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Entry
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- #250940 - HOMOCYSTINURIA-MEGALOBLASTIC ANEMIA, cblG TYPE; HMAG
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- OMIM
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<span class="h4">#250940</span>
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<br />
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<strong>Table of Contents</strong>
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<a href="#title"><strong>Title</strong></a>
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<a href="#phenotypeMap"><strong>Phenotype-Gene Relationships</strong></a>
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<a href="/clinicalSynopsis/250940"><strong>Clinical Synopsis</strong></a>
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<a href="/phenotypicSeries/PS236270"> <strong>Phenotypic Series</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="#biochemicalFeatures">Biochemical Features</a>
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<a href="#clinicalManagement">Clinical Management</a>
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<a href="#inheritance">Inheritance</a>
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<a href="#molecularGenetics">Molecular Genetics</a>
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<a href="#history">History</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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<a href="#editHistory"><strong>Edit History</strong></a>
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<div><a href="https://clinicaltrials.gov/search?cond=HOMOCYSTINURIA-MEGALOBLASTIC ANEMIA, cblG TYPE" 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="#mimEuroGentestFold" id="mimEuroGentestToggle" data-toggle="collapse" class="mim-tip-hint mimTriangleToggle" title="A list of European laboratories that offer genetic testing."><span id="mimEuroGentestToggleTriangle" class="small" style="margin-left: -0.8em;">►</span>EuroGentest</div>
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<div id="mimEuroGentestFold" class="collapse">
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<div style="margin-left: 0.5em;"><a href="https://www.orpha.net/consor/cgi-bin/ClinicalLabs_Search_Simple.php?lng=EN&LnkId=3351&Typ=Pat" title="Methylcobalamin deficiency type cblG" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'EuroGentest', 'domain': 'orpha.net'})">Methylcobalamin deficiency… </a></div><div style="margin-left: 0.5em;"><a href="https://www.orpha.net/consor/cgi-bin/ClinicalLabs_Search_Simple.php?lng=EN&LnkId=3369&Typ=Pat" title="Homocystinuria without methylmalonic aciduria" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'EuroGentest', 'domain': 'orpha.net'})">Homocystinuria without met… </a></div>
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</div>
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<div><a href="https://www.ncbi.nlm.nih.gov/books/NBK1328/" class="mim-tip-hint" title="Expert-authored, peer-reviewed descriptions of inherited disorders including the uses of genetic testing in diagnosis, management, and genetic counseling." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Gene Reviews', 'domain': 'ncbi.nlm.nih.gov'})">Gene Reviews</a></div>
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<div><a href="https://www.diseaseinfosearch.org/x/4711" 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>
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<div><a href="https://www.ncbi.nlm.nih.gov/gtr/all/tests/?term=250940[mim]" class="mim-tip-hint" title="Genetic Testing Registry." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'GTR', 'domain': 'ncbi.nlm.nih.gov'})">GTR</a></div>
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<div><a href="#mimOrphanetFold" id="mimOrphanetToggle" data-toggle="collapse" class="mim-tip-hint mimTriangleToggle" title="European reference portal for information on rare diseases and orphan drugs."><span id="mimOrphanetToggleTriangle" class="small" style="margin-left: -0.8em;">►</span>Orphanet</div>
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<div id="mimOrphanetFold" class="collapse">
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<div style="margin-left: 0.5em;"><a href="https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=2170" title="Methylcobalamin deficiency type cblG" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'OrphaNet', 'domain': 'orpha.net'})">Methylcobalamin deficiency…</a></div><div style="margin-left: 0.5em;"><a href="https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=622" title="Homocystinuria without methylmalonic aciduria" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'OrphaNet', 'domain': 'orpha.net'})">Homocystinuria without met…</a></div>
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<a href="#mimCellLinesLinksFold" id="mimCellLinesLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-cell;">Cell Lines</div>
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<div><a href="https://catalog.coriell.org/Search?q=OmimNum:250940" 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>
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<span class="mim-tip-bottom" qtip_title="<strong>Looking for this gene or this phenotype in other resources?</strong>" qtip_text="Select a related resource from the dropdown menu and click for a targeted link to information directly relevant.">
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<a href="#" class="mim-tip-icd" qtip_title="<strong>ICD+</strong>" qtip_text="
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<strong>ORPHA:</strong> 2170, 622<br />
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<strong>DO:</strong> 0112256<br />
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">ICD+</a>
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<span class="h3">
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<span class="mim-font mim-tip-hint" title="Phenotype description, molecular basis known">
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<span class="text-danger"><strong>#</strong></span>
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250940
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<a id="preferredTitle" class="mim-anchor"></a>
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<h3>
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<span class="mim-font">
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HOMOCYSTINURIA-MEGALOBLASTIC ANEMIA, cblG TYPE; HMAG
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</h3>
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</div>
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<div>
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<br />
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<a id="alternativeTitles" class="mim-anchor"></a>
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<span class="mim-font">
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<em>Alternative titles; symbols</em>
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<div>
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<h4>
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<span class="mim-font">
|
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HOMOCYSTINURIA-MEGALOBLASTIC ANEMIA DUE TO DEFECT IN COBALAMIN METABOLISM, cblG COMPLEMENTATION TYPE<br />
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METHYLCOBALAMIN DEFICIENCY, cblG TYPE<br />
|
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METHIONINE SYNTHASE DEFICIENCY
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</span>
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</h4>
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</div>
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<div>
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<br />
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<a id="phenotypeMap" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<strong>Phenotype-Gene Relationships</strong>
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</span>
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</h4>
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<div>
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<table class="table table-bordered table-condensed table-hover small mim-table-padding">
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<th>
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Location
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</th>
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<th>
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Phenotype
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</th>
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<th>
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Phenotype <br /> MIM number
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</th>
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<th>
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Inheritance
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</th>
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<th>
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Phenotype <br /> mapping key
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</th>
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<th>
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Gene/Locus
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</th>
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<th>
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Gene/Locus <br /> MIM number
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<span class="mim-font">
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<a href="/geneMap/1/1829?start=-3&limit=10&highlight=1829">
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1q43
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</a>
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</span>
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</td>
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<span class="mim-font">
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Homocystinuria-megaloblastic anemia, cblG complementation type
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</span>
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</td>
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<span class="mim-font">
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<a href="/entry/250940"> 250940 </a>
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</span>
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</td>
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<td>
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<span class="mim-font">
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<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
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</td>
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<td>
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<span class="mim-font">
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<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
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</span>
|
|
</td>
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<td>
|
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<span class="mim-font">
|
|
MTR
|
|
</span>
|
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</td>
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<td>
|
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<span class="mim-font">
|
|
<a href="/entry/156570"> 156570 </a>
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</span>
|
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</td>
|
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</tr>
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</tbody>
|
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</table>
|
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</div>
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</div>
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<div>
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|
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<div class="btn-group ">
|
|
<a href="/clinicalSynopsis/250940" 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>
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|
|
<div class="btn-group">
|
|
|
|
<a href="/phenotypicSeries/PS236270" class="btn btn-info" role="button"> Phenotypic Series </a>
|
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|
|
<button type="button" id="mimPhenotypicSeriesToggle" class="btn btn-info dropdown-toggle mimSingletonFoldToggle" data-toggle="collapse" href="#mimPhenotypicSeriesFold" onclick="ga('send', 'event', 'Unfurl', 'PhenotypicSeries', 'omim.org')">
|
|
<span class="caret"></span>
|
|
<span class="sr-only">Toggle Dropdown</span>
|
|
</button>
|
|
</div>
|
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<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/250940" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Linear'})"> Linear </a></li>
|
|
<li><a href="/graph/radial/250940" 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>
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|
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<div>
|
|
<p />
|
|
</div>
|
|
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|
|
<div id="mimClinicalSynopsisFold" class="well well-sm collapse mimSingletonToggleFold">
|
|
<div class="small" style="margin: 5px">
|
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|
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|
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<div>
|
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<div>
|
|
<span class="h5 mim-font">
|
|
<strong> INHERITANCE </strong>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
|
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<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;">
|
|
|
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|
|
|
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|
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<div>
|
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<div>
|
|
<span class="h5 mim-font">
|
|
<em> Other </em>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
<span class="mim-font">
|
|
|
|
