infusions at 4-week intervals, the child remained free of infection for 17 months. </p><p>Ziegler et al. (1980) reported a patient with SCID due to ADA deficiency who was treated with ADA-positive red cell infusions. Although there was some resolution of interstitial pneumonitis and skeletal abnormalities, there was no evidence of immunologic reconstitution, and the patient died at age 17 months. The authors noted that severe cases of SCID due to ADA deficiency may not respond to exogenous enzyme therapy. Markert et al. (1987) reported 5 ADA-deficient patients who showed no lasting benefit from red blood cell transfusions. </p><p>Hershfield et al. (1987) reported successful treatment of 2 SCID ADA-deficient patients with polyethylene glycol-modified bovine intestinal ADA (PEG-ADA). The modified enzyme was rapidly absorbed after intramuscular injection and had a half-life in plasma of 48 to 72 hours. Weekly doses maintained plasma ADA activity at 2 to 3 times the level of red cell ADA in normal subjects, resulting in a decrease in toxic deoxyadenosine nucleotides to less than 0.5% of total adenine nucleotides. The activity of S-adenosylhomocysteine hydrolase, which is inactivated by deoxyadenosine, increased to normal in red cells and nucleated marrow cells. Neither toxic effects nor hypersensitivity reactions were observed. In vitro tests of cellular immune function of each patient showed marked improvement, together with an increase in T lymphocytes. Covalent attachment of polyethylene glycol to ADA blocked access to vulnerable sites on the surface of the protein, inhibiting clearance from the circulation, attack by degrading enzymes, binding of antibodies, and processing by antigen-presenting cells. </p><p>Levy et al. (1988) reported a child who developed symptoms of SCID due to ADA deficiency at age 3 years. She had 0.6% and 1% of normal ADA activity in erythrocytes and mononuclear cells, respectively. Weekly treatment with PEG-modified ADA was well tolerated and her T lymphocyte numbers and response to mitogens became normal. </p><p>In a review, Hershfield (1995) noted that PEG-ADA works in the plasma by degrading adenosine (Ado) and deoxyadenosine (dAdo), followed by rapid equilibration with intracellular concentrations via a plasma membrane nucleoside transporter. After approximately 2 months of treatment, lymphocyte counts increase and show a proliferative response to mitogens in vitro, a thymic shadow may appear, and patients often develop persistent antibody titers. Although immune function is not normal, serious opportunistic infections usually resolve. Development of anti-ADA antibodies rarely occurs. Hershfield (1995) noted that PEG-ADA treatment is indicated for patients who lack an HLA-identical bone marrow donor, but are at too high a risk for HLA-haploidentical marrow transplantation. Mortality with PEG-ADA is lower than that with haploidentical bone marrow transplantation. </p><p><strong><em>Bone Marrow Transplantation</em></strong></p><p>
Bortin and Rimm (1977) reported on the characteristics and results of treatment in 69 patients with SCID due to various causes; 4 of 25 (16%) patients tested had ADA deficiency. The highest 6-month survival rate occurred in those who had undergone bone marrow transplant (BMT) from HLA genotypically identical donors. In surveying 18 of 80 SCID patients who survived bone marrow transplantation, Kenny and Hitzig (1979) found that 3 of the 18 patients had ADA deficiency. </p><p>Buckley et al. (1999) reported survival of 11 of 13 ADA-deficient patients who underwent bone marrow transplantation. Seven of 9 children who underwent haploidentical BMT were alive 1.6 to 15.6 years after transplantation, with hematopoietic chimerism demonstrable in 6. T-cell numbers and function improved approximately 3 to 4 months after transplantation; B-cell numbers and function improved to a lesser degree. </p>
</span>
<div>
<br />
</div>
<div>
<h4>
<span class="mim-font">
<strong>Inheritance</strong>
</span>
</h4>
</div>
<span class="mim-text-font">
<p>The transmission pattern of SCID due to ADA deficiency in the patients reported by Valerio et al. (1986) and Akeson et al. (1987) was consistent with autosomal recessive inheritance. </p>
</span>
<div>
<br />
</div>
<div>
<h4>
<span class="mim-font">
<strong>Molecular Genetics</strong>
</span>
</h4>
</div>
<span class="mim-text-font">
<p><strong><em>Severe Combined Immunodeficiency due to ADA Deficiency</em></strong></p><p>
