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<title>
Entry
- #236200 - HOMOCYSTINURIA DUE TO CYSTATHIONINE BETA-SYNTHASE DEFICIENCY
- OMIM
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<span class="h4">#236200</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/236200"><strong>Clinical Synopsis</strong></a>
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<a href="#text"><strong>Text</strong></a>
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<a href="#description">Description</a>
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<a href="#clinicalFeatures">Clinical Features</a>
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<a href="#otherFeatures">Other Features</a>
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<a href="#diagnosis">Diagnosis</a>
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<a href="#clinicalManagement">Clinical Management</a>
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<a href="#biochemicalFeatures">Biochemical Features</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="#pathogenesis">Pathogenesis</a>
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<a href="#populationGenetics">Population Genetics</a>
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<a href="#nomenclature">Nomenclature</a>
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<a href="#history">History</a>
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<a href="#seeAlso"><strong>See Also</strong></a>
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<a href="#references"><strong>References</strong></a>
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<a href="#contributors"><strong>Contributors</strong></a>
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<a href="#creationDate"><strong>Creation Date</strong></a>
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<div><a href="https://hprd.org/summary?hprd_id=01994&isoform_id=01994_1&isoform_name=Isoform_1" class="mim-tip-hint" title="The Human Protein Reference Database; manually extracted and visually depicted information on human proteins." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HPRD', 'domain': 'hprd.org'})">HPRD</a></div>
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<div><a href="https://clinicaltrials.gov/search?cond=HOMOCYSTINURIA DUE TO CYSTATHIONINE BETA-SYNTHASE 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/books/NBK1524/" class="mim-tip-hint" title="Expert-authored, peer-reviewed descriptions of inherited disorders including the uses of genetic testing in diagnosis, management, and genetic counseling." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Gene Reviews', 'domain': 'ncbi.nlm.nih.gov'})">Gene Reviews</a></div>
<div><a href="https://www.diseaseinfosearch.org/x/3462" class="mim-tip-hint" title="Network of disease-specific advocacy organizations, universities, private companies, government agencies, and public policy organizations." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Genetic Alliance', 'domain': 'diseaseinfosearch.org'})">Genetic Alliance</a></div>
<div><a href="https://www.ncbi.nlm.nih.gov/gtr/all/tests/?term=236200[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="#mimNewbornScreeningFold" id="mimNewbornScreeningToggle" data-toggle="collapse" class="mim-tip-hint mimTriangleToggle" title="Information and resources for newborn screening and genetics."><span id="mimNewbornScreeningToggleTriangle" class="small" style="margin-left: -0.8em;">&#9658;</span>Newborn Screening</div>
<div id="mimNewbornScreeningFold" class="collapse">
<div style="margin-left: 0.5em;"><a href="https://www.acmg.net/PDFLibrary/Methionine.pdf" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Newborn Screening', 'domain': 'www.acmg.net'})">ACMG ACT Sheet</a></div><div style="margin-left: 0.5em;"><a href="https://www.acmg.net/PDFLibrary/Methionine-Algorithm.pdf" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Newborn Screening', 'domain': 'www.acmg.net'})">ACMG Algorithm</a></div>
</div>
<div><a href="https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=394" 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><a href="https://www.possumcore.com/nuxeo/nxdoc/default/9a286c57-c9ac-4f33-9614-dc4e9ef585b8/view_documents?source=omim" class="mim-tip-hint" title="A dysmorphology database of multiple malformations; metabolic, teratogenic, chromosomal, and skeletal syndromes; and their images." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'POSSUM', 'domain': 'possum.net.au'})">POSSUM</a></div>
</div>
</div>
</div>
<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
<div class="panel-heading mim-panel-heading" role="tab" id="mimVariation">
<span class="panel-title">
<span class="small">
<a href="#mimVariationLinksFold" id="mimVariationLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
<span id="mimVariationLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">&#9658;</span> Variation
</a>
</span>
</span>
</div>
<div id="mimVariationLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
<div class="panel-body small mim-panel-body">
<div><a href="http://www.uchsc.edu/cbs/" class="mim-tip-hint" title="A gene-specific database of variation." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Locus Specific DB', 'domain': 'locus-specific-db.org'})">Locus Specific DBs</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:9263" 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/236200" 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:9263" 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:236200" 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> 24308003<br />
<strong>ORPHA:</strong> 394<br />
<strong>DO:</strong> 9263<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>
236200
</span>
</span>
</div>
</div>
<div>
<a id="preferredTitle" class="mim-anchor"></a>
<h3>
<span class="mim-font">
HOMOCYSTINURIA DUE TO CYSTATHIONINE BETA-SYNTHASE 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">
HOMOCYSTINURIA WITH OR WITHOUT RESPONSE TO PYRIDOXINE<br />
CYSTATHIONINE BETA-SYNTHASE DEFICIENCY<br />
CBS DEFICIENCY
</span>
</h4>
</div>
</div>
<div>
<br />
</div>
<div>
<a id="includedTitles" class="mim-anchor"></a>
<div>
<p>
<span class="mim-font">
Other entities represented in this entry:
</span>
</p>
</div>
<div>
<span class="h3 mim-font">
HYPERHOMOCYSTEINEMIA, THROMBOTIC, CBS-RELATED, 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/21/142?start=-3&limit=10&highlight=142">
21q22.3
</a>
</span>
</td>
<td>
<span class="mim-font">
Homocystinuria, B6-responsive and nonresponsive types
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/236200"> 236200 </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">
CBS
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/613381"> 613381 </a>
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/21/142?start=-3&limit=10&highlight=142">
21q22.3
</a>
</span>
</td>
<td>
<span class="mim-font">
Thrombosis, hyperhomocysteinemic
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/236200"> 236200 </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">
CBS
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/613381"> 613381 </a>
</span>
</td>
</tr>
</tbody>
</table>
</div>
</div>
<div>
<div class="btn-group ">
<a href="/clinicalSynopsis/236200" class="btn btn-warning" role="button"> Clinical Synopsis </a>
<button type="button" id="mimPhenotypicSeriesToggle" class="btn btn-warning dropdown-toggle mimSingletonFoldToggle" data-toggle="collapse" href="#mimClinicalSynopsisFold" onclick="ga('send', 'event', 'Unfurl', 'ClinicalSynopsis', 'omim.org')">
<span class="caret"></span>
<span class="sr-only">Toggle Dropdown</span>
</button>
</div>
&nbsp;
<div class="btn-group">
<button type="button" class="btn btn-success dropdown-toggle" data-toggle="dropdown" aria-haspopup="true" aria-expanded="false">
PheneGene Graphics <span class="caret"></span>
</button>
<ul class="dropdown-menu" style="width: 17em;">
<li><a href="/graph/linear/236200" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Linear'})"> Linear </a></li>
<li><a href="/graph/radial/236200" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Radial'})"> Radial </a></li>
</ul>
</div>
<span class="glyphicon glyphicon-question-sign mim-tip-hint" title="OMIM PheneGene graphics depict relationships between phenotypes, groups of related phenotypes (Phenotypic Series), and genes.<br /><a href='/static/omim/pdf/OMIM_Graphics.pdf' target='_blank'>A quick reference overview and guide (PDF)</a>"></span>
<div>
<p />
</div>
<div id="mimClinicalSynopsisFold" class="well well-sm collapse mimSingletonToggleFold">
<div class="small" style="margin: 5px">
<div>
<div>
<span class="h5 mim-font">
<strong> INHERITANCE </strong>
</span>
</div>
<div style="margin-left: 2em;">
<div>
<span class="mim-font">
- Autosomal recessive <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/258211005" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">258211005</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0441748&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0441748</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000007" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000007</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000007" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000007</a>]</span><br />
</span>
</div>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<strong> GROWTH </strong>
</span>
</div>
<div style="margin-left: 2em;">
<div>
<div>
<span class="h5 mim-font">
<em> Height </em>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
- Normal to tall stature <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1856085&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1856085</a>]</span><br />
</span>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<em> Other </em>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
- Occasional failure to thrive in infancy <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1856086&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1856086</a>]</span><br />
</span>
</div>
</div>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<strong> HEAD & NECK </strong>
</span>
</div>
<div style="margin-left: 2em;">
<div>
<div>
<span class="h5 mim-font">
<em> Eyes </em>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
- Ectopia lentis <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/74969002" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">74969002</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/Q12.1" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">Q12.1</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/743.37" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">743.37</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0013581&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0013581</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001083" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001083</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001083" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001083</a>]</span><br /> -
Myopia <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/57190000" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">57190000</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/H52.1" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">H52.1</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/367.1" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">367.1</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0027092&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0027092</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000545" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000545</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000545" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000545</a>]</span><br /> -
Glaucoma <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/23986001" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">23986001</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/H40-H42" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">H40-H42</a>, <a href="https://purl.bioontology.org/ontology/ICD10CM/H40" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">H40</a>, <a href="https://purl.bioontology.org/ontology/ICD10CM/H40.9" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">H40.9</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/365" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">365</a>, <a href="https://purl.bioontology.org/ontology/ICD9CM/365.9" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">365.9</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0017601&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0017601</a>, <a href="https://bioportal.bioontology.org/search?q=C0997768&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0997768</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000501" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000501</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000501" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000501</a>]</span><br />
</span>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<em> Mouth </em>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
- High-arched palate <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/27272007" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">27272007</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/Q38.5" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">Q38.5</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0240635&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0240635</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000218" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000218</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000218" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000218</a>]</span><br />
</span>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<em> Teeth </em>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
- Crowded teeth <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/12351004" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">12351004</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/524.31" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">524.31</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0040433&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0040433</a>, <a href="https://bioportal.bioontology.org/search?q=C4724341&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C4724341</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000678" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000678</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000678" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000678</a>]</span><br />
</span>
</div>
</div>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<strong> CARDIOVASCULAR </strong>
</span>
</div>
<div style="margin-left: 2em;">
<div>
<div>
<span class="h5 mim-font">
<em> Heart </em>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
- Myocardial infarction <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/22298006" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">22298006</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/I22" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">I22</a>, <a href="https://purl.bioontology.org/ontology/ICD10CM/I21" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">I21</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C2926063&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C2926063</a>, <a href="https://bioportal.bioontology.org/search?q=C0027051&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0027051</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001658" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001658</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001658" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001658</a>]</span><br /> -
Mitral valve prolapse <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/409712001" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">409712001</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/8074002" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">8074002</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0026267&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0026267</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001634" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001634</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001634" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001634</a>]</span><br />
</span>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<em> Vascular </em>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
- Peripheral vein thrombosis <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C5562948&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C5562948</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> Ribs Sternum Clavicles & Scapulae </em>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
- Pectus excavatum <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/391987005" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">391987005</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/391982004" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">391982004</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/Q67.6" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">Q67.6</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/754.81" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">754.81</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0016842&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0016842</a>, <a href="https://bioportal.bioontology.org/search?q=C2051831&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C2051831</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000767" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000767</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000767" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000767</a>]</span><br /> -
Pectus carinatum <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/205101001" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">205101001</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/38774000" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">38774000</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/Q67.7" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">Q67.7</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/754.82" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">754.82</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C2939416&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C2939416</a>, <a href="https://bioportal.bioontology.org/search?q=C0158731&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0158731</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000768" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000768</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000768" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000768</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> External Features </em>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
- Inguinal hernia <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/396232000" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">396232000</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/K40" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">K40</a>, <a href="https://purl.bioontology.org/ontology/ICD10CM/K40.90" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">K40.90</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/550" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">550</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0019294&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0019294</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000023" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000023</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000023" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000023</a>]</span><br />
</span>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<em> Liver </em>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
- Fatty changes in liver <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/197321007" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">197321007</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0015695&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0015695</a>]</span><br />
</span>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<em> Pancreas </em>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
- Pancreatitis <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/75694006" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">75694006</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/K85.9" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">K85.9</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0030305&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0030305</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001733" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001733</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001733" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001733</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>
<span class="mim-font">
- Generalized osteoporosis <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C4551680&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C4551680</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0040160" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0040160</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0040160" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0040160</a>]</span><br />
</span>
</div>
<div>
<div>
<span class="h5 mim-font">
<em> Spine </em>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
- Biconcave 'codfish' vertebrae <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1856087&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1856087</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0004586" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0004586</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0004586" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0004586</a>]</span><br /> -
Kyphoscoliosis <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/405771009" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">405771009</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/405772002" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">405772002</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/405773007" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">405773007</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/M41" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">M41</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0600033&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0600033</a>, <a href="https://bioportal.bioontology.org/search?q=C0575158&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0575158</a>, <a href="https://bioportal.bioontology.org/search?q=C0345392&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0345392</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002751" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002751</a>, <a href="https://hpo.jax.org/app/browse/term/HP:0008453" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0008453</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002751" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002751</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">
- Dolichostenomelia <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/62250003" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">62250003</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0003706&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0003706</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001166" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001166</a>, <a href="https://hpo.jax.org/app/browse/term/HP:0001519" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001519</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001519" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001519</a>]</span><br /> -
Arachnodactyly <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/62250003" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">62250003</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0003706&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0003706</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001166" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001166</a>, <a href="https://hpo.jax.org/app/browse/term/HP:0001519" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001519</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001166" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001166</a>]</span><br /> -
Limited joint mobility <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1857108&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1857108</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001376" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001376</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001376" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001376</a>]</span><br />
</span>
</div>
</div>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<strong> SKIN, NAILS, & HAIR </strong>
</span>
</div>
<div style="margin-left: 2em;">
<div>
<div>
<span class="h5 mim-font">
<em> Skin </em>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
- Hypopigmentation <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/18655006" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">18655006</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/23006000" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">23006000</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/89031001" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">89031001</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1876214&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1876214</a>, <a href="https://bioportal.bioontology.org/search?q=C0162835&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0162835</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001010" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001010</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001010" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001010</a>]</span><br /> -
Malar flush <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C3550384&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C3550384</a>]</span><br /> -
Livedo reticularis <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/238772004" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">238772004</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0085642&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0085642</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0033505" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0033505</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0033505" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0033505</a>]</span><br />
</span>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<em> Hair </em>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
- Hypopigmentation <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/18655006" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">18655006</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/23006000" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">23006000</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/89031001" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">89031001</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1876214&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1876214</a>, <a href="https://bioportal.bioontology.org/search?q=C0162835&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0162835</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001010" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001010</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001010" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001010</a>]</span><br /> -
Fine, brittle hair <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1844619&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1844619</a>]</span><br />
</span>
</div>
</div>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<strong> NEUROLOGIC </strong>
</span>
</div>
<div style="margin-left: 2em;">
<div>
<div>
<span class="h5 mim-font">
<em> Central Nervous System </em>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
- Seizures <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/91175000" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">91175000</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0036572&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0036572</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001250" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001250</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001250" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001250</a>]</span><br /> -
Mental retardation <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/228156007" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">228156007</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/110359009" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">110359009</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/317-319.99" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">317-319.99</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C3714756&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C3714756</a>, <a href="https://bioportal.bioontology.org/search?q=C0025362&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0025362</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001249" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001249</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001249" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001249</a>]</span><br /> -
Cerebrovascular accident <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/230690007" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">230690007</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/I63.9" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">I63.9</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0038454&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0038454</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001297" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001297</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001297" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001297</a>]</span><br />
</span>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<em> Behavioral Psychiatric Manifestations </em>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
- Psychiatric disorders <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/74732009" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">74732009</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/277843001" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">277843001</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/F99" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">F99</a>, <a href="https://purl.bioontology.org/ontology/ICD10CM/F99-F99" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">F99-F99</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0004936&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0004936</a>, <a href="https://bioportal.bioontology.org/search?q=C5886745&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C5886745</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000708" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000708</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000708" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000708</a>]</span><br /> -
