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Entry
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- #613985 - BETA-THALASSEMIA
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- OMIM
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<p>
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<span class="h4">#613985</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="#text"><strong>Text</strong></a>
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<a href="#description">Description</a>
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<a href="#clinicalFeatures">Clinical Features</a>
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<a href="#pathogenesis">Pathogenesis</a>
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<a href="#diagnosis">Diagnosis</a>
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<a href="#clinicalManagement">Clinical Management</a>
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<a href="#populationGenetics">Population Genetics</a>
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<a href="#molecularGenetics">Molecular Genetics</a>
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<a href="#seeAlso"><strong>See Also</strong></a>
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<a href="#references"><strong>References</strong></a>
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<a href="#contributors"><strong>Contributors</strong></a>
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<a href="#creationDate"><strong>Creation Date</strong></a>
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<li role="presentation">
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<a href="#editHistory"><strong>Edit History</strong></a>
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<div style="display: table-cell;">External Links</div>
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</div>
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</a>
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</h4>
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<span class="small">
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<a href="#mimClinicalResourcesLinksFold" id="mimClinicalResourcesLinksToggle" class=" mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimClinicalResourcesLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">▼</div>
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<div style="display: table-cell;">Clinical Resources</div>
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</div>
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</a>
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</span>
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<div id="mimClinicalResourcesLinksFold" class="panel-collapse collapse in mimLinksFold" role="tabpanel" aria-labelledby="clinicalResources">
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<div><a href="https://clinicaltrials.gov/search?cond=BETA-THALASSEMIA" 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=19171&Typ=Pat" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'EuroGentest', 'domain': 'orpha.net'})">Beta-thalassemia major </a></div><div style="margin-left: 0.5em;"><a href="https://www.orpha.net/consor/cgi-bin/ClinicalLabs_Search_Simple.php?lng=EN&LnkId=19172&Typ=Pat" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'EuroGentest', 'domain': 'orpha.net'})">Beta-thalassemia intermedia </a></div><div style="margin-left: 0.5em;"><a href="https://www.orpha.net/consor/cgi-bin/ClinicalLabs_Search_Simple.php?lng=EN&LnkId=51&Typ=Pat" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'EuroGentest', 'domain': 'orpha.net'})">Beta-thalassemia </a></div>
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</div>
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<div><a href="https://www.ncbi.nlm.nih.gov/books/NBK1426/" 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/814" 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://medlineplus.gov/genetics/condition/beta-thalassemia" class="mim-tip-hint" title="Consumer-friendly information about the effects of genetic variation on human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MedlinePlus Genetics', 'domain': 'medlineplus.gov'})">MedlinePlus Genetics</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/gtr/all/tests/?term=613985[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="#mimNewbornScreeningFold" id="mimNewbornScreeningToggle" data-toggle="collapse" class="mim-tip-hint mimTriangleToggle" title="Information and resources for newborn screening and genetics."><span id="mimNewbornScreeningToggleTriangle" class="small" style="margin-left: -0.8em;">►</span>Newborn Screening</div>
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<div id="mimNewbornScreeningFold" class="collapse">
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<div style="margin-left: 0.5em;"><a href="https://www.acmg.net/PDFLibrary/Beta-Thalassemia-Major-ACT-Sheet.pdf" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Newborn Screening', 'domain': 'www.acmg.net'})">ACMG ACT Sheet</a></div><div style="margin-left: 0.5em;"><a href="https://www.acmg.net/PDFLibrary/Hemoglobin-EE-ACT-Sheet.pdf" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Newborn Screening', 'domain': 'www.acmg.net'})">ACMG ACT Sheet</a></div><div style="margin-left: 0.5em;"><a href="https://www.acmg.net/PDFLibrary/Hemoglobin-S-ACT-Sheet.pdf" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Newborn Screening', 'domain': 'www.acmg.net'})">ACMG ACT Sheet</a></div><div style="margin-left: 0.5em;"><a href="https://www.acmg.net/PDFLibrary/HB-Screening-Algorithm.pdf" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Newborn Screening', 'domain': 'www.acmg.net'})">ACMG Algorithm</a></div><div style="margin-left: 0.5em;"><a href="https://www.acmg.net/PDFLibrary/HB-Screening-Algorithm.pdf" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Newborn Screening', 'domain': 'www.acmg.net'})">ACMG Altorithm</a></div>
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</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=231214" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'OrphaNet', 'domain': 'orpha.net'})">Beta-thalassemia major</a></div><div style="margin-left: 0.5em;"><a href="https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=231222" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'OrphaNet', 'domain': 'orpha.net'})">Beta-thalassemia intermedia</a></div><div style="margin-left: 0.5em;"><a href="https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=848" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'OrphaNet', 'domain': 'orpha.net'})">Beta-thalassemia</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimAnimalModels">
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<span class="panel-title">
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<span class="small">
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<a href="#mimAnimalModelsLinksFold" id="mimAnimalModelsLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimAnimalModelsLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Animal Models</div>
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</div>
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</a>
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</span>
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.alliancegenome.org/disease/DOID:12241" class="mim-tip-hint" title="Search Across Species; explore model organism and human comparative genomics." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Alliance Genome', 'domain': 'alliancegenome.org'})">Alliance Genome</a></div>
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<div><a href="http://www.informatics.jax.org/disease/613985" class="mim-tip-hint" title="Phenotypes, alleles, and disease models from Mouse Genome Informatics." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MGI Mouse Phenotype', 'domain': 'informatics.jax.org'})">MGI Mouse Phenotype</a></div>
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<div><a href="https://wormbase.org/resources/disease/DOID:12241" class="mim-tip-hint" title="Database of the biology and genome of Caenorhabditis elegans and related nematodes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Wormbase Disease Ontology', 'domain': 'wormbase.org'})">Wormbase Disease Ontology</a></div>
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<span>
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<span class="mim-tip-bottom" qtip_title="<strong>Looking for this gene or this phenotype in other resources?</strong>" qtip_text="Select a related resource from the dropdown menu and click for a targeted link to information directly relevant.">
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<div class="col-lg-8 col-lg-pull-2 col-md-8 col-md-pull-2 col-sm-8 col-sm-pull-2 col-xs-12">
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<div>
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<a id="title" class="mim-anchor"></a>
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<div>
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<a id="number" class="mim-anchor"></a>
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<div class="text-right">
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<a href="#" class="mim-tip-icd" qtip_title="<strong>ICD+</strong>" qtip_text="
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<strong>SNOMEDCT:</strong> 65959000<br />
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<strong>ICD10CM:</strong> D56.1<br />
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<strong>ICD9CM:</strong> 282.44<br />
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<strong>ORPHA:</strong> 231214, 231222, 848<br />
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<strong>DO:</strong> 12241<br />
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">ICD+</a>
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<div>
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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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613985
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</span>
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</span>
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</div>
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<div>
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<a id="preferredTitle" class="mim-anchor"></a>
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<h3>
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<span class="mim-font">
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BETA-THALASSEMIA
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</h3>
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<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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<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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<p>A number sign (#) is used with this entry because beta-thalassemia can be caused by homozygous or compound heterozygous mutation in the beta-globin gene (HBB; <a href="/entry/141900">141900</a>) on chromosome 11p15.</p><p>Beta-thalassemia may also be due to deletion of the entire beta-globin gene cluster or of sequences 5-prime from the beta-globin gene cluster; these sequences are referred to as the locus control region beta (LCRB; <a href="/entry/152424">152424</a>).</p>