In a patient with SCID due to ADA deficiency who was originally reported by Hirschhorn et al. (1975), Valerio et al. (1986) identified compound heterozygosity for 2 mutations in the ADA gene (608958.0001; 608958.0005). </p><p>Akeson et al. (1987) reported several biallelic mutations in the ADA gene in patients with ADA-deficient SCID (see, e.g., 608958.0004; 608958.0006; 608958.0017). </p><p>In 2 sisters with SCID due to ADA deficiency reported by Umetsu et al. (1994), Arredondo-Vega et al. (1994) identified compound heterozygosity for 2 splice site mutations in the ADA gene (608598.0022; 608598.0023). </p><p><strong><em>Delayed or Late-Onset SCID</em></strong></p><p>
In 7 patients with delayed or late onset of SCID due to ADA deficiency, Santisteban et al. (1993) identified mutations in the ADA gene (see, e.g., 608958.0020 and 608958.0032). </p><p><strong><em>Partial ADA Deficiency</em></strong></p><p>
In patients with partial ADA deficiency, Hirschhorn et al. (1989, 1990) identified several biallelic mutations in the ADA gene (608958.0009-608958.0015). </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>Hirschhorn et al. (1994) reported a patient diagnosed with SCID due to ADA deficiency at age 2.5 years because of life-threatening pneumonia, recurrent infections, failure of normal growth, and lymphopenia. However, he retained significant cellular immune function. His condition improved dramatically in the absence of specific therapy, and he was a healthy adolescent at age 16 years with no medical problems at age 20 years. A fibroblast cell line and a B-cell line, established at the time of diagnosis, lacked ADA activity. Genetic analysis identified compound heterozygosity for a splice site mutation (608958.0024) and a missense mutation (608958.0003). All clones isolated from the B-cell mRNA carried the missense mutation, indicating that the allele with the splice site mutation produced unstable mRNA. In striking contrast, a B-cell line established at age 16 expressed 50% of normal ADA; 50% of ADA mRNA had normal sequence, and 50% had the missense mutation. Genomic DNA contained the missense mutation, but not the splice site mutation. Genomic DNA from peripheral blood cells obtained at 16 years of age indicated in vivo somatic mosaicism; less than half the DNA carried the splice site mutation (P less than 0.002, vs original B-cell line). Consistent with the mosaicism, erythrocyte content of the toxic metabolite deoxy-ATP was only minimally elevated. Hirschhorn et al. (1994) postulated that somatic mosaicism could have arisen by somatic mutation or by reversion at the site of mutation. Selection in vivo for ADA normal hematopoietic cells likely played a role in the return to normal health in the absence of therapy. </p><p>Hirschhorn et al. (1996) reported a patient who presented during the first years of life with recurrent infections and lymphopenia. A prior sib died before age 3 years of SCID affecting both T and B cells. At age 5 years, the proband lacked ADA activity in erythrocytes, but concentrations of deoxy-ATP in red blood cells were only mildly elevated compared to concentrations found in severe SCID patients. Mononuclear cells had 15% of normal ADA activity. Both the mother and father had 50% and 20 to 25% normal activity in erythrocytes and lymphocytes, respectively. Between the ages of 8 and 12 years, the proband was clinically healthy, with normal growth and development, although he had persistent hyper-IgE, decreased numbers of CD4+ T cells and B cells, and increased numbers of CD8+ T cells. Genetic analysis identified compound heterozygosity for 2 mutations in the ADA gene: a splice site mutation (608958.0026), inherited from the father, and an R156H mutation (608958.0032) inherited from the mother. Peripheral blood from the proband at age 11 years showed the splice site and R156H mutations in 50% and 34%, respectively, of cells, whereas 17% of cells did not carry either mutation. Cell lines established showed virtual absence of the maternally derived R156H mutation, indicating in vivo reversion of the mutation to normal. </p><p>A similar moderation of phenotype had been observed involving a revertant mutation in the IL2RG gene (308380) in X-linked SCID (300400) (Stephan et al., 1996). Revertant cells have also been identified in patients with Fanconi anemia (see 227650 and 227645), Bloom syndrome (210900), Wiskott-Aldrich syndrome (301000), and epidermolysis bullosa (226650) due to mutations in the COL17A1 gene (113811). In addition to back mutation, allele