Depression <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/78667006" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">78667006</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/35489007" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">35489007</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/366979004" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">366979004</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/255339005" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">255339005</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/F34.1" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">F34.1</a>, <a href="https://purl.bioontology.org/ontology/ICD10CM/F32.A" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">F32.A</a>, <a href="https://purl.bioontology.org/ontology/ICD10CM/F33.9" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">F33.9</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0812393&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0812393</a>, <a href="https://bioportal.bioontology.org/search?q=C0011581&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0011581</a>, <a href="https://bioportal.bioontology.org/search?q=C0460137&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0460137</a>, <a href="https://bioportal.bioontology.org/search?q=C1579931&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1579931</a>, <a href="https://bioportal.bioontology.org/search?q=C0344315&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0344315</a>, <a href="https://bioportal.bioontology.org/search?q=C4085311&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C4085311</a>, <a href="https://bioportal.bioontology.org/search?q=C0011570&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0011570</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000716" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000716</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000716" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000716</a>]</span><br /> -
Personality disorder <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/33449004" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">33449004</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/F60.9" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">F60.9</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/301" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">301</a>, <a href="https://purl.bioontology.org/ontology/ICD9CM/301.9" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">301.9</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0031212&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0031212</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0012075" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0012075</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0012075" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0012075</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">
- Thromboembolism (25%) <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/13713005" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">13713005</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/371039008" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">371039008</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/453.9" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">453.9</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0040038&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0040038</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001907" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001907</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001907" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001907</a>]</span><br />
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<strong> LABORATORY ABNORMALITIES </strong>
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- Homocystinuria <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/11282001" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">11282001</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/E72.11" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">E72.11</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0019880&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0019880</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002156" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002156</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002156" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002156</a>]</span><br /> -
Methioninuria <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1856089&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1856089</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0032352" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0032352</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0032352" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0032352</a>]</span><br /> -
Cystathionine beta-synthase deficiency <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/24308003" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">24308003</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0751202&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0751202</a>]</span><br />
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<strong> MISCELLANEOUS </strong>
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- Fifty-percent of individuals responsive to pyridoxine (vitamin B6)<br /> -
Pyridoxine responsive individuals often have milder manifestations than those not responsive<br /> -
Management of homocystinuria includes low methionine, cystine supplemented diet for pyridoxine nonresponders and pyridoxine supplementation for pyridoxine responders<br /> -
Treatment with betaine, especially for pyridoxine nonresponders<br /> -
Thromboembolism is the most common cause of death<br /> -
Frequency between 1 in 58,000 to 1 in 1,000,000<br />
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<strong> MOLECULAR BASIS </strong>
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- Caused by mutation in the cystathionine beta-synthase gene (CBS, <a href="/entry/613381#0001">613381.0001</a>)<br />
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<p>A number sign (#) is used with this entry because homocystinuria with or without response to pyridoxine is caused by homozygous or compound heterozygous mutation in the gene encoding cystathionine beta-synthase (CBS; <a href="/entry/613381">613381</a>) on chromosome 21q22.</p>
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<p>Classic homocystinuria is an autosomal recessive metabolic disorder of sulfur metabolism. The clinical features of untreated homocystinuria due to CBS deficiency usually manifest in the first or second decade of life and include myopia, ectopia lentis, mental retardation, skeletal anomalies resembling Marfan syndrome (MFS; <a href="/entry/154700">154700</a>), and thromboembolic events. Light skin and hair can also be present. Biochemical features include increased urinary homocystine and methionine. There are 2 main phenotypes of the classic disorder: a milder pyridoxine (vitamin B6)-responsive form, and a more severe pyridoxine-nonresponsive form. Pyridoxine is a cofactor for the CBS enzyme, and can aid in the conversion of homocysteine to cysteine (summary by <a href="#75" class="mim-tip-reference" title="Reish, O., Townsend, D., Berry, S. A., Tsai, M. Y., King, R. A. &lt;strong&gt;Tyrosinase inhibition due to interaction of homocyst(e)ine with copper: the mechanism for reversible hypopigmentation in homocystinuria due to cystathionine beta-synthase deficiency.&lt;/strong&gt; Am. J. Hum. Genet. 57: 127-132, 1995.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/7611281/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;7611281&lt;/a&gt;]" pmid="7611281">Reish et al., 1995</a> and <a href="#88" class="mim-tip-reference" title="Testai, F. D., Gorelick, P. B. &lt;strong&gt;Inherited metabolic disorders and stroke part 2: homocystinuria, organic acidurias, and urea cycle disorders.&lt;/strong&gt; Arch. Neurol. 67: 148-153, 2010.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/20142522/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;20142522&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1001/archneurol.2009.333&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="20142522">Testai and Gorelick, 2010</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=20142522+7611281" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>Some patients have been reported to have a milder form of homocystinuria, which is characterized by increased plasma homocysteine and increased risk for thrombotic events in young adulthood, but without the other skeletal, ocular, or nervous system manifestations observed in classic homocystinuria (<a href="#39" class="mim-tip-reference" title="Kelly, P. J., Furie, K. L., Kistler, J. P., Barron, M., Picard, E. H., Mandell, R., Shih, V. E. &lt;strong&gt;Stroke in young patients with hyperhomocysteinemia due to cystathionine beta-synthase deficiency.&lt;/strong&gt; Neurology 60: 275-279, 2003.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/12552044/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;12552044&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1212/01.wnl.0000042479.55406.b3&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="12552044">Kelly et al., 2003</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12552044" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>Clinical Features</strong>
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<p>Homocystinuria was discovered independently by <a href="#27" class="mim-tip-reference" title="Gerritsen, T., Vaughn, J. G., Waisman, H. A. &lt;strong&gt;The identification of homocystine in the urine.&lt;/strong&gt; Biochem. Biophys. Res. Commun. 9: 493-496, 1962.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/13960563/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;13960563&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/0006-291x(62)90114-6&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="13960563">Gerritsen et al. (1962)</a> in Madison, Wisconsin, and by <a href="#12" class="mim-tip-reference" title="Carson, N. A. J., Neill, D. W. &lt;strong&gt;Metabolic abnormalities detected in a survey of mentally backward individuals in Northern Ireland.&lt;/strong&gt; Arch. Dis. Child. 37: 505-513, 1962.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/14018926/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;14018926&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1136/adc.37.195.505&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="14018926">Carson and Neill (1962)</a> in Belfast, Northern Ireland. The patients of both groups were studied because of mental retardation. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=13960563+14018926" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#68" class="mim-tip-reference" title="Mudd, S. H., Skovby, F., Levy, H. L., Pettigrew, K. D., Wilcken, B., Pyeritz, R. E., Andria, G., Boers, G. H. J., Bromberg, I. L., Cerone, R., Fowler, B., Grobe, H., Schmidt, H., Schweitzer, L. &lt;strong&gt;The natural history of homocystinuria due to cystathionine beta-synthase deficiency.&lt;/strong&gt; Am. J. Hum. Genet. 37: 1-31, 1985.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/3872065/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;3872065&lt;/a&gt;]" pmid="3872065">Mudd et al. (1985)</a> compiled data on 629 patients with homocystinuria collected from all parts of the world. Among patients not discovered by newborn screening, mental capabilities were higher in B6-responsive patients (mean IQ, 79) than in B6-nonresponsive patients (mean IQ, 57). Time-to-event curves for other major clinical abnormalities were also presented. For untreated B6-responsive and B6-nonresponsive patients, these were, respectively: chance of dislocation of lenses by age 10, 55% and 82%; chance of having clinically detected thromboembolic event by age 15, 12% and 27%; chance of radiologic detection of spinal osteoporosis by age 15, 36% and 64%,, and chance of not surviving to age 30, 4% and 23%. When initiated neonatally, methionine restriction prevented mental retardation, reduced the rate of lens dislocation, and may have reduced the incidence of seizures. Pyridoxine treatment of late-detected B6-responsive patients reduced the rate of occurrence of initial thromboembolic events. Following 586 surgical procedures, 25 postoperative thromboembolic complications occurred, of which 6 were fatal. Few abnormalities were found in the offspring of either male or female patients, and the evidence was inconclusive concerning the rate of fetal loss from mothers with untreated homocystinuria. Among patients detected neonatally, only 13% were B6-responsive as compared with 47% among late-detected B6-responders. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=3872065" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#1" class="mim-tip-reference" title="Abbott, M. H., Folstein, S. E., Abbey, H., Pyeritz, R. E. &lt;strong&gt;Psychiatric manifestations of homocystinuria due to cystathionine beta-synthase deficiency: prevalence, natural history, and relationship to neurologic impairment and vitamin B(6)-responsiveness.&lt;/strong&gt; Am. J. Med. Genet. 26: 959-969, 1987.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/3591841/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;3591841&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ajmg.1320260427&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="3591841">Abbott et al. (1987)</a> evaluated 63 patients with homocystinuria for psychiatric disturbance, intelligence, evidence of other CNS problems, and responsiveness to vitamin B6. Clinically significant psychiatric disorders were found in 51%. The average IQ was 80; IQ was lower among vitamin B6-nonresponsive patients. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=3591841" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>Hypopigmentation is a feature of homocystinuria and can be shown to be reversible in patients with pyridoxine-responsive homocystinuria. Instances have been observed in which darkening of newly growing hair is observed after initiation of pyridoxine therapy, creating a clear demarcation between the old, blond and the new, dark hair (<a href="#75" class="mim-tip-reference" title="Reish, O., Townsend, D., Berry, S. A., Tsai, M. Y., King, R. A. &lt;strong&gt;Tyrosinase inhibition due to interaction of homocyst(e)ine with copper: the mechanism for reversible hypopigmentation in homocystinuria due to cystathionine beta-synthase deficiency.&lt;/strong&gt; Am. J. Hum. Genet. 57: 127-132, 1995.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/7611281/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;7611281&lt;/a&gt;]" pmid="7611281">Reish et al., 1995</a>). The consistency of the hair also changed from a coarse to a softer texture. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7611281" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#103" class="mim-tip-reference" title="Yap, S., Rushe, H., Howard, P. M., Naughten, E. R. &lt;strong&gt;The intellectual abilities of early-treated individuals with pyridoxine-nonresponsive homocystinuria due to cystathionine beta-synthase deficiency.&lt;/strong&gt; J. Inherit. Metab. Dis. 24: 437-447, 2001.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/11596648/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;11596648&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1023/a:1010525528842&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="11596648">Yap et al. (2001)</a> studied mental capabilities of 23 pyridoxine-nonresponsive individuals with CBS deficiency with over 339 patient-years of treatment and compared these individuals to those of 10 unaffected sibs (controls). Of the 23 individuals, 19 were diagnosed through newborn screening with early treatment, 2 were late-detected, and 2 were untreated at the time of assessment. Thirteen of the newborn-screened group who were compliant with treatment had no complications, while the remaining 6, who were poorly compliant, developed complications. Good compliance was defined by a lifetime plasma free homocysteine median of less than 11 micromole per liter. The newborn-screened good-compliance group with a mean age of 14.4 years (range 4.4-24.9) had a full-scale IQ of 105.8 (range 84-120), while the poorly compliant group with a mean age of 19.9 years (range 13.8 to 25.5) had a mean full-scale IQ of 80.8 (range 40-103). The control group had a mean age of 19.4 years and a mean IQ of 102. The 2 late-detected patients had IQs of 80 and 102 at the age of almost 19 years, while the 2 untreated patients had IQs in the mid-fifties at the age of 22 and 11 years. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11596648" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="#88" class="mim-tip-reference" title="Testai, F. D., Gorelick, P. B. &lt;strong&gt;Inherited metabolic disorders and stroke part 2: homocystinuria, organic acidurias, and urea cycle disorders.&lt;/strong&gt; Arch. Neurol. 67: 148-153, 2010.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/20142522/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;20142522&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1001/archneurol.2009.333&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="20142522">Testai and Gorelick (2010)</a> noted that thromboembolic events are the most common cause of death in patients with classic homocystinuria and can manifest as peripheral vein thrombosis, pulmonary embolism, stroke, peripheral artery occlusion, and myocardial infarction. The risk of having a vascular event is 25% before age 16 years and 50% by age 30 years. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20142522" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>Clinical Variability: Thrombotic Hyperhomocysteinemia, CBS-Related</em></strong></p><p>
<a href="#24" class="mim-tip-reference" title="Gaustadnes, M., Rudiger, N., Rasmussen, K., Ingerslev, J. &lt;strong&gt;Intermediate and severe hyperhomocysteinemia with thrombosis: a study of genetic determinants.&lt;/strong&gt; Thromb. Haemost. 83: 554-558, 2000.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/10780316/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;10780316&lt;/a&gt;]" pmid="10780316">Gaustadnes et al. (2000)</a> found that 3 of 5 unrelated patients with severe hyperhomocysteinemia and thrombosis, but no other features of classic homocystinuria, were compound heterozygous for mutations in the CBS gene, consistent with CBS deficiency. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10780316" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#54" class="mim-tip-reference" title="Maclean, K. N., Gaustadnes, M., Oliveriusova, J., Janosik, M., Kraus, E., Kozich, V., Kery, V., Skovby, F., Rudiger, N., Ingerslev, J., Stabler, S. P., Allen, R. H., Kraus, J. P. &lt;strong&gt;High homocysteine and thrombosis without connective tissue disorders are associated with a novel class of cystathionine beta-synthase (CBS) mutations.&lt;/strong&gt; Hum. Mutat. 19: 641-655, 2002.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/12007221/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;12007221&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/humu.10089&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="12007221">Maclean et al. (2002)</a> reported 2 unrelated Danish patients who presented with transient ischemic attacks at age 36 and 22 years, respectively. Biochemical studies showed increased serum homocysteine, but neither had other features of classic homocystinuria such as mental retardation, ectopia lentis, or skeletal changes. Each patient was compound heterozygous for 2 mutations in the CBS gene: one with D444N (<a href="/entry/613381#0010">613381.0010</a>) and P422L (<a href="/entry/613381#0013">613381.0013</a>), and the other with I278T (<a href="/entry/613381#0004">613381.0004</a>) and S466L (<a href="/entry/613381#0014">613381.0014</a>). In vitro functional expression studies showed that the P422L and S466L mutant proteins were catalytically active and even had higher activity than wildtype, but were impaired in regulation by AdoMet. The findings illustrated the importance of AdoMet for the regulation of homocysteine metabolism. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12007221" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="Kelly, P. J., Furie, K. L., Kistler, J. P., Barron, M., Picard, E. H., Mandell, R., Shih, V. E. &lt;strong&gt;Stroke in young patients with hyperhomocysteinemia due to cystathionine beta-synthase deficiency.&lt;/strong&gt; Neurology 60: 275-279, 2003.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/12552044/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;12552044&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1212/01.wnl.0000042479.55406.b3&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="12552044">Kelly et al. (2003)</a> reported 3 unrelated patients with premature stroke and severe hyperhomocysteinemia. Excluding tall stature in 2 patients, none had clinical features of classic homocystinuria. All had increased serum methionine and increased urinary homocystine. Molecular analysis found that each patient was heterozygous for a different CBS mutation (I278T, <a href="/entry/613381#0004">613381.0004</a>; D444N, <a href="/entry/613381#0010">613381.0010</a>, and G307S, <a href="/entry/613381#0001">613381.0001</a>); however, the possibility for another unidentified CBS mutation could not be ruled out. The report expanded the phenotypic variability associated with CBS mutations to include premature stroke and hyperhomocysteinemia without the classic findings of CBS deficiency. The findings also suggested that increased serum homocysteine can be associated with early-onset stroke (see <a href="/entry/603174">603174</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12552044" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#30" class="mim-tip-reference" title="Harker, L. A., Slichter, S. J., Scott, C. R., Ross, R. &lt;strong&gt;Homocystinuria: vascular injury and arterial thrombosis.&lt;/strong&gt; New Eng. J. Med. 291: 537-543, 1974.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/4212055/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;4212055&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1056/NEJM197409122911101&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="4212055">Harker et al. (1974)</a> showed endothelial desquamation in baboons chronically perfused with homocystine. In human cases of homocystinuria, they demonstrated reduced survival and abnormally rapid turnover of platelets, fibrinogen, and plasminogen. These abnormalities were corrected by clearing the plasma of homocystine with pyridoxine (in B6-responsive cases) or by administration of dipyridamole (in B6-unresponsive cases), but not by heparin anticoagulation. Platelet function was normal in patients and in the animal model. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=4212055" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#15" class="mim-tip-reference" title="Collins, J. E., Brenton, D. P. &lt;strong&gt;Pancreatitis and homocystinuria.&lt;/strong&gt; J. Inherit. Metab. Dis. 13: 232-233, 1990.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/2116556/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;2116556&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1007/BF01799693&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="2116556">Collins and Brenton (1990)</a> described 2 children in whom pancreatitis was a complication of homocystinuria. One patient presented at age 6 with acute pancreatitis complicated by a pseudocyst requiring drainage on 2 occasions. The second patient presented at 15.5 years of age with severe colicky abdominal pain and a history of recurring abdominal pain for 6 years. Surgery was required for drainage of a large pseudocyst of the lesser sac in which necrotic portions of the body and tail of the pancreas were free floating. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2116556" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="#14" class="mim-tip-reference" title="Cochran, F. B., Sweetman, L., Schmidt, K., Barsh, G., Kraus, J., Packman, S. &lt;strong&gt;Pyridoxine-unresponsive homocystinuria with an unusual clinical course.&lt;/strong&gt; Am. J. Med. Genet. 35: 519-522, 1990.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/2333882/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;2333882&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ajmg.1320350415&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="2333882">Cochran et al. (1990)</a> described an unusual presentation of pyridoxine-unresponsive homocystinuria: an intelligent teenaged boy had had asthma from infancy and at age 14 was hospitalized for recurrent left pneumothoraces requiring chest tubes. Soon thereafter he developed a right pneumothorax and subsequently a superior sagittal sinus thrombosis with papilledema and transient right hemiparesis as well as deep venous thromboses. He was found to have a very low level of cystathionine beta-synthase despite normal eye examination, including repeated slit-lamp examinations. The homocystinuria did not respond to pyridoxine or folate administration, but was reduced by methionine restriction and betaine supplementation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2333882" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#4" class="mim-tip-reference" title="Bass, H. N., LaGrave, D., Mardach, R., Cederbaum, S. D., Fuster, C. D., Chetty, M. &lt;strong&gt;Spontaneous pneumothorax in association with pyridoxine-responsive homocystinuria.&lt;/strong&gt; J. Inherit. Metab. Dis. 20: 831-832, 1997.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/9427154/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;9427154&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1023/a:1005384121649&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="9427154">Bass et al. (1997)</a> noted that spontaneous pneumothorax had been reported previously in 2 homocystinuric patients, both with the pyridoxine-refractory form. They described an adolescent boy with the pyridoxine-responsive form who experienced 2 episodes of spontaneous pneumothorax. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9427154" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="Levy, H. L., Vargas, J. E., Waisbren, S. E., Kurczynski, T. W., Roeder, E. R., Schwartz, R. S., Rosengren, S., Prasad, C., Greenberg, C. R., Gilfix, B. M., MacGregor, D., Shih, V. E., Bao, L., Kraus, J. P. &lt;strong&gt;Reproductive fitness in maternal homocystinuria due to cystathionine beta-synthase deficiency.&lt;/strong&gt; J. Inherit. Metab. Dis. 25: 299-314, 2002.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/12227460/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;12227460&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1023/a:1016502408305&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="12227460">Levy et al. (2002)</a> reported the results of 15 pregnancies in 11 women with homocystinuria, 5 of whom were pyridoxine-nonresponsive and 6 of whom were pyridoxine-responsive. Complications of pregnancy included preeclampsia at term in 2 pregnancies and superficial venous thrombosis of the leg in a third pregnancy. One pregnancy was terminated and 2 pregnancies resulted in first-trimester spontaneous abortions. The remaining 12 pregnancies produced liveborn infants with normal or above-normal birth measurements. One offspring had multiple congenital anomalies that included colobomas of the iris and choroids, neural tube defect, and undescended testes. He was also mentally retarded and autistic. A second offspring had Beckwith-Wiedemann syndrome (<a href="/entry/130650">130650</a>). The remaining 10 offspring were normal at birth and remained normal. There was no relationship between the severity of the biochemical abnormalities or the therapies during pregnancy to either the pregnancy complications or the offspring outcomes. The infrequent occurrences of pregnancy complications, offspring abnormalities, and maternal thromboembolic events in this series suggested that pregnancy and outcome in maternal homocystinuria are usually normal. Nevertheless, <a href="#51" class="mim-tip-reference" title="Levy, H. L., Vargas, J. E., Waisbren, S. E., Kurczynski, T. W., Roeder, E. R., Schwartz, R. S., Rosengren, S., Prasad, C., Greenberg, C. R., Gilfix, B. M., MacGregor, D., Shih, V. E., Bao, L., Kraus, J. P. &lt;strong&gt;Reproductive fitness in maternal homocystinuria due to cystathionine beta-synthase deficiency.&lt;/strong&gt; J. Inherit. Metab. Dis. 25: 299-314, 2002.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/12227460/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;12227460&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1023/a:1016502408305&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="12227460">Levy et al. (2002)</a> suggested a cautious approach, which would include careful monitoring of these pregnancies with attention to metabolic therapy and possibly anticoagulation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12227460" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>Heterozygous Carriers</em></strong></p><p>