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<p>Beta-thalassemia is characterized by a reduced production of hemoglobin A (HbA, alpha-2/beta-2), which results from the reduced synthesis of beta-globin chains relative to alpha-globin chains, thus causing an imbalance in globin chain production and hence abnormal erythropoiesis. The disorder is clinically heterogeneous (summary by <a href="#25" class="mim-tip-reference" title="Ottolenghi,S., Lanyon, W. G., Williamson, R., Weatherall, D. J., Clegg, J. B., Pitcher, C. S. <strong>Human globin gene analysis for a patient with beta-zero/delta-beta-zero thalassemia.</strong> Proc. Nat. Acad. Sci. 72: 2294-2299, 1975.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/49057/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">49057</a>] [<a href="https://doi.org/10.1073/pnas.72.6.2294" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="49057">Ottolenghi et al., 1975</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=49057" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>Absence of beta globin causes beta-zero-thalassemia. Reduced amounts of detectable beta globin causes beta-plus-thalassemia. For clinical purposes, beta-thalassemia is divided into thalassemia major (transfusion dependent), thalassemia intermedia (of intermediate severity), and thalassemia minor (asymptomatic, carrier state). The molecular and clinical aspects of the beta-thalassemias were reviewed by <a href="#24" class="mim-tip-reference" title="Olivieri, N. F. <strong>The beta-thalassemias.</strong> New Eng. J. Med. 341: 99-109, 1999. Note: Erratum: New Eng. J. Med. 341: 1407 only, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10395635/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10395635</a>] [<a href="https://doi.org/10.1056/NEJM199907083410207" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10395635">Olivieri (1999)</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10395635" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>The remarkable phenotypic diversity of the beta-thalassemias reflects the heterogeneity of mutations at the HBB locus, the action of many secondary and tertiary modifiers, and a wide range of environmental factors (<a href="#36" class="mim-tip-reference" title="Weatherall, D. J. <strong>Phenotype-genotype relationships in monogenic disease: lessons from the thalassaemias.</strong> Nature Rev. Genet. 2: 245-255, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11283697/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11283697</a>] [<a href="https://doi.org/10.1038/35066048" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11283697">Weatherall, 2001</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11283697" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>For a review of beta-thalassemia, see <a href="#31" class="mim-tip-reference" title="Taher, A. T., Musallam, K. M., Cappellini, M. D. <strong>Beta-thalassemias.</strong> New Eng. J. Med. 384: 727-743, 2021.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/33626255/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">33626255</a>] [<a href="https://doi.org/10.1056/NEJMra2021838" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="33626255">Taher et al. (2021)</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=33626255" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 thalassemia major present in the first year of life with severe anemia; they are unable to maintain a hemoglobin level about 5 gm/dl. Clinical details of this disorder have been detailed extensively in numerous monographs and were summarized by <a href="#35" class="mim-tip-reference" title="Weatherall, D. J., Clegg, J. B., Higgs, D. R., Wood, W. G. <strong>The hemoglobinopathies.In: Scriver, C.; Beaudet, A. L.; Sly, W. S.; Valle, D. (eds.) : The Metabolic and Molecular Bases of Inherited Disease. (7th ed.)</strong> New York: McGraw-Hill 1995. Pp. 3417-3484."None>Weatherall et al. (1995)</a>. <a href="#20" class="mim-tip-reference" title="Modell, B., Khan, M., Darlison, M. <strong>Survival in beta-thalassaemia major in the UK: data from the UK Thalassaemia Register.</strong> Lancet 355: 2051-2052, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10885361/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10885361</a>] [<a href="https://doi.org/10.1016/S0140-6736(00)02357-6" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10885361">Modell et al. (2000)</a> found that about 50% of UK patients with beta-thalassemia major die before the age of 35 years, mainly because conventional iron-chelation therapy is too burdensome for full adherence. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10885361" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#4" class="mim-tip-reference" title="Cao, A., Galanello, R. <strong>Beta-thalassemia.</strong> Genet. Med. 12: 61-76, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20098328/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20098328</a>] [<a href="https://doi.org/10.1097/GIM.0b013e3181cd68ed" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20098328">Cao and Galanello (2010)</a> reviewed the clinical features of the 3 forms of beta-thalassemia. Affected infants with thalassemia major fail to thrive and become progressively pale. Feeding problems, diarrhea, irritability, recurrent bouts of fever, and enlargement of the abdomen, caused by splenomegaly, may occur. If an adequate transfusion program is followed, growth and development are normal until age 10 to 11 years. Afterwards, affected individuals are at risk of developing severe complications related to posttransfusional iron overload, depending on their compliance with chelation therapy. Patients with thalassemia intermedia show a markedly heterogeneous clinical picture. The principal symptoms are pallor, jaundice, cholelithiasis, liver and spleen enlargement, moderate to severe skeletal changes, leg ulcers, extramedullary masses of hyperplastic erythroid marrow, a tendency to develop osteopenia and osteoporosis, and thrombotic complications resulting from a hypercoagulable state because of the lipid membrane composition of the abnormal red blood cells (particularly in splenectomized patients). Transfusions are usually not required. Iron overload occurs mainly from increased intestinal absorption of iron caused by ineffective erythropoiesis. Carriers of beta-thalassemia are clinically asymptomatic. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20098328" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#4" class="mim-tip-reference" title="Cao, A., Galanello, R. <strong>Beta-thalassemia.</strong> Genet. Med. 12: 61-76, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20098328/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20098328</a>] [<a href="https://doi.org/10.1097/GIM.0b013e3181cd68ed" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20098328">Cao and Galanello (2010)</a> also reviewed the hematologic findings in the 3 forms. Patients with thalassemia major have a severe microcytic and hypochromic anemia, associated with increased number of red blood cells and low mean corpuscular volume (MCV) and mean corpuscular Hb (MCH). Peripheral blood smear shows, in addition to microcytosis and hypochromia, anisocytosis, poikilocytosis (spiculated tear drop and elongated cells), and nucleated red blood cells (i.e., erythroblasts). The number of erythroblasts is related to the degree of anemia and is markedly increased after splenectomy. Patients with thalassemia intermedia have a moderate anemia and show a markedly heterogeneous hematologic picture, ranging in severity from that of the beta-thalassemia carrier state to that of thalassemia major. The characteristic hematologic features in carriers are microcytosis (reduced red blood cell volume), hypochromia (reduced red blood cell Hb content), increased HbA2 level (the minor component of the adult Hb, alpha2delta2), and unbalanced alpha/nonalpha globin chain synthesis. However, several environmental or genetic factors may modify this phenotype, leading either to thalassemia intermedia, despite the presence of a single beta-globin gene affected, or to hematologically atypical carrier state. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20098328" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Some atypical beta-thalassemia heterozygotes have either normal red cell indices or normal HbA2 level, or both, with a completely silent hematologic phenotype. This condition is detected only by the imbalanced alpha-nonalpha globin chain synthesis and is referred to as silent beta-thalassemia (<a href="#5" class="mim-tip-reference" title="Cao, A., Moi, P. <strong>Genetic modifying factors in beta-thalassemia.</strong> Clin. Chem. Lab. Med. 38: 123-132, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10834399/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10834399</a>] [<a href="https://doi.org/10.1515/CCLM.2000.019" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10834399">Cao and Moi, 2000</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10834399" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#34" class="mim-tip-reference" title="Wainscoat, J. S., Kanavakis, E., Wood, W. G., Letsky, E. A., Huehns, E. R., Marsh, G. W., Higgs, D. R., Clegg, J. B., Weatherall, D. J. <strong>Thalassaemia intermedia in Cyprus: the interaction of alpha- and beta-thalassaemia.</strong> Brit. J. Haemat. 53: 411-416, 1983.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/6297530/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">6297530</a>] [<a href="https://doi.org/10.1111/j.1365-2141.1983.tb02041.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="6297530">Wainscoat et al. (1983)</a> showed that coinheritance of alpha-thalassemia with homozygous beta-thalassemia resulted in amelioration of the beta-thalassemia. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=6297530" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#13" class="mim-tip-reference" title="Kulozik, A. E., Thein, S. L., Wainscoat, J. S., Gale, R., Kay, L. A., Wood, J. K., Weatherall, D. J., Huehns, E. R. <strong>Thalassaemia intermedia: interaction of the triple alpha-globin gene arrangement and heterozygous beta-thalassaemia.</strong> Brit. J. Haemat. 66: 109-112, 1987.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3593645/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3593645</a>] [<a href="https://doi.org/10.1111/j.1365-2141.1987.tb06898.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3593645">Kulozik et al. (1987)</a> showed that heterozygous beta-thalassemia was associated with unusually severe clinical manifestations when coinherited with an extra alpha-globin gene; in each of 5 cases 1 chromosome 16 carried 3 alpha-globin genes. <a href="#3" class="mim-tip-reference" title="Camaschella, C., Bertero, M. T., Serra, A., Dall'Acqua, M., Gasparini, P., Trento, M., Vettore, L., Perona, G., Saglio, G., Mazza, U. <strong>A benign form of thalassaemia intermedia may be determined by the interaction of triplicated alpha locus and heterozygous beta-thalassaemia.</strong> Brit. J. Haemat. 66: 103-107, 1987.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3593644/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3593644</a>] [<a href="https://doi.org/10.1111/j.1365-2141.1987.tb06897.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3593644">Camaschella et al. (1987)</a> found the same aggravation of the clinical picture with triplicated alpha locus. This is a particularly instructive example of gene interaction. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=3593644+3593645" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>To gain insight into the cellular and structural alterations of thalassemic bone, <a href="#17" class="mim-tip-reference" title="Mahachoklertwattana, P., Sirikulchayanonta, V., Chuansumrit, A., Karnsombat, P., Choubtum, L., Sriphrapradang, A., Domrongkitchaiporn, S., Sirisriro, R., Rajatanavin, R. <strong>Bone histomorphometry in children and adolescents with beta-thalassemia disease: iron-associated focal osteomalacia.</strong> J. Clin. Endocr. Metab. 