- Failure to thrive <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/432788009" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">432788009</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/54840006" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">54840006</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/783.41" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">783.41</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0015544&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0015544</a>, <a href="https://bioportal.bioontology.org/search?q=C2315100&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C2315100</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001508" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001508</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001508" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001508</a>]</span><br />
|
|
|
|
</span>
|
|
</div>
|
|
</div>
|
|
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<strong> 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">
|
|
|
|
- Nystagmus (in some patients) <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/563001" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">563001</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/H55.0" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">H55.0</a>, <a href="https://purl.bioontology.org/ontology/ICD10CM/H55.00" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">H55.00</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/379.50" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">379.50</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0028738&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0028738</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000639" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000639</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000639" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000639</a>]</span><br /> -
|
|
Blindness (in some patients) <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0456909&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0456909</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000618" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000618</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000618" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000618</a>]</span><br />
|
|
|
|
</span>
|
|
</div>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
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|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<strong> MUSCLE, SOFT TISSUES </strong>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
|
|
<div>
|
|
<span class="mim-font">
|
|
|
|
- Hypotonia <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/398151007" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">398151007</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/398152000" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">398152000</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0026827&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0026827</a>, <a href="https://bioportal.bioontology.org/search?q=C1858120&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1858120</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001290" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001290</a>, <a href="https://hpo.jax.org/app/browse/term/HP:0001252" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001252</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001252" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001252</a>]</span><br />
|
|
|
|
</span>
|
|
</div>
|
|
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<strong> NEUROLOGIC </strong>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
|
|
|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<em> Central Nervous System </em>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
<span class="mim-font">
|
|
|
|
- Delayed psychomotor development <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/224958001" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">224958001</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/F88" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">F88</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0557874&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0557874</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001263" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001263</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001263" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001263</a>]</span><br /> -
|
|
Hypotonia <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/398151007" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">398151007</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/398152000" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">398152000</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0026827&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0026827</a>, <a href="https://bioportal.bioontology.org/search?q=C1858120&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1858120</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001290" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001290</a>, <a href="https://hpo.jax.org/app/browse/term/HP:0001252" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001252</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001252" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001252</a>]</span><br /> -
|
|
Abnormal gait <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/22325002" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">22325002</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/781.2" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">781.2</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0575081&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0575081</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001288" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001288</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001288" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001288</a>]</span><br /> -
|
|
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 /> -
|
|
Cerebral atrophy <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/278849000" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">278849000</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0235946&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0235946</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002059" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002059</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002059" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002059</a>]</span><br />
|
|
|
|
</span>
|
|
</div>
|
|
</div>
|
|
|
|
|
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|
|
</div>
|
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|
|
</div>
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|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<strong> HEMATOLOGY </strong>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
|
|
<div>
|
|
<span class="mim-font">
|
|
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- Megaloblastic anemia <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/53165003" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">53165003</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/D53.1" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">D53.1</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0002888&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0002888</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001889" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001889</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001889" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001889</a>]</span><br />
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<div>
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<span class="h5 mim-font">
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<strong> LABORATORY ABNORMALITIES </strong>
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<div style="margin-left: 2em;">
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<span class="mim-font">
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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 /> -
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Hyperhomocystinemia <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C3806347&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C3806347</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002160" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002160</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002160" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002160</a>]</span><br /> -
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Hypomethioninemia <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1848555&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1848555</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003658" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003658</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003658" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003658</a>]</span><br />
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<span class="h5 mim-font">
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<strong> MISCELLANEOUS </strong>
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</span>
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<div style="margin-left: 2em;">
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<div>
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<span class="mim-font">
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- Onset in infancy <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1848924&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1848924</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003593" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003593</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003593" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003593</a>]</span><br /> -
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Later onset has been reported<br /> -
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Symptoms are responsive to cobalamin treatment<br />
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</span>
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<div>
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<span class="h5 mim-font">
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<strong> MOLECULAR BASIS </strong>
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</span>
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<div style="margin-left: 2em;">
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<span class="mim-font">
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- Caused by mutation in the methionine synthase gene (MTR, <a href="/entry/156570#0001">156570.0001</a>)<br />
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</span>
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<div class="text-right">
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<a href="#mimClinicalSynopsisFold" data-toggle="collapse">▲ Close</a>
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</div>
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<div id="mimPhenotypicSeriesFold" class="well well-sm collapse mimSingletonToggleFold">
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<div class="small">
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<div class="row">
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<div class="col-lg-12 col-md-12 col-sm-12 col-xs-12">
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<h5>
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Homocystinuria-megaloblastic anemia
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- <a href="/phenotypicSeries/PS236270">PS236270</a>
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- 3 Entries
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</h5>
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</div>
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</div>
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<div class="row" style="margin-left: 0.125em; margin-right: 0.125em;">
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<table class="table table-bordered table-condensed table-hover mim-table-padding">
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<thead>
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<tr>
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<th class="col-lg-1 col-md-1 col-sm-1 col-xs-1 text-nowrap">
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<strong>Location</strong>
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</th>
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<th class="col-lg-5 col-md-5 col-sm-5 col-xs-6 text-nowrap">
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<strong>Phenotype</strong>
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</th>
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<th class="col-lg-1 col-md-1 col-sm-1 col-xs-1 text-nowrap">
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<strong>Inheritance</strong>
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</th>
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<th class="col-lg-1 col-md-1 col-sm-1 col-xs-1 text-nowrap">
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<strong>Phenotype<br />mapping key</strong>
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</th>
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<th class="col-lg-1 col-md-1 col-sm-1 col-xs-1 text-nowrap">
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<strong>Phenotype<br />MIM number</strong>
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</th>
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<th class="col-lg-1 col-md-1 col-sm-1 col-xs-1 text-nowrap">
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<strong>Gene/Locus</strong>
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</th>
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<th class="col-lg-1 col-md-1 col-sm-1 col-xs-1 text-nowrap">
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<strong>Gene/Locus<br />MIM number</strong>
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</th>
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</tr>
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</thead>
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<tbody>
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<tr>
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<td>
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<span class="mim-font">
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<a href="/geneMap/1/1829?start=-3&limit=10&highlight=1829"> 1q43 </a>
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</span>
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</td>
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<td>
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<span class="mim-font">