Based on the findings of <a href="#99" class="mim-tip-reference" title="Wilcken, D. E., Wilcken, B. &lt;strong&gt;The pathogenesis of coronary artery disease: a possible role for methionine metabolism.&lt;/strong&gt; J. Clin. Invest. 57: 1079-1082, 1976.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/947949/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;947949&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1172/JCI108350&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="947949">Wilcken and Wilcken (1976)</a>, who found an association between increased plasma homocysteine and ischemic heart disease in males under age 50 years, it was hypothesized that heterozygous CBS mutation carriers may be at increased risk for cardiovascular disease (see, e.g., <a href="#6" class="mim-tip-reference" title="Boers, G. H. J., Smals, A. G. H., Trijbels, F. J. M., Fowler, B., Bakkeren, J. A. J. M., Schoonderwaldt, H. C., Kleijer, W. J., Kloppenborg, P. W. C. &lt;strong&gt;Heterozygosity for homocystinuria in premature peripheral and cerebral occlusive arterial disease.&lt;/strong&gt; New Eng. J. Med. 313: 709-715, 1985.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/4033695/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;4033695&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1056/NEJM198509193131201&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="4033695">Boers et al., 1985</a>). However, there has been conflicting evidence about whether or not heterozygous mutation carriers are at increased risk (review by <a href="#29" class="mim-tip-reference" title="Guttormsen, A. B., Ueland, P. M., Kruger, W. D., Kim, C. E., Ose, L., Folling, I., Refsum, H. &lt;strong&gt;Disposition of homocysteine in subjects heterozygous for homocystinuria due to cystathionine beta-synthase deficiency: relationship between genotype and phenotype.&lt;/strong&gt; Am. J. Med. Genet. 100: 204-213, 2001.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/11343305/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;11343305&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ajmg.1247&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="11343305">Guttormsen et al., 2001</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=947949+4033695+11343305" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 study of 203 families, <a href="#64" class="mim-tip-reference" title="Mudd, S. H., Havlik, R., Levy, H. L., McKusick, V. A., Feinleib, M. &lt;strong&gt;A study of cardiovascular risk in heterozygotes for homocystinuria.&lt;/strong&gt; Am. J. Hum. Genet. 33: 883-893, 1981.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/7325153/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;7325153&lt;/a&gt;]" pmid="7325153">Mudd et al. (1981)</a> could find no evidence of increased frequency of heart attacks or strokes in parents or grandparents of homocystinuric children. The data available were sufficient to exclude a 5-fold increase in cardiovascular risk for homocystinuria heterozygotes and to make very improbable a relative risk of as much as 3-fold. <a href="#64" class="mim-tip-reference" title="Mudd, S. H., Havlik, R., Levy, H. L., McKusick, V. A., Feinleib, M. &lt;strong&gt;A study of cardiovascular risk in heterozygotes for homocystinuria.&lt;/strong&gt; Am. J. Hum. Genet. 33: 883-893, 1981.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/7325153/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;7325153&lt;/a&gt;]" pmid="7325153">Mudd et al. (1981)</a> concluded that less than 5% of homocystinuria heterozygotes are likely to have a heart attack by age 50 years. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7325153" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="Boers, G. H. J., Fowler, B., Smals, A. G. H., Trijbels, F. J. M., Leermakers, A. I., Kleijer, W. J., Kloppenborg, P. W. C. &lt;strong&gt;Improved identification of heterozygotes for homocystinuria due to cystathionine synthase deficiency by the combination of methionine loading and enzyme determination in cultured fibroblasts.&lt;/strong&gt; Hum. Genet. 69: 164-169, 1985.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/3972418/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;3972418&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1007/BF00293290&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="3972418">Boers et al. (1985)</a> tested for heterozygosity for homocystinuria by the finding of pathologic homocysteinemia after methionine loading and cystathionine synthase deficiency in cultured fibroblasts. Using these biochemical screening methods, <a href="#6" class="mim-tip-reference" title="Boers, G. H. J., Smals, A. G. H., Trijbels, F. J. M., Fowler, B., Bakkeren, J. A. J. M., Schoonderwaldt, H. C., Kleijer, W. J., Kloppenborg, P. W. C. &lt;strong&gt;Heterozygosity for homocystinuria in premature peripheral and cerebral occlusive arterial disease.&lt;/strong&gt; New Eng. J. Med. 313: 709-715, 1985.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/4033695/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;4033695&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1056/NEJM198509193131201&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="4033695">Boers et al. (1985)</a> identified putative heterozygotes for mutations in the CBS gene (<a href="/entry/613381">613381</a>), although this was not confirmed by genetic analysis. Seven of 25 patients with occlusive peripheral vascular disease manifest before age 50, and 7 of 25 patients with occlusive cerebrovascular disease manifest before age 50, were found to have increased serum homocysteine. However, none of 25 patients with myocardial infarction manifest before age 50 had increased serum homocysteine. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=4033695+3972418" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="Kozich, V., Kraus, E., de Franchis, R., Fowler, B., Boers, G. H. J., Graham, I., Kraus, J. P. &lt;strong&gt;Hyperhomocysteinemia in premature arterial disease: examination of cystathionine beta-synthase alleles at the molecular level.&lt;/strong&gt; Hum. Molec. Genet. 4: 623-629, 1995.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/7633411/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;7633411&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1093/hmg/4.4.623&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="7633411">Kozich et al. (1995)</a> investigated the relationship between premature occlusive arterial disease (POAD) associated with hyperhomocysteinemia and heterozygosity for mutations in the CBS gene. Molecular studies of 4 patients with POAD who had hyperhomocysteinemia and reduced CBS activities (see, e.g., <a href="#6" class="mim-tip-reference" title="Boers, G. H. J., Smals, A. G. H., Trijbels, F. J. M., Fowler, B., Bakkeren, J. A. J. M., Schoonderwaldt, H. C., Kleijer, W. J., Kloppenborg, P. W. C. &lt;strong&gt;Heterozygosity for homocystinuria in premature peripheral and cerebral occlusive arterial disease.&lt;/strong&gt; New Eng. J. Med. 313: 709-715, 1985.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/4033695/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;4033695&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1056/NEJM198509193131201&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="4033695">Boers et al., 1985</a>) failed to find mutations in the CBS gene in 7 of 8 alleles. The cDNAs encoded catalytically active, stable CBS that exhibited normal response to both S-adenosylmethionine and pyridoxal 5-prime-phosphate. In contrast, the screening method correctly distinguished mutant from normal alleles in all 4 obligatory CBS heterozygotes studied. <a href="#44" class="mim-tip-reference" title="Kozich, V., Kraus, E., de Franchis, R., Fowler, B., Boers, G. H. J., Graham, I., Kraus, J. P. &lt;strong&gt;Hyperhomocysteinemia in premature arterial disease: examination of cystathionine beta-synthase alleles at the molecular level.&lt;/strong&gt; Hum. Molec. Genet. 4: 623-629, 1995.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/7633411/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;7633411&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1093/hmg/4.4.623&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="7633411">Kozich et al. (1995)</a> concluded that the homocysteinemia observed in these 4 POAD patients was not due to defective CBS protein. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=4033695+7633411" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In an editorial, <a href="#60" class="mim-tip-reference" title="Motulsky, A. G. &lt;strong&gt;Nutritional ecogenetics: homocysteine-related arteriosclerotic vascular disease, neural tube defects, and folic acid. (Editorial)&lt;/strong&gt; Am. J. Hum. Genet. 58: 17-20, 1996. Note: Erratum: Am. J. Hum. Genet. 58: 648 only, 1996.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/8554053/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;8554053&lt;/a&gt;]" pmid="8554053">Motulsky (1996)</a> reviewed evidence that heterozygotes for homocystinuria do not appear to have elevated homocysteine levels. They noted that the mutations responsible for 70% of homocystinuria in Ireland and 50% of homocystinuria in Holland had never been found in heterozygote state in Irish or Dutch patients, respectively, with various types of premature vascular disease. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8554053" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Although an I278Y mutation in the CBS gene (<a href="/entry/613381#0004">613381.0004</a>) is found in 50% of the CBS alleles in Dutch homozygous CBS-deficient patients, <a href="#42" class="mim-tip-reference" title="Kluijtmans, L. A. J., van den Heuvel, L. P. W. J., Boers, G. H. J., Frosst, P., Stevens, E. M. B., van Oost, B. A., den Heijer, M., Trijbels, F. J. M., Rozen, R., Blom, H. J. &lt;strong&gt;Molecular genetic analysis in mild hyperhomocysteinemia: a common mutation in the methylenetetrahydrofolate reductase gene is a genetic risk factor for cardiovascular disease.&lt;/strong&gt; Am. J. Hum. Genet. 58: 35-41, 1996.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/8554066/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;8554066&lt;/a&gt;]" pmid="8554066">Kluijtmans et al. (1996)</a> found it in none of 60 patients with premature cardiovascular disease. This led them to conclude that heterozygosity for CBS deficiency is not involved in premature cardiovascular disease. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8554066" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>There is some evidence that CBS heterozygosity may interact with other risk factors to increase the risk of cardiovascular disease. <a href="#57" class="mim-tip-reference" title="Mandel, H., Brenner, B., Berant, M., Rosenberg, N., Lanir, N., Jakobs, C., Fowler, B., Seligsohn, U. &lt;strong&gt;Coexistence of hereditary homocystinuria and factor V Leiden: effect on thrombosis.&lt;/strong&gt; New Eng. J. Med. 334: 763-768, 1996.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/8592550/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;8592550&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1056/NEJM199603213341204&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="8592550">Mandel et al. (1996)</a> concluded that patients with concurrent homocystinuria due to CBS deficiency have an increased risk of thrombosis when they also have the factor V Leiden mutation (<a href="/entry/612309#0001">612309.0001</a>). They studied 7 unrelated consanguineous kindreds in which at least 1 member was homozygous for homocystinuria. Thrombosis (venous, arterial, or both) occurred in 6 of 11 patients with homocystinuria (aged 0.2 to 8 years). All 6 also had the factor V Leiden mutation. One patient with prenatally diagnosed homocystinuria who was also heterozygous for factor V Leiden received warfarin therapy from birth and by the age of 18 months had not had thrombosis. Of 4 patients with homocystinuria who did not have factor V Leiden, none had thrombosis (aged 1 to 17 years). Three women who were heterozygous for both homocystinuria and factor V Leiden had recurrent fetal loss and placental infarctions. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8592550" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#29" class="mim-tip-reference" title="Guttormsen, A. B., Ueland, P. M., Kruger, W. D., Kim, C. E., Ose, L., Folling, I., Refsum, H. &lt;strong&gt;Disposition of homocysteine in subjects heterozygous for homocystinuria due to cystathionine beta-synthase deficiency: relationship between genotype and phenotype.&lt;/strong&gt; Am. J. Med. Genet. 100: 204-213, 2001.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/11343305/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;11343305&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ajmg.1247&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="11343305">Guttormsen et al. (2001)</a> found that 20 heterozygotes for CBS deficiency had normal fasting homocysteine levels, but increased urinary homocysteine excretion compared to controls. An abnormal homocysteine response after methionine loading was observed in 73% of pyridoxine nonresponders and in only 33% of pyridoxine responders, but the test did not completely discriminate heterozygous mutation carriers from controls. The authors concluded that unequivocal identification of CBS carrier status required DNA analysis, and also noted that it was uncertain whether or not altered homocysteine metabolism in these individuals conveys an increased risk of cardiovascular disease. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11343305" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="Elsaid, M. F., Bener, A., Lindner, M., Alzyoud, M., Shahbek, N., Abdelrahman, M. O., Abdoh, G., Bessisso, M. S., Zschocke, J., Hoffmann, G. F. &lt;strong&gt;Are heterocygotes (sic) for classical homocystinuria at risk of vitamin B12 and folic acid deficiency?&lt;/strong&gt; Molec. Genet. Metab. 92: 100-103, 2007.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/17686644/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;17686644&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/j.ymgme.2007.06.010&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="17686644">Elsaid et al. (2007)</a> found that 34 heterozygous CBS mutation carriers had mildly increased fasting levels of homocysteine compared to controls. Heterozygous carriers also had decreased folic acid and vitamin B12 levels compared to controls, but similar vitamin B6 levels. None were reported to have had cardiovascular events. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17686644" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="diagnosis" class="mim-anchor"></a>
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<strong>Diagnosis</strong>
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<p><a href="#85" class="mim-tip-reference" title="Spaeth, G. L., Barber, G. W. &lt;strong&gt;Prevalence of homocystinuria among the mentally retarded: evaluation of a specific screening test.&lt;/strong&gt; Pediatrics 40: 586-589, 1967.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/6051058/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;6051058&lt;/a&gt;]" pmid="6051058">Spaeth and Barber (1967)</a> described a silver-nitroprusside test that was almost completely specific for homocystine. <a href="#93" class="mim-tip-reference" title="Wadman, S. K., Cats, B. P., de Bree, P. K. &lt;strong&gt;Sulfite oxidase deficiency and the detection of urinary sulfite. (Letter)&lt;/strong&gt; Europ. J. Pediat. 141: 62-63, 1983."None>Wadman et al. (1983)</a> referred to the cyanide-nitroprusside reaction used in the detection of cystinuria and homocystinuria as the Brand reaction. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=6051058" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="Uhlendorf, B. W., Mudd, S. H. &lt;strong&gt;Cystathionine synthase in tissue culture derived from human skin: enzyme defect in homocystinuria.&lt;/strong&gt; Science 160: 1007-1009, 1968.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/5647845/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;5647845&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1126/science.160.3831.1007&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="5647845">Uhlendorf and Mudd (1968)</a> found that cultured fibroblasts derived from normal skin, as well as cells in amniotic fluid, have cystathionine synthase activity, although the enzyme is not detectable in intact normal skin. Fibroblasts grown from the skin of homocystinuric persons are deficient in the enzyme. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=5647845" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>Neonatal Screening</em></strong></p><p>
<a href="#72" class="mim-tip-reference" title="Peterschmitt, M. J., Simmons, J. R., Levy, H. L. &lt;strong&gt;Reduction of false negative results in screening of newborns for homocystinuria.&lt;/strong&gt; New Eng. J. Med. 341: 1572-1576, 1999.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/10564686/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;10564686&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1056/NEJM199911183412103&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="10564686">Peterschmitt et al. (1999)</a> reviewed the results of neonatal screening for homocystinuria over a period of 32 years in New England. For the first 23.5 years of the review, the blood methionine cutoff value was 2 mg per deciliter (134 micromole per liter). Among the 2.2 million infants screened during that period, 8 with homocystinuria were identified, giving a frequency of 1 in 275,000. In 1990, the cutoff value was reduced to 1 mg per deciliter (67 micromole per liter). Among the 1.1 million infants screened in the subsequent 8.5 years, 7 with the disorder were identified, giving a frequency of 1 in 157,000. During the latter period, the specimens were collected from 6 of the 7 infants when they were 2 days of age or less; 5 of the 6 had blood methionine concentrations below 2 mg per deciliter. Use of the reduced cutoff level increased the false-positive rate from 0.006% to 0.03%. <a href="#72" class="mim-tip-reference" title="Peterschmitt, M. J., Simmons, J. R., Levy, H. L. &lt;strong&gt;Reduction of false negative results in screening of newborns for homocystinuria.&lt;/strong&gt; New Eng. J. Med. 341: 1572-1576, 1999.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/10564686/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;10564686&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1056/NEJM199911183412103&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="10564686">Peterschmitt et al. (1999)</a> concluded that a cutoff level for blood methionine of 1 mg per deciliter in neonatal screening tests for homocystinuria should identify affected infants who have only slightly elevated concentrations of methionine and reduce the frequency of false-negative results. They commented, furthermore, that the increased false-positive rate would not represent an undue burden in terms of requests for repeat analysis. Indeed, the false-positive rates were considerably lower than those associated with neonatal screening for other disorders such as congenital adrenal hyperplasia, congenital hypothyroidism, and phenylketonuria. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10564686" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#29" class="mim-tip-reference" title="Guttormsen, A. B., Ueland, P. M., Kruger, W. D., Kim, C. E., Ose, L., Folling, I., Refsum, H. &lt;strong&gt;Disposition of homocysteine in subjects heterozygous for homocystinuria due to cystathionine beta-synthase deficiency: relationship between genotype and phenotype.&lt;/strong&gt; Am. J. Med. Genet. 100: 204-213, 2001.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/11343305/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;11343305&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ajmg.1247&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="11343305">Guttormsen et al. (2001)</a> concluded that abnormal response of total urinary homocysteine after methionine loading was the most sensitive test and a satisfactory way for studying mild disturbances in homocysteine metabolism. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11343305" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>Differential Diagnosis</em></strong></p><p>
Homocysteinemia also occurs in homocystinuria due to N(5,10)-methylenetetrahydrofolate reductase deficiency (<a href="/entry/236250">236250</a>) and in transcobalamin II deficiency (<a href="/entry/275350">275350</a>).</p><p>Homocysteinemia/homocystinuria and megaloblastic anemia can result from defects in vitamin B12 (cobalamin; cbl) metabolism, which have been classified according to complementation groups of cells in vitro, e.g., cblE (<a href="/entry/236270">236270</a>) and cblG (<a href="/entry/250940">250940</a>). Combined methylmalonic aciduria (MMA) and homocystinuria due to defects in cobalamin include cblC (<a href="/entry/277400">277400</a>), cblD (<a href="/entry/277410">277410</a>), and cblF (<a href="/entry/277380">277380</a>).</p>
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<p><a href="#9" class="mim-tip-reference" title="Carey, M. C., Fennelly, J. J., Fitzgerald, O. &lt;strong&gt;Homocystinuria. II. Subnormal serum folate levels, increased folate clearance and effects of folic acid therapy.&lt;/strong&gt; Am. J. Med. 45: 26-31, 1968.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/5658866/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;5658866&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/0002-9343(68)90004-1&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="5658866">Carey et al. (1968)</a> suggested that folic acid in pharmacologic doses is therapeutically valuable in this disease. Decrease in urinary excretion of homocystine and increase in methionine was noted during treatment. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=5658866" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="#97" class="mim-tip-reference" title="Wilcken, D. E. L., Dudman, N. P. B., Tyrrell, P. A. &lt;strong&gt;Homocystinuria due to cystathionine beta-synthase deficiency--the effects of betaine treatment in pyridoxine-responsive patients.&lt;/strong&gt; Metabolism 34: 1115-1121, 1985.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/3934499/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;3934499&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/0026-0495(85)90156-8&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="3934499">Wilcken et al. (1985)</a> concluded that additional benefit can be realized from betaine in B6-responsive patients. Homocysteine that is not metabolized to cystine is remethylated to methionine in reactions that use either N5-methyltetrahydrofolate or betaine (trimethylglycine) as methyl donors. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=3934499" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="#31" class="mim-tip-reference" title="Harrison, D. A., Mullaney, P. B., Mesfer, S. A., Awad, A. H., Dhindsa, H. &lt;strong&gt;Management of ophthalmic complications of homocystinuria.&lt;/strong&gt; Ophthalmology 105: 1886-1890, 1998.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/9787359/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;9787359&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/S0161-6420(98)91035-1&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="9787359">Harrison et al. (1998)</a> reviewed the management of ophthalmic complications of homocystinuria on the basis of an extraordinarily large experience with 45 patients reviewed retrospectively in Saudi Arabia. Eighty-four surgical procedures were performed on 40 patients; 82 procedures were done under general anesthesia and 2 under local anesthesia. Five patients had only medical treatment. All patients had lens subluxation or dislocation. Mental retardation was present in 29 (64%). <a href="#31" class="mim-tip-reference" title="Harrison, D. A., Mullaney, P. B., Mesfer, S. A., Awad, A. H., Dhindsa, H. &lt;strong&gt;Management of ophthalmic complications of homocystinuria.&lt;/strong&gt; Ophthalmology 105: 1886-1890, 1998.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/9787359/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;9787359&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/S0161-6420(98)91035-1&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="9787359">Harrison et al. (1998)</a> suggested that surgical treatment should be considered, especially for cases of repeated lens dislocation into the anterior chamber or pupillary block glaucoma. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9787359" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#26" class="mim-tip-reference" title="Gerding, H. &lt;strong&gt;Ocular complications and a new surgical approach to lens dislocation in homocystinuria due to cystathionine-beta-synthetase deficiency.&lt;/strong&gt; Europ. J. Pediat. 157 (suppl. 2): S94-S101, 1998.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/9587034/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;9587034&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1007/pl00014312&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="9587034">Gerding (1998)</a> reviewed the ocular manifestations of homocystinuria and described a surgical approach to lens dislocation that allowed minimally invasive removal of the lens, complete preservation of the anterior vitreous cortex, and stable fixation of an artificial intraocular lens. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9587034" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>Several reports indicated a likely role for homocysteine in the pathogenesis of atherosclerosis, including those of <a href="#98" class="mim-tip-reference" title="Wilcken, D. E. L., Wilcken, B., Dudman, N. P. B., Tyrrell, P. A. &lt;strong&gt;Homocystinuria--the effects of betaine in the treatment of patients not responsive to pyridoxine.&lt;/strong&gt; New Eng. J. Med. 309: 448-453, 1983.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/6877313/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;6877313&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1056/NEJM198308253090802&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="6877313">Wilcken et al. (1983)</a>, <a href="#38" class="mim-tip-reference" title="Kang, S.-S., Wong, P. W. K., Cook, H. Y., Norusis, M., Messer, J. V. &lt;strong&gt;Protein-bound homocyst(e)ine: a possible risk factor for coronary artery disease.&lt;/strong&gt; J. Clin. Invest. 77: 1482-1486, 1986.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/3700650/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;3700650&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1172/JCI112461&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="3700650">Kang et al. (1986)</a>, <a href="#89" class="mim-tip-reference" title="Tsai, M. Y., Bignell, M., Schwichtenberg, K., Hanson, N. Q. &lt;strong&gt;High prevalence of a mutation in the cystathionine beta-synthase gene.&lt;/strong&gt; Am. J. Hum. Genet. 59: 1262-1267, 1996.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/8940271/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;8940271&lt;/a&gt;]" pmid="8940271">Tsai et al. (1996)</a>, and <a href="#13" class="mim-tip-reference" title="Chao, C.-L., Tsai, H.-H., Lee, C.-M., Hsu, S.-M., Kao, J.-T., Chien, K.-L., Sung, F.-C., Lee, Y.-T. &lt;strong&gt;The graded effect of hyperhomocysteinemia on the severity and extent of coronary atherosclerosis.&lt;/strong&gt; Atherosclerosis 147: 379-386, 1999.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/10559524/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;10559524&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/s0021-9150(99)00208-7&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="10559524">Chao et al. (1999)</a>. <a href="#77" class="mim-tip-reference" title="Schnyder, G., Roffi, M., Pin, R., Flammer, Y., Lange, H., Eberli, F. R., Meier, B., Turi, Z. G., Hess, O. M. &lt;strong&gt;Decreased rate of coronary restenosis after lowering of plasma homocysteine levels.&lt;/strong&gt; New Eng. J. Med. 345: 1593-1600, 2001.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/11757505/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;11757505&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1056/NEJMoa011364&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="11757505">Schnyder et al. (2001)</a> found that treatment with a combination of folic acid, vitamin B12, and pyridoxine significantly reduced homocysteine levels and decreased the rate of restenosis and the need for revascularization of the target lesion after coronary angioplasty. They proposed that this inexpensive treatment, which has minimal side effects, should be considered as adjunctive therapy for patients undergoing coronary angioplasty. The benefit in relation to the vascular disease of homocystinuria would be dependent on the responsiveness of the particular mutation to this form of therapy. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=3700650+10559524+8940271+11757505+6877313" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Treatment of B6-nonresponsive patients centers on lowering homocysteine and its disulfide derivatives by adherence to a methionine-restricted diet. However, lifelong dietary control is difficult. Betaine supplementation is used extensively in CBS-deficient patients to lower plasma disulfide derivatives. With betaine therapy, methionine levels increase over baseline, but usually remain at levels that are not associated with adverse affects. <a href="#101" class="mim-tip-reference" title="Yaghmai, R., Kashani, A. H., Geraghty, M. T., Okoh, J., Pomper, M., Tangerman, A., Wagner, C., Stabler, S. P., Allen, R. H., Mudd, S. H., Braverman, N. &lt;strong&gt;Progressive cerebral edema associated with high methionine levels and betaine therapy in a patient with cystathionine beta-synthase (CBS) deficiency.&lt;/strong&gt; Am. J. Med. Genet. 108: 57-63, 2002.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/11857551/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;11857551&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ajmg.10186&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="11857551">Yaghmai et al. (2002)</a> reported the case of a child with B6-nonresponsive CBS deficiency and dietary noncompliance whose methionine reached very high levels on betaine and who subsequently developed massive cerebral edema without evidence of thrombosis. They concluded that the cerebral edema was most likely precipitated by the betaine therapy, although the exact mechanism was uncertain. This case cautioned that methionine levels should be monitored in CBS-deficient patients on betaine and that betaine should be considered as an adjunct, not an alternative, to dietary control. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11857551" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="Pullin, C. H., Bonham, J. R., McDowell, I. F. W., Lee, P. J., Powers, H. J., Wilson, J. F., Lewis, M. J., Moat, S. J. &lt;strong&gt;Vitamin C therapy ameliorates vascular endothelial dysfunction in treated patients with homocystinuria.&lt;/strong&gt; J. Inherit. Metab. Dis. 25: 107-118, 2002.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/12118525/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;12118525&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1023/a:1015672625913&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="12118525">Pullin et al. (2002)</a> investigated the endothelial effect of acute (2 g single dose) and chronic (1 g/day for 6 months) administration of oral vitamin C in 5 patients with homocystinuria (mean age 26 years, 1 male) and 5 age- and sex-matched controls. Brachial artery endothelium-dependent flow-mediated dilatation and endothelium-independent responses to nitroglycerin were measured using high-resolution ultrasonic vessel wall-tracking. At baseline, plasma total homocysteine was 100.8 +/- 61.6 and 9.2 +/- 1.9 micromol/L in the patient and control groups, respectively. Flow-mediated dilatation responses were impaired in the patient group (20 +/- 40 micro m) compared with the controls (116 +/- 30 micro m). With vitamin C administration, flow-mediated dilatation responses in the patient group improved both acutely and chronically at 2 weeks and at 6 months. Flow-mediated dilatation responses in the control group were unaltered. Within both groups, neither the vascular response to nitroglycerin nor plasma homocysteine was altered. <a href="#73" class="mim-tip-reference" title="Pullin, C. H., Bonham, J. R., McDowell, I. F. W., Lee, P. J., Powers, H. J., Wilson, J. F., Lewis, M. J., Moat, S. J. &lt;strong&gt;Vitamin C therapy ameliorates vascular endothelial dysfunction in treated patients with homocystinuria.&lt;/strong&gt; J. Inherit. Metab. Dis. 25: 107-118, 2002.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/12118525/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;12118525&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1023/a:1015672625913&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="12118525">Pullin et al. (2002)</a> concluded that vitamin C ameliorates endothelial dysfunction in patients with homocystinuria, independent of changes in homocysteine concentration, and should therefore be considered as an additional adjunct to therapy to reduce the potential long-term risk of atherothrombotic disease. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12118525" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>From study of fibroblast lines, <a href="#19" class="mim-tip-reference" title="Fowler, B., Kraus, J., Packman, S., Rosenberg, L. E. &lt;strong&gt;Homocystinuria: evidence for three distinct classes of cystathionine beta-synthetase mutants in cultured fibroblasts.&lt;/strong&gt; J. Clin. Invest. 61: 645-653, 1978.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/641146/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;641146&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1172/JCI108976&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="641146">Fowler et al. (1978)</a> found 3 types of cystathionine synthetase deficiency: one with no residual activity; one with reduced activity and normal affinity for the cofactor pyridoxal-phosphate; and one with reduced activity and reduced affinity for the cofactor. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=641146" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="#84" class="mim-tip-reference" title="Skovby, F., Kraus, J., Redlich, C., Rosenberg, L. E. &lt;strong&gt;Immunochemical studies on cultured fibroblasts from patients with homocystinuria due to cystathionine beta-synthase deficiency.&lt;/strong&gt; Am. J. Hum. Genet. 34: 73-83, 1982.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/7081217/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;7081217&lt;/a&gt;]" pmid="7081217">Skovby et al. (1982)</a> studied fibroblast extracts from 20 patients for immunoreactive cystathionine beta-synthase antigen. Each of 14 mutant extracts with residual synthase activity had cross-reactive material (CRM) ranging from 5 to 100% of controls. There was no correlation between the percent residual activity and the percent CRM. Of 6 mutant extracts without detectable catalytic activity, 3 had no CRM, while 3 had 13%, 17%, and 26% CRM. The findings provided a basis for biochemical heterogeneity of the disorder and indicated that a wide array of mutations in the CBS gene that affect enzyme structure are responsible for the disorder. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7081217" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>With a rabbit antiserum against human hepatic CBS, <a href="#83" class="mim-tip-reference" title="Skovby, F., Kraus, J. P., Rosenberg, L. E. &lt;strong&gt;Homocystinuria: biogenesis of cystathionine beta-synthase subunits in cultured fibroblasts and in an in vitro translation system programmed with fibroblast messenger RNA.&lt;/strong&gt; Am. J. Hum. Genet. 36: 452-459, 1984.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/6711564/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;6711564&lt;/a&gt;]" pmid="6711564">Skovby et al. (1984)</a> studied the enzyme in cultured fibroblasts derived from 17 homocystinuric patients. In 15 of the 17 lines, the enzyme had subunits indistinguishable in size from the normal (molecular mass of 63 kD). Material from one homocystinuric patient showed 2 mRNA species coding for equal amounts of 2 immunoprecipitable polypeptides: one of normal size and one smaller (mass of 56 kD). The father had 2 mRNAs also; the mother had only normal mRNA. Thus, the patient is a compound heterozygote; one of his mutant alleles codes for a synthase polypeptide missing about 60 amino acids. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=6711564" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#47" class="mim-tip-reference" title="Kruger, W. D., Cox, D. R. &lt;strong&gt;A yeast assay for functional detection of mutations in the human cystathionine beta-synthase gene.&lt;/strong&gt; Hum. Molec. Genet. 4: 1155-1161, 1995.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/8528202/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;8528202&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1093/hmg/4.7.1155&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="8528202">Kruger and Cox (1995)</a> showed that expression of 3 different CBS mutants known to be associated with reduced enzyme activity in humans failed to complement growth in the yeast assay. In addition, they used the yeast CBS assay to identify 8 mutant CBS alleles in cell lines from patients with CBS deficiency. These mutant alleles included 2 previously identified and 5 novel CBS mutations. The results also demonstrated that the yeast CBS assay can detect a large percentage of individuals heterozygous for mutations in CBS. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8528202" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="Kraus, J. P. &lt;strong&gt;Molecular basis of phenotype expression in homocystinuria.&lt;/strong&gt; J. Inherit. Metab. Dis. 17: 383-390, 1994.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/7967489/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;7967489&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1007/BF00711354&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="7967489">Kraus (1994)</a> tabulated 14 mutations in the CBS gene that he and his colleagues had demonstrated in homocystinuria. The G307S mutation (<a href="/entry/613381#0001">613381.0001</a>) is the most common cause of homocystinuria in patients of Celtic origin. <a href="#45" class="mim-tip-reference" title="Kraus, J. P. &lt;strong&gt;Molecular basis of phenotype expression in homocystinuria.&lt;/strong&gt; J. Inherit. Metab. Dis. 17: 383-390, 1994.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/7967489/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;7967489&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1007/BF00711354&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="7967489">Kraus (1994)</a> indicated that even though patients have no measurable CBS activity in their fibroblasts and despite the fact that CBS subunits are undetectable in fibroblast extracts of some of these individuals, many of them are pyridoxine-responsive. Examples were cited in which the identical genotype resulted in a different phenotype within the family. In general, G307S is a pyridoxine-nonresponsive mutation, whereas the I278T (<a href="/entry/613381#0004">613381.0004</a>) is a pyridoxine-responsive mutation (<a href="#34" class="mim-tip-reference" title="Hu, F. L., Gu, Z., Kozich, V., Kraus, J. P., Ramesh, V., Shih, V. E. &lt;strong&gt;Molecular basis of cystathionine beta-synthase deficiency in pyridoxine responsive and nonresponsive homocystinuria.&lt;/strong&gt; Hum. Molec. Genet. 2: 1857-1860, 1993.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/7506602/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;7506602&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1093/hmg/2.11.1857&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="7506602">Hu et al., 1993</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=7506602+7967489" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#78" class="mim-tip-reference" title="Sebastio, G., Sperandeo, M. P., Panico, M., de Franchis, R., Kraus, J. P., Andria, G. &lt;strong&gt;The molecular basis of homocystinuria due to cystathionine beta-synthase deficiency in Italian families, and report of four novel mutations.&lt;/strong&gt; Am. J. Hum. Genet. 56: 1324-1333, 1995.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/7762555/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;7762555&lt;/a&gt;]" pmid="7762555">Sebastio et al. (1995)</a> identified a 68-bp insertion in exon 8 of the CBS gene (<a href="/entry/613381#0017">613381.0017</a>) in a patient with homocystinuria and predicted that it would introduce a premature termination codon and result in a nonfunctional CBS enzyme. However, <a href="#89" class="mim-tip-reference" title="Tsai, M. Y., Bignell, M., Schwichtenberg, K., Hanson, N. Q. &lt;strong&gt;High prevalence of a mutation in the cystathionine beta-synthase gene.&lt;/strong&gt; Am. J. Hum. Genet. 59: 1262-1267, 1996.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/8940271/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;8940271&lt;/a&gt;]" pmid="8940271">Tsai et al. (1996)</a> found that this mutation is highly prevalent. In a case-control study involving patients with premature coronary artery disease, they identified the mutation in heterozygosity in 11.7% of controls and in slightly higher prevalence in the patients, although the difference did not reach statistical significance. In all cases, the insertion was present in cis with the 833T-C (I278T) mutation. <a href="#89" class="mim-tip-reference" title="Tsai, M. Y., Bignell, M., Schwichtenberg, K., Hanson, N. Q. &lt;strong&gt;High prevalence of a mutation in the cystathionine beta-synthase gene.&lt;/strong&gt; Am. J. Hum. Genet. 59: 1262-1267, 1996.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/8940271/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;8940271&lt;/a&gt;]" pmid="8940271">Tsai et al. (1996)</a> suggested that the insertion created an alternate splicing site that eliminated not only the inserted intronic sequences, but also the 833T-C mutation associated with this insertion. The net result was the generation of both quantitatively and qualitatively normal mRNA and CBS enzyme. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=8940271+7762555" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#46" class="mim-tip-reference" title="Kraus, J. P., Janosik, M., Kozich, V., Mandell, R., Shih, V., Sperandeo, M. P., Sebastio, G., de Franchis, R., Andria, G., Kluijtmans, L. A. J., Blom, H., Boers, G. H. J., Gordon, R. B., Kamoun, P., Tsai, M. Y., Kruger, W. D., Koch, H. G., Ohura, T., Gaustadnes, M. &lt;strong&gt;Cystathionine beta-synthase mutations in homocystinuria.&lt;/strong&gt; Hum. Mutat. 13: 362-375, 1999.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/10338090/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;10338090&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/(SICI)1098-1004(1999)13:5&lt;362::AID-HUMU4&gt;3.0.CO;2-K&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="10338090">Kraus et al. (1999)</a> stated that 92 different disease-associated mutations of the CBS gene had been identified in 310 examined homocystinuric alleles in more than a dozen laboratories around the world. Most of these mutations were missense, and the vast majority of these were private mutations occurring in only 1 or a very small number of families. The 2 most frequently encountered mutations were the pyridoxine-responsive I278T (<a href="/entry/613381#0004">613381.0004</a>) and the pyridoxine-nonresponsive G307S (<a href="/entry/613381#0001">613381.0001</a>). Mutations due to deaminations of methylcytosines represented 53% of all point substitutions in the coding region of the CBS gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10338090" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 6 patients from 5 Korean families with homocystinuria, <a href="#50" class="mim-tip-reference" title="Lee, S.-J., Lee, D. H., Yoo, H.-W., Koo, S. K., Park, E.-S., Park, J.-W., Lim, H. G., Jung, S.-C. &lt;strong&gt;Identification and functional analysis of cystathionine beta-synthase gene mutations in patients with homocystinuria.&lt;/strong&gt; J. Hum. Genet. 50: 648-654, 2005.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/16205833/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;16205833&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1007/s10038-005-0312-2&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="16205833">Lee et al. (2005)</a> identified 8 different mutations in the CBS gene, including 4 novel mutations. In vitro functional expression studies showed that the mutant enzymes had significantly decreased activities. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16205833" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#41" class="mim-tip-reference" title="Kluijtmans, L. A. J., Boers, G. H. J., Kraus, J. P., van den Heuvel, L. P. W. J., Cruysberg, J. R. M., Trijbels, F. J. M., Blom, H. J. &lt;strong&gt;The molecular basis of cystathionine beta-synthase deficiency in Dutch patients with homocystinuria: effect of CBS genotype on biochemical and clinical phenotype and on response to treatment.&lt;/strong&gt; Am. J. Hum. Genet. 65: 59-67, 1999.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/10364517/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;10364517&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1086/302439&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="10364517">Kluijtmans et al. (1999)</a> investigated the molecular basis of CBS deficiency in 29 Dutch patients from 21 unrelated pedigrees and studied the possibility of a genotype-phenotype relationship with regard to biochemical and clinical expression and response to homocysteine-lowering treatment. Of 10 different mutations detected in the CBS gene, 833T-C (I278T; <a href="/entry/613381#0004">613381.0004</a>) was predominant, being present in 23 (55%) of 42 independent alleles. At diagnosis, all 12 homozygotes for this mutation tended to have higher homocysteine levels than the 17 patients with other genotypes, but similar clinical manifestations. During follow-up, I278T homozygotes responded more efficiently to homocysteine-lowering treatment. After 378 patient-years of treatment, only 2 vascular events were recorded; without treatment, at least 30 would have been expected (P less than 0.01). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10364517" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#54" class="mim-tip-reference" title="Maclean, K. N., Gaustadnes, M., Oliveriusova, J., Janosik, M., Kraus, E., Kozich, V., Kery, V., Skovby, F., Rudiger, N., Ingerslev, J., Stabler, S. P., Allen, R. H., Kraus, J. P. &lt;strong&gt;High homocysteine and thrombosis without connective tissue disorders are associated with a novel class of cystathionine beta-synthase (CBS) mutations.&lt;/strong&gt; Hum. Mutat. 19: 641-655, 2002.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/12007221/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;12007221&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/humu.10089&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="12007221">Maclean et al. (2002)</a> described a novel class of 3 missense mutations, including P422L (<a href="/entry/613381#0013">613381.0013</a>) and S466L (<a href="/entry/613381#0014">613381.0014</a>), that are located in the noncatalytic C-terminal region of CBS and yield enzymes that are catalytically active but deficient in their response to S-adenosylmethionine (AdoMet). The P422L and S466L mutations were found in patients with premature thrombosis and homocystinuric levels of homocysteine (see <a href="/entry/603174">603174</a>), but lacking any of the connective tissue disorders typical of homocystinuria due to CBS deficiency. These 2 mutants demonstrated a level of CBS activity comparable to that of the AdoMet-stimulated wildtype CBS but could not be further induced by the addition of AdoMet. In terms of temperature stability, oligomeric organization, and heme saturation the 3 mutants were indistinguishable from wildtype CBS. The findings illustrated the importance of AdoMet for the regulation of homocysteine metabolism and were consistent with the possibility that the characteristic connective tissue disturbances observed in homocystinuria due to CBS deficiency may not be due to elevated homocysteine. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12007221" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#25" class="mim-tip-reference" title="Gaustadnes, M., Wilcken, B., Oliveriusova, J., McGill, J., Fletcher, J., Kraus, J. P., Wilcken, D. E. &lt;strong&gt;The molecular basis of cystathionine beta-synthase deficiency in Australian patients: genotype-phenotype correlations and response to treatment.&lt;/strong&gt; Hum. Mutat. 20: 117-126, 2002.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/12124992/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;12124992&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/humu.10104&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="12124992">Gaustadnes et al. (2002)</a> determined the molecular basis of CBS deficiency in 36 Australian patients from 28 unrelated families, using direct sequencing of the entire coding region of the CBS gene. Seven novel and 20 known mutations were detected. The G307S and I278T mutations were the most common and were present in 19% and 18% of independent alleles, respectively. Expression studies of 2 novel mutations (C109R and G347S), as well as 2 known mutations (L101P and N228K), showed complete lack of catalytic activity by the mutant proteins. <a href="#25" class="mim-tip-reference" title="Gaustadnes, M., Wilcken, B., Oliveriusova, J., McGill, J., Fletcher, J., Kraus, J. P., Wilcken, D. E. &lt;strong&gt;The molecular basis of cystathionine beta-synthase deficiency in Australian patients: genotype-phenotype correlations and response to treatment.&lt;/strong&gt; Hum. Mutat. 20: 117-126, 2002.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/12124992/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;12124992&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/humu.10104&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="12124992">Gaustadnes et al. (2002)</a> studied the correlation between genotype and biochemical response to pyridoxine treatment in 13 pyridoxine-responsive, 21 nonresponsive, and 2 partially responsive patients. The G307S mutation always resulted in a severe nonresponsive phenotype, whereas I278T resulted in a milder B6-responsive phenotype. From their results, <a href="#25" class="mim-tip-reference" title="Gaustadnes, M., Wilcken, B., Oliveriusova, J., McGill, J., Fletcher, J., Kraus, J. P., Wilcken, D. E. &lt;strong&gt;The molecular basis of cystathionine beta-synthase deficiency in Australian patients: genotype-phenotype correlations and response to treatment.&lt;/strong&gt; Hum. Mutat. 20: 117-126, 2002.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/12124992/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;12124992&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/humu.10104&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="12124992">Gaustadnes et al. (2002)</a> were also able to establish 3 other mild mutations: P49L, R369C, and V371M. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12124992" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#48" class="mim-tip-reference" title="Kruger, W. D., Wang, L., Jhee, K. H., Singh, R. H., Elsas, L. J., II. &lt;strong&gt;Cystathionine beta-synthase deficiency in Georgia (USA): correlation of clinical and biochemical phenotype with genotype.&lt;/strong&gt; Hum. Mutat. 22: 434-441, 2003.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/14635102/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;14635102&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/humu.10290&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="14635102">Kruger et al. (2003)</a> examined the relationship of the clinical and biochemical phenotypes with the genotypes of 12 CBS-deficient patients from 11 families in the state of Georgia (USA). By DNA sequencing of all of the coding exons, they identified mutations in the CBS gene in 21 of the 22 possible mutant alleles. Ten different missense mutations were identified and 1 novel splice site mutation was found. Five of the missense mutations were previously described, whereas 5 were novel. Each missense mutation was tested for function by expression in S. cerevisiae and all were found to cause decreased growth rate and to have significantly decreased levels of CBS enzyme activity. The I278T (<a href="/entry/613381#0004">613381.0004</a>) and T353M (<a href="/entry/613381#0015">613381.0015</a>) mutations accounted for 45% of the mutant alleles in this patient cohort. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14635102" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="pathogenesis" class="mim-anchor"></a>
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<strong>Pathogenesis</strong>
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<p>Thrombotic lesions of arteries and veins are major features of homocystinuria. The observations of <a href="#74" class="mim-tip-reference" title="Ratnoff, O. D. &lt;strong&gt;Activation of Hageman factor by L-homocystine.&lt;/strong&gt; Science 162: 1007-1009, 1968.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/5748939/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;5748939&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1126/science.162.3857.1007-a&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="5748939">Ratnoff (1968)</a> may have a bearing on the mechanism of the thrombotic accidents. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=5748939" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>Reviewing the nature of the ocular zonule, <a href="#86" class="mim-tip-reference" title="Streeten, B. W. &lt;strong&gt;The nature of the ocular zonule.&lt;/strong&gt; Trans. Am. Ophthal. Soc. 80: 823-854, 1982.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/6763807/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;6763807&lt;/a&gt;]" pmid="6763807">Streeten (1982)</a> pointed out that the zonular fibers are composed of glycoprotein with a high concentration of cysteine, which undoubtedly explains their susceptibility to abnormal formation in diseases of sulfur metabolism. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=6763807" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="Di Minno, G., Davi, G., Margaglione, M., Cirillo, F., Grandone, E., Ciabattoni, G., Catalano, I., Strisciuglio, P., Andria, G., Patrono, C., Mancini, M. &lt;strong&gt;Abnormally high thromboxane biosynthesis in homozygous homocystinuria: evidence for platelet involvement and probucol-sensitive mechanism.&lt;/strong&gt; J. Clin. Invest. 92: 1400-1406, 1993.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/8376592/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;8376592&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1172/JCI116715&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="8376592">Di Minno et al. (1993)</a> found evidence for enhanced thromboxane biosynthesis in homocystinuria and concluded from the response to administration of the antioxidant drug probucol that the enhanced thromboxane biosynthesis was dependent in part on probucol-sensitive mechanisms. High urinary excretion of 11-dehydro-TXB2, a major enzymatic derivative of TXA2, was observed in all 11 homocystinuric patients studied. The elevated thromboxane biosynthesis was thought to reflect, at least in part, in vivo platelet activation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8376592" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#56" class="mim-tip-reference" title="Malinow, M. R., Stampfer, M. J. &lt;strong&gt;Role of plasma homocyst(e)ine in arterial occlusive disease. (Editorial)&lt;/strong&gt; Clin. Chem. 40: 857-858, 1994.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/8087977/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;8087977&lt;/a&gt;]" pmid="8087977">Malinow and Stampfer (1994)</a> reviewed the role of plasma homocysteine in arterial occlusive diseases. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8087977" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="Reish, O., Townsend, D., Berry, S. A., Tsai, M. Y., King, R. A. &lt;strong&gt;Tyrosinase inhibition due to interaction of homocyst(e)ine with copper: the mechanism for reversible hypopigmentation in homocystinuria due to cystathionine beta-synthase deficiency.&lt;/strong&gt; Am. J. Hum. Genet. 57: 127-132, 1995.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/7611281/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;7611281&lt;/a&gt;]" pmid="7611281">Reish et al. (1995)</a> demonstrated that DL-homocysteine inhibits tyrosinase (TYR; see <a href="/entry/606933">606933</a>), the major pigment enzyme. The activity of tyrosinase extracted from pigmented human melanoma cells that were grown in the presence of homocysteine was reduced in comparison to that extracted from cells grown without homocysteine. Copper sulfate restored homocysteine-inhibited tyrosinase activity when added to the culture cell medium. The results suggested that the probable mechanism of the inhibition is the interaction of homocysteine with copper at the active site of tyrosinase. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7611281" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#59" class="mim-tip-reference" title="McKusick, V. A. &lt;strong&gt;Heritable Disorders of Connective Tissue. (3rd ed.)&lt;/strong&gt; St. Louis: C. V. Mosby (pub.) 1966. P. 155."None>McKusick (1966)</a> suggested that excess homocysteine may interfere with the normal synthesis of collagen crosslinks, thus accounting for the development of osteoporosis. <a href="#53" class="mim-tip-reference" title="Lubec, B., Fang-Kircher, S., Lubec, T., Blom, H. J., Boers, G. H. J. &lt;strong&gt;Evidence for McKusick&#x27;s hypothesis of deficient collagen cross-linking in patients with homocystinuria.&lt;/strong&gt; Biochim. Biophys. Acta 1315: 159-162, 1996.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/8611653/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;8611653&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/0925-4439(95)00119-0&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="8611653">Lubec et al. (1996)</a> studied collagen synthesis and crosslinking by noninvasive tests in 10 patients with homocystinuria. Synthesis of collagen type I and type III was not different from age-matched healthy controls as reflected by comparable plasma levels of C-terminal propeptide of type I procollagen and of plasma levels of N-terminal propeptide of procollagen type III. Collagen type I crosslinks expressed by serum C-terminal telopeptide of collagen type I in the patient group were, however, only about one-third of the values found in the control group. This significant reduction of crosslinks in the patients with homocystinuria did not correlate with serum homocysteine or homocystic acid concentrations. The data supported the disturbed crosslinking hypothesis and indicated that the bone manifestations of homocystinuria are not due to deficient collagen synthesis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8611653" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 cultured human hepatocytes and vascular endothelial and aortic smooth muscle cells, <a href="#96" class="mim-tip-reference" title="Werstuck, G. H., Lentz, S. R., Dayal, S., Hossain, G. S., Sood, S. K., Shi, Y. Y., Zhou, J., Maeda, N., Krisans, S. K., Malinow, M. R., Austin, R. C. &lt;strong&gt;Homocysteine-induced endoplasmic reticulum stress causes dysregulation of the cholesterol and triglyceride biosynthetic pathways.&lt;/strong&gt; J. Clin. Invest. 107: 1263-1273, 2001.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/11375416/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;11375416&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=11375416[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/JCI11596&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="11375416">Werstuck et al. (2001)</a> found that homocysteine-induced endoplasmic reticulum (ER) stress activated both the unfolded protein response and sterol regulatory element-binding proteins (SREBPs). Activation of the SREBPs was associated with increased expression of genes responsible for cholesterol/triglyceride biosynthesis and uptake, and with intracellular accumulation of cholesterol. Mice with diet-induced hyperhomocysteinemia had significantly increased cholesterol and triglycerides in liver, but not plasma, due to increased lipid biosynthesis, not impaired hepatic export of lipids. The findings suggested a mechanism by which homocysteine-induced ER stress causes dysregulation of the endogenous sterol response pathway, leading to increased hepatic biosynthesis and uptake of cholesterol and triglycerides, which contribute to hepatic steatosis and possibly atherosclerotic lesions observed in hyperhomocysteinemia. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11375416" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="#33" class="mim-tip-reference" title="Hubmacher, D., Tiedemann, K., Bartels, R., Brinckmann, J., Vollbrandt, T., Batge, B., Notbohm, H., Reinhardt, D. P. &lt;strong&gt;Modification of the structure and function of fibrillin-1 by homocysteine suggests a potential pathogenetic mechanism in homocystinuria.&lt;/strong&gt; J. Biol. Chem. 280: 34946-34955, 2005.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/16096271/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;16096271&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1074/jbc.M504748200&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="16096271">Hubmacher et al. (2005)</a> noted that the skeletal and ocular findings of patients with homocystinuria resemble those seen in Marfan syndrome (MFS; <a href="/entry/154700">154700</a>), which is caused by mutation in the fibrillin-1 gene (FBN1; <a href="/entry/134797">134797</a>). By in vitro studies, <a href="#33" class="mim-tip-reference" title="Hubmacher, D., Tiedemann, K., Bartels, R., Brinckmann, J., Vollbrandt, T., Batge, B., Notbohm, H., Reinhardt, D. P. &lt;strong&gt;Modification of the structure and function of fibrillin-1 by homocysteine suggests a potential pathogenetic mechanism in homocystinuria.&lt;/strong&gt; J. Biol. Chem. 280: 34946-34955, 2005.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/16096271/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;16096271&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1074/jbc.M504748200&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="16096271">Hubmacher et al. (2005)</a> found that homocysteine concentrations in patients with homocystinuria caused structural modifications of recombinant human fibrillin-1 fragments and loss of calcium binding. These molecular changes resulted in enhanced protease sensitivity of the fibrillin fragments. The changes likely occurred through covalent modification of cysteine residues in fibrillin and/or disufide bond shuffling. The findings suggested that degradation of fibrillin-1 in the connective tissues of patients with homocystinuria plays a major role in the pathogenesis of this disorder. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16096271" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="#35" class="mim-tip-reference" title="Jakubowski, H., Boers, G. H. J., Strauss, K. A. &lt;strong&gt;Mutations in cystathionine beta-synthase or methylenetetrahydrofolate reductase gene increase N-homocysteinylated protein levels in humans.&lt;/strong&gt; FASEB J. 22: 4071-4076, 2008.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/18708589/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;18708589&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1096/fj.08-112086&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="18708589">Jakubowski et al. (2008)</a> found that patients with homocysteinemia due to MTHFR deficiency (<a href="/entry/236250">236250</a>) or CBS deficiency had increased plasma levels of N-homocysteine (Hcy)-linked proteins, including the prothrombotic N-Hcy-fibrinogen (<a href="/entry/134820">134820</a>). N-Hcy-proteins are detrimental by contributing to both thrombogenesis and immune activation. The authors suggested that increased levels of N-Hcy-fibrinogen may explain the increased susceptibility to thrombogenesis in these individuals. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18708589" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="populationGenetics" class="mim-anchor"></a>
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<strong>Population Genetics</strong>