function has been restored by mitotic recombination or gene conversion, which can eliminate the original mutation, and by 'second-site' events that restore reading frame or led to an amino acid substitution better tolerated than the original. In Bloom syndrome, intragenic recombination or gene conversion are the usual mechanisms, consistent with reversion being much more common in heteroallelic than in homoallelic patients (Ellis et al., 1995). Arredondo-Vega et al. (2002) reported 1 member of a Saudi Arabian family with delayed onset of SCID due to a homozygous splice site mutation in the ADA gene (608958.0030) who also carried an acquired second distinct splice site mutation (608958.0031) that suppressed the defect of the first mutation. The patient had a milder phenotype than his sister who did not carry the second mutation. </p><p>Arredondo-Vega et al. (1998) noted that the phenotype of ADA deficiency is strongly associated with the sum of ADA activity provided by both alleles. Many mutations are private and patients are often heteroallelic, precluding definite genotype/phenotype correlations. Functional expression analysis of 29 different missense mutations expressed in an ADA-deleted E. coli strain showed that alleles from immunodeficient patients expressed 0.001 to 0.6% ADA activity compared to wildtype. Alleles found only in healthy individuals with partial deficiency showed 1 to 28% of normal activity. In all, the activity levels spanned 5 orders of magnitude. The authors found that 1 to 1.5% residual ADA activity was consistent with sustaining immune function. There was a strong inverse correlation between red cell dAXP concentration and the sum of ADA activity expressed by both alleles, establishing a direct link between the effects of genotype on residual ADA activity, metabolism, and clinical expression. </p>
</span>
<div>
<br />
</div>
<div>
<h4>
<span class="mim-font">
<strong>Animal Model</strong>
</span>
</h4>
</div>
<span class="mim-text-font">
<p>Abbott et al. (1986) presented evidence that 'wasted' (wst) in mice is caused by a mutation in the structural gene for ADA. As occurs in humans with ADA deficiency, wasted mice are immunodeficient, develop neurologic abnormalities, and die soon after weaning. </p><p>Unlike humans, mice that express no adenosine deaminase die perinatally of severe hepatocellular degeneration (Migchielsen et al., 1995; Wakamiya et al., 1995). </p><p>Blackburn et al. (1998) reported the use of a 2-stage genetic engineering strategy to generate ADA-deficient mice that retained many features associated with ADA deficiency in humans, including a combined immunodeficiency. Severe T- and B-cell lymphopenia was accompanied by a pronounced accumulation of 2-deoxyadenosine and dATP in the thymus and spleen, and a marked inhibition of S-adenosylhomocysteine hydrolase in the same organs. Accumulation of adenosine was widespread among all tissues examined. ADA-deficient mice also exhibited severe pulmonary insufficiency, bone abnormalities, and kidney pathology. </p>
</span>
<div>
<br />
</div>
</div>
<div>
<h4>
<span class="mim-font">
<strong>See Also:</strong>
</span>
</h4>
<span class="mim-text-font">
Aiuti et al. (2009); Aiuti et al. (2002); Arredondo-Vega et al.
(1990); Blaese et al. (1995); Bordignon et al. (1995); Chen et al.
(1979); Chen et al. (1978); Chen et al. (1974); Cook et al. (1970);
Culver (1996); Daddona and Kelley (1979); Detter et al. (1970);
Dissing and Knudsen (1972); Dissing and Knudsen (1969); Dyminski et
al. (1979); Egashira et al. (1998); Ferrari et al. (1991); Hershfield
and Krodich (1978); Hirschhorn et al. (1974); Hirschhorn et al.
(1979); Hirschhorn et al. (1994); Honig et al. (1984); Hopkinson et
al. (1969); Hutton et al. (1981); Jenkins et al. (1979); Kaitila et
al. (1976); Kellems et al. (1985); Kredich and Martin (1977); Markert
et al. (1987); Markert et al. (1988); Moen et al. (1987); Onodera et
al. (1998); Palmer et al. (1987); Ritter et al. (1971); Rubinstein et
al. (1979); Schmalstieg et al. (1983); Schrader et al. (1978); Scott
et al. (1974); Shovlin et al. (1994); Valerio et al. (1984); Van der
Weyden and Kelley (1974); Weitkamp (1971); Weitkamp (1972); Wiginton
and Hutton (1982); Yokoyama et al. (1979); Yount et al. (1974)
</span>
<div>
<br />
</div>
</div>
<div>
<h4>
<span class="mim-font">
<strong>REFERENCES</strong>
</span>
</h4>
<div>
<p />
</div>
<div>
<ol>
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Abbott, C. M., Skidmore, C. J., Searle, A. G., Peters, J.