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<a href="/entry/250940"> Homocystinuria-megaloblastic anemia, cblG complementation type </a>
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</span>
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</td>
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<td>
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<span class="mim-font">
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<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
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</span>
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</td>
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<td>
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<span class="mim-font">
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<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
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</span>
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</td>
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<td>
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<span class="mim-font">
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<a href="/entry/250940"> 250940 </a>
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</span>
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</td>
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<td>
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<span class="mim-font">
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<a href="/entry/156570"> MTR </a>
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</span>
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</td>
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<td>
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<span class="mim-font">
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<a href="/entry/156570"> 156570 </a>
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</span>
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</td>
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</tr>
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<tr>
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<td>
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<span class="mim-font">
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<a href="/geneMap/2/683?start=-3&limit=10&highlight=683"> 2q23.2 </a>
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</span>
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</td>
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<td>
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<span class="mim-font">
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<a href="/entry/620952"> Homocystinuria-megaloblastic anemia, cblD type </a>
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</span>
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</td>
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<td>
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<span class="mim-font">
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<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
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</span>
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</td>
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<td>
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<span class="mim-font">
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<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
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</span>
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</td>
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<td>
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<span class="mim-font">
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<a href="/entry/620952"> 620952 </a>
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</span>
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</td>
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<td>
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<span class="mim-font">
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<a href="/entry/611935"> MMADHC </a>
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</span>
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</td>
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<td>
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<span class="mim-font">
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<a href="/entry/611935"> 611935 </a>
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</span>
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</td>
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</tr>
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<tr>
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<td>
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<span class="mim-font">
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<a href="/geneMap/5/43?start=-3&limit=10&highlight=43"> 5p15.31 </a>
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</span>
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</td>
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<td>
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<span class="mim-font">
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<a href="/entry/236270"> Homocystinuria-megaloblastic anemia, cbl E type </a>
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</span>
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</td>
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<td>
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<span class="mim-font">
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<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
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</span>
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</td>
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<td>
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<span class="mim-font">
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<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
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</span>
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</td>
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<td>
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<span class="mim-font">
|
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<a href="/entry/236270"> 236270 </a>
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</span>
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</td>
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<td>
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<span class="mim-font">
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<a href="/entry/602568"> MTRR </a>
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</span>
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</td>
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<td>
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<span class="mim-font">
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<a href="/entry/602568"> 602568 </a>
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</span>
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</td>
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</tr>
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</tbody>
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</table>
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<div class="text-right small">
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<a href="#mimPhenotypicSeriesFold" data-toggle="collapse">▲ Close</a>
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</div>
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</div>
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</div>
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</div>
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<div>
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<br />
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</div>
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<div>
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<a id="text" class="mim-anchor"></a>
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<h4 href="#mimTextFold" id="mimTextToggle" class="mimTriangleToggle" style="cursor: pointer;" data-toggle="collapse">
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<span id="mimTextToggleTriangle" class="small mimTextToggleTriangle">▼</span>
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<span class="mim-font">
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<span class="mim-tip-floating" qtip_title="<strong>Looking For More References?</strong>" qtip_text="Click the 'reference plus' icon <span class='glyphicon glyphicon-plus-sign'></span> at the end of each OMIM text paragraph to see more references related to the content of the preceding paragraph.">
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<strong>TEXT</strong>
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</span>
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</span>
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</h4>
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<div id="mimTextFold" class="collapse in ">
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<span class="mim-text-font">
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<p>A number sign (#) is used with this entry because homocystinuria-megaloblastic anemia cblG type is caused by homozygous or compound heterozygous mutation in the MTR gene (<a href="/entry/156570">156570</a>) on chromosome 1q43.</p>
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</span>
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<br />
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</div>
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<div>
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<a id="description" class="mim-anchor"></a>
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<h4 href="#mimDescriptionFold" id="mimDescriptionToggle" class="mimTriangleToggle" style="cursor: pointer;" data-toggle="collapse">
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<span id="mimDescriptionToggleTriangle" class="small mimTextToggleTriangle">▼</span>
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<span class="mim-font">
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<strong>Description</strong>
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</span>
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</h4>
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<div id="mimDescriptionFold" class="collapse in ">
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<span class="mim-text-font">
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<p>Homocystinuria and megaloblastic anemia is an autosomal recessive inborn error of metabolism resulting from defects in the cobalamin (vitamin B12)-dependent pathway that converts homocysteine to methionine, which is catalyzed by methionine synthase. Clinical features are somewhat variable, but include delayed psychomotor development, megaloblastic anemia, homocystinuria, and hypomethioninemia, all of which respond to cobalamin supplementation. Methylmalonic aciduria is not present. Two complementation groups have been described based on fibroblast studies: CblE (<a href="/entry/236270">236270</a>) and CblG (<a href="#13" class="mim-tip-reference" title="Watkins, D., Rosenblatt, D. S. <strong>Genetic heterogeneity among patients with methylcobalamin deficiency: definition of two complementation groups, cblE and cblG.</strong> J. Clin. Invest. 81: 1690-1694, 1988.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3384945/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3384945</a>] [<a href="https://doi.org/10.1172/JCI113507" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3384945">Watkins and Rosenblatt, 1988</a>). Most patients present in early infancy, but some patients with CblG have shown later onset (<a href="#9" class="mim-tip-reference" title="Outteryck, O., de Seze, J., Stojkovic, T., Cuisset, J.-M., Dobbelaere, D., Delalande, S., Lacour, A., Cabaret, M., Lepoutre, A.-C., Deramecourt, V., Zephir, H., Fowler, B., Vermersch, P. <strong>Methionine synthase deficiency: a rare cause of adult-onset leukoencephalopathy.</strong> Neurology 79: 386-388, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22786600/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22786600</a>] [<a href="https://doi.org/10.1212/WNL.0b013e318260451b" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22786600">Outteryck et al., 2012</a>). Cells from patients with CblE fail to incorporate methyltetrahydrofolate into methionine in whole cells, but cell extracts show normal methionine synthase activity in the presence of a reducing agent. Cells from patients with CblG have defects in the methionine synthase enzyme under both conditions (summary by <a href="#7" class="mim-tip-reference" title="Leclerc, D., Campeau, E., Goyette, P., Adjalla, C. E., Christensen, B., Ross, M., Eydoux, P., Rosenblatt, D. S., Rozen, R., Gravel, R. A. <strong>Human methionine synthase: cDNA cloning and identification of mutations in patients of the cblG complementation group of folate/cobalamin disorders.</strong> Hum. Molec. Genet. 5: 1867-1874, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8968737/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8968737</a>] [<a href="https://doi.org/10.1093/hmg/5.12.1867" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8968737">Leclerc et al., 1996</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=3384945+22786600+8968737" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>CblE is caused by mutation in the MTRR gene (<a href="/entry/602568">602568</a>).</p><p><a href="#14" class="mim-tip-reference" title="Watkins, D., Rosenblatt, D. S. <strong>Functional methionine synthase deficiency (cblE and cblG): clinical and biochemical heterogeneity.</strong> Am. J. Med. Genet. 34: 427-434, 1989.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2688421/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2688421</a>] [<a href="https://doi.org/10.1002/ajmg.1320340320" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2688421">Watkins and Rosenblatt (1989)</a> commented on the clinical and biochemical heterogeneity in patients with cblE and cblG. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2688421" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div>
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<br />