88: 3966-3972, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12915694/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12915694</a>] [<a href="https://doi.org/10.1210/jc.2002-021548" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12915694">Mahachoklertwattana et al. (2003)</a> studied bone histomorphometry and biochemical and hormonal profiles in children and adolescents with suboptimally treated beta-thalassemia disease. Seventeen patients underwent iliac crest bone biopsy for histomorphometric analyses. Most patients had growth retardation and delayed bone age. Bone mineral density (BMD) was low especially at the lumbar spine. Serum IGF1 (<a href="/entry/147440">147440</a>) levels were almost always low. Bone histomorphometry revealed increased osteoid thickness, osteoid maturation time, and mineralization lag time, which indicate impaired bone matrix maturation and defective mineralization. In addition, iron deposits appeared along mineralization fronts and osteoid surfaces. The authors concluded that delayed bone maturation and focal osteomalacia are the pathogenesis of bone disease in suboptimally blood-transfused thalassemics with iron overload. They suggested that iron deposits in bone and low circulating IGF1 levels may partly contribute to the above findings. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12915694" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="#27" class="mim-tip-reference" title="Premawardhena, A., Fisher, C. A., Olivieri, N. F., de Silva, S., Arambepola, M., Perera, W., O'Donnell, A., Peto, T. E. A., Viprakasit, V., Merson, L., Muraca, G., Weatherall, D. J. <strong>Haemoglobin E beta-thalassemia in Sri Lanka.</strong> Lancet 366: 1467-1470, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16243092/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16243092</a>] [<a href="https://doi.org/10.1016/S0140-6736(05)67396-5" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16243092">Premawardhena et al. (2005)</a> studied 109 Sri Lankan hemoglobin E beta-thalassemia patients over 5 years. They found that 25 patients were not receiving transfusion, and transfusion was discontinued in an additional 37 patients without deleterious effect. <a href="#27" class="mim-tip-reference" title="Premawardhena, A., Fisher, C. A., Olivieri, N. F., de Silva, S., Arambepola, M., Perera, W., O'Donnell, A., Peto, T. E. A., Viprakasit, V., Merson, L., Muraca, G., Weatherall, D. J. <strong>Haemoglobin E beta-thalassemia in Sri Lanka.</strong> Lancet 366: 1467-1470, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16243092/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16243092</a>] [<a href="https://doi.org/10.1016/S0140-6736(05)67396-5" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16243092">Premawardhena et al. (2005)</a> identified several genetic and environmental factors that may contribute to the phenotypic diversity of the disorder, including modifiers of hemoglobin F (see <a href="/entry/142250">142250</a>) production, malaria (see <a href="/entry/611162">611162</a>), and age-related changes in adaptive function. They proposed that hemoglobin E beta-thalassemia can be managed without transfusion in many patients and that age-related changes in the adaptation to anemia indicate that more cost-effective management approaches should be explored. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16243092" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#22" class="mim-tip-reference" title="O'Donnell, A., Premawardhena, A., Arambepola, M., Samaranayake, R., Allen, S. J., Peto, T. E. A., Fisher, C. A., Cook, J., Corran, P. H., Olivieri, N. F., Weatherall, D. J. <strong>Interaction of malaria with a common form of severe thalassemia in an Asian population.</strong> Proc. Nat. Acad. Sci. 106: 18716-18721, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19841268/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19841268</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19841268[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/10.1073/pnas.0910142106" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19841268">O'Donnell et al. (2009)</a> studied Sri Lankan patients with HbE beta-thalassemia for exposure to malaria caused by Plasmodium falciparum or P. vivax. They found that there were high frequencies of antibodies to both malaria parasites, as well as DNA-based evidence of current infection with P. vivax. Comparisons with age-matched controls showed that there was a higher frequency of antibodies in thalassemic patients, particularly against P. vivax and in young children, that was unlikely to be related to transfusion. A higher frequency was also found in patients who had undergone splenectomy. <a href="#22" class="mim-tip-reference" title="O'Donnell, A., Premawardhena, A., Arambepola, M., Samaranayake, R., Allen, S. J., Peto, T. E. A., Fisher, C. A., Cook, J., Corran, P. H., Olivieri, N. F., Weatherall, D. J. <strong>Interaction of malaria with a common form of severe thalassemia in an Asian population.</strong> Proc. Nat. Acad. Sci. 106: 18716-18721, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19841268/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19841268</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19841268[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/10.1073/pnas.0910142106" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19841268">O'Donnell et al. (2009)</a> proposed that patients with HbE beta-thalassemia may be more prone to malaria, particularly P. vivax malaria. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19841268" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="#28" class="mim-tip-reference" title="Ribeil, J.-A., Zermati, Y., Vandekerckhove, J., Cathelin, S., Kersual, J., Dussiot, M., Coulon, S., Moura, I. C., Zeuner, A., Kirkegaard-Sorensen, T., Varet, B., Solary, E., Garrido, C., Hermine, O. <strong>Hsp70 regulates erythropoiesis by preventing caspase-3-mediated cleavage of GATA-1.</strong> Nature 445: 102-105, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17167422/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17167422</a>] [<a href="https://doi.org/10.1038/nature05378" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17167422">Ribeil et al. (2007)</a> demonstrated that in human erythroblasts, the chaperone HSP70 (see <a href="/entry/140550">140550</a>) is constitutively expressed and, at later stages of maturation, translocates into the nucleus and protects GATA1 (<a href="/entry/305371">305371</a>) from CASP3 (<a href="/entry/600636">600636</a>) cleavage. The primary role of this ubiquitous chaperone is to participate in the refolding of proteins denatured by cytoplasmic stress, thus preventing their aggregation (<a href="#10" class="mim-tip-reference" title="Hartl, F. U., Bracher, A., Hayer-Hartl, M. <strong>Molecular chaperones in protein folding and proteostasis.</strong> Nature 475: 324-332, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21776078/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21776078</a>] [<a href="https://doi.org/10.1038/nature10317" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21776078">Hartl et al., 2011</a>). <a href="#1" class="mim-tip-reference" title="Arlet, J.-B., Ribeil, J.-A., Guillem, F., Negre, O., Hazoume, A., Marcion, G., Beuzard, Y., Dussiot, M., Moura, I. C., Demarest, S., de Beauchene, I. C., Belaid-Choucair, Z., and 12 others. <strong>HSP70 sequestration by free alpha-globin promotes ineffective erythropoiesis in beta-thalassaemia.</strong> Nature 514: 242-246, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25156257/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25156257</a>] [<a href="https://doi.org/10.1038/nature13614" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25156257">Arlet et al. (2014)</a> showed in vitro that, during the maturation of beta-thalassemia major erythroblasts, HSP70 interacts directly with free alpha-globin chains. Consequently, HSP70 is sequestered in the cytoplasm and GATA1 is no longer protected, resulting in end-stage maturation arrest and apoptosis. Transduction of a nuclear-targeted HSP70 mutant or a CASP3-uncleavable GATA1 mutant restored terminal maturation of beta-thalassemia major erythroblasts, providing a rationale for targeted therapies. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=21776078+17167422+25156257" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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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By means of a simplified method for trophoblast biopsy together with restriction endonuclease analysis of fetal DNA, <a href="#23" class="mim-tip-reference" title="Old, J. M., Ward, R. H. T., Petrou, M., Karagozlu, F., Modell, B., Weatherall, D. J. <strong>First-trimester fetal diagnosis for hemoglobinopathies: three cases.</strong> Lancet 320: 1413-1416, 1982. Note: Originally Volume II.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/6129504/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">6129504</a>] [<a href="https://doi.org/10.1016/s0140-6736(82)91324-1" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="6129504">Old et al. (1982)</a> made first-trimester prenatal diagnosis in the case of 3 fetuses at risk for hemoglobinopathy: 2 at risk for homozygous beta-thalassemia and 1 at risk for sickle cell anemia. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=6129504" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="#30" class="mim-tip-reference" title="Saiki, R. K., Chang, C.-A., Levenson, C. H., Warren, T. C., Boehm, C. D., Kazazian, H. H., Jr., Erlich, H. A. <strong>Diagnosis of sickle cell anemia and beta-thalassemia with enzymatically amplified DNA and nonradioactive allele-specific oligonucleotide probes.</strong> New Eng. J. Med. 319: 537-541, 1988.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3405266/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3405266</a>] [<a href="https://doi.org/10.1056/NEJM198809013190903" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3405266">Saiki et al. (1988)</a> devised a simple and rapid nonradioactive method for detecting genetic variation and applied it to the diagnosis of sickle cell anemia and beta-thalassemia. The procedure involved the selective amplification of a segment of the human beta-globin gene with oligonucleotide primers and a thermostable DNA polymerase, followed by hybridization of the amplified DNA with allele-specific oligonucleotide probes covalently labeled with horseradish peroxidase. The hybridized probes were detected with a simple colorimetric assay. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=3405266" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 Sardinia, <a href="#29" class="mim-tip-reference" title="Rosatelli, C., Falchi, A. M., Tuveri, T., Scalas, M. T., Di Tucci, A., Monni, G., Cao, A. <strong>Prenatal diagnosis of beta-thalassaemia with the synthetic-oligomer technique.</strong> Lancet 325: 241-243, 1985. Note: Originally Volume I.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2857318/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2857318</a>] [<a href="https://doi.org/10.1016/s0140-6736(85)91026-8" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2857318">Rosatelli et al. (1985)</a> used the synthetic oligonucleotide method for prenatal detection of the beta-zero-39 (nonsense) mutation type of beta-thalassemia. In a mouse model for beta-thalassemia, <a href="#11" class="mim-tip-reference" title="Holding, C., Monk, M. <strong>Diagnosis of beta-thalassemia by DNA amplification in single blastomeres from mouse preimplantation embryos.</strong> Lancet 334: 532-535, 1989. Note: Originally Volume II.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2570237/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2570237</a>] [<a href="https://doi.org/10.1016/s0140-6736(89)90655-7" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2570237">Holding and Monk (1989)</a> were able to make the diagnosis in single blastomeres removed from embryos of 4 to 8 cells by PCR amplification. <a href="#21" class="mim-tip-reference" title="Monk, M., Holding, C. <strong>Amplification of a beta-haemoglobin sequence in individual human oocytes and polar bodies.</strong> Lancet 335: 985-988, 1990.