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Aitken, D. A., Kleijer, W. J., Niermeijer, M. F., Herbschleb-Voogt, E., Galjaard, H.
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<p class="mim-text-font">
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<p class="mim-text-font">
Apasov, S. G., Blackburn, M. R., Kellems, R. E., Smith, P. T., Sitkovsky, M. V.
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<p class="mim-text-font">
Arredondo-Vega, F. X., Santisteban, I., Richard, E., Bali, P., Koleilat, M., Loubser, M., Al-Ghonaium, A., Al-Helali, M., Hershfield, M. S.
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<p class="mim-text-font">
Blackburn, M. R., Datta, S. K., Kellems, R. E.
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Bollinger, M. E., Arredondo-Vega, F. X., Santisteban, I., Schwarz, K., Hershfield, M. S., Lederman, H. M.
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Bortin, M. M., Rimm, A. A. (eds.).
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<p class="mim-text-font">
Boss, G. R., Thompson, L. F., O'Connor, R. D., Ziering, R. W., Seegmiller, J. E.
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<p class="mim-text-font">
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Ritter, H., Wendt, G. G., Tariverdian, G., Zelch, J., Rube, M., Kirchberg, G.
<strong>Genetics and linkage analysis of adenosine deaminase.</strong>
Humangenetik 14: 69-71, 1971.
[PubMed: 5144905]
[Full Text: https://doi.org/10.1007/BF00273036]
</p>
</li>
<li>
<p class="mim-text-font">
Rogers, M. H., Lwin, R., Fairbanks, L., Gerritsen, B., Gaspar, H. B.
<strong>Cognitive and behavioral abnormalities in adenosine deaminase deficient severe combined immunodeficiency.</strong>
J. Pediat. 139: 44-50, 2001.
[PubMed: 11445793]
[Full Text: https://doi.org/10.1067/mpd.2001.115023]
</p>
</li>
<li>
<p class="mim-text-font">
Rubinstein, A., Hirschhorn, R., Sicklick, M., Murphy, R. A.
<strong>In vivo and in vitro effects of thymosin and adenosine deaminase on adenosine-deaminase-deficient lymphocytes.</strong>
New Eng. J. Med. 300: 387-392, 1979.
[PubMed: 310515]
[Full Text: https://doi.org/10.1056/NEJM197902223000802]
</p>
</li>
<li>
<p class="mim-text-font">
Santisteban, I., Arredondo-Vega, F. X., Kelly, S., Mary, A., Fischer, A., Hummell, D. S., Lawton, A., Sorensen, R. U., Stiehm, E. R., Uribe, L., Weinberg, K., Hershfield, M. S.
<strong>Novel splicing, missense, and deletion mutations in seven adenosine deaminase-deficient patients with late/delayed onset of combined immunodeficiency disease: contribution of genotype to phenotype.</strong>
J. Clin. Invest. 92: 2291-2302, 1993.
[PubMed: 8227344]
[Full Text: https://doi.org/10.1172/JCI116833]
</p>
</li>
<li>
<p class="mim-text-font">
Schmalstieg, F. C., Mills, G. C., Tsuda, H., Goldman, A. S.
<strong>Severe combined immunodeficiency in a child with a healthy adenosine deaminase deficient mother.</strong>
Pediat. Res. 17: 935-940, 1983.
[PubMed: 6606796]
[Full Text: https://doi.org/10.1203/00006450-198312000-00002]
</p>
</li>
<li>
<p class="mim-text-font">
Schrader, W. P., Pollara, B., Meuwissen, H. J.
<strong>Characterization of the residual adenosine deaminating activity in the spleen of a patient with combined immunodeficiency disease and adenosine deaminase deficiency.</strong>
Proc. Nat. Acad. Sci. 75: 446-450, 1978.
[PubMed: 24216]
[Full Text: https://doi.org/10.1073/pnas.75.1.446]
</p>
</li>
<li>
<p class="mim-text-font">
Scott, C. R., Chen, S.-H., Giblett, E. R.