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<p><a href="#12" class="mim-tip-reference" title="Thomas, I. T., Rosenblatt, D. S., Erbe, R. W. <strong>Vitamin B-12-responsive homocystinuria and megaloblastic anemia (cbl E). (Abstract)</strong> Am. J. Hum. Genet. 37: A19 only, 1985."None>Thomas et al. (1985)</a> and <a href="#11" class="mim-tip-reference" title="Rosenblatt, D. S., Thomas, I. T., Watkins, D., Cooper, B. A., Erbe, R. W. <strong>Vitamin B-12 responsive homocystinuria and megaloblastic anemia: heterogeneity in methylcobalamin deficiency.</strong> Am. J. Med. Genet. 26: 377-383, 1987.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3812589/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3812589</a>] [<a href="https://doi.org/10.1002/ajmg.1320260216" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3812589">Rosenblatt et al. (1987)</a> reported a boy with methylcobalamin deficiency who presented at age 6 weeks with lethargy, staring spells and vomiting after varicella infection. He was hypotonic and unresponsive to stimuli and required intubation and ventilation. Findings included homocystinuria, hypomethioninemia, megaloblastic anemia, and normal serum folate and B12 levels. No methylmalonic aciduria was detected. Skin fibroblasts could not grow when methionine was replaced by homocysteine in the medium. Clinical response to vitamin B12 (hydroxocobalamin) was dramatic, with disappearance of homocystine and rise in blood methionine. Although the patient was originally thought to have CblE, methionine synthetase activity was decreased in patient fibroblasts when the assay was performed under both optimal and suboptimal reducing conditions, consistent with CblG. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=3812589" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="#3" class="mim-tip-reference" title="Gulati, S., Baker, P., Li, Y. N., Fowler, B., Kruger, W., Brody, L. C., Banerjee, R. <strong>Defects in human methionine synthase in cblG patients.</strong> Hum. Molec. Genet. 5: 1859-1865, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8968736/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8968736</a>] [<a href="https://doi.org/10.1093/hmg/5.12.1859" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8968736">Gulati et al. (1996)</a> analyzed cell lines derived from 2 cblG patients: 1 patient had onset in the first 4 months of life of severe neurologic dysfunction and homocystinuria, but no megaloblastic anemia, whereas the other patient had mental retardation, macrocytic anemia, and homocystinuria. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8968736" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#7" class="mim-tip-reference" title="Leclerc, D., Campeau, E., Goyette, P., Adjalla, C. E., Christensen, B., Ross, M., Eydoux, P., Rosenblatt, D. S., Rozen, R., Gravel, R. A. <strong>Human methionine synthase: cDNA cloning and identification of mutations in patients of the cblG complementation group of folate/cobalamin disorders.</strong> Hum. Molec. Genet. 5: 1867-1874, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8968737/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8968737</a>] [<a href="https://doi.org/10.1093/hmg/5.12.1867" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8968737">Leclerc et al. (1996)</a> studied cell lines from 2 Caucasian boys with methylcobalamin deficiency. One presented at age 3 months with failure to thrive, severe eczema, megaloblastic anemia, methylmalonic aciduria, homocystinuria, and methylmalonic aciduria; the other presented at age 4 years with developmental delay, tremors, gait instability, megaloblastic anemia, and homocystinuria. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8968737" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="Kvittingen, E. A., Spangen, S., Lindemans, J., Fowler, B. <strong>Methionine synthase deficiency without megaloblastic anaemia.</strong> Europ. J. Pediat. 156: 925-930, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9453374/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9453374</a>] [<a href="https://doi.org/10.1007/s004310050744" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9453374">Kvittingen et al. (1997)</a> reported a child with methionine synthase deficiency who presented with neonatal homocystinuria, hypomethioninemia, and severe neurologic symptoms, including developmental delay and seizures. Over an 8-year period both off and on treatment, the patient did not develop megaloblastic anemia. The activity of methionine synthase in fibroblasts was severely deficient, and formation of methylcobalamin from labeled cyanocobalamin was very low. Complementation studies indicated a cblG defect. In addition, the patient was homozygous for the 677C-T mutation in the methylenetetrahydrofolate reductase (MTHFR) gene (<a href="/entry/607093#0003">607093.0003</a>). <a href="#5" class="mim-tip-reference" title="Kvittingen, E. A., Spangen, S., Lindemans, J., Fowler, B. <strong>Methionine synthase deficiency without megaloblastic anaemia.</strong> Europ. J. Pediat. 156: 925-930, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9453374/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9453374</a>] [<a href="https://doi.org/10.1007/s004310050744" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9453374">Kvittingen et al. (1997)</a> hypothesized that the MTHFR polymorphism protected the patient against anemia, and speculated that homozygosity for the MTHFR 677C-T mutation may cause the dissociation between hematologic and neurologic disease seen in some patients with vitamin B12 deficiency. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9453374" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="Wilson, A., Leclerc, D., Saberi, F., Campeau, E., Hwang, H. Y., Shane, B., Phillips, J. A., III, Rosenblatt, D. S., Gravel, R. A. <strong>Functionally null mutations in patients with the cblG-variant form of methionine synthase deficiency.</strong> Am. J. Hum. Genet. 63: 409-414, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9683607/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9683607</a>] [<a href="https://doi.org/10.1086/301976" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9683607">Wilson et al. (1998)</a> reported a brother and sister what they termed the 'cblG variant form' of methionine synthase deficiency, defined as no detectable methionine synthase activity and lack of binding of the cobalamin cofactor to the enzyme. The boy developed generalized seizures at 3 days of age, became progressively hypotonic, and developed respiratory failure at 10 weeks of age. An initial diagnosis of methylenetetrahydrofolate reductase (MTHFR) deficiency (<a href="/entry/236250">236250</a>) was made on the basis of elevated plasma and urine homocysteine but low plasma methionine without macrocytic anemia. With treatment based on that diagnosis, he was well enough to be weaned from the respirator by 14 weeks of age. At 2 years of age, he had severe psychomotor retardation and microcephaly. A definitive diagnosis of methionine synthase deficiency was made by means of complementation analysis of cultured fibroblasts, which placed him in the cblG complementation group. He was subsequently treated with vitamin B12, betaine, and aspirin, and, at age 8 years, methionine was added. He required femoral osteotomies and bilateral adductor- and heel-cord release for neuromuscular hip dislocations and contractures. At age 10 years, he had short stature, microcephaly, rotary nystagmus, thin fingers, and spasticity. He smiled but was not able to sit or speak. The younger sister was found to have elevated plasma homocysteine and low methionine at 6 days of age. She also was presumed to have MTHFR deficiency and was started on therapy for that, but medications were discontinued by her mother after a few days because the child appeared to be doing well. At 3 months of age, she had seizures and respiratory distress, and medication was restarted. By 18 months of age, she was microcephalic and severely developmentally delayed. The diagnosis of cblG was established at 2 years of age, and she was treated in the same manner as her brother. At 9 years, she had short stature, microcephaly, rotary nystagmus, and pes planus. She was able to walk, responded to simple commands, and could speak a few words. <a href="#17" class="mim-tip-reference" title="Wilson, A., Leclerc, D., Saberi, F., Campeau, E., Hwang, H. Y., Shane, B., Phillips, J. A., III, Rosenblatt, D. S., Gravel, R. A. <strong>Functionally null mutations in patients with the cblG-variant form of methionine synthase deficiency.</strong> Am. J. Hum. Genet. 63: 409-414, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9683607/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9683607</a>] [<a href="https://doi.org/10.1086/301976" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9683607">Wilson et al. (1998)</a> reported another boy with the so-called cblG variant. He presented with short stature, failure to thrive, progressive weakness, hypotonia, ocular nystagmus, jaundice, feeding difficulties, and diarrhea at 7 to 10 weeks of age (<a href="#16" class="mim-tip-reference" title="Wildin, R. S., Scott, C. R. <strong>Cbl-G: presentation, treatment, and prolonged followup in a patient with absence of methionine synthase. (Abstract)</strong> Am. J. Hum. Genet. 51: A357 only, 1992."None>Wildin and Scott, 1992</a>). He had severe megaloblastic anemia and neutropenia, homocysteinemia, hypomethioninemia, and formiminoglutamic aciduria without methylmalonic aciduria, which led to the diagnosis of a defect in methionine synthesis. Treatment resulted in improved metabolite levels, improvement of tone, and reduction of nystagmus, but poor growth, developmental delay, feeding difficulties requiring a gastrostomy, persistent anemia, and immunologic deficits were present at age 4 years. All 3 of these patients were found to have biallelic null mutations in the MTR gene (<a href="/entry/156570#0004">156570.0004</a>-<a href="/entry/156570#0007">156570.0007</a>), resulting in absence of the protein. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9683607" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#6" class="mim-tip-reference" title="Labrune, P., Zittoun, J., Duvaltier, I., Trioche, P., Marquet, J., Niaudet, P., Odievre, M. <strong>Haemolytic uraemic syndrome and pulmonary hypertension in a patient with methionine synthase deficiency.</strong> Europ. J. Pediat. 158: 734-739, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10485306/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10485306</a>] [<a href="https://doi.org/10.1007/s004310051190" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10485306">Labrune et al. (1999)</a> described a girl, born of first-cousin parents, who presented at the age of 18 months with megaloblastic anemia. One month later, she developed pulmonary hypertension and renal failure, leading after renal biopsy to the diagnosis of hemolytic uremic syndrome. Investigations showed reduced methionine synthase activity under standard reducing conditions, compatible with cblG complementation group. At age 13 years, this girl required hemodialysis after acute rejection of a renal transplant. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10485306" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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</em></strong></p><p>
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<a href="#2" class="mim-tip-reference" title="Carmel, R., Watkins, D., Goodman, S. I., Rosenblatt, D. S. <strong>Hereditary defect of cobalamin metabolism (cblG mutation) presenting as a neurologic disorder in adulthood.</strong> New Eng. J. Med. 318: 1738-1741, 1988.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2897628/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2897628</a>] [<a href="https://doi.org/10.1056/NEJM198806303182607" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2897628">Carmel et al. (1988)</a> described the cblG mutation in a 21-year-old white woman who had been misdiagnosed as having multiple sclerosis. Her manifestations closely resembled subacute combined degeneration. Mild macrocytic anemia was present. Throughout childhood she had been awkward and had poor coordination. Urinary homocystine excretion was elevated, plasma methionine was decreased, and urinary cystathionine excretion was normal. No methylmalonic acid was detected in the urine. This constellation of findings suggested either the cblE or cblG mutation. Complementation analysis showed complementation with fibroblasts from 2 patients with the cblE mutation, but not with cells from 2 patients with the cblG mutation, indicating that the patient's defect corresponded to the latter mutation. Methionine synthase activity in fibroblast extracts was subnormal. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2897628" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#9" class="mim-tip-reference" title="Outteryck, O., de Seze, J., Stojkovic, T., Cuisset, J.-M., Dobbelaere, D., Delalande, S., Lacour, A., Cabaret, M., Lepoutre, A.-C., Deramecourt, V., Zephir, H., Fowler, B., Vermersch, P. <strong>Methionine synthase deficiency: a rare cause of adult-onset leukoencephalopathy.</strong> Neurology 79: 386-388, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22786600/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22786600</a>] [<a href="https://doi.org/10.1212/WNL.0b013e318260451b" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22786600">Outteryck et al. (2012)</a> reported a young woman who presented at age 23 years with pain in the lower limbs. She had macrocytosis without anemia. Over the following 6 years, she developed progressive paraparesis and cognitive dysfunction. Brain and spinal cord MRI showed moderate cerebral atrophy with periventricular leukoencephalopathy and mild thinning of the cervical spinal cord; she also had optic neuropathy. Biochemical studies showed hyperhomocysteinemia, homocystinuria, hypomethioninemia, and absence of methylmalonic aciduria. Studies of cultured fibroblasts showed a defect in homocysteine remethylation, and complementation studies confirmed a cblG defect. Treatment with hydroxycobalamin and oral betaine resulted in rapid biochemical and slower clinical improvement. <a href="#9" class="mim-tip-reference" title="Outteryck, O., de Seze, J., Stojkovic, T., Cuisset, J.-M., Dobbelaere, D., Delalande, S., Lacour, A., Cabaret, M., Lepoutre, A.-C., Deramecourt, V., Zephir, H., Fowler, B., Vermersch, P. <strong>Methionine synthase deficiency: a rare cause of adult-onset leukoencephalopathy.</strong> Neurology 79: 386-388, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22786600/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22786600</a>] [<a href="https://doi.org/10.1212/WNL.0b013e318260451b" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22786600">Outteryck et al. (2012)</a> noted the unusual presentation of the disorder in this patient. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22786600" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>Patients with cblG have reduced methionine synthase activity even under standard assay conditions. <a href="#4" class="mim-tip-reference" title="Hall, C. A., Lindenbaum, R. H., Arenson, E., Begley, J. A., Chu, R. C. <strong>The nature of the defect in cobalamin G mutation.</strong> Clin. Invest. Med. 12: 262-269, 1989.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2535439/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2535439</a>]" pmid="2535439">Hall et al. (1989)</a> presented evidence suggesting a defect in S-adenosyl methionine binding in cblG cells. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2535439" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="#10" class="mim-tip-reference" title="Rosenblatt, D. S., Cooper, B. A. <strong>Inherited disorders of vitamin B12 utilization.</strong> BioEssays 12: 331-334, 1990.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2203337/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2203337</a>] [<a href="https://doi.org/10.1002/bies.950120705" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2203337">Rosenblatt and Cooper (1990)</a> commented that, whereas therapy with OH-Cbl has been effective in many cblE patients, a few of the cblG patients have been more difficult to treat and have required additional treatment with folates and betaine. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2203337" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>The transmission pattern of methionine synthase deficiency in the family reported by <a href="#17" class="mim-tip-reference" title="Wilson, A., Leclerc, D., Saberi, F., Campeau, E., Hwang, H. Y., Shane, B., Phillips, J. A., III, Rosenblatt, D. S., Gravel, R. A. <strong>Functionally null mutations in patients with the cblG-variant form of methionine synthase deficiency.</strong> Am. J. Hum. Genet. 63: 409-414, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9683607/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9683607</a>] [<a href="https://doi.org/10.1086/301976" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9683607">Wilson et al. (1998)</a> was consistent with autosomal recessive inheritance. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9683607" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#3" class="mim-tip-reference" title="Gulati, S., Baker, P., Li, Y. N., Fowler, B., Kruger, W., Brody, L. C., Banerjee, R. <strong>Defects in human methionine synthase in cblG patients.</strong> Hum. Molec. Genet. 5: 1859-1865, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8968736/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8968736</a>] [<a href="https://doi.org/10.1093/hmg/5.12.1859" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8968736">Gulati et al. (1996)</a> analyzed the molecular basis for methionine synthase deficiency in cell lines derived from 2 cblG patients. The 79/76 cell line had low levels of methionine synthase activity and a diminished level of methionine synthase mRNA. In the WG1892 cell line, they detected compound heterozygous mutations in the MTR gene (<a href="/entry/156570#0001">156570.0001</a> and <a href="/entry/156570#0002">156570.0002</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8968736" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#7" class="mim-tip-reference" title="Leclerc, D., Campeau, E., Goyette, P., Adjalla, C. E., Christensen, B., Ross, M., Eydoux, P., Rosenblatt, D. S., Rozen, R., Gravel, R. A. <strong>Human methionine synthase: cDNA cloning and identification of mutations in patients of the cblG complementation group of folate/cobalamin disorders.</strong> Hum. Molec. Genet. 5: 1867-1874, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8968737/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8968737</a>] [<a href="https://doi.org/10.1093/hmg/5.12.1867" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8968737">Leclerc et al. (1996)</a> cloned the gene for methionine synthase and demonstrated mutations in this gene in 2 cblG cell lines which had deficient methionine synthase enzyme activity (see <a href="/entry/156570#0003">156570.0003</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8968737" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In 2 sibs with severe cblG, <a href="#17" class="mim-tip-reference" title="Wilson, A., Leclerc, D., Saberi, F., Campeau, E., Hwang, H. Y., Shane, B., Phillips, J. A., III, Rosenblatt, D. S., Gravel, R. A. <strong>Functionally null mutations in patients with the cblG-variant form of methionine synthase deficiency.</strong> Am. J. Hum. Genet. 63: 409-414, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9683607/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9683607</a>] [<a href="https://doi.org/10.1086/301976" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9683607">Wilson et al. (1998)</a> identified compound heterozygosity for 2 null mutations in the MTR gene (<a href="/entry/156570#0004">156570.0004</a> and <a href="/entry/156570#0005">156570.0005</a>). Another patient with a severe form of the disorder was compound heterozygous for 2 null mutations in the MTR gene (<a href="/entry/156570#0006">156570.0006</a> and <a href="/entry/156570#0007">156570.0007</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9683607" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 panel of 21 patients with methylcobalamin deficiency G (cblG) disorder, <a href="#15" class="mim-tip-reference" title="Watkins, D., Ru, M., Hwang, H.-Y., Kim, C. D., Murray, A., Philip, N. S., Kim, W., Legakis, H., Wai, T., Hilton, J. F., Ge, B., Dore, C., Hosack, A., Wilson, A., Gravel, R. A., Shane, B., Hudson, T. J., Rosenblatt, D. S. <strong>Hyperhomocysteinemia due to methionine synthase deficiency, cblG: structure of the MTR gene, genotype diversity, and recognition of a common mutation, P1173L.</strong> Am. J. Hum. Genet. 71: 143-153, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12068375/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12068375</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=12068375[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1086/341354" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12068375">Watkins et al. (2002)</a> identified 13 novel mutations. These included 5 deletions and 2 nonsense mutations that resulted in synthesis of truncated proteins that lacked portions critical for enzyme function. In addition, a previously described missense mutation, P1173L (<a href="/entry/156570#0001">156570.0001</a>), was detected in 16 patients in an expanded panel of 24 patients with cblG. Analysis of haplotypes constructed using sequence polymorphisms identified within the MTR gene demonstrated that this mutation, a C-to-T transition in a CpG island, has occurred on at least 2 separate genetic backgrounds. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12068375" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 possible case of deficiency of methionine synthase was reported by <a href="#1" class="mim-tip-reference" title="Arakawa, T., Narisawa, K., Tanno, K., Ohara, K., Higashi, O., Honda, Y., Tamura, T., Wada, Y., Mizuno, T., Hayashi, T., Hirooka, Y., Ohno, T., Ikeda, M. <strong>Megaloblastic anemia and mental retardation associated with hyperfolic-acidemia: probably due to N-5-methyltetrahydrofolate transferase deficiency.</strong> Tohoku J. Exp. Med. 93: 1-22, 1967.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/5300832/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">5300832</a>] [<a href="https://doi.org/10.1620/tjem.93.1" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="5300832">Arakawa et al. (1967)</a>, but the evidence was at best equivocal (<a href="#8" class="mim-tip-reference" title="Mudd, S. H. <strong>Cobalamin-responsive genetic disorders. In: Shimazono, N.; Arakawa, T. (eds.): Nutritional deficiency secondary to inborn errors of metabolism its relationship to physical and mental development.</strong> Ichikawa: Jap. Panel Maln. U.S.-Japan Coop. Med. Sci. Program 1977."None>Mudd, 1977</a>). The patient was a 6-month-old girl with mental retardation, megaloblastic anemia, and high folate activity in the serum and red cells. Assays of liver showed the specific activity of N-5-methyltetrahydrofolate-homocysteine methyltransferase, measured in the presence of cyanocobalamin, to be 32 to 45% of that in control liver. The patient was not homocystinuric. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=5300832" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>REFERENCES</strong>
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Arakawa, T., Narisawa, K., Tanno, K., Ohara, K., Higashi, O., Honda, Y., Tamura, T., Wada, Y., Mizuno, T., Hayashi, T., Hirooka, Y., Ohno, T., Ikeda, M.
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<strong>Megaloblastic anemia and mental retardation associated with hyperfolic-acidemia: probably due to N-5-methyltetrahydrofolate transferase deficiency.</strong>
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Tohoku J. Exp. Med. 93: 1-22, 1967.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/5300832/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">5300832</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=5300832" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1620/tjem.93.1" target="_blank">Full Text</a>]
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Carmel, R., Watkins, D., Goodman, S. I., Rosenblatt, D. S.
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<strong>Hereditary defect of cobalamin metabolism (cblG mutation) presenting as a neurologic disorder in adulthood.</strong>
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New Eng. J. Med. 318: 1738-1741, 1988.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2897628/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2897628</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2897628" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1056/NEJM198806303182607" target="_blank">Full Text</a>]
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<a id="Gulati1996" class="mim-anchor"></a>
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Gulati, S., Baker, P., Li, Y. N., Fowler, B., Kruger, W., Brody, L. C., Banerjee, R.
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<strong>Defects in human methionine synthase in cblG patients.</strong>
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Hum. Molec. Genet. 5: 1859-1865, 1996.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8968736/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8968736</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8968736" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1093/hmg/5.12.1859" target="_blank">Full Text</a>]
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<a id="Hall1989" class="mim-anchor"></a>
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Hall, C. A., Lindenbaum, R. H., Arenson, E., Begley, J. A., Chu, R. C.
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<strong>The nature of the defect in cobalamin G mutation.</strong>
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Clin. Invest. Med. 12: 262-269, 1989.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2535439/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2535439</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2535439" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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Kvittingen, E. A., Spangen, S., Lindemans, J., Fowler, B.
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<strong>Methionine synthase deficiency without megaloblastic anaemia.</strong>
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Europ. J. Pediat. 156: 925-930, 1997.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9453374/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9453374</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9453374" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1007/s004310050744" target="_blank">Full Text</a>]
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Labrune, P., Zittoun, J., Duvaltier, I., Trioche, P., Marquet, J., Niaudet, P., Odievre, M.
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<strong>Haemolytic uraemic syndrome and pulmonary hypertension in a patient with methionine synthase deficiency.</strong>
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Europ. J. Pediat. 158: 734-739, 1999.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10485306/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10485306</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10485306" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1007/s004310051190" target="_blank">Full Text</a>]
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Leclerc, D., Campeau, E., Goyette, P., Adjalla, C. E., Christensen, B., Ross, M., Eydoux, P., Rosenblatt, D. S., Rozen, R., Gravel, R. A.
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<strong>Human methionine synthase: cDNA cloning and identification of mutations in patients of the cblG complementation group of folate/cobalamin disorders.</strong>
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Hum. Molec. Genet. 5: 1867-1874, 1996.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8968737/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8968737</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8968737" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1093/hmg/5.12.1867" target="_blank">Full Text</a>]
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Mudd, S. H.
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<strong>Cobalamin-responsive genetic disorders. In: Shimazono, N.; Arakawa, T. (eds.): Nutritional deficiency secondary to inborn errors of metabolism its relationship to physical and mental development.</strong>
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Ichikawa: Jap. Panel Maln. U.S.-Japan Coop. Med. Sci. Program 1977.
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Outteryck, O., de Seze, J., Stojkovic, T., Cuisset, J.-M., Dobbelaere, D., Delalande, S., Lacour, A., Cabaret, M., Lepoutre, A.-C., Deramecourt, V., Zephir, H., Fowler, B., Vermersch, P.
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<strong>Methionine synthase deficiency: a rare cause of adult-onset leukoencephalopathy.</strong>
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Neurology 79: 386-388, 2012.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22786600/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22786600</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22786600" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1212/WNL.0b013e318260451b" target="_blank">Full Text</a>]
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Rosenblatt, D. S., Cooper, B. A.