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<p>Homocystinuria has been observed in Japan (<a href="#87" class="mim-tip-reference" title="Tada, K., Yoshida, T., Hirono, H., Arakawa, T. &lt;strong&gt;Homocystinuria: amino acid pattern of the liver.&lt;/strong&gt; Tohoku J. Exp. Med. 92: 325-332, 1967.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/6081779/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;6081779&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1620/tjem.92.325&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="6081779">Tada et al., 1967</a>) and in persons of many different ethnic extractions living in the United States (<a href="#76" class="mim-tip-reference" title="Schimke, R. N., McKusick, V. A., Huang, T., Pollack, A. D. &lt;strong&gt;Homocystinuria: studies of 20 families with 38 affected members.&lt;/strong&gt; JAMA 193: 711-719, 1965.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/14328469/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;14328469&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1001/jama.1965.03090090017003&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="14328469">Schimke et al., 1965</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=14328469+6081779" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="Carey, M. C., Donovan, D. E., Fitzgerald, O., McAuley, F. D. &lt;strong&gt;Homocystinuria: a clinical and pathological study of nine subjects in six families.&lt;/strong&gt; Am. J. Med. 45: 7-25, 1968.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/5658872/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;5658872&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/0002-9343(68)90003-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="5658872">Carey et al. (1968)</a> pointed out that 27 cases had been found in Ireland. <a href="#45" class="mim-tip-reference" title="Kraus, J. P. &lt;strong&gt;Molecular basis of phenotype expression in homocystinuria.&lt;/strong&gt; J. Inherit. Metab. Dis. 17: 383-390, 1994.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/7967489/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;7967489&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1007/BF00711354&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="7967489">Kraus (1994)</a> reported that the G307S mutation (<a href="/entry/613381#0001">613381.0001</a>) in the CBS gene is the most common cause of homocystinuria in patients of Celtic origin. <a href="#22" class="mim-tip-reference" title="Gallagher, P. M., Ward, P., Tan, S., Naughten, E., Kraus, J. P., Sellar, G. C., McConnell, D. J., Graham, I., Whitehead, A. S. &lt;strong&gt;High frequency (71%) of cystathionine beta-synthase mutation G307S in Irish homocystinuria patients.&lt;/strong&gt; Hum. Mutat. 6: 177-180, 1995.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/7581402/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;7581402&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/humu.1380060211&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="7581402">Gallagher et al. (1995)</a> estimated that the G307S mutation accounted for 71% of alleles in Irish homocystinuria patients. <a href="#21" class="mim-tip-reference" title="Gallagher, P. M., Naughten, E., Hanson, N. Q., Schwichtenberg, K., Bignell, M., Yuan, M., Ward, P., Yap, S., Whitehead, A. S., Tsai, M. Y. &lt;strong&gt;Characterization of mutations in the cystathionine beta-synthase gene in Irish patients with homocystinuria.&lt;/strong&gt; Molec. Genet. Metab. 65: 298-302, 1998.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/9889017/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;9889017&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1006/mgme.1998.2771&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="9889017">Gallagher et al. (1998)</a> identified 3 new CBS mutations in Irish patients. They estimated that more than 40 CBS mutations in homocystinuria in various ethnic groups had been identified. Most of these were missense mutations; however, 7 deletions had been documented, 2 of which were total deletions of exons 11 and 12. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=5658872+7581402+9889017+7967489" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#67" class="mim-tip-reference" title="Mudd, S. H., Levy, H. L., Skovby, F. &lt;strong&gt;Disorders of transsulfuration. In: Scriver, C. R.; Beaudet, A. L.; Sly, W. S.; Valle, D. (eds.): The Metabolic and Molecular Bases of Inherited Disease. Vol. I. (7th ed.)&lt;/strong&gt; New York: McGraw-Hill (pub.) 1995. Pp. 1279-1327."None>Mudd et al. (1995)</a> found estimates of the frequency of homocystinuria ranging from 1 in 58,000 to 1 in 1,000,000 in countries that systematically screen newborns.</p><p>The worldwide frequency of homocystinuria has been reported to be 1 in 344,000, while that in Ireland is much higher at 1 in 65,000, based on newborn screening and cases detected clinically. The national newborn screening program for homocystinuria in Ireland was started in 1971 using the bacterial inhibition assay. <a href="#102" class="mim-tip-reference" title="Yap, S., Naughten, E. &lt;strong&gt;Homocystinuria due to cystathionine beta-synthase deficiency in Ireland: 25 years&#x27; experience of a newborn screened and treated population with reference to clinical outcome and biochemical control.&lt;/strong&gt; J. Inherit. Metab. Dis. 21: 738-747, 1998.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/9819703/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;9819703&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1023/a:1005445132327&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="9819703">Yap and Naughten (1998)</a> reported that a total of 1.58 million newborn infants had been screened over a 25-year period up to 1996. Twenty-five homocystinuria cases were diagnosed, 21 of whom were identified on screening. The remaining 4 cases were missed and presented clinically; 3 of these were breastfed and 1 was pyridoxine-responsive. Twenty-four of the 25 patients were nonresponsive to pyridoxine. All but one of the pyridoxine-nonresponsive cases were started on a low methionine, cystine-enhanced diet supplemented with pyridoxine, vitamin B12, and folate. The data suggested that ectopia lentis, osteoporosis, mental handicap, and thromboembolic events could be prevented by this regimen. Three patients with relatively high lifetime medians of free homocysteine developed increasing myopia, an ocular feature that often precedes ectopia lentis (<a href="#7" class="mim-tip-reference" title="Burke, J. P., O&#x27;Keefe, M., Bowell, R., Naughten, E. R. &lt;strong&gt;Ocular complications in homocystinuria: early and late treated.&lt;/strong&gt; Brit. J. Ophthal. 73: 427-431, 1989.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/2751974/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;2751974&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1136/bjo.73.6.427&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="2751974">Burke et al., 1989</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=9819703+2751974" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="#23" class="mim-tip-reference" title="Gaustadnes, M., Ingerslev, J., Rutiger, N. &lt;strong&gt;Prevalence of congenital homocystinuria in Denmark. (Letter)&lt;/strong&gt; New Eng. J. Med. 340: 1513 only, 1999.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/10328723/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;10328723&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1056/NEJM199905133401915&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="10328723">Gaustadnes et al. (1999)</a> stated that the I278T mutation (<a href="/entry/613381#0004">613381.0004</a>), which results from an 833T-C insertion, is geographically widespread. They determined the frequency of this mutation among Danish newborns by screening 500 consecutive Guthrie cards (specimens of infants' blood collected on filter paper). The frequent genetic insertion variant, 844ins68 (see <a href="/entry/613381#0017">613381.0017</a>), which occurs in cis with the 833T-C mutation, was simultaneously sought. A surprisingly high prevalence of the 833T-C mutation was detected among newborns who did not carry the 844ins68 variant, which is a benign polymorphism. This led the authors to suggest that the incidence of homocystinuria due to homozygosity for 833T-C may be at least 1 per 20,500 live births in Denmark. The 844ins68 variant was present in 10% of the Danish newborns. This neutral variant was thought to be deleted from mRNA during splicing. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10328723" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="Janosik, M., Oliveriusova, J., Janosikova, B., Sokolova, J., Kraus, E., Kraus, J. P., Kozich, V. &lt;strong&gt;Impaired heme binding and aggregation of mutant cystathionine beta-synthase subunits in homocystinuria.&lt;/strong&gt; Am. J. Hum. Genet. 68: 1506-1513, 2001.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/11359213/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;11359213&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=11359213[PMID]&amp;report=imagesdocsum&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed Image&#x27;, &#x27;domain&#x27;: &#x27;ncbi.nlm.nih.gov&#x27;})&quot;&gt;images&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1086/320597&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="11359213">Janosik et al. (2001)</a> reported that during the previous 20 years, CBS deficiency had been detected in the former Czechoslovakia with a calculated frequency of 1 in 349,000. About half of 21 Czech and Slovak patients they studied were not responsive to pyridoxine. Twelve distinct mutations were detected in 30 independent homocystinuric alleles. One-half of the mutated alleles carried either the 833T-C or the IVS11-2A-C mutation (<a href="/entry/613381#0012">613381.0012</a>); the remaining alleles contained private mutations. The high prevalence of the 833T-C allele, which confers pyridoxine-responsiveness, was not surprising because it is one of the most prevalent pathogenic CBS mutation in whites (<a href="#46" class="mim-tip-reference" title="Kraus, J. P., Janosik, M., Kozich, V., Mandell, R., Shih, V., Sperandeo, M. P., Sebastio, G., de Franchis, R., Andria, G., Kluijtmans, L. A. J., Blom, H., Boers, G. H. J., Gordon, R. B., Kamoun, P., Tsai, M. Y., Kruger, W. D., Koch, H. G., Ohura, T., Gaustadnes, M. &lt;strong&gt;Cystathionine beta-synthase mutations in homocystinuria.&lt;/strong&gt; Hum. Mutat. 13: 362-375, 1999.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/10338090/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;10338090&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/(SICI)1098-1004(1999)13:5&lt;362::AID-HUMU4&gt;3.0.CO;2-K&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="10338090">Kraus et al., 1999</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=10338090+11359213" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#92" class="mim-tip-reference" title="Urreizti, R., Asteggiano, C., Bermudez, M., Cordoba, A., Szlago, M., Grosso, C., de Kremer, R. D., Vilarinho, L., D&#x27;Almeida, V., Martinez-Pardo, M., Pena-Quintana, L., Dalmau, J., Bernal, J., Briceno, I., Couce, M. L., Rodes, M., Vilaseca, M. A., Balcells, S., Grinberg, D. &lt;strong&gt;The p.T191M mutation of the CBS gene is highly prevalent among homocystinuric patients from Spain, Portugal and South America.&lt;/strong&gt; J. Hum. Genet. 51: 305-313, 2006. Note: Erratum: J. Hum. Genet. 52: 388-389, 2007.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/16479318/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;16479318&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1007/s10038-006-0362-0&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="16479318">Urreizti et al. (2006)</a> reported a high frequency of the T191M mutation (<a href="/entry/613381#0016">613381.0016</a>) among patients with homocystinuria from the Iberian peninsula and several South American countries. Combined with previously reported studies, the prevalence of T191M among mutant CBS alleles in different countries was 0.75 in Colombia, 0.52 in Spain, 0.33 in Portugal, 0.25 in Venezuela, 0.20 in Argentina, and 0.14 in Brazil. Haplotype analysis suggested a double origin for this mutation, which conferred a B6-nonresponsive phenotype. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16479318" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="nomenclature" class="mim-anchor"></a>
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<p>Plasma homocysteine is the sum of the thiol-containing amino acid homocysteine and the homocysteinyl moiety of the disulfides homocystine and cysteine-homocysteine, whether free or bound to proteins (<a href="#56" class="mim-tip-reference" title="Malinow, M. R., Stampfer, M. J. &lt;strong&gt;Role of plasma homocyst(e)ine in arterial occlusive disease. (Editorial)&lt;/strong&gt; Clin. Chem. 40: 857-858, 1994.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/8087977/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;8087977&lt;/a&gt;]" pmid="8087977">Malinow and Stampfer, 1994</a>). <a href="#55" class="mim-tip-reference" title="Malinow, M. R., Kang, S. S., Taylor, L. M., Wong, P. W. K., Coull, B., Inahara, T., Mukerjee, D., Sexton, G., Upson, B. &lt;strong&gt;Prevalence of hyperhomocyst(e)inemia in patients with peripheral arterial occlusive disease.&lt;/strong&gt; Circulation 79: 1180-1188, 1989.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/2785871/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;2785871&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1161/01.cir.79.6.1180&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="2785871">Malinow et al. (1989)</a> introduced the term hyperhomocyst(e)inemia for above-normal concentrations of plasma/serum homocysteine. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=8087977+2785871" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#65" class="mim-tip-reference" title="Mudd, S. H., Levy, H. L. &lt;strong&gt;Plasma homocyst(e)ine or homocysteine? (Letter)&lt;/strong&gt; New Eng. J. Med. 333: 325 only, 1995.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/7596391/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;7596391&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1056/NEJM199508033330520&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="7596391">Mudd and Levy (1995)</a> noted the distinction between the term 'homocysteine,' which refers to the reduced sulfhydryl form of cysteine, and 'homocystine,' which refers to the oxidized disulfide form of cysteine (cystine). The measurement of plasma levels includes both of these homocysteine-derived moieties in either the sulfhydryl or disulfide form, but the distinction is important because many of the pathologic effects of the excess compound depend on the presence of the sulfhydryl group of homocysteine. The authors suggested use of the term hyperhomocyst(e)inemia to describe the composite of these forms, since in speech it is difficult to distinguish 'homocyst(e)ine' from 'homocysteine.' They suggested that an alternative useful in communicating orally is to substitute 'total Hcy' for homocyst(e)ine, spelling out the 'Hcy.' The term 'homocyst(e)ine' with parentheses around the 'e' in the middle of the word is used to define the combined pool of homocysteine, homocystine, mixed disulfides involving homocysteine, and homocysteine thiolactone found in the plasma of patients with hyperhomocyst(e)inemia. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7596391" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="#70" class="mim-tip-reference" title="Nugent, A., Hadden, D. R., Carson, N. A. J. &lt;strong&gt;Long-term survival of homocystinuria: the first case.&lt;/strong&gt; Lancet 352: 624-625, 1998.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/9746031/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;9746031&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/S0140-6736(05)79579-9&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="9746031">Nugent et al. (1998)</a> gave follow-up information on 'the first case' of homocystinuria. This was a patient who was identified during a survey of a group of mentally retarded children in Northern Ireland in 1960 by <a href="#12" class="mim-tip-reference" title="Carson, N. A. J., Neill, D. W. &lt;strong&gt;Metabolic abnormalities detected in a survey of mentally backward individuals in Northern Ireland.&lt;/strong&gt; Arch. Dis. Child. 37: 505-513, 1962.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/14018926/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;14018926&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1136/adc.37.195.505&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="14018926">Carson and Neill (1962)</a>. He was followed at the Royal Belfast Hospital for Sick Children until age 39 years when he was transferred to the Adult Metabolic Clinic at the Royal Victoria Hospital, Belfast. Despite early difficulties and the late start in treatment to lower his serum homocysteine, the patient had remained in reasonable health. He was initially reported at age 7 years as an unusual case of Marfan syndrome with renal abnormalities, case 4 of <a href="#52" class="mim-tip-reference" title="Loughridge, L. W. &lt;strong&gt;Renal abnormalities in the Marfan syndrome.&lt;/strong&gt; Quart. J. Med. 28: 531-544, 1959.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/14418426/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;14418426&lt;/a&gt;]" pmid="14418426">Loughridge (1959)</a>. He had recovered from acute glomerulonephritis at the age of 6 years and was found to be hypertensive the next year. He was mentally slow and thin, with fair hair, pale skin, and flushed cheeks. He had arachnodactyly, dolichostenomelia, pes cavus, high-arched palate, and bilateral dislocated lenses. At age 10 years, during a survey of urinary amino acid chromatography of mentally retarded people in Northern Ireland, his urine was found to contain a large quantity of homocysteine accompanied by a positive nitroprusside cyanide test (<a href="#12" class="mim-tip-reference" title="Carson, N. A. J., Neill, D. W. &lt;strong&gt;Metabolic abnormalities detected in a survey of mentally backward individuals in Northern Ireland.&lt;/strong&gt; Arch. Dis. Child. 37: 505-513, 1962.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/14018926/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;14018926&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1136/adc.37.195.505&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="14018926">Carson and Neill, 1962</a>). His left eye was enucleated because of staphylococcal infection after acute pupillary-block glaucoma; his right lens dislocated into the anterior chamber and had to be removed. His hypertension disappeared after removal of his left kidney at the age of 13 years; thick-walled medial hypertrophic intrarenal arteries and pads of intimal fibrous tissue were found histologically. When supplementation with pyridoxine was initiated at the age of 18 years, his plasma homocysteine fell to low normal values. Daily folic acid supplementation was added 1 year later since his plasma folate concentration was low. At age 20 years he had a perforated duodenal ulcer. Chest pain occurred at age 27 years and recurred at age 34 years; it was considered to be angina and was successfully treated. At age 50 years, his plasma homocysteine remained low. He developed acute gout which responded to indomethacin. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=14418426+14018926+9746031" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="#95" class="mim-tip-reference" title="Watanabe, M., Osada, J., Aratani, Y., Kluckman, K., Reddick, R., Malinow, M. R., Maeda, N. &lt;strong&gt;Mice deficient in cystathionine beta-synthase: animal models for mild and severe homocyst(e)inemia.&lt;/strong&gt; Proc. Nat. Acad. Sci. 92: 1585-1589, 1995.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/7878023/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;7878023&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1073/pnas.92.5.1585&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="7878023">Watanabe et al. (1995)</a> generated mice that were moderately and severely homocysteinemic, using homologous recombination in mouse embryonic stem cells to inactivate the Cbs gene. Homozygous mutants completely lacking cystathionine beta-synthase were born at the expected frequency from matings of heterozygotes, but they suffered from severe growth retardation and most of them died within 5 weeks after birth. Histologic examination showed that the hepatocytes of homozygotes were enlarged, multinucleated, and filled with microvesicular lipid droplets (resembling the finding in some severe homocystinuric patients). Plasma homocysteine levels of the homozygotes were approximately 40 times normal. Heterozygous mutants had approximately 50% reduction in CBS mRNA and enzyme activity in the liver and had twice normal plasma homocysteine levels. <a href="#95" class="mim-tip-reference" title="Watanabe, M., Osada, J., Aratani, Y., Kluckman, K., Reddick, R., Malinow, M. R., Maeda, N. &lt;strong&gt;Mice deficient in cystathionine beta-synthase: animal models for mild and severe homocyst(e)inemia.&lt;/strong&gt; Proc. Nat. Acad. Sci. 92: 1585-1589, 1995.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/7878023/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;7878023&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1073/pnas.92.5.1585&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="7878023">Watanabe et al. (1995)</a> concluded that homozygotes are a useful model for the clinical disorder homocystinuria and the heterozygotes should be useful for studying the role of elevated levels of homocysteine in the causation of cardiovascular disease. They noted that most of the homozygous mutant mice had eyes with delayed and narrow eye openings but without obvious histologic abnormalities. Seemingly, the homozygotes did not survive long enough to develop osteoporosis and vascular occlusions. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7878023" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#94" class="mim-tip-reference" title="Wang, L., Chen, X., Tang, B., Hua, X., Klein-Szanto, A., Kruger, W. D. &lt;strong&gt;Expression of mutant human cystathionine beta-synthase rescues neonatal lethality but not homocystinuria in a mouse model.&lt;/strong&gt; Hum. Molec. Genet. 14: 2201-2208, 2005.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/15972722/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;15972722&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=15972722[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/10.1093/hmg/ddi224&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="15972722">Wang et al. (2005)</a> engineered mice that expressed the common human mutant I278T and I278T/T424N Cbs proteins. These transgene-containing mice were then bred to Cbs +/- mice to generate Cbs -/- mice that expressed only the I278T or I278T/T424N human transgenes. Both the I278T and the I278T/T424N transgenes were able to entirely rescue the neonatal mortality phenotype of Cbs -/- mice (see <a href="#95" class="mim-tip-reference" title="Watanabe, M., Osada, J., Aratani, Y., Kluckman, K., Reddick, R., Malinow, M. R., Maeda, N. &lt;strong&gt;Mice deficient in cystathionine beta-synthase: animal models for mild and severe homocyst(e)inemia.&lt;/strong&gt; Proc. Nat. Acad. Sci. 92: 1585-1589, 1995.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/7878023/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;7878023&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1073/pnas.92.5.1585&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="7878023">Watanabe et al., 1995</a>) despite these mice having a mean homocysteine level of 250 micromoles. The transgenic Cbs -/- animals exhibited facial alopecia, had moderate liver steatosis, and were slightly smaller than heterozygous littermates. In contrast to human CBS deficiency, these mice did not exhibit hypermethioninemia. The mutant proteins were stable in several tissues, although liver extracts had only 2 to 3% of the Cbs enzyme activity found in wildtype mice. The I278T/T424N enzyme had exactly the same activity as the I278T enzyme, indicating that T424N was unable to suppress I278T in mice. <a href="#94" class="mim-tip-reference" title="Wang, L., Chen, X., Tang, B., Hua, X., Klein-Szanto, A., Kruger, W. D. &lt;strong&gt;Expression of mutant human cystathionine beta-synthase rescues neonatal lethality but not homocystinuria in a mouse model.&lt;/strong&gt; Hum. Molec. Genet. 14: 2201-2208, 2005.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/15972722/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;15972722&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=15972722[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/10.1093/hmg/ddi224&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="15972722">Wang et al. (2005)</a> concluded that elevated homocysteine levels per se were not responsible for the neonatal lethality observed in Cbs -/- animals and suggested that CBS protein may have other functions in addition to its role in homocysteine catabolism. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=15972722+7878023" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="seeAlso" class="mim-anchor"></a>
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<span class="mim-text-font">
<a href="#Almgren1978" class="mim-tip-reference" title="Almgren, B., Eriksson, H., Hemmingsson, A., Hillerdal, G., Larsson, E., Aberg, H. &lt;strong&gt;Abdominal aortic aneurysm in homocystinuria.&lt;/strong&gt; Acta Chir. Scand. 144: 545-546, 1978.">Almgren et al. (1978)</a>; <a href="#Barber1967" class="mim-tip-reference" title="Barber, G. W., Spaeth, G. L. &lt;strong&gt;Pyridoxine therapy in homocystinuria. (Letter)&lt;/strong&gt; Lancet 289: 337 only, 1967. Note: Originally Volume I.">Barber and Spaeth (1967)</a>; <a href="#Carson1969" class="mim-tip-reference" title="Carson, N. A. J., Carre, I. J. &lt;strong&gt;Treatment of homocystinuria with pyridoxine: a preliminary study.&lt;/strong&gt; Arch. Dis. Child. 44: 387-392, 1969.">Carson and Carre
(1969)</a>; <a href="#Carson1963" class="mim-tip-reference" title="Carson, N. A. J., Cusworth, D. C., Dent, C. E., Field, C. M. B., Neill, D. W., Westall, R. G. &lt;strong&gt;Homocystinuria: a new inborn error of metabolism associated with mental deficiency.&lt;/strong&gt; Arch. Dis. Child. 38: 425-436, 1963.">Carson et al. (1963)</a>; <a href="#Field1962" class="mim-tip-reference" title="Field, C. M. B., Carson, N. A. J., Cusworth, D. C., Dent, C. E., Neill, D. W. &lt;strong&gt;Homocystinuria, a new disorder of metabolism. (Abstract)&lt;/strong&gt; Proceedings of the 10th International Congress of Pediatrics, Lisbon 1962. Pp. 274-275.">Field et al. (1962)</a>; <a href="#Frimpter1969" class="mim-tip-reference" title="Frimpter, G. W. &lt;strong&gt;Homocystinuria: vitamin B6 dependent or not? (Editorial)&lt;/strong&gt; Ann. Intern. Med. 71: 209-211, 1969.">Frimpter (1969)</a>; <a href="#Goldstein1973" class="mim-tip-reference" title="Goldstein, J. L., Campbell, B. K., Gartler, S. M. &lt;strong&gt;Homocystinuria: heterozygote detection using phytohemagglutinin-stimulated lymphocytes.&lt;/strong&gt; J. Clin. Invest. 52: 218, 1973.">Goldstein et al. (1973)</a>; <a href="#Hooft1967" class="mim-tip-reference" title="Hooft, C., Carton, D., Samyn, W. &lt;strong&gt;Pyridoxine treatment in homocystinuria. (Letter)&lt;/strong&gt; Lancet 289: 1384 only, 1967. Note: Originally Volume I.">Hooft et al. (1967)</a>; <a href="#Kaeser1969" class="mim-tip-reference" title="Kaeser, A. C., Rodnight, R., Ellis, B. A. &lt;strong&gt;Psychiatric and biochemical aspects of a case of homocystinuria.&lt;/strong&gt; J. Neurol. Neurosurg. Psychiat. 32: 88-93, 1969.">Kaeser et al. (1969)</a>; <a href="#Kim1974" class="mim-tip-reference" title="Kim, Y. J., Rosenberg, L. E. &lt;strong&gt;On the mechanism of pyridoxine responsive homocystinuria. II. Properties of normal and mutant cystathionine beta-synthase from cultured fibroblasts.&lt;/strong&gt; Proc. Nat. Acad. Sci. 71: 4821-4825, 1974.">Kim and Rosenberg (1974)</a>; <a href="#Komrower1967" class="mim-tip-reference" title="Komrower, G. M. &lt;strong&gt;Dietary treatment of homocystinuria.&lt;/strong&gt; Am. J. Dis. Child. 113: 98-100, 1967.">Komrower (1967)</a>; <a href="#Kurczynski1980" class="mim-tip-reference" title="Kurczynski, T. W., Muir, W. A., Fleisher, L. D., Palomaki, J. F., Gaull, G. E., Rassin, D. K., Abramowsky, C. &lt;strong&gt;Maternal homocystinuria: studies of an untreated mother and fetus.&lt;/strong&gt; Arch. Dis. Child. 55: 721-723, 1980.">Kurczynski et al. (1980)</a>; <a href="#McCully1970" class="mim-tip-reference" title="McCully, K. S., Ragsdale, B. D. &lt;strong&gt;Production of arteriosclerosis by homocystinuria.&lt;/strong&gt; Am. J. Path. 61: 1-12, 1970.">McCully and Ragsdale (1970)</a>; <a href="#Mudd1985" class="mim-tip-reference" title="Mudd, S. H., Skovby, F., Levy, H. L., Pettigrew, K. D., Wilcken, B., Pyeritz, R. E., Andria, G., Boers, G. H. J., Bromberg, I. L., Cerone, R., Fowler, B., Grobe, H., Schmidt, H., Schweitzer, L. &lt;strong&gt;The natural history of homocystinuria due to cystathionine beta-synthase deficiency.&lt;/strong&gt; Am. J. Hum. Genet. 37: 1-31, 1985.">Mudd (1985)</a>; <a href="#Mudd1970" class="mim-tip-reference" title="Mudd, S. H., Edwards, W. A., Loeb, P. M., Brown, M. S., Laster, L. &lt;strong&gt;Homocystinuria due to cystathionine synthase deficiency: the effect of pyridoxine.&lt;/strong&gt; J. Clin. Invest. 49: 1762-1773, 1970.">Mudd et al. (1970)</a>; <a href="#Mudd1964" class="mim-tip-reference" title="Mudd, S. H., Finkelstein, J. D., Irreverre, F., Laster, L. &lt;strong&gt;Homocystinuria: an enzymatic defect.&lt;/strong&gt; Science 143: 1443-1445, 1964.">Mudd et
al. (1964)</a>; <a href="#Mudd1969" class="mim-tip-reference" title="Mudd, S. H., Levy, H. L., Abeles, R. H. &lt;strong&gt;A derangement in B12 metabolism leading to homocystinemia, cystathioninemia and methylmalonic aciduria.&lt;/strong&gt; Biochem. Biophys. Res. Commun. 35: 121-126, 1969.">Mudd et al. (1969)</a>; <a href="#Munnich1983" class="mim-tip-reference" title="Munnich, A., Saudubray, J.-M., Dautzenberg, M.-D., Parvy, P., Ogier, H., Girot, R., Manigne, P., Frezal, J. &lt;strong&gt;Diet-responsive proconvertin (factor VII) deficiency in homocystinuria.&lt;/strong&gt; J. Pediat. 102: 730-734, 1983.">Munnich et al. (1983)</a>; <a href="#Perry1968" class="mim-tip-reference" title="Perry, T. L., Hansen, S., Love, D. L., Crawford, L. E., Tischler, B. &lt;strong&gt;Treatment of homocystinuria with a low-methionine diet, supplemental cystine and a methyl donor.&lt;/strong&gt; Lancet 292: 474-478, 1968. Note: Originally Volume II.">Perry et al.
(1968)</a>; <a href="#Shelley1972" class="mim-tip-reference" title="Shelley, W. B., Rawnsley, H. M., Morrow, G., III. &lt;strong&gt;Pyridoxine-dependent hair pigmentation in association with homocystinuria.&lt;/strong&gt; Arch. Derm. 106: 228-230, 1972.">Shelley et al. (1972)</a>; <a href="#Shih1970" class="mim-tip-reference" title="Shih, V. E., Efron, M. L. &lt;strong&gt;Pyridoxine-unresponsive homocystinuria.&lt;/strong&gt; New Eng. J. Med. 283: 1206-1208, 1970.">Shih and Efron (1970)</a>; <a href="#Shipman1969" class="mim-tip-reference" title="Shipman, R. T., Townley, R. R. W., Danks, D. M. &lt;strong&gt;Homocystinuria, Addisonian pernicious anaemia, and partial deletion of a G chromosome.&lt;/strong&gt; Lancet 294: 693-694, 1969. Note: Originally Volume II.">Shipman et al.
(1969)</a>; <a href="#Skovby1985" class="mim-tip-reference" title="Skovby, F. &lt;strong&gt;Homocystinuria: clinical, biochemical and genetic aspects of cystathionine beta-synthase and its deficiency in man.&lt;/strong&gt; Acta Paediat. Scand. Suppl. 321: 1-21, 1985.">Skovby (1985)</a>; <a href="#Uhlemann1976" class="mim-tip-reference" title="Uhlemann, E. R., TenPas, J. H., Lucky, A. W., Schulman, J. D., Mudd, S. H., Shulman, N. R. &lt;strong&gt;Platelet survival and morphology in homocystinuria due to cystathionine synthase deficiency.&lt;/strong&gt; New Eng. J. Med. 295: 1283-1286, 1976.">Uhlemann et al. (1976)</a>; <a href="#Wong1968" class="mim-tip-reference" title="Wong, P. W. K., Schwarz, V., Komrower, G. M. &lt;strong&gt;The biosynthesis of cystathionine in patients with homocystinuria.&lt;/strong&gt; Pediat. Res. 2: 149-160, 1968.">Wong et al. (1968)</a>
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<span class="mim-font">
<span id="mimReferencesToggleTriangle" class="small mimTextToggleTriangle">&#9660;</span>
<strong>REFERENCES</strong>
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</h4>
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</div>
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<a id="1" class="mim-anchor"></a>
<a id="Abbott1987" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Abbott, M. H., Folstein, S. E., Abbey, H., Pyeritz, R. E.
<strong>Psychiatric manifestations of homocystinuria due to cystathionine beta-synthase deficiency: prevalence, natural history, and relationship to neurologic impairment and vitamin B(6)-responsiveness.</strong>
Am. J. Med. Genet. 26: 959-969, 1987.
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[<a href="https://doi.org/10.1002/ajmg.1320260427" target="_blank">Full Text</a>]
</p>
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<a id="2" class="mim-anchor"></a>
<a id="Almgren1978" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Almgren, B., Eriksson, H., Hemmingsson, A., Hillerdal, G., Larsson, E., Aberg, H.
<strong>Abdominal aortic aneurysm in homocystinuria.</strong>
Acta Chir. Scand. 144: 545-546, 1978.
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</p>
</div>
</li>
<li>
<a id="3" class="mim-anchor"></a>
<a id="Barber1967" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Barber, G. W., Spaeth, G. L.
<strong>Pyridoxine therapy in homocystinuria. (Letter)</strong>
Lancet 289: 337 only, 1967. Note: Originally Volume I.
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<a id="4" class="mim-anchor"></a>
<a id="Bass1997" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Bass, H. N., LaGrave, D., Mardach, R., Cederbaum, S. D., Fuster, C. D., Chetty, M.