<strong>Deletion of the carrier state in combined immunodeficiency disease associated with deaminase deficiency.</strong>
J. Clin. Invest. 53: 1194-1196, 1974.
[PubMed: 4815083]
[Full Text: https://doi.org/10.1172/JCI107658]
</p>
</li>
<li>
<p class="mim-text-font">
Shovlin, C. L., Hughes, J. M. B., Simmonds, H. A., Fairbanks, L., Deacock, S., Lechler, R., Roberts, I., Webster, A. D. B.
<strong>Adult presentation of adenosine deaminase deficiency. (Letter)</strong>
Lancet 341: 1471, 1993.
[PubMed: 8099155]
[Full Text: https://doi.org/10.1016/0140-6736(93)90910-9]
</p>
</li>
<li>
<p class="mim-text-font">
Shovlin, C. L., Simmonds, H. A., Fairbanks, L. D., Deacock, S. J., Hughes, J. M. B., Lechler, R. I., Webster, A. D. B., Sun, X.-M., Webb, J. C., Soutar, A. K.
<strong>Adult onset immunodeficiency caused by inherited adenosine deaminase deficiency.</strong>
J. Immun. 153: 2331-2339, 1994.
[PubMed: 8051429]
</p>
</li>
<li>
<p class="mim-text-font">
Stephan, V., Wahn, V., Le Deist, F., Dirksen, U., Broker, B., Muller-Fleckenstein, I., Horneff, G., Schroten, H., Fischer, A., de Saint Basile, G.
<strong>Atypical X-linked severe combined immunodeficiency due to possible spontaneous reversion of the genetic defect in T cells.</strong>
New Eng. J. Med. 335: 1563-1567, 1996.
[PubMed: 8900089]
[Full Text: https://doi.org/10.1056/NEJM199611213352104]
</p>
</li>
<li>
<p class="mim-text-font">
Umetsu, D. T., Schlossman, C. M., Ochs, H. D., Hershfield, M. S.
<strong>Heterogeneity of phenotype in two siblings with adenosine deaminase deficiency.</strong>
J. Allergy Clin. Immun. 93: 543-550, 1994.
[PubMed: 8120281]
[Full Text: https://doi.org/10.1016/0091-6749(94)90365-4]
</p>
</li>
<li>
<p class="mim-text-font">
Valerio, D., Dekker, B. M. M., Duyvesteyn, M. G. C., van der Voorn, L., Berkvens, T. M., van Ormondt, H., van der Eb, A. J.
<strong>One adenosine deaminase allele in a patient with severe combined immunodeficiency contains a point mutation abolishing enzyme activity.</strong>
EMBO J. 5: 113-119, 1986.
[PubMed: 3007108]
[Full Text: https://doi.org/10.1002/j.1460-2075.1986.tb04184.x]
</p>
</li>
<li>
<p class="mim-text-font">
Valerio, D., Duyvesteyn, M. G. C., van Ormondt, H., Meera Khan, P., van der Eb, A. J.
<strong>Adenosine deaminase (ADA) deficiency in cells derived from humans with severe combined immunodeficiency is due to an aberration of the ADA protein.</strong>
Nucleic Acids Res. 12: 1015-1024, 1984.
[PubMed: 6198631]
[Full Text: https://doi.org/10.1093/nar/12.2.1015]
</p>
</li>
<li>
<p class="mim-text-font">
Van de Wiele, C. J., Vaughn, J. G., Blackburn, M. R., Ledent, C. A., Jacobson, M., Jiang, H., Thompson, L. F.
<strong>Adenosine kinase inhibition promotes survival of fetal adenosine deaminase-deficient thymocytes by blocking dATP accumulation.</strong>
J. Clin. Invest. 110: 395-402, 2002.
[PubMed: 12163459]
[Full Text: https://doi.org/10.1172/JCI15683]
</p>
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<li>
<p class="mim-text-font">
Van der Weyden, M. B., Kelley, W. N.
<strong>Adenosine deaminase deficiency in severe combined immunodeficiency: evidence for a posttranslational defect. (Abstract)</strong>
J. Clin. Invest. 53: 81A-82A, 1974.
</p>
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<li>
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Wakamiya, M., Blackburn, M. R., Jurecic, R., McArthur, M. J., Geske, R. S., Cartwright, J., Jr., Mitani, K., Vaishnav, S., Belmont, J. W., Kellems, R. E., Finegold, M. J., Montgomery, Jr., C. A., Bradley, A., Caskey, C. T.