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1691429/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1691429</a>] [<a href="https://doi.org/10.1016/0140-6736(90)91060-n" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1691429">Monk and Holding (1990)</a> demonstrated reproducible amplification of a 680-basepair sequence within the human beta-globin gene from individual human oocytes and the first polar bodies isolated from them. They used restriction enzyme digestion of the amplified DNA to confirm the identity of the fragment. The authors proposed that analysis of the DNA from the first polar body will facilitate preimplantation diagnosis of sickle cell anemia. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=2857318+1691429+2570237" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#8" class="mim-tip-reference" title="Ding, C., Chiu, R. W. K., Lau, T. K., Leung, T. N., Chan, L. C., Chan, A. Y. Y., Charoenkwan, P., Ng, I. S. L., Law, H., Ma, E. S. K., Xu, X., Wanapirak, C., Sanguansermsri, T., Liao, C., Ai, M. A. T. J., Chui, D. H. K., Cantor, C. R. <strong>MS analysis of single-nucleotide differences in circulating nucleic acids: application to noninvasive prenatal diagnosis.</strong> Proc. Nat. Acad. Sci. 101: 10762-10767, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15247415/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15247415</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15247415[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/10.1073/pnas.0403962101" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15247415">Ding et al. (2004)</a> described a method for noninvasive prenatal diagnosis by analysis of circulating nucleic acids. Circulating fetal-specific DNA sequences have been detected and constitute a fraction of the total DNA in maternal plasma. The robust discrimination of single-nucleotide differences between circulating DNA species is technically challenging and demanded the adoption of highly sensitive and specific analytical systems. <a href="#8" class="mim-tip-reference" title="Ding, C., Chiu, R. W. K., Lau, T. K., Leung, T. N., Chan, L. C., Chan, A. Y. Y., Charoenkwan, P., Ng, I. S. L., Law, H., Ma, E. S. K., Xu, X., Wanapirak, C., Sanguansermsri, T., Liao, C., Ai, M. A. T. J., Chui, D. H. K., Cantor, C. R. <strong>MS analysis of single-nucleotide differences in circulating nucleic acids: application to noninvasive prenatal diagnosis.</strong> Proc. Nat. Acad. Sci. 101: 10762-10767, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15247415/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15247415</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15247415[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/10.1073/pnas.0403962101" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15247415">Ding et al. (2004)</a> developed a method based on single-allele base extension reaction and mass spectrometry which allowed for the reliable detection of fetal-specific alleles, including point mutations and SNPs, in maternal plasma. The approach was applied to exclude the fetal inheritance of the 4 most common Southeast Asian beta-thalassemia mutations in at-risk pregnancies between weeks 7 and 21 of gestation: 41/42delCTTT (<a href="/entry/141900#0326">141900.0326</a>), IVS2 654C-T (<a href="/entry/141900#0368">141900.0368</a>), -28A-G (<a href="/entry/141900#0381">141900.0381</a>), and 17A-T (<a href="/entry/141900#0311">141900.0311</a>). Fetal genotypes were correctly predicted in all cases studied. Fetal haplotype analysis based on a SNP linked to the HBB gene in maternal plasma also was achieved. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15247415" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><strong><em>Bone Marrow Transplantation</em></strong></p><p>
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<a href="#14" class="mim-tip-reference" title="Ley, T. J., DeSimone, J., Anagnou, N. P., Keller, G. H., Humphries, R. K., Turner, P. H., Young, N. S., Heller, P., Nienhuis, A. W. <strong>5-Azacytidine selectively increases gamma-globin synthesis in a patient with beta(+)-thalassemia.</strong> New Eng. J. Med. 307: 1469-1475, 1982.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/6183586/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">6183586</a>] [<a href="https://doi.org/10.1056/NEJM198212093072401" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="6183586">Ley et al. (1982)</a> treated homozygous beta-plus-thalassemia in a 42-year-old black American man with 5-azacytidine. An increase in hemoglobin concentration occurred. Hypomethylation of both the gamma-globin and the epsilon-globin gene was shown, as well as an increase in gamma-globin mRNA. <a href="#16" class="mim-tip-reference" title="Lucarelli, G., Galimberti, M., Polchi, P., Angelucci, E., Baronciani, D., Giardini, C., Politi, P., Durazzi, S. M. T., Muretto, P., Albertini, F. <strong>Bone marrow transplantation in patients with thalassemia.</strong> New Eng. J. Med. 322: 417-421, 1990.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2300104/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2300104</a>] [<a href="https://doi.org/10.1056/NEJM199002153220701" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2300104">Lucarelli et al. (1990)</a> reviewed results from 222 consecutive patients in whom bone marrow transplantation (BMT) was performed for thalassemia since 1983. The results were analyzed, in particular, in the 116 consecutive patients treated since June 1985. The allogeneic marrow came from HLA-identical donors, and the patients all had beta-thalassemia and were less than 16 years old. They concluded that bone marrow transplantation offered a high probability of complication-free survival, if the recipient did not have hepatomegaly or portal fibrosis. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=6183586+2300104" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Gene Therapy</em></strong></p><p>
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Gene therapy for beta-thalassemia is particularly challenging given the requirement for massive hemoglobin production in a lineage-specific manner and the lack of selective advantage for corrected hematopoietic stem cells. Compound beta-E/beta-0-thalassemia is the most common form of severe thalassemia in southeast Asian countries and their diasporas. The beta-E-globin allele (<a href="/entry/141900#0071">141900.0071</a>) bears a point mutation that causes alternative splicing. The abnormally spliced form is noncoding, whereas the correctly spliced mRNA expresses a mutated beta-E-globin with partial instability. When this is compounded with a nonfunctional beta-0 allele, a profound decrease in beta-globin synthesis results, and approximately half of beta-E/beta-0-thalassemia patients are transfusion-dependent. The only available curative therapy is allogeneic hematopoietic stem cell transplantation, although most patients do not have a human leukocyte antigen (HLA)-matched, genoidentical donor, and those who do still risk rejection or graft-versus-host disease (GVHD; see <a href="/entry/614395">614395</a>). <a href="#7" class="mim-tip-reference" title="Cavazzana-Calvo, M., Payen, E., Negre, O., Wang, G., Hehir, K., Fusil, F., Down, J., Denaro, M., Brady, T., Westerman, K., Cavallesco, R., Gillet-Legrand, B., and 26 others. <strong>Transfusion independence and HMGA2 activation after gene therapy of human beta-thalassaemia.</strong> Nature 467: 318-322, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20844535/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20844535</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20844535[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/10.1038/nature09328" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20844535">Cavazzana-Calvo et al. (2010)</a> showed that, 33 months after lentiviral beta-globin gene transfer, an adult patient with severe beta-E/beta-0-thalassemia dependent on monthly transfusions since early childhood had become transfusion-independent for the preceding 21 months. Blood hemoglobin was maintained between 9 and 10 g/dL, of which one-third contained vector-encoded beta-globin. Most of the therapeutic benefit resulted from a dominant, myeloid-biased cell clone, in which the integrated vector caused transcriptional activation of HMGA2 (<a href="/entry/600698">600698</a>) in erythroid cells with further increased expression of a truncated HMGA2 mRNA insensitive to degradation by let-7 microRNAs (see <a href="/entry/605386">605386</a>). <a href="#7" class="mim-tip-reference" title="Cavazzana-Calvo, M., Payen, E., Negre, O., Wang, G., Hehir, K., Fusil, F., Down, J., Denaro, M., Brady, T., Westerman, K., Cavallesco, R., Gillet-Legrand, B., and 26 others. <strong>Transfusion independence and HMGA2 activation after gene therapy of human beta-thalassaemia.</strong> Nature 467: 318-322, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20844535/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20844535</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20844535[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/10.1038/nature09328" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20844535">Cavazzana-Calvo et al. (2010)</a> suggested that the clonal dominance that accompanies therapeutic efficacy may be coincidental and stochastic or result from a hitherto benign cell expansion caused by dysregulation of the HMGA2 gene in stem/progenitor cells. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20844535" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="#32" class="mim-tip-reference" title="Thompson, A. A., Walters, M. C., Kwiatkowski, J., Rasko, J. E. J., Ribeil, J. A., Hongeng, S., Magrin, E., Schiller, G. J., Payen, E., Semeraro, M., Moshous, D., Lefrere, F., and 35 others. <strong>Gene therapy in patients with transfusion-dependent beta-thalassemia.</strong> New Eng. J. Med. 378: 1479-1493, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29669226/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29669226</a>] [<a href="https://doi.org/10.1056/NEJMoa1705342" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="29669226">Thompson et al. (2018)</a> reported the results of 2 phase 1/2 studies using autologous CD34+ cells transduced with LentiGlobin BB305 vector, which encodes adult hemoglobin (HbA) with a T87Q amino acid substitution for monitoring. This study comprised 22 patients who had undergone myeloablative busulfan conditioning prior to reinfusion. At a median of 26 months (range, 15 to 42) after infusion of the gene-modified cells, all but 1 of the 13 patients who had a non-beta-0/beta-0 genotype had stopped receiving red-cell transfusions; the levels of HbA(T87Q) ranged from 3.4 to 10.0 g/dl, and the levels of total hemoglobin ranged from 8.2 to 13.7 g/dl. Correction of biologic markers of dyserythropoiesis was achieved in evaluated patients with hemoglobin levels near normal ranges. In 9 patients with a beta-0/beta-0 genotype or 2 copies of the IVS1-110 mutation (<a href="/entry/141900#0364">141900.0364</a>), the median annualized transfusion volume was decreased by 73%, and red-cell transfusions were discontinued in 3. Treatment-related adverse events were typical of those associated with autologous stem-cell transplantation. No clonal dominance related to vector integration was observed. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=29669226" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="Frangoul, H., Altshuler, D., Cappellini, M. D., Chen, Y.-S., Domm, J., Eustace, B. K., Foell, J., de la Fuente, J., Grupp, S., Handgretinger, R., Ho, T. W., Kattamis, A., and 14 others. <strong>CRISPR-Cas9 gene editing for sickle cell disease and beta-thalassemia.</strong> New Eng. J. Med. 384: 252-260, 2021.