<strong>Spontaneous pneumothorax in association with pyridoxine-responsive homocystinuria.</strong>
J. Inherit. Metab. Dis. 20: 831-832, 1997.
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[<a href="https://doi.org/10.1023/a:1005384121649" target="_blank">Full Text</a>]
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<a id="5" class="mim-anchor"></a>
<a id="Boers1985" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Boers, G. H. J., Fowler, B., Smals, A. G. H., Trijbels, F. J. M., Leermakers, A. I., Kleijer, W. J., Kloppenborg, P. W. C.
<strong>Improved identification of heterozygotes for homocystinuria due to cystathionine synthase deficiency by the combination of methionine loading and enzyme determination in cultured fibroblasts.</strong>
Hum. Genet. 69: 164-169, 1985.
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[<a href="https://doi.org/10.1007/BF00293290" target="_blank">Full Text</a>]
</p>
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<a id="6" class="mim-anchor"></a>
<a id="Boers1985" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Boers, G. H. J., Smals, A. G. H., Trijbels, F. J. M., Fowler, B., Bakkeren, J. A. J. M., Schoonderwaldt, H. C., Kleijer, W. J., Kloppenborg, P. W. C.
<strong>Heterozygosity for homocystinuria in premature peripheral and cerebral occlusive arterial disease.</strong>
New Eng. J. Med. 313: 709-715, 1985.
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[<a href="https://doi.org/10.1056/NEJM198509193131201" target="_blank">Full Text</a>]
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<a id="7" class="mim-anchor"></a>
<a id="Burke1989" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Burke, J. P., O'Keefe, M., Bowell, R., Naughten, E. R.
<strong>Ocular complications in homocystinuria: early and late treated.</strong>
Brit. J. Ophthal. 73: 427-431, 1989.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2751974/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2751974</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2751974" 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/bjo.73.6.427" target="_blank">Full Text</a>]
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<a id="Carey1968" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Carey, M. C., Donovan, D. E., Fitzgerald, O., McAuley, F. D.
<strong>Homocystinuria: a clinical and pathological study of nine subjects in six families.</strong>
Am. J. Med. 45: 7-25, 1968.
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[<a href="https://doi.org/10.1016/0002-9343(68)90003-x" target="_blank">Full Text</a>]
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<a id="Carey1968" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Carey, M. C., Fennelly, J. J., Fitzgerald, O.
<strong>Homocystinuria. II. Subnormal serum folate levels, increased folate clearance and effects of folic acid therapy.</strong>
Am. J. Med. 45: 26-31, 1968.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/5658866/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">5658866</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=5658866" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1016/0002-9343(68)90004-1" target="_blank">Full Text</a>]
</p>
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<a id="10" class="mim-anchor"></a>
<a id="Carson1969" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Carson, N. A. J., Carre, I. J.
<strong>Treatment of homocystinuria with pyridoxine: a preliminary study.</strong>
Arch. Dis. Child. 44: 387-392, 1969.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/5785188/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">5785188</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=5785188" 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.44.235.387" target="_blank">Full Text</a>]
</p>
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<a id="11" class="mim-anchor"></a>
<a id="Carson1963" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Carson, N. A. J., Cusworth, D. C., Dent, C. E., Field, C. M. B., Neill, D. W., Westall, R. G.
<strong>Homocystinuria: a new inborn error of metabolism associated with mental deficiency.</strong>
Arch. Dis. Child. 38: 425-436, 1963.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14065982/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14065982</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14065982" 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.38.201.425" target="_blank">Full Text</a>]
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<a id="12" class="mim-anchor"></a>
<a id="Carson1962" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Carson, N. A. J., Neill, D. W.
<strong>Metabolic abnormalities detected in a survey of mentally backward individuals in Northern Ireland.</strong>
Arch. Dis. Child. 37: 505-513, 1962.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14018926/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14018926</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14018926" 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.37.195.505" target="_blank">Full Text</a>]
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<a id="13" class="mim-anchor"></a>
<a id="Chao1999" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Chao, C.-L., Tsai, H.-H., Lee, C.-M., Hsu, S.-M., Kao, J.-T., Chien, K.-L., Sung, F.-C., Lee, Y.-T.
<strong>The graded effect of hyperhomocysteinemia on the severity and extent of coronary atherosclerosis.</strong>
Atherosclerosis 147: 379-386, 1999.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10559524/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10559524</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10559524" 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/s0021-9150(99)00208-7" target="_blank">Full Text</a>]
</p>
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<a id="14" class="mim-anchor"></a>
<a id="Cochran1990" class="mim-anchor"></a>
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<p class="mim-text-font">
Cochran, F. B., Sweetman, L., Schmidt, K., Barsh, G., Kraus, J., Packman, S.
<strong>Pyridoxine-unresponsive homocystinuria with an unusual clinical course.</strong>
Am. J. Med. Genet. 35: 519-522, 1990.
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[<a href="https://doi.org/10.1002/ajmg.1320350415" target="_blank">Full Text</a>]
</p>
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<a id="15" class="mim-anchor"></a>
<a id="Collins1990" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Collins, J. E., Brenton, D. P.
<strong>Pancreatitis and homocystinuria.</strong>
J. Inherit. Metab. Dis. 13: 232-233, 1990.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2116556/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2116556</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2116556" 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/BF01799693" target="_blank">Full Text</a>]
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<a id="Di Minno1993" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Di Minno, G., Davi, G., Margaglione, M., Cirillo, F., Grandone, E., Ciabattoni, G., Catalano, I., Strisciuglio, P., Andria, G., Patrono, C., Mancini, M.
<strong>Abnormally high thromboxane biosynthesis in homozygous homocystinuria: evidence for platelet involvement and probucol-sensitive mechanism.</strong>
J. Clin. Invest. 92: 1400-1406, 1993.
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[<a href="https://doi.org/10.1172/JCI116715" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1016/j.ymgme.2007.06.010" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1172/JCI108976" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.7326/0003-4819-71-1-209" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1006/mgme.1998.2771" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1002/humu.1380060211" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1056/NEJM199905133401915" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1002/humu.10104" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1007/pl00014312" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1016/0006-291x(62)90114-6" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1172/JCI107170" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1002/ajmg.1247" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1056/NEJM197409122911101" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1016/S0161-6420(98)91035-1" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1074/jbc.M504748200" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1093/hmg/2.11.1857" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1096/fj.08-112086" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1086/320597" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1136/jnnp.32.2.88" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1172/JCI112461" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1212/01.wnl.0000042479.55406.b3" target="_blank">Full Text</a>]
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Kim, Y. J., Rosenberg, L. E.
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[<a href="https://doi.org/10.1073/pnas.71.12.4821" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1086/302439" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1001/archpedi.1967.02090160148022" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1093/hmg/4.4.623" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1007/BF00711354" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1002/(SICI)1098-1004(1999)13:5&lt;362::AID-HUMU4&gt;3.0.CO;2-K" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1093/hmg/4.7.1155" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1002/humu.10290" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1136/adc.55.9.721" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1007/s10038-005-0312-2" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1023/a:1016502408305" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1016/0925-4439(95)00119-0" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1002/humu.10089" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1056/NEJM198509193131210" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1172/JCI106394" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1126/science.143.3613.1443" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1056/NEJM199508033330520" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1016/s0022-3476(83)80247-9" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1016/S0140-6736(05)79579-9" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1016/s0140-6736(68)90646-6" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1023/a:1015672625913" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1126/science.162.3857.1007-a" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1001/jama.1965.03090090017003" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1620/tjem.92.325" target="_blank">Full Text</a>]
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Testai, F. D., Gorelick, P. B.
<strong>Inherited metabolic disorders and stroke part 2: homocystinuria, organic acidurias, and urea cycle disorders.</strong>
Arch. Neurol. 67: 148-153, 2010.
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[<a href="https://doi.org/10.1001/archneurol.2009.333" target="_blank">Full Text</a>]
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<a id="89" class="mim-anchor"></a>
<a id="Tsai1996" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Tsai, M. Y., Bignell, M., Schwichtenberg, K., Hanson, N. Q.
<strong>High prevalence of a mutation in the cystathionine beta-synthase gene.</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8940271/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8940271</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8940271" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
</p>
</div>
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<a id="90" class="mim-anchor"></a>
<a id="Uhlemann1976" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Uhlemann, E. R., TenPas, J. H., Lucky, A. W., Schulman, J. D., Mudd, S. H., Shulman, N. R.
<strong>Platelet survival and morphology in homocystinuria due to cystathionine synthase deficiency.</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/980060/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">980060</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=980060" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1056/NEJM197612022952303" target="_blank">Full Text</a>]
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<a id="91" class="mim-anchor"></a>
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<p class="mim-text-font">
Uhlendorf, B. W., Mudd, S. H.
<strong>Cystathionine synthase in tissue culture derived from human skin: enzyme defect in homocystinuria.</strong>
Science 160: 1007-1009, 1968.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/5647845/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">5647845</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=5647845" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1126/science.160.3831.1007" target="_blank">Full Text</a>]
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<a id="92" class="mim-anchor"></a>
<a id="Urreizti2006" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Urreizti, R., Asteggiano, C., Bermudez, M., Cordoba, A., Szlago, M., Grosso, C., de Kremer, R. D., Vilarinho, L., D'Almeida, V., Martinez-Pardo, M., Pena-Quintana, L., Dalmau, J., Bernal, J., Briceno, I., Couce, M. L., Rodes, M., Vilaseca, M. A., Balcells, S., Grinberg, D.
<strong>The p.T191M mutation of the CBS gene is highly prevalent among homocystinuric patients from Spain, Portugal and South America.</strong>
J. Hum. Genet. 51: 305-313, 2006. Note: Erratum: J. Hum. Genet. 52: 388-389, 2007.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16479318/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16479318</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16479318" 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/s10038-006-0362-0" target="_blank">Full Text</a>]
</p>
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<a id="93" class="mim-anchor"></a>
<a id="Wadman1983" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Wadman, S. K., Cats, B. P., de Bree, P. K.
<strong>Sulfite oxidase deficiency and the detection of urinary sulfite. (Letter)</strong>
Europ. J. Pediat. 141: 62-63, 1983.
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Wang, L., Chen, X., Tang, B., Hua, X., Klein-Szanto, A., Kruger, W. D.
<strong>Expression of mutant human cystathionine beta-synthase rescues neonatal lethality but not homocystinuria in a mouse model.</strong>
Hum. Molec. Genet. 14: 2201-2208, 2005.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15972722/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15972722</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15972722[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15972722" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1093/hmg/ddi224" target="_blank">Full Text</a>]
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<a id="95" class="mim-anchor"></a>
<a id="Watanabe1995" class="mim-anchor"></a>
<div class="">
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Watanabe, M., Osada, J., Aratani, Y., Kluckman, K., Reddick, R., Malinow, M. R., Maeda, N.
<strong>Mice deficient in cystathionine beta-synthase: animal models for mild and severe homocyst(e)inemia.</strong>
Proc. Nat. Acad. Sci. 92: 1585-1589, 1995.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7878023/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7878023</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7878023" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1073/pnas.92.5.1585" target="_blank">Full Text</a>]
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<a id="Werstuck2001" class="mim-anchor"></a>
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Werstuck, G. H., Lentz, S. R., Dayal, S., Hossain, G. S., Sood, S. K., Shi, Y. Y., Zhou, J., Maeda, N., Krisans, S. K., Malinow, M. R., Austin, R. C.
<strong>Homocysteine-induced endoplasmic reticulum stress causes dysregulation of the cholesterol and triglyceride biosynthetic pathways.</strong>
J. Clin. Invest. 107: 1263-1273, 2001.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11375416/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11375416</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11375416[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11375416" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1172/JCI11596" target="_blank">Full Text</a>]
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<a id="97" class="mim-anchor"></a>
<a id="Wilcken1985" class="mim-anchor"></a>
<div class="">
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Wilcken, D. E. L., Dudman, N. P. B., Tyrrell, P. A.
<strong>Homocystinuria due to cystathionine beta-synthase deficiency--the effects of betaine treatment in pyridoxine-responsive patients.</strong>
Metabolism 34: 1115-1121, 1985.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3934499/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3934499</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=3934499" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1016/0026-0495(85)90156-8" target="_blank">Full Text</a>]
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<a id="98" class="mim-anchor"></a>
<a id="Wilcken1983" class="mim-anchor"></a>
<div class="">
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Wilcken, D. E. L., Wilcken, B., Dudman, N. P. B., Tyrrell, P. A.
<strong>Homocystinuria--the effects of betaine in the treatment of patients not responsive to pyridoxine.</strong>
New Eng. J. Med. 309: 448-453, 1983.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/6877313/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">6877313</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=6877313" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1056/NEJM198308253090802" target="_blank">Full Text</a>]
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<a id="99" class="mim-anchor"></a>
<a id="Wilcken1976" class="mim-anchor"></a>
<div class="">
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Wilcken, D. E., Wilcken, B.
<strong>The pathogenesis of coronary artery disease: a possible role for methionine metabolism.</strong>
J. Clin. Invest. 57: 1079-1082, 1976.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/947949/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">947949</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=947949" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1172/JCI108350" target="_blank">Full Text</a>]
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<a id="Wong1968" class="mim-anchor"></a>
<div class="">
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Wong, P. W. K., Schwarz, V., Komrower, G. M.
<strong>The biosynthesis of cystathionine in patients with homocystinuria.</strong>
Pediat. Res. 2: 149-160, 1968.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/5659087/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">5659087</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=5659087" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1203/00006450-196805000-00001" target="_blank">Full Text</a>]
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<a id="Yaghmai2002" class="mim-anchor"></a>
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Yaghmai, R., Kashani, A. H., Geraghty, M. T., Okoh, J., Pomper, M., Tangerman, A., Wagner, C., Stabler, S. P., Allen, R. H., Mudd, S. H., Braverman, N.
<strong>Progressive cerebral edema associated with high methionine levels and betaine therapy in a patient with cystathionine beta-synthase (CBS) deficiency.</strong>
Am. J. Med. Genet. 108: 57-63, 2002.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11857551/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11857551</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11857551" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1002/ajmg.10186" target="_blank">Full Text</a>]
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<a id="Yap1998" class="mim-anchor"></a>
<div class="">
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Yap, S., Naughten, E.
<strong>Homocystinuria due to cystathionine beta-synthase deficiency in Ireland: 25 years' experience of a newborn screened and treated population with reference to clinical outcome and biochemical control.</strong>
J. Inherit. Metab. Dis. 21: 738-747, 1998.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9819703/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9819703</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9819703" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1023/a:1005445132327" target="_blank">Full Text</a>]
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<a id="Yap2001" class="mim-anchor"></a>
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Yap, S., Rushe, H., Howard, P. M., Naughten, E. R.
<strong>The intellectual abilities of early-treated individuals with pyridoxine-nonresponsive homocystinuria due to cystathionine beta-synthase deficiency.</strong>
J. Inherit. Metab. Dis. 24: 437-447, 2001.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11596648/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11596648</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11596648" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1023/a:1010525528842" target="_blank">Full Text</a>]
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Cassandra L. Kniffin - updated : 10/11/2010
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Cassandra L. Kniffin - reorganized : 5/4/2010<br>Cassandra L. Kniffin - updated : 4/28/2010<br>Cassandra L. Kniffin - updated : 9/3/2009<br>George E. Tiller - updated : 11/20/2008<br>Cassandra L. Kniffin - updated : 5/24/2006<br>Cassandra L. Kniffin - updated : 2/17/2006<br>Victor A. McKusick - updated : 2/10/2004<br>Victor A. McKusick - updated : 1/12/2004<br>Ada Hamosh - updated : 10/8/2003<br>Ada Hamosh - updated : 10/6/2003<br>Victor A. McKusick - updated : 8/20/2002<br>Victor A. McKusick - updated : 6/14/2002<br>Victor A. McKusick - updated : 2/8/2002<br>Ada Hamosh - updated : 1/16/2002<br>Victor A. McKusick - updated : 1/10/2002<br>Victor A. McKusick - updated : 9/7/2001<br>Victor A. McKusick - updated : 6/27/2001<br>Carol A. Bocchini - updated : 6/27/2001<br>George E. Tiller - updated : 5/29/2001<br>Victor A. McKusick - updated : 5/15/2001<br>Paul J. Converse - updated : 6/8/2000<br>Victor A. McKusick - updated : 12/21/1999<br>Victor A. McKusick - updated : 6/30/1999<br>Victor A. McKusick - updated : 6/18/1999<br>Victor A. McKusick - updated : 6/7/1999<br>Victor A. McKusick - updated : 5/14/1999<br>Ada Hamosh - updated : 4/21/1999<br>Victor A. McKusick - updated : 2/25/1999<br>Victor A. McKusick - updated : 2/3/1999<br>Victor A. McKusick - updated : 12/2/1998<br>Ada Hamosh - updated : 10/26/1998<br>Victor A. McKusick - updated : 9/17/1998<br>John F. Jackson - reorganized : 9/2/1998<br>Victor A. McKusick - updated : 4/28/1998<br>Victor A. McKusick - updated : 4/15/1998<br>Victor A. McKusick - updated : 2/25/1998<br>Victor A. McKusick - updated : 2/17/1998<br>Victor A. McKusick - updated : 2/12/1998<br>Victor A. McKusick - updated : 1/29/1998<br>Victor A. McKusick - updated : 12/19/1997<br>Victor A. McKusick - updated : 6/5/1997<br>Victor A. McKusick - updated : 4/24/1997<br>Victor A. McKusick - updated : 4/4/1997<br>Victor A. McKusick - updated : 2/28/1997<br>Moyra Smith - updated : 5/21/1996
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Victor A. McKusick : 6/3/1986
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carol : 08/03/2016
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<strong>#</strong> 236200
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HOMOCYSTINURIA DUE TO CYSTATHIONINE BETA-SYNTHASE DEFICIENCY
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<em>Alternative titles; symbols</em>
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HOMOCYSTINURIA WITH OR WITHOUT RESPONSE TO PYRIDOXINE<br />
CYSTATHIONINE BETA-SYNTHASE DEFICIENCY<br />
CBS DEFICIENCY
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Other entities represented in this entry:
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HYPERHOMOCYSTEINEMIA, THROMBOTIC, CBS-RELATED, INCLUDED
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<strong>SNOMEDCT:</strong> 24308003; &nbsp;
<strong>ORPHA:</strong> 394; &nbsp;
<strong>DO:</strong> 9263; &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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21q22.3
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Homocystinuria, B6-responsive and nonresponsive types
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236200
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Autosomal recessive
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3
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CBS
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613381
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21q22.3
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Thrombosis, hyperhomocysteinemic
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236200
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Autosomal recessive
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3
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CBS
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613381
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<strong>TEXT</strong>
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<p>A number sign (#) is used with this entry because homocystinuria with or without response to pyridoxine is caused by homozygous or compound heterozygous mutation in the gene encoding cystathionine beta-synthase (CBS; 613381) on chromosome 21q22.</p>
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<strong>Description</strong>
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<p>Classic homocystinuria is an autosomal recessive metabolic disorder of sulfur metabolism. The clinical features of untreated homocystinuria due to CBS deficiency usually manifest in the first or second decade of life and include myopia, ectopia lentis, mental retardation, skeletal anomalies resembling Marfan syndrome (MFS; 154700), and thromboembolic events. Light skin and hair can also be present. Biochemical features include increased urinary homocystine and methionine. There are 2 main phenotypes of the classic disorder: a milder pyridoxine (vitamin B6)-responsive form, and a more severe pyridoxine-nonresponsive form. Pyridoxine is a cofactor for the CBS enzyme, and can aid in the conversion of homocysteine to cysteine (summary by Reish et al., 1995 and Testai and Gorelick, 2010). </p><p>Some patients have been reported to have a milder form of homocystinuria, which is characterized by increased plasma homocysteine and increased risk for thrombotic events in young adulthood, but without the other skeletal, ocular, or nervous system manifestations observed in classic homocystinuria (Kelly et al., 2003). </p>
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<strong>Clinical Features</strong>