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<strong>Inherited disorders of vitamin B12 utilization.</strong>
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BioEssays 12: 331-334, 1990.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2203337/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2203337</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2203337" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1002/bies.950120705" target="_blank">Full Text</a>]
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</p>
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<li>
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<a id="11" class="mim-anchor"></a>
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<a id="Rosenblatt1987" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Rosenblatt, D. S., Thomas, I. T., Watkins, D., Cooper, B. A., Erbe, R. W.
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<strong>Vitamin B-12 responsive homocystinuria and megaloblastic anemia: heterogeneity in methylcobalamin deficiency.</strong>
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Am. J. Med. Genet. 26: 377-383, 1987.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3812589/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3812589</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=3812589" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1002/ajmg.1320260216" target="_blank">Full Text</a>]
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</p>
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<li>
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<a id="12" class="mim-anchor"></a>
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<a id="Thomas1985" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Thomas, I. T., Rosenblatt, D. S., Erbe, R. W.
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<strong>Vitamin B-12-responsive homocystinuria and megaloblastic anemia (cbl E). (Abstract)</strong>
|
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Am. J. Hum. Genet. 37: A19 only, 1985.
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</p>
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</div>
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</li>
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<li>
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<a id="13" class="mim-anchor"></a>
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<a id="Watkins1988" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Watkins, D., Rosenblatt, D. S.
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<strong>Genetic heterogeneity among patients with methylcobalamin deficiency: definition of two complementation groups, cblE and cblG.</strong>
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J. Clin. Invest. 81: 1690-1694, 1988.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3384945/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3384945</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=3384945" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1172/JCI113507" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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<li>
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<a id="14" class="mim-anchor"></a>
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<a id="Watkins1989" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Watkins, D., Rosenblatt, D. S.
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<strong>Functional methionine synthase deficiency (cblE and cblG): clinical and biochemical heterogeneity.</strong>
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Am. J. Med. Genet. 34: 427-434, 1989.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2688421/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2688421</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2688421" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1002/ajmg.1320340320" target="_blank">Full Text</a>]
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</p>
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<li>
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<a id="15" class="mim-anchor"></a>
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<a id="Watkins2002" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Watkins, D., Ru, M., Hwang, H.-Y., Kim, C. D., Murray, A., Philip, N. S., Kim, W., Legakis, H., Wai, T., Hilton, J. F., Ge, B., Dore, C., Hosack, A., Wilson, A., Gravel, R. A., Shane, B., Hudson, T. J., Rosenblatt, D. S.
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<strong>Hyperhomocysteinemia due to methionine synthase deficiency, cblG: structure of the MTR gene, genotype diversity, and recognition of a common mutation, P1173L.</strong>
|
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Am. J. Hum. Genet. 71: 143-153, 2002.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12068375/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12068375</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=12068375[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=12068375" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1086/341354" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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<li>
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<a id="16" class="mim-anchor"></a>
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<a id="Wildin1992" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Wildin, R. S., Scott, C. R.
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<strong>Cbl-G: presentation, treatment, and prolonged followup in a patient with absence of methionine synthase. (Abstract)</strong>
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Am. J. Hum. Genet. 51: A357 only, 1992.
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</p>
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<a id="17" class="mim-anchor"></a>
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<a id="Wilson1998" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Wilson, A., Leclerc, D., Saberi, F., Campeau, E., Hwang, H. Y., Shane, B., Phillips, J. A., III, Rosenblatt, D. S., Gravel, R. A.
|
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<strong>Functionally null mutations in patients with the cblG-variant form of methionine synthase deficiency.</strong>
|
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Am. J. Hum. Genet. 63: 409-414, 1998.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9683607/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9683607</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9683607" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1086/301976" target="_blank">Full Text</a>]
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</ol>
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<br />
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<a id="contributors" class="mim-anchor"></a>
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<span class="mim-text-font">
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<a href="#mimCollapseContributors" role="button" data-toggle="collapse"> Contributors: </a>
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</div>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Cassandra L. Kniffin - reorganized : 7/12/2013
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<div class="row collapse" id="mimCollapseContributors">
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<div class="col-lg-offset-2 col-md-offset-4 col-sm-offset-4 col-xs-offset-2 col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Cassandra L. Kniffin - updated : 7/11/2013<br>Victor A. McKusick - updated : 7/22/2002<br>Armand Bottani - updated : 10/11/1999
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</span>
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<a id="creationDate" class="mim-anchor"></a>
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
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<span class="text-nowrap mim-text-font">
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Creation Date:
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</span>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Victor A. McKusick : 12/21/1988
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</span>
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<a id="editHistory" class="mim-anchor"></a>
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<a href="#mimCollapseEditHistory" role="button" data-toggle="collapse"> Edit History: </a>
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</span>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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carol : 09/25/2024
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<div class="row collapse" id="mimCollapseEditHistory">
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<div class="col-lg-offset-2 col-md-offset-2 col-sm-offset-4 col-xs-offset-4 col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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carol : 04/25/2017<br>carol : 07/12/2013<br>carol : 7/12/2013<br>ckniffin : 7/11/2013<br>carol : 5/3/2013<br>alopez : 10/29/2010<br>tkritzer : 7/29/2002<br>tkritzer : 7/29/2002<br>terry : 7/22/2002<br>carol : 10/11/1999<br>alopez : 7/25/1997<br>mark : 1/22/1997<br>terry : 1/22/1997<br>terry : 1/22/1997<br>mark : 1/22/1997<br>mimadm : 2/19/1994<br>carol : 1/6/1993<br>supermim : 3/17/1992<br>supermim : 3/20/1990<br>supermim : 1/12/1990<br>supermim : 1/3/1990
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</span>
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<h3>
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<span class="mim-font">
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<strong>#</strong> 250940
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</span>
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</h3>
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<div>
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<h3>
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<span class="mim-font">
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HOMOCYSTINURIA-MEGALOBLASTIC ANEMIA, cblG TYPE; HMAG
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</span>
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</h3>
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</div>
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<div>
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<br />
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<span class="mim-font">
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<em>Alternative titles; symbols</em>
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<h4>
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<span class="mim-font">
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HOMOCYSTINURIA-MEGALOBLASTIC ANEMIA DUE TO DEFECT IN COBALAMIN METABOLISM, cblG COMPLEMENTATION TYPE<br />
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METHYLCOBALAMIN DEFICIENCY, cblG TYPE<br />
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METHIONINE SYNTHASE DEFICIENCY
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</span>
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</h4>
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</div>
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<br />
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<p>
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<span class="mim-text-font">
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<strong>ORPHA:</strong> 2170, 622;
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<strong>DO:</strong> 0112256;
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</span>
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<h4>
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<span class="mim-font">
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<strong>Phenotype-Gene Relationships</strong>
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</span>
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</h4>
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<div>
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<table class="table table-bordered table-condensed small mim-table-padding">
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<thead>
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<tr class="active">
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<th>
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Location
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</th>
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<th>
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Phenotype
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</th>
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<th>
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Phenotype <br /> MIM number
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</th>
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<th>
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Inheritance
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</th>
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<th>
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Phenotype <br /> mapping key
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</th>
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<th>
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Gene/Locus
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<th>
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Gene/Locus <br /> MIM number
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<tbody>
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<tr>
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<td>
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<span class="mim-font">
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1q43
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</span>
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</td>
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<td>
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<span class="mim-font">
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Homocystinuria-megaloblastic anemia, cblG complementation type
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</span>
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</td>
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<td>
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<span class="mim-font">
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250940
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</span>
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</td>
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<td>
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<span class="mim-font">
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Autosomal recessive
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</span>
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</td>
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<td>
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<span class="mim-font">
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3
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</span>
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</td>
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<td>
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<span class="mim-font">
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MTR
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</span>
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</td>