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/33283989/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">33283989</a>] [<a href="https://doi.org/10.1056/NEJMoa2031054" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="33283989">Frangoul et al. (2021)</a> reported targeting the BCL11 (<a href="/entry/606557">606557</a>) erythroid-specific enhancer with CRISPR-Cas9 in autologous CD34+ cells and investigational administration following myeloablation in 2 patients, one with transfusion-dependent sickle cell disease (<a href="/entry/603903">603903</a>) and the other with transfusion-dependent beta-thalassemia (<a href="/entry/613985">613985</a>). One year later each had high levels of allelic editing in bone marrow and blood, increases in fetal hemoglobin that were distributed pancellularly, transfusion independence, and, for the patient with sickle cell disease, elimination of vasoocclusive episodes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=33283989" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#15" class="mim-tip-reference" title="Locatelli, F., Lang, P., Wall, D., Meisel, R., Corbacioglu, S., Li, A. M., de la Fuente, J., Shah, A. J., Carpenter, B., Kwiatkowski, J. L., Mapara, M., Liem, R. I., and 16 others. <strong>Exagamglogene autotemcel for transfusion-dependent beta-thalassemia.</strong> New Eng. J. Med. 390: 1663-1676, 2024.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/38657265/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">38657265</a>] [<a href="https://doi.org/10.1056/NEJMoa2309673" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="38657265">Locatelli et al. (2024)</a> conducted an open-label, single-group, phase 3 study of exagamglogene autotemcel (exa-cel), a nonviral cell therapy designed to reactivate fetal hemoglobin, in 52 patients aged 12 to 35 years with transfusion-dependent beta-thalassemia and a beta-0/beta-0, beta-0/beta-0-like, or non-beta-0/beta-0-like genotype. CD34+ hematopoietic stem and progenitor cells (HSPCs) were edited by means of CRISPR-Cas9 with a guide mRNA targeting the BCL11A locus. Before the exa-cel infusion, patients underwent myeloablative conditioning with pharmacokinetically dose-adjusted busulfan. The primary endpoint was transfusion independence, defined as a weighted average hemoglobin level of 9 g/dL or higher without red cell transfusion for at least 12 consecutive months. Total and fetal hemoglobin concentrations and safety were also assessed. Among the 52 patients included in this prespecified interim analysis, the median follow-up was 20.4 months (range, 2.1 to 48.1) and all had neutrophil and platelet engraftment. Among 35 patients with sufficient follow-up for evaluation, transfusion independence occurred in 32 (91%, 95% CI 77-98, p less than 0.001 against the null hypothesis of a 50% response). During transfusion independence, mean hemoglobin was 13.1 g/dL and mean fetal hemoglobin was 11.9 g/dL. Fetal hemoglobin was detected in 94% or more of red cells. The safety profile of exa-cel was generally consistent with that of myeloablative busulfan conditioning and autologous HSPC transplantation. No deaths or cancers occurred. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=38657265" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>Luspatercept</em></strong></p><p>
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Luspatercept is a recombinant fusion protein that binds to select transforming growth factor-beta superfamily ligands and may enhance erythroid maturation and reduce the transfusion burden in beta-thalassemia patients. <a href="#6" class="mim-tip-reference" title="Cappellini, M. D., Viprakasit, V., Taher, A. T., Georgiev, P., Kuo, K. H. M., Coates, T., Voskaridou, E., Liew, H.-K., Pazgal-Kobrowski, I., Forni, G. L., Perrotta, S., Khelif, A., and 28 others. <strong>A phase 3 trial of luspatercept in patients with transfusion-dependent beta-thalassemia.</strong> New Eng. J. Med. 382: 1219-1231, 2020.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/32212518/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">32212518</a>] [<a href="https://doi.org/10.1056/NEJMoa1910182" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="32212518">Cappellini et al. (2020)</a> reported a randomized, double-blind, phase 3 trial, in which adults with transfusion-dependent beta-thalassemia were randomized in a 2:1 ratio, to receive best supportive care plus luspatercept (at a dose of 1.00-1.25 mg/kg of body weight) or placebo for at least 48 weeks. The primary end point was the percentage of patients who had a reduction in the transfusion burden of at least 33% from baseline during weeks 13 through 24 plus a reduction of at least 2 red-cell units over this 12-week interval. Other efficacy end points included reductions in the transfusion burden during any 12-week interval and results of iron studies. A total of 224 patients were assigned to the luspatercept group and 112 to the placebo group. Luspatercept or placebo was administered for a median of approximately 64 weeks in both groups. The percentage of patients who achieved the primary end point was significantly greater in the luspatercept group than in the placebo group (21.4% vs 4.5%, p less than 0.001). During any 12-week interval, the percentage of patients who had a reduction in transfusion burden of at least 33% was greater in the luspatercept group than in the placebo group (70.5% vs 29.5%), as was the percentage of those who had a reduction of at least 50% (40.2% vs 6.3%). The least-squares mean difference between the groups in serum ferritin levels at week 48 was -348 microgram/liter in favor of luspatercept. Adverse events of transient bone pain, arthralgia, dizziness, hypertension, and hyperuricemia were more common with luspatercept than placebo. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=32212518" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>Beta-thalassemia is one of the most common autosomal recessive disorders worldwide. It is highly prevalent in populations in the Mediterranean, Middle East, Transcaucasus, Central Asia, Indian subcontinent, and Far East. It is also relatively common in populations of African descent. The highest incidences are reported in Cyprus (14%), Sardinia (12%), and Southeast Asia (<a href="#4" class="mim-tip-reference" title="Cao, A., Galanello, R. <strong>Beta-thalassemia.</strong> Genet. Med. 12: 61-76, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20098328/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20098328</a>] [<a href="https://doi.org/10.1097/GIM.0b013e3181cd68ed" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20098328">Cao and Galanello, 2010</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20098328" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 Lebanon, beta-thalassemia is the predominant genetic defect. <a href="#18" class="mim-tip-reference" title="Makhoul, N. J., Wells, R. S., Kaspar, H., Shbaklo, H., Taher, A., Chakar, N., Zalloua, P. A. <strong>Genetic heterogeneity of beta thalassemia in Lebanon reflects historic and recent population migration.</strong> Ann. Hum. Genet. 69: 55-66, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15638828/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15638828</a>] [<a href="https://doi.org/10.1046/j.1529-8817.2004.00138.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15638828">Makhoul et al. (2005)</a> investigated the religious and geographic distribution of beta-thalassemia mutations in Lebanon and traced their origins. Sunni Muslims had the highest beta-thalassemia carrier rate and presented the greatest heterogeneity, with 16 different mutations. Shiite Muslims followed closely with 13 mutations, whereas Maronites represented 11.9% of all beta-thalassemic subjects and carried 7 different mutations. RFLP haplotype analysis showed that the observed genetic diversity originated from both new mutational events and gene flow from population migration. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15638828" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>The estimated number of worldwide annual births of patients with beta-thalassemia major is 22,989; for beta-E-thalassemia, 19,128; and for S-beta thalassemia, 11,074 (<a href="#19" class="mim-tip-reference" title="Modell, B., Darlison, M. <strong>Global epidemiology of haemoglobin disorders and derived service indicators.</strong> Bull. World Health Organ. 86: 480-487, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18568278/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18568278</a>] [<a href="https://doi.org/10.2471/blt.06.036673" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18568278">Modell and Darlison, 2008</a> and <a href="#37" class="mim-tip-reference" title="Weatherall, D. J. <strong>The inherited diseases of hemoglobin are an emerging global health burden.</strong> Blood 115: 4331-4336, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20233970/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20233970</a>] [<a href="https://doi.org/10.1182/blood-2010-01-251348" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20233970">Weatherall, 2010</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=18568278+20233970" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>Molecular Genetics</strong>
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<p>For a review of mutations in the HBB gene and the beta-globin gene cluster causing beta-thalassemia, see <a href="/entry/141900">141900</a>.</p><p><a href="#33" class="mim-tip-reference" title="Uda, M., Galanello, R., Sanna, S., Lettre, G., Sankaran, V. G., Chen, W., Usala, G., Busonero, F., Maschio, A., Albai, G., Piras, M. G., Sestu, N., and 18 others. <strong>Genome-wide association study shows BCL11A associated with persistent fetal hemoglobin and amelioration of the phenotype of beta-thalassemia.</strong> Proc. Nat. Acad. Sci. 105: 1620-1625, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18245381/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18245381</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18245381[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/10.1073/pnas.0711566105" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18245381">Uda et al. (2008)</a> found that the C allele of <a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs11886868;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs11886868</a> in the BCL11A gene (<a href="/entry/606557">606557</a>) was associated with an ameliorated phenotype in patients with beta-thalassemia due to increased production of fetal hemoglobin. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18245381" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a href="#Cai1989" class="mim-tip-reference" title="Cai, S.-P., Zhang, J.-Z., Doherty, M., Kan, Y. W. <strong>A new TATA box mutation detected at prenatal diagnosis for beta-thalassemia.</strong> Am. J. Hum. Genet. 45: 112-114, 1989.">Cai et al. (1989)</a>; <a href="#Kazazian1982" class="mim-tip-reference" title="Kazazian, H. H., Jr., Fearon, E. R., Waber, P. G., Lee, J. I., Antonarakis, S. E., Orkin, S. H., Vanin, E. F., Heathorn, P. S., Grosveld, F. G., Buchanan, G. R. <strong>Gamma-delta-beta thalassemia: deletion of the entire beta-globin gene cluster. (Abstract)</strong> Blood 60: 54A, 1982.">Kazazian et al. (1982)</a>; <a href="#Pirastu1983" class="mim-tip-reference" title="Pirastu, M., Kan, Y. W., Cao, A., Conner, B. J., Teplitz, R. L., Wallace, R. B. <strong>Prenatal diagnosis of beta-thalassemia: detection of a single nucleotide mutation in DNA.</strong> New Eng. J. Med. 309: 284-287, 1983.">Pirastu et al. (1983)</a>
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Arlet, J.-B., Ribeil, J.-A., Guillem, F., Negre, O., Hazoume, A., Marcion, G., Beuzard, Y., Dussiot, M., Moura, I. C., Demarest, S., de Beauchene, I. C., Belaid-Choucair, Z., and 12 others.
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<strong>HSP70 sequestration by free alpha-globin promotes ineffective erythropoiesis in beta-thalassaemia.</strong>
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Nature 514: 242-246, 2014.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25156257/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25156257</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25156257" 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/10.1038/nature13614" target="_blank">Full Text</a>]
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Cai, S.-P., Zhang, J.-Z., Doherty, M., Kan, Y. W.