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<p>Homocystinuria was discovered independently by Gerritsen et al. (1962) in Madison, Wisconsin, and by Carson and Neill (1962) in Belfast, Northern Ireland. The patients of both groups were studied because of mental retardation. </p><p>Mudd et al. (1985) compiled data on 629 patients with homocystinuria collected from all parts of the world. Among patients not discovered by newborn screening, mental capabilities were higher in B6-responsive patients (mean IQ, 79) than in B6-nonresponsive patients (mean IQ, 57). Time-to-event curves for other major clinical abnormalities were also presented. For untreated B6-responsive and B6-nonresponsive patients, these were, respectively: chance of dislocation of lenses by age 10, 55% and 82%; chance of having clinically detected thromboembolic event by age 15, 12% and 27%; chance of radiologic detection of spinal osteoporosis by age 15, 36% and 64%,, and chance of not surviving to age 30, 4% and 23%. When initiated neonatally, methionine restriction prevented mental retardation, reduced the rate of lens dislocation, and may have reduced the incidence of seizures. Pyridoxine treatment of late-detected B6-responsive patients reduced the rate of occurrence of initial thromboembolic events. Following 586 surgical procedures, 25 postoperative thromboembolic complications occurred, of which 6 were fatal. Few abnormalities were found in the offspring of either male or female patients, and the evidence was inconclusive concerning the rate of fetal loss from mothers with untreated homocystinuria. Among patients detected neonatally, only 13% were B6-responsive as compared with 47% among late-detected B6-responders. </p><p>Abbott et al. (1987) evaluated 63 patients with homocystinuria for psychiatric disturbance, intelligence, evidence of other CNS problems, and responsiveness to vitamin B6. Clinically significant psychiatric disorders were found in 51%. The average IQ was 80; IQ was lower among vitamin B6-nonresponsive patients. </p><p>Hypopigmentation is a feature of homocystinuria and can be shown to be reversible in patients with pyridoxine-responsive homocystinuria. Instances have been observed in which darkening of newly growing hair is observed after initiation of pyridoxine therapy, creating a clear demarcation between the old, blond and the new, dark hair (Reish et al., 1995). The consistency of the hair also changed from a coarse to a softer texture. </p><p>Yap et al. (2001) studied mental capabilities of 23 pyridoxine-nonresponsive individuals with CBS deficiency with over 339 patient-years of treatment and compared these individuals to those of 10 unaffected sibs (controls). Of the 23 individuals, 19 were diagnosed through newborn screening with early treatment, 2 were late-detected, and 2 were untreated at the time of assessment. Thirteen of the newborn-screened group who were compliant with treatment had no complications, while the remaining 6, who were poorly compliant, developed complications. Good compliance was defined by a lifetime plasma free homocysteine median of less than 11 micromole per liter. The newborn-screened good-compliance group with a mean age of 14.4 years (range 4.4-24.9) had a full-scale IQ of 105.8 (range 84-120), while the poorly compliant group with a mean age of 19.9 years (range 13.8 to 25.5) had a mean full-scale IQ of 80.8 (range 40-103). The control group had a mean age of 19.4 years and a mean IQ of 102. The 2 late-detected patients had IQs of 80 and 102 at the age of almost 19 years, while the 2 untreated patients had IQs in the mid-fifties at the age of 22 and 11 years. </p><p>In a review, Testai and Gorelick (2010) noted that thromboembolic events are the most common cause of death in patients with classic homocystinuria and can manifest as peripheral vein thrombosis, pulmonary embolism, stroke, peripheral artery occlusion, and myocardial infarction. The risk of having a vascular event is 25% before age 16 years and 50% by age 30 years. </p><p><strong><em>Clinical Variability: Thrombotic Hyperhomocysteinemia, CBS-Related</em></strong></p><p>
Gaustadnes et al. (2000) found that 3 of 5 unrelated patients with severe hyperhomocysteinemia and thrombosis, but no other features of classic homocystinuria, were compound heterozygous for mutations in the CBS gene, consistent with CBS deficiency. </p><p>Maclean et al. (2002) reported 2 unrelated Danish patients who presented with transient ischemic attacks at age 36 and 22 years, respectively. Biochemical studies showed increased serum homocysteine, but neither had other features of classic homocystinuria such as mental retardation, ectopia lentis, or skeletal changes. Each patient was compound heterozygous for 2 mutations in the CBS gene: one with D444N (613381.0010) and P422L (613381.0013), and the other with I278T (613381.0004) and S466L (613381.0014). In vitro functional expression studies showed that the P422L and S466L mutant proteins were catalytically active and even had higher activity than wildtype, but were impaired in regulation by AdoMet. The findings illustrated the importance of AdoMet for the regulation of homocysteine metabolism. </p><p>Kelly et al. (2003) reported 3 unrelated patients with premature stroke and severe hyperhomocysteinemia. Excluding tall stature in 2 patients, none had clinical features of classic homocystinuria. All had increased serum methionine and increased urinary homocystine. Molecular analysis found that each patient was heterozygous for a different CBS mutation (I278T, 613381.0004; D444N, 613381.0010, and G307S, 613381.0001); however, the possibility for another unidentified CBS mutation could not be ruled out. The report expanded the phenotypic variability associated with CBS mutations to include premature stroke and hyperhomocysteinemia without the classic findings of CBS deficiency. The findings also suggested that increased serum homocysteine can be associated with early-onset stroke (see 603174). </p>
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<strong>Other Features</strong>
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<p>Harker et al. (1974) showed endothelial desquamation in baboons chronically perfused with homocystine. In human cases of homocystinuria, they demonstrated reduced survival and abnormally rapid turnover of platelets, fibrinogen, and plasminogen. These abnormalities were corrected by clearing the plasma of homocystine with pyridoxine (in B6-responsive cases) or by administration of dipyridamole (in B6-unresponsive cases), but not by heparin anticoagulation. Platelet function was normal in patients and in the animal model. </p><p>Collins and Brenton (1990) described 2 children in whom pancreatitis was a complication of homocystinuria. One patient presented at age 6 with acute pancreatitis complicated by a pseudocyst requiring drainage on 2 occasions. The second patient presented at 15.5 years of age with severe colicky abdominal pain and a history of recurring abdominal pain for 6 years. Surgery was required for drainage of a large pseudocyst of the lesser sac in which necrotic portions of the body and tail of the pancreas were free floating. </p><p>Cochran et al. (1990) described an unusual presentation of pyridoxine-unresponsive homocystinuria: an intelligent teenaged boy had had asthma from infancy and at age 14 was hospitalized for recurrent left pneumothoraces requiring chest tubes. Soon thereafter he developed a right pneumothorax and subsequently a superior sagittal sinus thrombosis with papilledema and transient right hemiparesis as well as deep venous thromboses. He was found to have a very low level of cystathionine beta-synthase despite normal eye examination, including repeated slit-lamp examinations. The homocystinuria did not respond to pyridoxine or folate administration, but was reduced by methionine restriction and betaine supplementation. </p><p>Bass et al. (1997) noted that spontaneous pneumothorax had been reported previously in 2 homocystinuric patients, both with the pyridoxine-refractory form. They described an adolescent boy with the pyridoxine-responsive form who experienced 2 episodes of spontaneous pneumothorax. </p><p>Levy et al. (2002) reported the results of 15 pregnancies in 11 women with homocystinuria, 5 of whom were pyridoxine-nonresponsive and 6 of whom were pyridoxine-responsive. Complications of pregnancy included preeclampsia at term in 2 pregnancies and superficial venous thrombosis of the leg in a third pregnancy. One pregnancy was terminated and 2 pregnancies resulted in first-trimester spontaneous abortions. The remaining 12 pregnancies produced liveborn infants with normal or above-normal birth measurements. One offspring had multiple congenital anomalies that included colobomas of the iris and choroids, neural tube defect, and undescended testes. He was also mentally retarded and autistic. A second offspring had Beckwith-Wiedemann syndrome (130650). The remaining 10 offspring were normal at birth and remained normal. There was no relationship between the severity of the biochemical abnormalities or the therapies during pregnancy to either the pregnancy complications or the offspring outcomes. The infrequent occurrences of pregnancy complications, offspring abnormalities, and maternal thromboembolic events in this series suggested that pregnancy and outcome in maternal homocystinuria are usually normal. Nevertheless, Levy et al. (2002) suggested a cautious approach, which would include careful monitoring of these pregnancies with attention to metabolic therapy and possibly anticoagulation. </p><p><strong><em>Heterozygous Carriers</em></strong></p><p>
Based on the findings of Wilcken and Wilcken (1976), who found an association between increased plasma homocysteine and ischemic heart disease in males under age 50 years, it was hypothesized that heterozygous CBS mutation carriers may be at increased risk for cardiovascular disease (see, e.g., Boers et al., 1985). However, there has been conflicting evidence about whether or not heterozygous mutation carriers are at increased risk (review by Guttormsen et al., 2001). </p><p>In a study of 203 families, Mudd et al. (1981) could find no evidence of increased frequency of heart attacks or strokes in parents or grandparents of homocystinuric children. The data available were sufficient to exclude a 5-fold increase in cardiovascular risk for homocystinuria heterozygotes and to make very improbable a relative risk of as much as 3-fold. Mudd et al. (1981) concluded that less than 5% of homocystinuria heterozygotes are likely to have a heart attack by age 50 years. </p><p>Boers et al. (1985) tested for heterozygosity for homocystinuria by the finding of pathologic homocysteinemia after methionine loading and cystathionine synthase deficiency in cultured fibroblasts. Using these biochemical screening methods, Boers et al. (1985) identified putative heterozygotes for mutations in the CBS gene (613381), although this was not confirmed by genetic analysis. Seven of 25 patients with occlusive peripheral vascular disease manifest before age 50, and 7 of 25 patients with occlusive cerebrovascular disease manifest before age 50, were found to have increased serum homocysteine. However, none of 25 patients with myocardial infarction manifest before age 50 had increased serum homocysteine. </p><p>Kozich et al. (1995) investigated the relationship between premature occlusive arterial disease (POAD) associated with hyperhomocysteinemia and heterozygosity for mutations in the CBS gene. Molecular studies of 4 patients with POAD who had hyperhomocysteinemia and reduced CBS activities (see, e.g., Boers et al., 1985) failed to find mutations in the CBS gene in 7 of 8 alleles. The cDNAs encoded catalytically active, stable CBS that exhibited normal response to both S-adenosylmethionine and pyridoxal 5-prime-phosphate. In contrast, the screening method correctly distinguished mutant from normal alleles in all 4 obligatory CBS heterozygotes studied. Kozich et al. (1995) concluded that the homocysteinemia observed in these 4 POAD patients was not due to defective CBS protein. </p><p>In an editorial, Motulsky (1996) reviewed evidence that heterozygotes for homocystinuria do not appear to have elevated homocysteine levels. They noted that the mutations responsible for 70% of homocystinuria in Ireland and 50% of homocystinuria in Holland had never been found in heterozygote state in Irish or Dutch patients, respectively, with various types of premature vascular disease. </p><p>Although an I278Y mutation in the CBS gene (613381.0004) is found in 50% of the CBS alleles in Dutch homozygous CBS-deficient patients, Kluijtmans et al. (1996) found it in none of 60 patients with premature cardiovascular disease. This led them to conclude that heterozygosity for CBS deficiency is not involved in premature cardiovascular disease. </p><p>There is some evidence that CBS heterozygosity may interact with other risk factors to increase the risk of cardiovascular disease. Mandel et al. (1996) concluded that patients with concurrent homocystinuria due to CBS deficiency have an increased risk of thrombosis when they also have the factor V Leiden mutation (612309.0001). They studied 7 unrelated consanguineous kindreds in which at least 1 member was homozygous for homocystinuria. Thrombosis (venous, arterial, or both) occurred in 6 of 11 patients with homocystinuria (aged 0.2 to 8 years). All 6 also had the factor V Leiden mutation. One patient with prenatally diagnosed homocystinuria who was also heterozygous for factor V Leiden received warfarin therapy from birth and by the age of 18 months had not had thrombosis. Of 4 patients with homocystinuria who did not have factor V Leiden, none had thrombosis (aged 1 to 17 years). Three women who were heterozygous for both homocystinuria and factor V Leiden had recurrent fetal loss and placental infarctions. </p><p>Guttormsen et al. (2001) found that 20 heterozygotes for CBS deficiency had normal fasting homocysteine levels, but increased urinary homocysteine excretion compared to controls. An abnormal homocysteine response after methionine loading was observed in 73% of pyridoxine nonresponders and in only 33% of pyridoxine responders, but the test did not completely discriminate heterozygous mutation carriers from controls. The authors concluded that unequivocal identification of CBS carrier status required DNA analysis, and also noted that it was uncertain whether or not altered homocysteine metabolism in these individuals conveys an increased risk of cardiovascular disease. </p><p>Elsaid et al. (2007) found that 34 heterozygous CBS mutation carriers had mildly increased fasting levels of homocysteine compared to controls. Heterozygous carriers also had decreased folic acid and vitamin B12 levels compared to controls, but similar vitamin B6 levels. None were reported to have had cardiovascular events. </p>
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<strong>Diagnosis</strong>
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<p>Spaeth and Barber (1967) described a silver-nitroprusside test that was almost completely specific for homocystine. Wadman et al. (1983) referred to the cyanide-nitroprusside reaction used in the detection of cystinuria and homocystinuria as the Brand reaction. </p><p>Uhlendorf and Mudd (1968) found that cultured fibroblasts derived from normal skin, as well as cells in amniotic fluid, have cystathionine synthase activity, although the enzyme is not detectable in intact normal skin. Fibroblasts grown from the skin of homocystinuric persons are deficient in the enzyme. </p><p><strong><em>Neonatal Screening</em></strong></p><p>
Peterschmitt et al. (1999) reviewed the results of neonatal screening for homocystinuria over a period of 32 years in New England. For the first 23.5 years of the review, the blood methionine cutoff value was 2 mg per deciliter (134 micromole per liter). Among the 2.2 million infants screened during that period, 8 with homocystinuria were identified, giving a frequency of 1 in 275,000. In 1990, the cutoff value was reduced to 1 mg per deciliter (67 micromole per liter). Among the 1.1 million infants screened in the subsequent 8.5 years, 7 with the disorder were identified, giving a frequency of 1 in 157,000. During the latter period, the specimens were collected from 6 of the 7 infants when they were 2 days of age or less; 5 of the 6 had blood methionine concentrations below 2 mg per deciliter. Use of the reduced cutoff level increased the false-positive rate from 0.006% to 0.03%. Peterschmitt et al. (1999) concluded that a cutoff level for blood methionine of 1 mg per deciliter in neonatal screening tests for homocystinuria should identify affected infants who have only slightly elevated concentrations of methionine and reduce the frequency of false-negative results. They commented, furthermore, that the increased false-positive rate would not represent an undue burden in terms of requests for repeat analysis. Indeed, the false-positive rates were considerably lower than those associated with neonatal screening for other disorders such as congenital adrenal hyperplasia, congenital hypothyroidism, and phenylketonuria. </p><p>Guttormsen et al. (2001) concluded that abnormal response of total urinary homocysteine after methionine loading was the most sensitive test and a satisfactory way for studying mild disturbances in homocysteine metabolism. </p><p><strong><em>Differential Diagnosis</em></strong></p><p>
Homocysteinemia also occurs in homocystinuria due to N(5,10)-methylenetetrahydrofolate reductase deficiency (236250) and in transcobalamin II deficiency (275350).</p><p>Homocysteinemia/homocystinuria and megaloblastic anemia can result from defects in vitamin B12 (cobalamin; cbl) metabolism, which have been classified according to complementation groups of cells in vitro, e.g., cblE (236270) and cblG (250940). Combined methylmalonic aciduria (MMA) and homocystinuria due to defects in cobalamin include cblC (277400), cblD (277410), and cblF (277380).</p>
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<strong>Clinical Management</strong>
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<span class="mim-text-font">
<p>Carey et al. (1968) suggested that folic acid in pharmacologic doses is therapeutically valuable in this disease. Decrease in urinary excretion of homocystine and increase in methionine was noted during treatment. </p><p>Wilcken et al. (1985) concluded that additional benefit can be realized from betaine in B6-responsive patients. Homocysteine that is not metabolized to cystine is remethylated to methionine in reactions that use either N5-methyltetrahydrofolate or betaine (trimethylglycine) as methyl donors. </p><p>Harrison et al. (1998) reviewed the management of ophthalmic complications of homocystinuria on the basis of an extraordinarily large experience with 45 patients reviewed retrospectively in Saudi Arabia. Eighty-four surgical procedures were performed on 40 patients; 82 procedures were done under general anesthesia and 2 under local anesthesia. Five patients had only medical treatment. All patients had lens subluxation or dislocation. Mental retardation was present in 29 (64%). Harrison et al. (1998) suggested that surgical treatment should be considered, especially for cases of repeated lens dislocation into the anterior chamber or pupillary block glaucoma. </p><p>Gerding (1998) reviewed the ocular manifestations of homocystinuria and described a surgical approach to lens dislocation that allowed minimally invasive removal of the lens, complete preservation of the anterior vitreous cortex, and stable fixation of an artificial intraocular lens. </p><p>Several reports indicated a likely role for homocysteine in the pathogenesis of atherosclerosis, including those of Wilcken et al. (1983), Kang et al. (1986), Tsai et al. (1996), and Chao et al. (1999). Schnyder et al. (2001) found that treatment with a combination of folic acid, vitamin B12, and pyridoxine significantly reduced homocysteine levels and decreased the rate of restenosis and the need for revascularization of the target lesion after coronary angioplasty. They proposed that this inexpensive treatment, which has minimal side effects, should be considered as adjunctive therapy for patients undergoing coronary angioplasty. The benefit in relation to the vascular disease of homocystinuria would be dependent on the responsiveness of the particular mutation to this form of therapy. </p><p>Treatment of B6-nonresponsive patients centers on lowering homocysteine and its disulfide derivatives by adherence to a methionine-restricted diet. However, lifelong dietary control is difficult. Betaine supplementation is used extensively in CBS-deficient patients to lower plasma disulfide derivatives. With betaine therapy, methionine levels increase over baseline, but usually remain at levels that are not associated with adverse affects. Yaghmai et al. (2002) reported the case of a child with B6-nonresponsive CBS deficiency and dietary noncompliance whose methionine reached very high levels on betaine and who subsequently developed massive cerebral edema without evidence of thrombosis. They concluded that the cerebral edema was most likely precipitated by the betaine therapy, although the exact mechanism was uncertain. This case cautioned that methionine levels should be monitored in CBS-deficient patients on betaine and that betaine should be considered as an adjunct, not an alternative, to dietary control. </p><p>Pullin et al. (2002) investigated the endothelial effect of acute (2 g single dose) and chronic (1 g/day for 6 months) administration of oral vitamin C in 5 patients with homocystinuria (mean age 26 years, 1 male) and 5 age- and sex-matched controls. Brachial artery endothelium-dependent flow-mediated dilatation and endothelium-independent responses to nitroglycerin were measured using high-resolution ultrasonic vessel wall-tracking. At baseline, plasma total homocysteine was 100.8 +/- 61.6 and 9.2 +/- 1.9 micromol/L in the patient and control groups, respectively. Flow-mediated dilatation responses were impaired in the patient group (20 +/- 40 micro m) compared with the controls (116 +/- 30 micro m). With vitamin C administration, flow-mediated dilatation responses in the patient group improved both acutely and chronically at 2 weeks and at 6 months. Flow-mediated dilatation responses in the control group were unaltered. Within both groups, neither the vascular response to nitroglycerin nor plasma homocysteine was altered. Pullin et al. (2002) concluded that vitamin C ameliorates endothelial dysfunction in patients with homocystinuria, independent of changes in homocysteine concentration, and should therefore be considered as an additional adjunct to therapy to reduce the potential long-term risk of atherothrombotic disease. </p>
</span>
<div>
<br />
</div>
<div>
<h4>
<span class="mim-font">
<strong>Biochemical Features</strong>
</span>
</h4>
</div>
<span class="mim-text-font">
<p>From study of fibroblast lines, Fowler et al. (1978) found 3 types of cystathionine synthetase deficiency: one with no residual activity; one with reduced activity and normal affinity for the cofactor pyridoxal-phosphate; and one with reduced activity and reduced affinity for the cofactor. </p><p>Skovby et al. (1982) studied fibroblast extracts from 20 patients for immunoreactive cystathionine beta-synthase antigen. Each of 14 mutant extracts with residual synthase activity had cross-reactive material (CRM) ranging from 5 to 100% of controls. There was no correlation between the percent residual activity and the percent CRM. Of 6 mutant extracts without detectable catalytic activity, 3 had no CRM, while 3 had 13%, 17%, and 26% CRM. The findings provided a basis for biochemical heterogeneity of the disorder and indicated that a wide array of mutations in the CBS gene that affect enzyme structure are responsible for the disorder. </p>
</span>
<div>
<br />
</div>
<div>
<h4>
<span class="mim-font">
<strong>Molecular Genetics</strong>
</span>
</h4>
</div>
<span class="mim-text-font">
<p>With a rabbit antiserum against human hepatic CBS, Skovby et al. (1984) studied the enzyme in cultured fibroblasts derived from 17 homocystinuric patients. In 15 of the 17 lines, the enzyme had subunits indistinguishable in size from the normal (molecular mass of 63 kD). Material from one homocystinuric patient showed 2 mRNA species coding for equal amounts of 2 immunoprecipitable polypeptides: one of normal size and one smaller (mass of 56 kD). The father had 2 mRNAs also; the mother had only normal mRNA. Thus, the patient is a compound heterozygote; one of his mutant alleles codes for a synthase polypeptide missing about 60 amino acids. </p><p>Kruger and Cox (1995) showed that expression of 3 different CBS mutants known to be associated with reduced enzyme activity in humans failed to complement growth in the yeast assay. In addition, they used the yeast CBS assay to identify 8 mutant CBS alleles in cell lines from patients with CBS deficiency. These mutant alleles included 2 previously identified and 5 novel CBS mutations. The results also demonstrated that the yeast CBS assay can detect a large percentage of individuals heterozygous for mutations in CBS. </p><p>Kraus (1994) tabulated 14 mutations in the CBS gene that he and his colleagues had demonstrated in homocystinuria. The G307S mutation (613381.0001) is the most common cause of homocystinuria in patients of Celtic origin. Kraus (1994) indicated that even though patients have no measurable CBS activity in their fibroblasts and despite the fact that CBS subunits are undetectable in fibroblast extracts of some of these individuals, many of them are pyridoxine-responsive. Examples were cited in which the identical genotype resulted in a different phenotype within the family. In general, G307S is a pyridoxine-nonresponsive mutation, whereas the I278T (613381.0004) is a pyridoxine-responsive mutation (Hu et al., 1993). </p><p>Sebastio et al. (1995) identified a 68-bp insertion in exon 8 of the CBS gene (613381.0017) in a patient with homocystinuria and predicted that it would introduce a premature termination codon and result in a nonfunctional CBS enzyme. However, Tsai et al. (1996) found that this mutation is highly prevalent. In a case-control study involving patients with premature coronary artery disease, they identified the mutation in heterozygosity in 11.7% of controls and in slightly higher prevalence in the patients, although the difference did not reach statistical significance. In all cases, the insertion was present in cis with the 833T-C (I278T) mutation. Tsai et al. (1996) suggested that the insertion created an alternate splicing site that eliminated not only the inserted intronic sequences, but also the 833T-C mutation associated with this insertion. The net result was the generation of both quantitatively and qualitatively normal mRNA and CBS enzyme. </p><p>Kraus et al. (1999) stated that 92 different disease-associated mutations of the CBS gene had been identified in 310 examined homocystinuric alleles in more than a dozen laboratories around the world. Most of these mutations were missense, and the vast majority of these were private mutations occurring in only 1 or a very small number of families. The 2 most frequently encountered mutations were the pyridoxine-responsive I278T (613381.0004) and the pyridoxine-nonresponsive G307S (613381.0001). Mutations due to deaminations of methylcytosines represented 53% of all point substitutions in the coding region of the CBS gene. </p><p>In 6 patients from 5 Korean families with homocystinuria, Lee et al. (2005) identified 8 different mutations in the CBS gene, including 4 novel mutations. In vitro functional expression studies showed that the mutant enzymes had significantly decreased activities. </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>Kluijtmans et al. (1999) investigated the molecular basis of CBS deficiency in 29 Dutch patients from 21 unrelated pedigrees and studied the possibility of a genotype-phenotype relationship with regard to biochemical and clinical expression and response to homocysteine-lowering treatment. Of 10 different mutations detected in the CBS gene, 833T-C (I278T; 613381.0004) was predominant, being present in 23 (55%) of 42 independent alleles. At diagnosis, all 12 homozygotes for this mutation tended to have higher homocysteine levels than the 17 patients with other genotypes, but similar clinical manifestations. During follow-up, I278T homozygotes responded more efficiently to homocysteine-lowering treatment. After 378 patient-years of treatment, only 2 vascular events were recorded; without treatment, at least 30 would have been expected (P less than 0.01). </p><p>Maclean et al. (2002) described a novel class of 3 missense mutations, including P422L (613381.0013) and S466L (613381.0014), that are located in the noncatalytic C-terminal region of CBS and yield enzymes that are catalytically active but deficient in their response to S-adenosylmethionine (AdoMet). The P422L and S466L mutations were found in patients with premature thrombosis and homocystinuric levels of homocysteine (see 603174), but lacking any of the connective tissue disorders typical of homocystinuria due to CBS deficiency. These 2 mutants demonstrated a level of CBS activity comparable to that of the AdoMet-stimulated wildtype CBS but could not be further induced by the addition of AdoMet. In terms of temperature stability, oligomeric organization, and heme saturation the 3 mutants were indistinguishable from wildtype CBS. The findings illustrated the importance of AdoMet for the regulation of homocysteine metabolism and were consistent with the possibility that the characteristic connective tissue disturbances observed in homocystinuria due to CBS deficiency may not be due to elevated homocysteine. </p><p>Gaustadnes et al. (2002) determined the molecular basis of CBS deficiency in 36 Australian patients from 28 unrelated families, using direct sequencing of the entire coding region of the CBS gene. Seven novel and 20 known mutations were detected. The G307S and I278T mutations were the most common and were present in 19% and 18% of independent alleles, respectively. Expression studies of 2 novel mutations (C109R and G347S), as well as 2 known mutations (L101P and N228K), showed complete lack of catalytic activity by the mutant proteins. Gaustadnes et al. (2002) studied the correlation between genotype and biochemical response to pyridoxine treatment in 13 pyridoxine-responsive, 21 nonresponsive, and 2 partially responsive patients. The G307S mutation always resulted in a severe nonresponsive phenotype, whereas I278T resulted in a milder B6-responsive phenotype. From their results, Gaustadnes et al. (2002) were also able to establish 3 other mild mutations: P49L, R369C, and V371M. </p><p>Kruger et al. (2003) examined the relationship of the clinical and biochemical phenotypes with the genotypes of 12 CBS-deficient patients from 11 families in the state of Georgia (USA). By DNA sequencing of all of the coding exons, they identified mutations in the CBS gene in 21 of the 22 possible mutant alleles. Ten different missense mutations were identified and 1 novel splice site mutation was found. Five of the missense mutations were previously described, whereas 5 were novel. Each missense mutation was tested for function by expression in S. cerevisiae and all were found to cause decreased growth rate and to have significantly decreased levels of CBS enzyme activity. The I278T (613381.0004) and T353M (613381.0015) mutations accounted for 45% of the mutant alleles in this patient cohort. </p>