<strong>Disruption of the adenosine deaminase gene causes hepatocellular impairment and perinatal lethality in mice.</strong>
Proc. Nat. Acad. Sci. 92: 3673-3677, 1995.
[PubMed: 7731963]
[Full Text: https://doi.org/10.1073/pnas.92.9.3673]
</p>
</li>
<li>
<p class="mim-text-font">
Weitkamp, L. R.
<strong>Further data on the genetic linkage relations of the adenosine deaminase locus.</strong>
Hum. Hered. 21: 351-356, 1971.
[PubMed: 5003128]
[Full Text: https://doi.org/10.1159/000152425]
</p>
</li>
<li>
<p class="mim-text-font">
Weitkamp, L. R.
<strong>Genetic linkage relationships of the ADA and 6-PGD loci in &#x27;Humangenetik.&#x27; (Letter)</strong>
Humangenetik 15: 359-360, 1972.
[PubMed: 4634454]
[Full Text: https://doi.org/10.1007/BF00281739]
</p>
</li>
<li>
<p class="mim-text-font">
Wiginton, D. A., Hutton, J. J.
<strong>Immunoreactive protein in adenosine deaminase deficient human lymphoblast cell lines.</strong>
J. Biol. Chem. 257: 3211-3217, 1982.
[PubMed: 6977542]
</p>
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Yokoyama, S., Hayashi, T., Yoshimura, Y., Irimada, K., Saito, T., Akiba, T., Tsuchiya, S.
<strong>Severe combined immunodeficiency disease with adenosine deaminase deficiency.</strong>
Tohoku J. Exp. Med. 129: 197-202, 1979.
[PubMed: 494270]
[Full Text: https://doi.org/10.1620/tjem.129.197]
</p>
</li>
<li>
<p class="mim-text-font">
Yount, J., Nichols, P., Ochs, H. D., Hammar, S. P., Scott, C. R., Chen, S.-H., Giblett, E. R., Wedgwood, R. J.
<strong>Absence of erythrocyte adenosine deaminase associated with severe combined immunodeficiency.</strong>
J. Pediat. 84: 173-177, 1974.
[PubMed: 4810724]
[Full Text: https://doi.org/10.1016/s0022-3476(74)80597-4]
</p>
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<p class="mim-text-font">
Ziegler, J. B., Lee, C. H., Van Der Weyden, M. B., Bagnara, A. S., Beveridge, J.
<strong>Severe combined immunodeficiency and adenosine deaminase deficiency: failure of enzyme replacement therapy.</strong>
Arch. Dis. Child. 55: 452-457, 1980.
[PubMed: 7436484]
[Full Text: https://doi.org/10.1136/adc.55.6.452]
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</li>
<li>
<p class="mim-text-font">
Ziegler, J. B., Van Der Weyden, M. B., Lee, C. H., Daniel, A.
<strong>Prenatal diagnosis for adenosine deaminase deficiency.</strong>
J. Med. Genet. 18: 154-156, 1981.
[PubMed: 7241535]
[Full Text: https://doi.org/10.1136/jmg.18.2.154]
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Cassandra L. Kniffin - updated : 2/4/2009<br>Cassandra L. Kniffin - updated : 11/11/2004<br>Cassandra L. Kniffin - reorganized : 10/28/2004<br>Cassandra L. Kniffin - updated : 10/20/2004<br>Ada Hamosh - updated : 7/29/2002<br>Victor A. McKusick - updated : 3/19/2002<br>Deborah L. Stone - updated : 10/3/2001<br>Victor A. McKusick - updated : 5/11/2001<br>Ada Hamosh - updated : 7/20/2000<br>Victor A. McKusick - updated : 3/25/1998<br>Victor A. McKusick - updated : 12/19/1997<br>Ethylin Wang Jabs - updated : 7/21/1997<br>Victor A. McKusick - updated : 6/5/1997<br>Victor A. McKusick - updated : 5/16/1997<br>Iosif W. Lurie - updated : 9/26/1996
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Victor A. McKusick : 6/4/1986
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