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<strong>A new TATA box mutation detected at prenatal diagnosis for beta-thalassemia.</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2741940/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2741940</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2741940" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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<a id="Camaschella1987" class="mim-anchor"></a>
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Camaschella, C., Bertero, M. T., Serra, A., Dall'Acqua, M., Gasparini, P., Trento, M., Vettore, L., Perona, G., Saglio, G., Mazza, U.
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<strong>A benign form of thalassaemia intermedia may be determined by the interaction of triplicated alpha locus and heterozygous beta-thalassaemia.</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3593644/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3593644</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=3593644" 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/10.1111/j.1365-2141.1987.tb06897.x" target="_blank">Full Text</a>]
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Cao, A., Galanello, R.
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[<a href="https://doi.org/10.1097/GIM.0b013e3181cd68ed" target="_blank">Full Text</a>]
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<a id="Cao2000" class="mim-anchor"></a>
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Cao, A., Moi, P.
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<strong>Genetic modifying factors in beta-thalassemia.</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10834399/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10834399</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10834399" 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/10.1515/CCLM.2000.019" target="_blank">Full Text</a>]
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<a id="Cappellini2020" class="mim-anchor"></a>
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Cappellini, M. D., Viprakasit, V., Taher, A. T., Georgiev, P., Kuo, K. H. M., Coates, T., Voskaridou, E., Liew, H.-K., Pazgal-Kobrowski, I., Forni, G. L., Perrotta, S., Khelif, A., and 28 others.
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<strong>A phase 3 trial of luspatercept in patients with transfusion-dependent beta-thalassemia.</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/32212518/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">32212518</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=32212518" 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/NEJMoa1910182" target="_blank">Full Text</a>]
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Cavazzana-Calvo, M., Payen, E., Negre, O., Wang, G., Hehir, K., Fusil, F., Down, J., Denaro, M., Brady, T., Westerman, K., Cavallesco, R., Gillet-Legrand, B., and 26 others.
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Nature 467: 318-322, 2010.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20844535/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20844535</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20844535[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=20844535" 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/10.1038/nature09328" target="_blank">Full Text</a>]
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Ding, C., Chiu, R. W. K., Lau, T. K., Leung, T. N., Chan, L. C., Chan, A. Y. Y., Charoenkwan, P., Ng, I. S. L., Law, H., Ma, E. S. K., Xu, X., Wanapirak, C., Sanguansermsri, T., Liao, C., Ai, M. A. T. J., Chui, D. H. K., Cantor, C. R.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15247415/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15247415</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15247415[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=15247415" 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/10.1073/pnas.0403962101" target="_blank">Full Text</a>]
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<a id="Frangoul2021" class="mim-anchor"></a>
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Frangoul, H., Altshuler, D., Cappellini, M. D., Chen, Y.-S., Domm, J., Eustace, B. K., Foell, J., de la Fuente, J., Grupp, S., Handgretinger, R., Ho, T. W., Kattamis, A., and 14 others.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/33283989/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">33283989</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=33283989" 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/NEJMoa2031054" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1038/nature10317" target="_blank">Full Text</a>]
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<a id="Holding1989" class="mim-anchor"></a>
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<strong>Diagnosis of beta-thalassemia by DNA amplification in single blastomeres from mouse preimplantation embryos.</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2570237/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2570237</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2570237" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1016/s0140-6736(89)90655-7" target="_blank">Full Text</a>]
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<a id="Kazazian1982" class="mim-anchor"></a>
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<div class="">
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Kazazian, H. H., Jr., Fearon, E. R., Waber, P. G., Lee, J. I., Antonarakis, S. E., Orkin, S. H., Vanin, E. F., Heathorn, P. S., Grosveld, F. G., Buchanan, G. R.
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<strong>Gamma-delta-beta thalassemia: deletion of the entire beta-globin gene cluster. (Abstract)</strong>
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Blood 60: 54A, 1982.
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<strong>Thalassaemia intermedia: interaction of the triple alpha-globin gene arrangement and heterozygous beta-thalassaemia.</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3593645/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3593645</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=3593645" 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/10.1111/j.1365-2141.1987.tb06898.x" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1056/NEJM198212093072401" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1056/NEJMoa2309673" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1056/NEJM199002153220701" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1210/jc.2002-021548" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1046/j.1529-8817.2004.00138.x" target="_blank">Full Text</a>]
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3405266/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3405266</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=3405266" 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/NEJM198809013190903" target="_blank">Full Text</a>]
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</p>
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<a id="31" class="mim-anchor"></a>
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<a id="Taher2021" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Taher, A. T., Musallam, K. M., Cappellini, M. D.
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<strong>Beta-thalassemias.</strong>
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New Eng. J. Med. 384: 727-743, 2021.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/33626255/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">33626255</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=33626255" 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/NEJMra2021838" target="_blank">Full Text</a>]
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<a id="32" class="mim-anchor"></a>
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<a id="Thompson2018" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Thompson, A. A., Walters, M. C., Kwiatkowski, J., Rasko, J. E. J., Ribeil, J. A., Hongeng, S., Magrin, E., Schiller, G. J., Payen, E., Semeraro, M., Moshous, D., Lefrere, F., and 35 others.
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<strong>Gene therapy in patients with transfusion-dependent beta-thalassemia.</strong>
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New Eng. J. Med. 378: 1479-1493, 2018.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29669226/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29669226</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=29669226" 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/NEJMoa1705342" target="_blank">Full Text</a>]
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<li>
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<a id="33" class="mim-anchor"></a>
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<a id="Uda2008" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Uda, M., Galanello, R., Sanna, S., Lettre, G., Sankaran, V. G., Chen, W., Usala, G., Busonero, F., Maschio, A., Albai, G., Piras, M. G., Sestu, N., and 18 others.
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|
<strong>Genome-wide association study shows BCL11A associated with persistent fetal hemoglobin and amelioration of the phenotype of beta-thalassemia.</strong>
|
|
Proc. Nat. Acad. Sci. 105: 1620-1625, 2008.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18245381/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18245381</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18245381[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=18245381" 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/10.1073/pnas.0711566105" target="_blank">Full Text</a>]
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<li>
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<a id="34" class="mim-anchor"></a>
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<a id="Wainscoat1983" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Wainscoat, J. S., Kanavakis, E., Wood, W. G., Letsky, E. A., Huehns, E. R., Marsh, G. W., Higgs, D. R., Clegg, J. B., Weatherall, D. J.
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<strong>Thalassaemia intermedia in Cyprus: the interaction of alpha- and beta-thalassaemia.</strong>
|
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Brit. J. Haemat. 53: 411-416, 1983.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/6297530/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">6297530</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=6297530" 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/10.1111/j.1365-2141.1983.tb02041.x" target="_blank">Full Text</a>]
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<li>
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<a id="35" class="mim-anchor"></a>
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<a id="Weatherall1995" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Weatherall, D. J., Clegg, J. B., Higgs, D. R., Wood, W. G.
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<strong>The hemoglobinopathies.In: Scriver, C.; Beaudet, A. L.; Sly, W. S.; Valle, D. (eds.) : The Metabolic and Molecular Bases of Inherited Disease. (7th ed.)</strong>
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New York: McGraw-Hill 1995. Pp. 3417-3484.
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</div>
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<a id="36" class="mim-anchor"></a>
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<a id="Weatherall2001" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Weatherall, D. J.
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<strong>Phenotype-genotype relationships in monogenic disease: lessons from the thalassaemias.</strong>
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Nature Rev. Genet. 2: 245-255, 2001.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11283697/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11283697</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11283697" 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/10.1038/35066048" target="_blank">Full Text</a>]
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<a id="37" class="mim-anchor"></a>
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<a id="Weatherall2010" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Weatherall, D. J.