</span>
<div>
<br />
</div>
<div>
<h4>
<span class="mim-font">
<strong>Pathogenesis</strong>
</span>
</h4>
</div>
<span class="mim-text-font">
<p>Thrombotic lesions of arteries and veins are major features of homocystinuria. The observations of Ratnoff (1968) may have a bearing on the mechanism of the thrombotic accidents. </p><p>Reviewing the nature of the ocular zonule, Streeten (1982) pointed out that the zonular fibers are composed of glycoprotein with a high concentration of cysteine, which undoubtedly explains their susceptibility to abnormal formation in diseases of sulfur metabolism. </p><p>Di Minno et al. (1993) found evidence for enhanced thromboxane biosynthesis in homocystinuria and concluded from the response to administration of the antioxidant drug probucol that the enhanced thromboxane biosynthesis was dependent in part on probucol-sensitive mechanisms. High urinary excretion of 11-dehydro-TXB2, a major enzymatic derivative of TXA2, was observed in all 11 homocystinuric patients studied. The elevated thromboxane biosynthesis was thought to reflect, at least in part, in vivo platelet activation. </p><p>Malinow and Stampfer (1994) reviewed the role of plasma homocysteine in arterial occlusive diseases. </p><p>Reish et al. (1995) demonstrated that DL-homocysteine inhibits tyrosinase (TYR; see 606933), the major pigment enzyme. The activity of tyrosinase extracted from pigmented human melanoma cells that were grown in the presence of homocysteine was reduced in comparison to that extracted from cells grown without homocysteine. Copper sulfate restored homocysteine-inhibited tyrosinase activity when added to the culture cell medium. The results suggested that the probable mechanism of the inhibition is the interaction of homocysteine with copper at the active site of tyrosinase. </p><p>McKusick (1966) suggested that excess homocysteine may interfere with the normal synthesis of collagen crosslinks, thus accounting for the development of osteoporosis. Lubec et al. (1996) studied collagen synthesis and crosslinking by noninvasive tests in 10 patients with homocystinuria. Synthesis of collagen type I and type III was not different from age-matched healthy controls as reflected by comparable plasma levels of C-terminal propeptide of type I procollagen and of plasma levels of N-terminal propeptide of procollagen type III. Collagen type I crosslinks expressed by serum C-terminal telopeptide of collagen type I in the patient group were, however, only about one-third of the values found in the control group. This significant reduction of crosslinks in the patients with homocystinuria did not correlate with serum homocysteine or homocystic acid concentrations. The data supported the disturbed crosslinking hypothesis and indicated that the bone manifestations of homocystinuria are not due to deficient collagen synthesis. </p><p>In cultured human hepatocytes and vascular endothelial and aortic smooth muscle cells, Werstuck et al. (2001) found that homocysteine-induced endoplasmic reticulum (ER) stress activated both the unfolded protein response and sterol regulatory element-binding proteins (SREBPs). Activation of the SREBPs was associated with increased expression of genes responsible for cholesterol/triglyceride biosynthesis and uptake, and with intracellular accumulation of cholesterol. Mice with diet-induced hyperhomocysteinemia had significantly increased cholesterol and triglycerides in liver, but not plasma, due to increased lipid biosynthesis, not impaired hepatic export of lipids. The findings suggested a mechanism by which homocysteine-induced ER stress causes dysregulation of the endogenous sterol response pathway, leading to increased hepatic biosynthesis and uptake of cholesterol and triglycerides, which contribute to hepatic steatosis and possibly atherosclerotic lesions observed in hyperhomocysteinemia. </p><p>Hubmacher et al. (2005) noted that the skeletal and ocular findings of patients with homocystinuria resemble those seen in Marfan syndrome (MFS; 154700), which is caused by mutation in the fibrillin-1 gene (FBN1; 134797). By in vitro studies, Hubmacher et al. (2005) found that homocysteine concentrations in patients with homocystinuria caused structural modifications of recombinant human fibrillin-1 fragments and loss of calcium binding. These molecular changes resulted in enhanced protease sensitivity of the fibrillin fragments. The changes likely occurred through covalent modification of cysteine residues in fibrillin and/or disufide bond shuffling. The findings suggested that degradation of fibrillin-1 in the connective tissues of patients with homocystinuria plays a major role in the pathogenesis of this disorder. </p><p>Jakubowski et al. (2008) found that patients with homocysteinemia due to MTHFR deficiency (236250) or CBS deficiency had increased plasma levels of N-homocysteine (Hcy)-linked proteins, including the prothrombotic N-Hcy-fibrinogen (134820). N-Hcy-proteins are detrimental by contributing to both thrombogenesis and immune activation. The authors suggested that increased levels of N-Hcy-fibrinogen may explain the increased susceptibility to thrombogenesis in these individuals. </p>
</span>
<div>
<br />
</div>
<div>
<h4>
<span class="mim-font">
<strong>Population Genetics</strong>
</span>
</h4>
</div>
<span class="mim-text-font">
<p>Homocystinuria has been observed in Japan (Tada et al., 1967) and in persons of many different ethnic extractions living in the United States (Schimke et al., 1965). </p><p>Carey et al. (1968) pointed out that 27 cases had been found in Ireland. Kraus (1994) reported that the G307S mutation (613381.0001) in the CBS gene is the most common cause of homocystinuria in patients of Celtic origin. Gallagher et al. (1995) estimated that the G307S mutation accounted for 71% of alleles in Irish homocystinuria patients. Gallagher et al. (1998) identified 3 new CBS mutations in Irish patients. They estimated that more than 40 CBS mutations in homocystinuria in various ethnic groups had been identified. Most of these were missense mutations; however, 7 deletions had been documented, 2 of which were total deletions of exons 11 and 12. </p><p>Mudd et al. (1995) found estimates of the frequency of homocystinuria ranging from 1 in 58,000 to 1 in 1,000,000 in countries that systematically screen newborns.</p><p>The worldwide frequency of homocystinuria has been reported to be 1 in 344,000, while that in Ireland is much higher at 1 in 65,000, based on newborn screening and cases detected clinically. The national newborn screening program for homocystinuria in Ireland was started in 1971 using the bacterial inhibition assay. Yap and Naughten (1998) reported that a total of 1.58 million newborn infants had been screened over a 25-year period up to 1996. Twenty-five homocystinuria cases were diagnosed, 21 of whom were identified on screening. The remaining 4 cases were missed and presented clinically; 3 of these were breastfed and 1 was pyridoxine-responsive. Twenty-four of the 25 patients were nonresponsive to pyridoxine. All but one of the pyridoxine-nonresponsive cases were started on a low methionine, cystine-enhanced diet supplemented with pyridoxine, vitamin B12, and folate. The data suggested that ectopia lentis, osteoporosis, mental handicap, and thromboembolic events could be prevented by this regimen. Three patients with relatively high lifetime medians of free homocysteine developed increasing myopia, an ocular feature that often precedes ectopia lentis (Burke et al., 1989). </p><p>Gaustadnes et al. (1999) stated that the I278T mutation (613381.0004), which results from an 833T-C insertion, is geographically widespread. They determined the frequency of this mutation among Danish newborns by screening 500 consecutive Guthrie cards (specimens of infants' blood collected on filter paper). The frequent genetic insertion variant, 844ins68 (see 613381.0017), which occurs in cis with the 833T-C mutation, was simultaneously sought. A surprisingly high prevalence of the 833T-C mutation was detected among newborns who did not carry the 844ins68 variant, which is a benign polymorphism. This led the authors to suggest that the incidence of homocystinuria due to homozygosity for 833T-C may be at least 1 per 20,500 live births in Denmark. The 844ins68 variant was present in 10% of the Danish newborns. This neutral variant was thought to be deleted from mRNA during splicing. </p><p>Janosik et al. (2001) reported that during the previous 20 years, CBS deficiency had been detected in the former Czechoslovakia with a calculated frequency of 1 in 349,000. About half of 21 Czech and Slovak patients they studied were not responsive to pyridoxine. Twelve distinct mutations were detected in 30 independent homocystinuric alleles. One-half of the mutated alleles carried either the 833T-C or the IVS11-2A-C mutation (613381.0012); the remaining alleles contained private mutations. The high prevalence of the 833T-C allele, which confers pyridoxine-responsiveness, was not surprising because it is one of the most prevalent pathogenic CBS mutation in whites (Kraus et al., 1999). </p><p>Urreizti et al. (2006) reported a high frequency of the T191M mutation (613381.0016) among patients with homocystinuria from the Iberian peninsula and several South American countries. Combined with previously reported studies, the prevalence of T191M among mutant CBS alleles in different countries was 0.75 in Colombia, 0.52 in Spain, 0.33 in Portugal, 0.25 in Venezuela, 0.20 in Argentina, and 0.14 in Brazil. Haplotype analysis suggested a double origin for this mutation, which conferred a B6-nonresponsive phenotype. </p>
</span>
<div>
<br />
</div>
<div>
<h4>
<span class="mim-font">
<strong>Nomenclature</strong>
</span>
</h4>
</div>
<span class="mim-text-font">
<p>Plasma homocysteine is the sum of the thiol-containing amino acid homocysteine and the homocysteinyl moiety of the disulfides homocystine and cysteine-homocysteine, whether free or bound to proteins (Malinow and Stampfer, 1994). Malinow et al. (1989) introduced the term hyperhomocyst(e)inemia for above-normal concentrations of plasma/serum homocysteine. </p><p>Mudd and Levy (1995) noted the distinction between the term 'homocysteine,' which refers to the reduced sulfhydryl form of cysteine, and 'homocystine,' which refers to the oxidized disulfide form of cysteine (cystine). The measurement of plasma levels includes both of these homocysteine-derived moieties in either the sulfhydryl or disulfide form, but the distinction is important because many of the pathologic effects of the excess compound depend on the presence of the sulfhydryl group of homocysteine. The authors suggested use of the term hyperhomocyst(e)inemia to describe the composite of these forms, since in speech it is difficult to distinguish 'homocyst(e)ine' from 'homocysteine.' They suggested that an alternative useful in communicating orally is to substitute 'total Hcy' for homocyst(e)ine, spelling out the 'Hcy.' The term 'homocyst(e)ine' with parentheses around the 'e' in the middle of the word is used to define the combined pool of homocysteine, homocystine, mixed disulfides involving homocysteine, and homocysteine thiolactone found in the plasma of patients with hyperhomocyst(e)inemia. </p>
</span>
<div>
<br />
</div>
<div>
<h4>
<span class="mim-font">
<strong>History</strong>
</span>
</h4>
</div>
<span class="mim-text-font">
<p>Nugent et al. (1998) gave follow-up information on 'the first case' of homocystinuria. This was a patient who was identified during a survey of a group of mentally retarded children in Northern Ireland in 1960 by Carson and Neill (1962). He was followed at the Royal Belfast Hospital for Sick Children until age 39 years when he was transferred to the Adult Metabolic Clinic at the Royal Victoria Hospital, Belfast. Despite early difficulties and the late start in treatment to lower his serum homocysteine, the patient had remained in reasonable health. He was initially reported at age 7 years as an unusual case of Marfan syndrome with renal abnormalities, case 4 of Loughridge (1959). He had recovered from acute glomerulonephritis at the age of 6 years and was found to be hypertensive the next year. He was mentally slow and thin, with fair hair, pale skin, and flushed cheeks. He had arachnodactyly, dolichostenomelia, pes cavus, high-arched palate, and bilateral dislocated lenses. At age 10 years, during a survey of urinary amino acid chromatography of mentally retarded people in Northern Ireland, his urine was found to contain a large quantity of homocysteine accompanied by a positive nitroprusside cyanide test (Carson and Neill, 1962). His left eye was enucleated because of staphylococcal infection after acute pupillary-block glaucoma; his right lens dislocated into the anterior chamber and had to be removed. His hypertension disappeared after removal of his left kidney at the age of 13 years; thick-walled medial hypertrophic intrarenal arteries and pads of intimal fibrous tissue were found histologically. When supplementation with pyridoxine was initiated at the age of 18 years, his plasma homocysteine fell to low normal values. Daily folic acid supplementation was added 1 year later since his plasma folate concentration was low. At age 20 years he had a perforated duodenal ulcer. Chest pain occurred at age 27 years and recurred at age 34 years; it was considered to be angina and was successfully treated. At age 50 years, his plasma homocysteine remained low. He developed acute gout which responded to indomethacin. </p>
</span>
<div>
<br />
</div>
<div>
<h4>
<span class="mim-font">
<strong>Animal Model</strong>
</span>
</h4>
</div>
<span class="mim-text-font">
<p>Watanabe et al. (1995) generated mice that were moderately and severely homocysteinemic, using homologous recombination in mouse embryonic stem cells to inactivate the Cbs gene. Homozygous mutants completely lacking cystathionine beta-synthase were born at the expected frequency from matings of heterozygotes, but they suffered from severe growth retardation and most of them died within 5 weeks after birth. Histologic examination showed that the hepatocytes of homozygotes were enlarged, multinucleated, and filled with microvesicular lipid droplets (resembling the finding in some severe homocystinuric patients). Plasma homocysteine levels of the homozygotes were approximately 40 times normal. Heterozygous mutants had approximately 50% reduction in CBS mRNA and enzyme activity in the liver and had twice normal plasma homocysteine levels. Watanabe et al. (1995) concluded that homozygotes are a useful model for the clinical disorder homocystinuria and the heterozygotes should be useful for studying the role of elevated levels of homocysteine in the causation of cardiovascular disease. They noted that most of the homozygous mutant mice had eyes with delayed and narrow eye openings but without obvious histologic abnormalities. Seemingly, the homozygotes did not survive long enough to develop osteoporosis and vascular occlusions. </p><p>Wang et al. (2005) engineered mice that expressed the common human mutant I278T and I278T/T424N Cbs proteins. These transgene-containing mice were then bred to Cbs +/- mice to generate Cbs -/- mice that expressed only the I278T or I278T/T424N human transgenes. Both the I278T and the I278T/T424N transgenes were able to entirely rescue the neonatal mortality phenotype of Cbs -/- mice (see Watanabe et al., 1995) despite these mice having a mean homocysteine level of 250 micromoles. The transgenic Cbs -/- animals exhibited facial alopecia, had moderate liver steatosis, and were slightly smaller than heterozygous littermates. In contrast to human CBS deficiency, these mice did not exhibit hypermethioninemia. The mutant proteins were stable in several tissues, although liver extracts had only 2 to 3% of the Cbs enzyme activity found in wildtype mice. The I278T/T424N enzyme had exactly the same activity as the I278T enzyme, indicating that T424N was unable to suppress I278T in mice. Wang et al. (2005) concluded that elevated homocysteine levels per se were not responsible for the neonatal lethality observed in Cbs -/- animals and suggested that CBS protein may have other functions in addition to its role in homocysteine catabolism. </p>
</span>
<div>
<br />
</div>
</div>
<div>
<h4>
<span class="mim-font">
<strong>See Also:</strong>
</span>
</h4>
<span class="mim-text-font">
Almgren et al. (1978); Barber and Spaeth (1967); Carson and Carre
(1969); Carson et al. (1963); Field et al. (1962); Frimpter (1969);
Goldstein et al. (1973); Hooft et al. (1967); Kaeser et al. (1969);
Kim and Rosenberg (1974); Komrower (1967); Kurczynski et al. (1980);
McCully and Ragsdale (1970); Mudd (1985); Mudd et al. (1970); Mudd et
al. (1964); Mudd et al. (1969); Munnich et al. (1983); Perry et al.
(1968); Shelley et al. (1972); Shih and Efron (1970); Shipman et al.
(1969); Skovby (1985); Uhlemann et al. (1976); Wong et al. (1968)
</span>
<div>
<br />
</div>
</div>
<div>
<h4>
<span class="mim-font">
<strong>REFERENCES</strong>
</span>
</h4>
<div>
<p />
</div>
<div>
<ol>
<li>
<p class="mim-text-font">
Abbott, M. H., Folstein, S. E., Abbey, H., Pyeritz, R. E.
<strong>Psychiatric manifestations of homocystinuria due to cystathionine beta-synthase deficiency: prevalence, natural history, and relationship to neurologic impairment and vitamin B(6)-responsiveness.</strong>
Am. J. Med. Genet. 26: 959-969, 1987.
[PubMed: 3591841]
[Full Text: https://doi.org/10.1002/ajmg.1320260427]
</p>
</li>
<li>
<p class="mim-text-font">
Almgren, B., Eriksson, H., Hemmingsson, A., Hillerdal, G., Larsson, E., Aberg, H.
<strong>Abdominal aortic aneurysm in homocystinuria.</strong>
Acta Chir. Scand. 144: 545-546, 1978.
[PubMed: 747076]
</p>
</li>
<li>
<p class="mim-text-font">
Barber, G. W., Spaeth, G. L.
<strong>Pyridoxine therapy in homocystinuria. (Letter)</strong>
Lancet 289: 337 only, 1967. Note: Originally Volume I.
</p>
</li>
<li>
<p class="mim-text-font">
Bass, H. N., LaGrave, D., Mardach, R., Cederbaum, S. D., Fuster, C. D., Chetty, M.
<strong>Spontaneous pneumothorax in association with pyridoxine-responsive homocystinuria.</strong>
J. Inherit. Metab. Dis. 20: 831-832, 1997.
[PubMed: 9427154]
[Full Text: https://doi.org/10.1023/a:1005384121649]
</p>
</li>
<li>
<p class="mim-text-font">
Boers, G. H. J., Fowler, B., Smals, A. G. H., Trijbels, F. J. M., Leermakers, A. I., Kleijer, W. J., Kloppenborg, P. W. C.
<strong>Improved identification of heterozygotes for homocystinuria due to cystathionine synthase deficiency by the combination of methionine loading and enzyme determination in cultured fibroblasts.</strong>
Hum. Genet. 69: 164-169, 1985.
[PubMed: 3972418]
[Full Text: https://doi.org/10.1007/BF00293290]
</p>
</li>
<li>
<p class="mim-text-font">
Boers, G. H. J., Smals, A. G. H., Trijbels, F. J. M., Fowler, B., Bakkeren, J. A. J. M., Schoonderwaldt, H. C., Kleijer, W. J., Kloppenborg, P. W. C.
<strong>Heterozygosity for homocystinuria in premature peripheral and cerebral occlusive arterial disease.</strong>
New Eng. J. Med. 313: 709-715, 1985.
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Contributors:
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Cassandra L. Kniffin - updated : 10/11/2010<br>Cassandra L. Kniffin - reorganized : 5/4/2010<br>Cassandra L. Kniffin - updated : 4/28/2010<br>Cassandra L. Kniffin - updated : 9/3/2009<br>George E. Tiller - updated : 11/20/2008<br>Cassandra L. Kniffin - updated : 5/24/2006<br>Cassandra L. Kniffin - updated : 2/17/2006<br>Victor A. McKusick - updated : 2/10/2004<br>Victor A. McKusick - updated : 1/12/2004<br>Ada Hamosh - updated : 10/8/2003<br>Ada Hamosh - updated : 10/6/2003<br>Victor A. McKusick - updated : 8/20/2002<br>Victor A. McKusick - updated : 6/14/2002<br>Victor A. McKusick - updated : 2/8/2002<br>Ada Hamosh - updated : 1/16/2002<br>Victor A. McKusick - updated : 1/10/2002<br>Victor A. McKusick - updated : 9/7/2001<br>Victor A. McKusick - updated : 6/27/2001<br>Carol A. Bocchini - updated : 6/27/2001<br>George E. Tiller - updated : 5/29/2001<br>Victor A. McKusick - updated : 5/15/2001<br>Paul J. Converse - updated : 6/8/2000<br>Victor A. McKusick - updated : 12/21/1999<br>Victor A. McKusick - updated : 6/30/1999<br>Victor A. McKusick - updated : 6/18/1999<br>Victor A. McKusick - updated : 6/7/1999<br>Victor A. McKusick - updated : 5/14/1999<br>Ada Hamosh - updated : 4/21/1999<br>Victor A. McKusick - updated : 2/25/1999<br>Victor A. McKusick - updated : 2/3/1999<br>Victor A. McKusick - updated : 12/2/1998<br>Ada Hamosh - updated : 10/26/1998<br>Victor A. McKusick - updated : 9/17/1998<br>John F. Jackson - reorganized : 9/2/1998<br>Victor A. McKusick - updated : 4/28/1998<br>Victor A. McKusick - updated : 4/15/1998<br>Victor A. McKusick - updated : 2/25/1998<br>Victor A. McKusick - updated : 2/17/1998<br>Victor A. McKusick - updated : 2/12/1998<br>Victor A. McKusick - updated : 1/29/1998<br>Victor A. McKusick - updated : 12/19/1997<br>Victor A. McKusick - updated : 6/5/1997<br>Victor A. McKusick - updated : 4/24/1997<br>Victor A. McKusick - updated : 4/4/1997<br>Victor A. McKusick - updated : 2/28/1997<br>Moyra Smith - updated : 5/21/1996
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Creation Date:
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Victor A. McKusick : 6/3/1986
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Edit History:
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carol : 08/03/2016<br>carol : 08/02/2016<br>carol : 07/08/2016<br>carol : 11/29/2012<br>wwang : 10/29/2010<br>wwang : 10/29/2010<br>terry : 10/13/2010<br>ckniffin : 10/11/2010<br>terry : 9/9/2010<br>terry : 5/12/2010<br>carol : 5/5/2010<br>carol : 5/4/2010<br>ckniffin : 5/3/2010<br>terry : 4/30/2010<br>ckniffin : 4/28/2010<br>wwang : 9/15/2009<br>ckniffin : 9/3/2009<br>terry : 6/3/2009<br>terry : 4/9/2009<br>wwang : 4/1/2009<br>terry : 2/26/2009<br>wwang : 11/20/2008<br>carol : 10/8/2008<br>ckniffin : 5/15/2007<br>terry : 11/15/2006<br>wwang : 5/31/2006<br>ckniffin : 5/24/2006<br>wwang : 3/14/2006<br>ckniffin : 2/17/2006<br>carol : 3/17/2004<br>tkritzer : 2/17/2004<br>terry : 2/10/2004<br>cwells : 1/14/2004<br>terry : 1/12/2004<br>cwells : 10/8/2003<br>cwells : 10/6/2003<br>tkritzer : 8/26/2002<br>tkritzer : 8/23/2002<br>terry : 8/20/2002<br>ckniffin : 7/9/2002<br>cwells : 6/19/2002<br>terry : 6/14/2002<br>ckniffin : 5/15/2002<br>terry : 3/5/2002<br>alopez : 2/18/2002<br>terry : 2/8/2002<br>alopez : 1/18/2002<br>terry : 1/16/2002<br>carol : 1/10/2002<br>terry : 1/10/2002<br>mcapotos : 12/27/2001<br>cwells : 10/31/2001<br>carol : 10/1/2001<br>carol : 9/10/2001<br>alopez : 9/7/2001<br>mcapotos : 6/27/2001<br>mcapotos : 6/27/2001<br>cwells : 6/22/2001<br>cwells : 6/4/2001<br>cwells : 5/29/2001<br>cwells : 5/25/2001<br>terry : 5/15/2001<br>alopez : 3/8/2001<br>joanna : 11/9/2000<br>carol : 6/8/2000<br>carol : 4/24/2000<br>mcapotos : 1/19/2000<br>mcapotos : 1/13/2000<br>terry : 12/21/1999<br>mgross : 7/16/1999<br>carol : 7/15/1999<br>jlewis : 7/14/1999<br>terry : 6/30/1999<br>jlewis : 6/30/1999<br>terry : 6/18/1999<br>mgross : 6/16/1999<br>terry : 6/7/1999<br>mgross : 6/3/1999<br>mgross : 5/28/1999<br>terry : 5/14/1999<br>alopez : 4/21/1999<br>carol : 3/9/1999<br>terry : 2/25/1999<br>carol : 2/12/1999<br>terry : 2/3/1999<br>dkim : 12/14/1998<br>carol : 12/8/1998<br>terry : 12/2/1998<br>carol : 10/26/1998<br>carol : 10/23/1998<br>dkim : 10/21/1998<br>carol : 10/21/1998<br>carol : 10/21/1998<br>carol : 9/24/1998<br>terry : 9/17/1998<br>carol : 9/3/1998<br>carol : 9/2/1998<br>alopez : 4/29/1998<br>terry : 4/28/1998<br>carol : 4/17/1998<br>terry : 4/15/1998<br>alopez : 3/16/1998<br>alopez : 3/16/1998<br>alopez : 3/16/1998<br>terry : 2/25/1998<br>terry : 2/12/1998<br>mark : 2/2/1998<br>terry : 1/29/1998<br>dholmes : 1/12/1998<br>mark : 1/2/1998<br>terry : 12/19/1997<br>mark : 6/14/1997<br>terry : 6/5/1997<br>terry : 4/24/1997<br>terry : 4/21/1997<br>jenny : 4/4/1997<br>terry : 3/31/1997<br>mark : 2/28/1997<br>terry : 2/26/1997<br>jamie : 1/15/1997<br>terry : 1/10/1997<br>terry : 1/7/1997<br>terry : 12/10/1996<br>terry : 11/13/1996<br>mark : 10/21/1996<br>terry : 7/9/1996<br>terry : 7/9/1996<br>mark : 5/21/1996<br>mark : 5/21/1996<br>terry : 5/21/1996<br>mark : 4/12/1996<br>terry : 4/5/1996<br>mark : 3/6/1996<br>terry : 3/4/1996<br>mark : 1/25/1996<br>terry : 1/23/1996<br>mark : 11/6/1995<br>terry : 4/19/1995<br>carol : 2/9/1995<br>davew : 8/19/1994<br>jason : 6/17/1994<br>mimadm : 4/18/1994
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