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<td>
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<span class="mim-font">
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156570
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</tbody>
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</table>
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<span class="mim-font">
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<strong>TEXT</strong>
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<span class="mim-text-font">
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<p>A number sign (#) is used with this entry because homocystinuria-megaloblastic anemia cblG type is caused by homozygous or compound heterozygous mutation in the MTR gene (156570) on chromosome 1q43.</p>
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<div>
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<br />
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<h4>
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<span class="mim-font">
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<strong>Description</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Homocystinuria and megaloblastic anemia is an autosomal recessive inborn error of metabolism resulting from defects in the cobalamin (vitamin B12)-dependent pathway that converts homocysteine to methionine, which is catalyzed by methionine synthase. Clinical features are somewhat variable, but include delayed psychomotor development, megaloblastic anemia, homocystinuria, and hypomethioninemia, all of which respond to cobalamin supplementation. Methylmalonic aciduria is not present. Two complementation groups have been described based on fibroblast studies: CblE (236270) and CblG (Watkins and Rosenblatt, 1988). Most patients present in early infancy, but some patients with CblG have shown later onset (Outteryck et al., 2012). Cells from patients with CblE fail to incorporate methyltetrahydrofolate into methionine in whole cells, but cell extracts show normal methionine synthase activity in the presence of a reducing agent. Cells from patients with CblG have defects in the methionine synthase enzyme under both conditions (summary by Leclerc et al., 1996). </p><p>CblE is caused by mutation in the MTRR gene (602568).</p><p>Watkins and Rosenblatt (1989) commented on the clinical and biochemical heterogeneity in patients with cblE and cblG. </p>
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</span>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Clinical Features</strong>
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</span>
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<span class="mim-text-font">
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<p>Thomas et al. (1985) and Rosenblatt et al. (1987) reported a boy with methylcobalamin deficiency who presented at age 6 weeks with lethargy, staring spells and vomiting after varicella infection. He was hypotonic and unresponsive to stimuli and required intubation and ventilation. Findings included homocystinuria, hypomethioninemia, megaloblastic anemia, and normal serum folate and B12 levels. No methylmalonic aciduria was detected. Skin fibroblasts could not grow when methionine was replaced by homocysteine in the medium. Clinical response to vitamin B12 (hydroxocobalamin) was dramatic, with disappearance of homocystine and rise in blood methionine. Although the patient was originally thought to have CblE, methionine synthetase activity was decreased in patient fibroblasts when the assay was performed under both optimal and suboptimal reducing conditions, consistent with CblG. </p><p>Gulati et al. (1996) analyzed cell lines derived from 2 cblG patients: 1 patient had onset in the first 4 months of life of severe neurologic dysfunction and homocystinuria, but no megaloblastic anemia, whereas the other patient had mental retardation, macrocytic anemia, and homocystinuria. </p><p>Leclerc et al. (1996) studied cell lines from 2 Caucasian boys with methylcobalamin deficiency. One presented at age 3 months with failure to thrive, severe eczema, megaloblastic anemia, methylmalonic aciduria, homocystinuria, and methylmalonic aciduria; the other presented at age 4 years with developmental delay, tremors, gait instability, megaloblastic anemia, and homocystinuria. </p><p>Kvittingen et al. (1997) reported a child with methionine synthase deficiency who presented with neonatal homocystinuria, hypomethioninemia, and severe neurologic symptoms, including developmental delay and seizures. Over an 8-year period both off and on treatment, the patient did not develop megaloblastic anemia. The activity of methionine synthase in fibroblasts was severely deficient, and formation of methylcobalamin from labeled cyanocobalamin was very low. Complementation studies indicated a cblG defect. In addition, the patient was homozygous for the 677C-T mutation in the methylenetetrahydrofolate reductase (MTHFR) gene (607093.0003). Kvittingen et al. (1997) hypothesized that the MTHFR polymorphism protected the patient against anemia, and speculated that homozygosity for the MTHFR 677C-T mutation may cause the dissociation between hematologic and neurologic disease seen in some patients with vitamin B12 deficiency. </p><p>Wilson et al. (1998) reported a brother and sister what they termed the 'cblG variant form' of methionine synthase deficiency, defined as no detectable methionine synthase activity and lack of binding of the cobalamin cofactor to the enzyme. The boy developed generalized seizures at 3 days of age, became progressively hypotonic, and developed respiratory failure at 10 weeks of age. An initial diagnosis of methylenetetrahydrofolate reductase (MTHFR) deficiency (236250) was made on the basis of elevated plasma and urine homocysteine but low plasma methionine without macrocytic anemia. With treatment based on that diagnosis, he was well enough to be weaned from the respirator by 14 weeks of age. At 2 years of age, he had severe psychomotor retardation and microcephaly. A definitive diagnosis of methionine synthase deficiency was made by means of complementation analysis of cultured fibroblasts, which placed him in the cblG complementation group. He was subsequently treated with vitamin B12, betaine, and aspirin, and, at age 8 years, methionine was added. He required femoral osteotomies and bilateral adductor- and heel-cord release for neuromuscular hip dislocations and contractures. At age 10 years, he had short stature, microcephaly, rotary nystagmus, thin fingers, and spasticity. He smiled but was not able to sit or speak. The younger sister was found to have elevated plasma homocysteine and low methionine at 6 days of age. She also was presumed to have MTHFR deficiency and was started on therapy for that, but medications were discontinued by her mother after a few days because the child appeared to be doing well. At 3 months of age, she had seizures and respiratory distress, and medication was restarted. By 18 months of age, she was microcephalic and severely developmentally delayed. The diagnosis of cblG was established at 2 years of age, and she was treated in the same manner as her brother. At 9 years, she had short stature, microcephaly, rotary nystagmus, and pes planus. She was able to walk, responded to simple commands, and could speak a few words. Wilson et al. (1998) reported another boy with the so-called cblG variant. He presented with short stature, failure to thrive, progressive weakness, hypotonia, ocular nystagmus, jaundice, feeding difficulties, and diarrhea at 7 to 10 weeks of age (Wildin and Scott, 1992). He had severe megaloblastic anemia and neutropenia, homocysteinemia, hypomethioninemia, and formiminoglutamic aciduria without methylmalonic aciduria, which led to the diagnosis of a defect in methionine synthesis. Treatment resulted in improved metabolite levels, improvement of tone, and reduction of nystagmus, but poor growth, developmental delay, feeding difficulties requiring a gastrostomy, persistent anemia, and immunologic deficits were present at age 4 years. All 3 of these patients were found to have biallelic null mutations in the MTR gene (156570.0004-156570.0007), resulting in absence of the protein. </p><p>Labrune et al. (1999) described a girl, born of first-cousin parents, who presented at the age of 18 months with megaloblastic anemia. One month later, she developed pulmonary hypertension and renal failure, leading after renal biopsy to the diagnosis of hemolytic uremic syndrome. Investigations showed reduced methionine synthase activity under standard reducing conditions, compatible with cblG complementation group. At age 13 years, this girl required hemodialysis after acute rejection of a renal transplant. </p><p><strong><em>Clinical Variability</em></strong></p><p>
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Carmel et al. (1988) described the cblG mutation in a 21-year-old white woman who had been misdiagnosed as having multiple sclerosis. Her manifestations closely resembled subacute combined degeneration. Mild macrocytic anemia was present. Throughout childhood she had been awkward and had poor coordination. Urinary homocystine excretion was elevated, plasma methionine was decreased, and urinary cystathionine excretion was normal. No methylmalonic acid was detected in the urine. This constellation of findings suggested either the cblE or cblG mutation. Complementation analysis showed complementation with fibroblasts from 2 patients with the cblE mutation, but not with cells from 2 patients with the cblG mutation, indicating that the patient's defect corresponded to the latter mutation. Methionine synthase activity in fibroblast extracts was subnormal. </p><p>Outteryck et al. (2012) reported a young woman who presented at age 23 years with pain in the lower limbs. She had macrocytosis without anemia. Over the following 6 years, she developed progressive paraparesis and cognitive dysfunction. Brain and spinal cord MRI showed moderate cerebral atrophy with periventricular leukoencephalopathy and mild thinning of the cervical spinal cord; she also had optic neuropathy. Biochemical studies showed hyperhomocysteinemia, homocystinuria, hypomethioninemia, and absence of methylmalonic aciduria. Studies of cultured fibroblasts showed a defect in homocysteine remethylation, and complementation studies confirmed a cblG defect. Treatment with hydroxycobalamin and oral betaine resulted in rapid biochemical and slower clinical improvement. Outteryck et al. (2012) noted the unusual presentation of the disorder in this patient. </p>
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<strong>Biochemical Features</strong>
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<span class="mim-text-font">
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<p>Patients with cblG have reduced methionine synthase activity even under standard assay conditions. Hall et al. (1989) presented evidence suggesting a defect in S-adenosyl methionine binding in cblG cells. </p>
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<strong>Clinical Management</strong>
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<p>Rosenblatt and Cooper (1990) commented that, whereas therapy with OH-Cbl has been effective in many cblE patients, a few of the cblG patients have been more difficult to treat and have required additional treatment with folates and betaine. </p>
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<strong>Inheritance</strong>
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<p>The transmission pattern of methionine synthase deficiency in the family reported by Wilson et al. (1998) was consistent with autosomal recessive inheritance. </p>
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<strong>Molecular Genetics</strong>
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<span class="mim-text-font">
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<p>Gulati et al. (1996) analyzed the molecular basis for methionine synthase deficiency in cell lines derived from 2 cblG patients. The 79/76 cell line had low levels of methionine synthase activity and a diminished level of methionine synthase mRNA. In the WG1892 cell line, they detected compound heterozygous mutations in the MTR gene (156570.0001 and 156570.0002). </p><p>Leclerc et al. (1996) cloned the gene for methionine synthase and demonstrated mutations in this gene in 2 cblG cell lines which had deficient methionine synthase enzyme activity (see 156570.0003). </p><p>In 2 sibs with severe cblG, Wilson et al. (1998) identified compound heterozygosity for 2 null mutations in the MTR gene (156570.0004 and 156570.0005). Another patient with a severe form of the disorder was compound heterozygous for 2 null mutations in the MTR gene (156570.0006 and 156570.0007). </p><p>In a panel of 21 patients with methylcobalamin deficiency G (cblG) disorder, Watkins et al. (2002) identified 13 novel mutations. These included 5 deletions and 2 nonsense mutations that resulted in synthesis of truncated proteins that lacked portions critical for enzyme function. In addition, a previously described missense mutation, P1173L (156570.0001), was detected in 16 patients in an expanded panel of 24 patients with cblG. Analysis of haplotypes constructed using sequence polymorphisms identified within the MTR gene demonstrated that this mutation, a C-to-T transition in a CpG island, has occurred on at least 2 separate genetic backgrounds. </p>
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<h4>
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<span class="mim-font">
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<strong>History</strong>
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</span>
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<span class="mim-text-font">
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<p>A possible case of deficiency of methionine synthase was reported by Arakawa et al. (1967), but the evidence was at best equivocal (Mudd, 1977). The patient was a 6-month-old girl with mental retardation, megaloblastic anemia, and high folate activity in the serum and red cells. Assays of liver showed the specific activity of N-5-methyltetrahydrofolate-homocysteine methyltransferase, measured in the presence of cyanocobalamin, to be 32 to 45% of that in control liver. The patient was not homocystinuric. </p>
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<h4>
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<span class="mim-font">
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<strong>REFERENCES</strong>
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</span>
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</h4>
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<div>
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<p />
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</div>
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<div>
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<ol>
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<p class="mim-text-font">
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Arakawa, T., Narisawa, K., Tanno, K., Ohara, K., Higashi, O., Honda, Y., Tamura, T., Wada, Y., Mizuno, T., Hayashi, T., Hirooka, Y., Ohno, T., Ikeda, M.
|
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<strong>Megaloblastic anemia and mental retardation associated with hyperfolic-acidemia: probably due to N-5-methyltetrahydrofolate transferase deficiency.</strong>
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Tohoku J. Exp. Med. 93: 1-22, 1967.