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<strong>The inherited diseases of hemoglobin are an emerging global health burden.</strong>
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Blood 115: 4331-4336, 2010.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20233970/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20233970</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20233970" 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/10.1182/blood-2010-01-251348" target="_blank">Full Text</a>]
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</ol>
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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 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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Ada Hamosh - updated : 05/14/2024
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</span>
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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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Ada Hamosh - updated : 03/08/2021<br>Ada Hamosh - updated : 06/05/2020<br>Ada Hamosh - updated : 05/08/2018<br>Ada Hamosh - updated : 01/26/2015<br>Cassandra L. Kniffin - updated : 2/14/2013<br>Paul J. Converse - updated : 2/13/2012
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</span>
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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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<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 A. Bocchini : 5/19/2011
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<a id="editHistory" class="mim-anchor"></a>
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<span class="text-nowrap mim-text-font">
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<a href="#mimCollapseEditHistory" role="button" data-toggle="collapse"> Edit History: </a>
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<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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alopez : 05/14/2024
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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 : 09/09/2022<br>alopez : 03/08/2021<br>alopez : 06/05/2020<br>alopez : 05/08/2018<br>alopez : 05/08/2018<br>alopez : 01/26/2015<br>alopez : 2/20/2013<br>ckniffin : 2/14/2013<br>terry : 10/10/2012<br>mgross : 2/16/2012<br>mgross : 2/16/2012<br>terry : 2/13/2012<br>mgross : 12/16/2011<br>carol : 5/24/2011<br>carol : 5/23/2011<br>terry : 5/20/2011<br>carol : 5/20/2011
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</span>
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<h3>
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<span class="mim-font">
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<strong>#</strong> 613985
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</span>
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</h3>
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</div>
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<div>
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<h3>
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<span class="mim-font">
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BETA-THALASSEMIA
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<span class="mim-text-font">
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<strong>SNOMEDCT:</strong> 65959000;
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<strong>ICD10CM:</strong> D56.1;
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<strong>ICD9CM:</strong> 282.44;
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<strong>ORPHA:</strong> 231214, 231222, 848;
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<strong>DO:</strong> 12241;
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Phenotype-Gene Relationships</strong>
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</span>
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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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<th>
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Gene/Locus <br /> MIM number
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</th>
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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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11p15.4
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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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Thalassemia, beta
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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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613985
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<span class="mim-font">
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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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HBB
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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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141900
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<tr>
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<td>
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<span class="mim-font">
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11p15.4
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</td>
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<td>
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<span class="mim-font">
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Thalassemia, Hispanic gamma-delta-beta
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<td>
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<span class="mim-font">
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613985
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<td>
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<span class="mim-font">
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<td>
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<span class="mim-font">
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3
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</td>
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<td>
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<span class="mim-font">
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LCRB
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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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152424
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</table>
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<br />
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<div>
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<h4>
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<span class="mim-font">
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<strong>TEXT</strong>
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</span>
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</h4>
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<span class="mim-text-font">
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<p>A number sign (#) is used with this entry because beta-thalassemia can be caused by homozygous or compound heterozygous mutation in the beta-globin gene (HBB; 141900) on chromosome 11p15.</p><p>Beta-thalassemia may also be due to deletion of the entire beta-globin gene cluster or of sequences 5-prime from the beta-globin gene cluster; these sequences are referred to as the locus control region beta (LCRB; 152424).</p>
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</span>
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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>Beta-thalassemia is characterized by a reduced production of hemoglobin A (HbA, alpha-2/beta-2), which results from the reduced synthesis of beta-globin chains relative to alpha-globin chains, thus causing an imbalance in globin chain production and hence abnormal erythropoiesis. The disorder is clinically heterogeneous (summary by Ottolenghi et al., 1975). </p><p>Absence of beta globin causes beta-zero-thalassemia. Reduced amounts of detectable beta globin causes beta-plus-thalassemia. For clinical purposes, beta-thalassemia is divided into thalassemia major (transfusion dependent), thalassemia intermedia (of intermediate severity), and thalassemia minor (asymptomatic, carrier state). The molecular and clinical aspects of the beta-thalassemias were reviewed by Olivieri (1999). </p><p>The remarkable phenotypic diversity of the beta-thalassemias reflects the heterogeneity of mutations at the HBB locus, the action of many secondary and tertiary modifiers, and a wide range of environmental factors (Weatherall, 2001). </p><p>For a review of beta-thalassemia, see Taher et al. (2021). </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<strong>Clinical Features</strong>
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<p>Patients with thalassemia major present in the first year of life with severe anemia; they are unable to maintain a hemoglobin level about 5 gm/dl. Clinical details of this disorder have been detailed extensively in numerous monographs and were summarized by Weatherall et al. (1995). Modell et al. (2000) found that about 50% of UK patients with beta-thalassemia major die before the age of 35 years, mainly because conventional iron-chelation therapy is too burdensome for full adherence. </p><p>Cao and Galanello (2010) reviewed the clinical features of the 3 forms of beta-thalassemia. Affected infants with thalassemia major fail to thrive and become progressively pale. Feeding problems, diarrhea, irritability, recurrent bouts of fever, and enlargement of the abdomen, caused by splenomegaly, may occur. If an adequate transfusion program is followed, growth and development are normal until age 10 to 11 years. Afterwards, affected individuals are at risk of developing severe complications related to posttransfusional iron overload, depending on their compliance with chelation therapy. Patients with thalassemia intermedia show a markedly heterogeneous clinical picture. The principal symptoms are pallor, jaundice, cholelithiasis, liver and spleen enlargement, moderate to severe skeletal changes, leg ulcers, extramedullary masses of hyperplastic erythroid marrow, a tendency to develop osteopenia and osteoporosis, and thrombotic complications resulting from a hypercoagulable state because of the lipid membrane composition of the abnormal red blood cells (particularly in splenectomized patients). Transfusions are usually not required. Iron overload occurs mainly from increased intestinal absorption of iron caused by ineffective erythropoiesis. Carriers of beta-thalassemia are clinically asymptomatic. </p><p>Cao and Galanello (2010) also reviewed the hematologic findings in the 3 forms. Patients with thalassemia major have a severe microcytic and hypochromic anemia, associated with increased number of red blood cells and low mean corpuscular volume (MCV) and mean corpuscular Hb (MCH). Peripheral blood smear shows, in addition to microcytosis and hypochromia, anisocytosis, poikilocytosis (spiculated tear drop and elongated cells), and nucleated red blood cells (i.e., erythroblasts). The number of erythroblasts is related to the degree of anemia and is markedly increased after splenectomy. Patients with thalassemia intermedia have a moderate anemia and show a markedly heterogeneous hematologic picture, ranging in severity from that of the beta-thalassemia carrier state to that of thalassemia major. The characteristic hematologic features in carriers are microcytosis (reduced red blood cell volume), hypochromia (reduced red blood cell Hb content), increased HbA2 level (the minor component of the adult Hb, alpha2delta2), and unbalanced alpha/nonalpha globin chain synthesis. However, several environmental or genetic factors may modify this phenotype, leading either to thalassemia intermedia, despite the presence of a single beta-globin gene affected, or to hematologically atypical carrier state. </p><p>Some atypical beta-thalassemia heterozygotes have either normal red cell indices or normal HbA2 level, or both, with a completely silent hematologic phenotype. This condition is detected only by the imbalanced alpha-nonalpha globin chain synthesis and is referred to as silent beta-thalassemia (Cao and Moi, 2000). </p><p>Wainscoat et al. (1983) showed that coinheritance of alpha-thalassemia with homozygous beta-thalassemia resulted in amelioration of the beta-thalassemia. </p><p>Kulozik et al. (1987) showed that heterozygous beta-thalassemia was associated with unusually severe clinical manifestations when coinherited with an extra alpha-globin gene; in each of 5 cases 1 chromosome 16 carried 3 alpha-globin genes. Camaschella et al. (1987) found the same aggravation of the clinical picture with triplicated alpha locus. This is a particularly instructive example of gene interaction. </p><p>To gain insight into the cellular and structural alterations of thalassemic bone, Mahachoklertwattana et al. (2003) studied bone histomorphometry and biochemical and hormonal profiles in children and adolescents with suboptimally treated beta-thalassemia disease. Seventeen patients underwent iliac crest bone biopsy for histomorphometric analyses. Most patients had growth retardation and delayed bone age. Bone mineral density (BMD) was low especially at the lumbar spine. Serum IGF1 (147440) levels were almost always low. Bone histomorphometry revealed increased osteoid thickness, osteoid maturation time, and mineralization lag time, which indicate impaired bone matrix maturation and defective mineralization. In addition, iron deposits appeared along mineralization fronts and osteoid surfaces. The authors concluded that delayed bone maturation and focal osteomalacia are the pathogenesis of bone disease in suboptimally blood-transfused thalassemics with iron overload. They suggested that iron deposits in bone and low circulating IGF1 levels may partly contribute to the above findings. </p><p>Premawardhena et al. (2005) studied 109 Sri Lankan hemoglobin E beta-thalassemia patients over 5 years. They found that 25 patients were not receiving transfusion, and transfusion was discontinued in an additional 37 patients without deleterious effect. Premawardhena et al. (2005) identified several genetic and environmental factors that may contribute to the phenotypic diversity of the disorder, including modifiers of hemoglobin F (see 142250) production, malaria (see 611162), and age-related changes in adaptive function. They proposed that hemoglobin E beta-thalassemia can be managed without transfusion in many patients and that age-related changes in the adaptation to anemia indicate that more cost-effective management approaches should be explored. </p><p>O'Donnell et al. (2009) studied Sri Lankan patients with HbE beta-thalassemia for exposure to malaria caused by Plasmodium falciparum or P. vivax. They found that there were high frequencies of antibodies to both malaria parasites, as well as DNA-based evidence of current infection with P. vivax. Comparisons with age-matched controls showed that there was a higher frequency of antibodies in thalassemic patients, particularly against P. vivax and in young children, that was unlikely to be related to transfusion. A higher frequency was also found in patients who had undergone splenectomy. O'Donnell et al. (2009) proposed that patients with HbE beta-thalassemia may be more prone to malaria, particularly P. vivax malaria. </p>