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[PubMed: 5300832]
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[Full Text: https://doi.org/10.1620/tjem.93.1]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Carmel, R., Watkins, D., Goodman, S. I., Rosenblatt, D. S.
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<strong>Hereditary defect of cobalamin metabolism (cblG mutation) presenting as a neurologic disorder in adulthood.</strong>
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New Eng. J. Med. 318: 1738-1741, 1988.
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[PubMed: 2897628]
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[Full Text: https://doi.org/10.1056/NEJM198806303182607]
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</p>
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<p class="mim-text-font">
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Gulati, S., Baker, P., Li, Y. N., Fowler, B., Kruger, W., Brody, L. C., Banerjee, R.
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<strong>Defects in human methionine synthase in cblG patients.</strong>
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Hum. Molec. Genet. 5: 1859-1865, 1996.
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[PubMed: 8968736]
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[Full Text: https://doi.org/10.1093/hmg/5.12.1859]
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</p>
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</li>
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<p class="mim-text-font">
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Hall, C. A., Lindenbaum, R. H., Arenson, E., Begley, J. A., Chu, R. C.
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<strong>The nature of the defect in cobalamin G mutation.</strong>
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Clin. Invest. Med. 12: 262-269, 1989.
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[PubMed: 2535439]
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</li>
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<p class="mim-text-font">
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Kvittingen, E. A., Spangen, S., Lindemans, J., Fowler, B.
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<strong>Methionine synthase deficiency without megaloblastic anaemia.</strong>
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Europ. J. Pediat. 156: 925-930, 1997.
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[PubMed: 9453374]
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[Full Text: https://doi.org/10.1007/s004310050744]
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<p class="mim-text-font">
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Labrune, P., Zittoun, J., Duvaltier, I., Trioche, P., Marquet, J., Niaudet, P., Odievre, M.
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<strong>Haemolytic uraemic syndrome and pulmonary hypertension in a patient with methionine synthase deficiency.</strong>
|
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Europ. J. Pediat. 158: 734-739, 1999.
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[PubMed: 10485306]
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[Full Text: https://doi.org/10.1007/s004310051190]
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</p>
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<li>
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<p class="mim-text-font">
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Leclerc, D., Campeau, E., Goyette, P., Adjalla, C. E., Christensen, B., Ross, M., Eydoux, P., Rosenblatt, D. S., Rozen, R., Gravel, R. A.
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<strong>Human methionine synthase: cDNA cloning and identification of mutations in patients of the cblG complementation group of folate/cobalamin disorders.</strong>
|
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Hum. Molec. Genet. 5: 1867-1874, 1996.
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[PubMed: 8968737]
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[Full Text: https://doi.org/10.1093/hmg/5.12.1867]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Mudd, S. H.
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<strong>Cobalamin-responsive genetic disorders. In: Shimazono, N.; Arakawa, T. (eds.): Nutritional deficiency secondary to inborn errors of metabolism its relationship to physical and mental development.</strong>
|
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Ichikawa: Jap. Panel Maln. U.S.-Japan Coop. Med. Sci. Program 1977.
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</p>
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<li>
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<p class="mim-text-font">
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Outteryck, O., de Seze, J., Stojkovic, T., Cuisset, J.-M., Dobbelaere, D., Delalande, S., Lacour, A., Cabaret, M., Lepoutre, A.-C., Deramecourt, V., Zephir, H., Fowler, B., Vermersch, P.
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<strong>Methionine synthase deficiency: a rare cause of adult-onset leukoencephalopathy.</strong>
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Neurology 79: 386-388, 2012.
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[PubMed: 22786600]
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[Full Text: https://doi.org/10.1212/WNL.0b013e318260451b]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Rosenblatt, D. S., Cooper, B. A.
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<strong>Inherited disorders of vitamin B12 utilization.</strong>
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BioEssays 12: 331-334, 1990.
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[PubMed: 2203337]
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[Full Text: https://doi.org/10.1002/bies.950120705]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Rosenblatt, D. S., Thomas, I. T., Watkins, D., Cooper, B. A., Erbe, R. W.
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<strong>Vitamin B-12 responsive homocystinuria and megaloblastic anemia: heterogeneity in methylcobalamin deficiency.</strong>
|
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Am. J. Med. Genet. 26: 377-383, 1987.
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[PubMed: 3812589]
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[Full Text: https://doi.org/10.1002/ajmg.1320260216]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Thomas, I. T., Rosenblatt, D. S., Erbe, R. W.
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<strong>Vitamin B-12-responsive homocystinuria and megaloblastic anemia (cbl E). (Abstract)</strong>
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Am. J. Hum. Genet. 37: A19 only, 1985.
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Watkins, D., Rosenblatt, D. S.
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<strong>Genetic heterogeneity among patients with methylcobalamin deficiency: definition of two complementation groups, cblE and cblG.</strong>
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J. Clin. Invest. 81: 1690-1694, 1988.
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[PubMed: 3384945]
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[Full Text: https://doi.org/10.1172/JCI113507]
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</li>
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<li>
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<p class="mim-text-font">
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Watkins, D., Rosenblatt, D. S.
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<strong>Functional methionine synthase deficiency (cblE and cblG): clinical and biochemical heterogeneity.</strong>
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Am. J. Med. Genet. 34: 427-434, 1989.
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[PubMed: 2688421]
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[Full Text: https://doi.org/10.1002/ajmg.1320340320]
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Watkins, D., Ru, M., Hwang, H.-Y., Kim, C. D., Murray, A., Philip, N. S., Kim, W., Legakis, H., Wai, T., Hilton, J. F., Ge, B., Dore, C., Hosack, A., Wilson, A., Gravel, R. A., Shane, B., Hudson, T. J., Rosenblatt, D. S.
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<strong>Hyperhomocysteinemia due to methionine synthase deficiency, cblG: structure of the MTR gene, genotype diversity, and recognition of a common mutation, P1173L.</strong>
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Am. J. Hum. Genet. 71: 143-153, 2002.
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[PubMed: 12068375]
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[Full Text: https://doi.org/10.1086/341354]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Wildin, R. S., Scott, C. R.
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<strong>Cbl-G: presentation, treatment, and prolonged followup in a patient with absence of methionine synthase. (Abstract)</strong>
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Am. J. Hum. Genet. 51: A357 only, 1992.
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Wilson, A., Leclerc, D., Saberi, F., Campeau, E., Hwang, H. Y., Shane, B., Phillips, J. A., III, Rosenblatt, D. S., Gravel, R. A.
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<strong>Functionally null mutations in patients with the cblG-variant form of methionine synthase deficiency.</strong>
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Am. J. Hum. Genet. 63: 409-414, 1998.
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[PubMed: 9683607]
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[Full Text: https://doi.org/10.1086/301976]
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<span class="text-nowrap mim-text-font">
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Contributors:
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</span>
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</div>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Cassandra L. Kniffin - reorganized : 7/12/2013<br>Cassandra L. Kniffin - updated : 7/11/2013<br>Victor A. McKusick - updated : 7/22/2002<br>Armand Bottani - updated : 10/11/1999
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Creation Date:
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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Victor A. McKusick : 12/21/1988
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carol : 09/25/2024<br>carol : 04/25/2017<br>carol : 07/12/2013<br>carol : 7/12/2013<br>ckniffin : 7/11/2013<br>carol : 5/3/2013<br>alopez : 10/29/2010<br>tkritzer : 7/29/2002<br>tkritzer : 7/29/2002<br>terry : 7/22/2002<br>carol : 10/11/1999<br>alopez : 7/25/1997<br>mark : 1/22/1997<br>terry : 1/22/1997<br>terry : 1/22/1997<br>mark : 1/22/1997<br>mimadm : 2/19/1994<br>carol : 1/6/1993<br>supermim : 3/17/1992<br>supermim : 3/20/1990<br>supermim : 1/12/1990<br>supermim : 1/3/1990
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