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<span class="mim-font">
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<strong>Pathogenesis</strong>
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</span>
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</h4>
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<p>Ribeil et al. (2007) demonstrated that in human erythroblasts, the chaperone HSP70 (see 140550) is constitutively expressed and, at later stages of maturation, translocates into the nucleus and protects GATA1 (305371) from CASP3 (600636) cleavage. The primary role of this ubiquitous chaperone is to participate in the refolding of proteins denatured by cytoplasmic stress, thus preventing their aggregation (Hartl et al., 2011). Arlet et al. (2014) showed in vitro that, during the maturation of beta-thalassemia major erythroblasts, HSP70 interacts directly with free alpha-globin chains. Consequently, HSP70 is sequestered in the cytoplasm and GATA1 is no longer protected, resulting in end-stage maturation arrest and apoptosis. Transduction of a nuclear-targeted HSP70 mutant or a CASP3-uncleavable GATA1 mutant restored terminal maturation of beta-thalassemia major erythroblasts, providing a rationale for targeted therapies. </p>
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<span class="mim-font">
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<strong>Diagnosis</strong>
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</span>
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<p><strong><em>Prenatal Diagnosis</em></strong></p><p>
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By means of a simplified method for trophoblast biopsy together with restriction endonuclease analysis of fetal DNA, Old et al. (1982) made first-trimester prenatal diagnosis in the case of 3 fetuses at risk for hemoglobinopathy: 2 at risk for homozygous beta-thalassemia and 1 at risk for sickle cell anemia. </p><p>Saiki et al. (1988) devised a simple and rapid nonradioactive method for detecting genetic variation and applied it to the diagnosis of sickle cell anemia and beta-thalassemia. The procedure involved the selective amplification of a segment of the human beta-globin gene with oligonucleotide primers and a thermostable DNA polymerase, followed by hybridization of the amplified DNA with allele-specific oligonucleotide probes covalently labeled with horseradish peroxidase. The hybridized probes were detected with a simple colorimetric assay. </p><p>In Sardinia, Rosatelli et al. (1985) used the synthetic oligonucleotide method for prenatal detection of the beta-zero-39 (nonsense) mutation type of beta-thalassemia. In a mouse model for beta-thalassemia, Holding and Monk (1989) were able to make the diagnosis in single blastomeres removed from embryos of 4 to 8 cells by PCR amplification. Monk and Holding (1990) demonstrated reproducible amplification of a 680-basepair sequence within the human beta-globin gene from individual human oocytes and the first polar bodies isolated from them. They used restriction enzyme digestion of the amplified DNA to confirm the identity of the fragment. The authors proposed that analysis of the DNA from the first polar body will facilitate preimplantation diagnosis of sickle cell anemia. </p><p>Ding et al. (2004) described a method for noninvasive prenatal diagnosis by analysis of circulating nucleic acids. Circulating fetal-specific DNA sequences have been detected and constitute a fraction of the total DNA in maternal plasma. The robust discrimination of single-nucleotide differences between circulating DNA species is technically challenging and demanded the adoption of highly sensitive and specific analytical systems. Ding et al. (2004) developed a method based on single-allele base extension reaction and mass spectrometry which allowed for the reliable detection of fetal-specific alleles, including point mutations and SNPs, in maternal plasma. The approach was applied to exclude the fetal inheritance of the 4 most common Southeast Asian beta-thalassemia mutations in at-risk pregnancies between weeks 7 and 21 of gestation: 41/42delCTTT (141900.0326), IVS2 654C-T (141900.0368), -28A-G (141900.0381), and 17A-T (141900.0311). Fetal genotypes were correctly predicted in all cases studied. Fetal haplotype analysis based on a SNP linked to the HBB gene in maternal plasma also was achieved. </p>
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<h4>
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<span class="mim-font">
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<strong>Clinical Management</strong>
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<p><strong><em>Bone Marrow Transplantation</em></strong></p><p>
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Ley et al. (1982) treated homozygous beta-plus-thalassemia in a 42-year-old black American man with 5-azacytidine. An increase in hemoglobin concentration occurred. Hypomethylation of both the gamma-globin and the epsilon-globin gene was shown, as well as an increase in gamma-globin mRNA. Lucarelli et al. (1990) reviewed results from 222 consecutive patients in whom bone marrow transplantation (BMT) was performed for thalassemia since 1983. The results were analyzed, in particular, in the 116 consecutive patients treated since June 1985. The allogeneic marrow came from HLA-identical donors, and the patients all had beta-thalassemia and were less than 16 years old. They concluded that bone marrow transplantation offered a high probability of complication-free survival, if the recipient did not have hepatomegaly or portal fibrosis. </p><p><strong><em>Gene Therapy</em></strong></p><p>
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Gene therapy for beta-thalassemia is particularly challenging given the requirement for massive hemoglobin production in a lineage-specific manner and the lack of selective advantage for corrected hematopoietic stem cells. Compound beta-E/beta-0-thalassemia is the most common form of severe thalassemia in southeast Asian countries and their diasporas. The beta-E-globin allele (141900.0071) bears a point mutation that causes alternative splicing. The abnormally spliced form is noncoding, whereas the correctly spliced mRNA expresses a mutated beta-E-globin with partial instability. When this is compounded with a nonfunctional beta-0 allele, a profound decrease in beta-globin synthesis results, and approximately half of beta-E/beta-0-thalassemia patients are transfusion-dependent. The only available curative therapy is allogeneic hematopoietic stem cell transplantation, although most patients do not have a human leukocyte antigen (HLA)-matched, genoidentical donor, and those who do still risk rejection or graft-versus-host disease (GVHD; see 614395). Cavazzana-Calvo et al. (2010) showed that, 33 months after lentiviral beta-globin gene transfer, an adult patient with severe beta-E/beta-0-thalassemia dependent on monthly transfusions since early childhood had become transfusion-independent for the preceding 21 months. Blood hemoglobin was maintained between 9 and 10 g/dL, of which one-third contained vector-encoded beta-globin. Most of the therapeutic benefit resulted from a dominant, myeloid-biased cell clone, in which the integrated vector caused transcriptional activation of HMGA2 (600698) in erythroid cells with further increased expression of a truncated HMGA2 mRNA insensitive to degradation by let-7 microRNAs (see 605386). Cavazzana-Calvo et al. (2010) suggested that the clonal dominance that accompanies therapeutic efficacy may be coincidental and stochastic or result from a hitherto benign cell expansion caused by dysregulation of the HMGA2 gene in stem/progenitor cells. </p><p>Thompson et al. (2018) reported the results of 2 phase 1/2 studies using autologous CD34+ cells transduced with LentiGlobin BB305 vector, which encodes adult hemoglobin (HbA) with a T87Q amino acid substitution for monitoring. This study comprised 22 patients who had undergone myeloablative busulfan conditioning prior to reinfusion. At a median of 26 months (range, 15 to 42) after infusion of the gene-modified cells, all but 1 of the 13 patients who had a non-beta-0/beta-0 genotype had stopped receiving red-cell transfusions; the levels of HbA(T87Q) ranged from 3.4 to 10.0 g/dl, and the levels of total hemoglobin ranged from 8.2 to 13.7 g/dl. Correction of biologic markers of dyserythropoiesis was achieved in evaluated patients with hemoglobin levels near normal ranges. In 9 patients with a beta-0/beta-0 genotype or 2 copies of the IVS1-110 mutation (141900.0364), the median annualized transfusion volume was decreased by 73%, and red-cell transfusions were discontinued in 3. Treatment-related adverse events were typical of those associated with autologous stem-cell transplantation. No clonal dominance related to vector integration was observed. </p><p>Frangoul et al. (2021) reported targeting the BCL11 (606557) erythroid-specific enhancer with CRISPR-Cas9 in autologous CD34+ cells and investigational administration following myeloablation in 2 patients, one with transfusion-dependent sickle cell disease (603903) and the other with transfusion-dependent beta-thalassemia (613985). One year later each had high levels of allelic editing in bone marrow and blood, increases in fetal hemoglobin that were distributed pancellularly, transfusion independence, and, for the patient with sickle cell disease, elimination of vasoocclusive episodes. </p><p>Locatelli et al. (2024) conducted an open-label, single-group, phase 3 study of exagamglogene autotemcel (exa-cel), a nonviral cell therapy designed to reactivate fetal hemoglobin, in 52 patients aged 12 to 35 years with transfusion-dependent beta-thalassemia and a beta-0/beta-0, beta-0/beta-0-like, or non-beta-0/beta-0-like genotype. CD34+ hematopoietic stem and progenitor cells (HSPCs) were edited by means of CRISPR-Cas9 with a guide mRNA targeting the BCL11A locus. Before the exa-cel infusion, patients underwent myeloablative conditioning with pharmacokinetically dose-adjusted busulfan. The primary endpoint was transfusion independence, defined as a weighted average hemoglobin level of 9 g/dL or higher without red cell transfusion for at least 12 consecutive months. Total and fetal hemoglobin concentrations and safety were also assessed. Among the 52 patients included in this prespecified interim analysis, the median follow-up was 20.4 months (range, 2.1 to 48.1) and all had neutrophil and platelet engraftment. Among 35 patients with sufficient follow-up for evaluation, transfusion independence occurred in 32 (91%, 95% CI 77-98, p less than 0.001 against the null hypothesis of a 50% response). During transfusion independence, mean hemoglobin was 13.1 g/dL and mean fetal hemoglobin was 11.9 g/dL. Fetal hemoglobin was detected in 94% or more of red cells. The safety profile of exa-cel was generally consistent with that of myeloablative busulfan conditioning and autologous HSPC transplantation. No deaths or cancers occurred. </p><p><strong><em>Luspatercept</em></strong></p><p>
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Luspatercept is a recombinant fusion protein that binds to select transforming growth factor-beta superfamily ligands and may enhance erythroid maturation and reduce the transfusion burden in beta-thalassemia patients. Cappellini et al. (2020) reported a randomized, double-blind, phase 3 trial, in which adults with transfusion-dependent beta-thalassemia were randomized in a 2:1 ratio, to receive best supportive care plus luspatercept (at a dose of 1.00-1.25 mg/kg of body weight) or placebo for at least 48 weeks. The primary end point was the percentage of patients who had a reduction in the transfusion burden of at least 33% from baseline during weeks 13 through 24 plus a reduction of at least 2 red-cell units over this 12-week interval. Other efficacy end points included reductions in the transfusion burden during any 12-week interval and results of iron studies. A total of 224 patients were assigned to the luspatercept group and 112 to the placebo group. Luspatercept or placebo was administered for a median of approximately 64 weeks in both groups. The percentage of patients who achieved the primary end point was significantly greater in the luspatercept group than in the placebo group (21.4% vs 4.5%, p less than 0.001). During any 12-week interval, the percentage of patients who had a reduction in transfusion burden of at least 33% was greater in the luspatercept group than in the placebo group (70.5% vs 29.5%), as was the percentage of those who had a reduction of at least 50% (40.2% vs 6.3%). The least-squares mean difference between the groups in serum ferritin levels at week 48 was -348 microgram/liter in favor of luspatercept. Adverse events of transient bone pain, arthralgia, dizziness, hypertension, and hyperuricemia were more common with luspatercept than placebo. </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>Population Genetics</strong>
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</span>
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</h4>
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<span class="mim-text-font">
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<p>Beta-thalassemia is one of the most common autosomal recessive disorders worldwide. It is highly prevalent in populations in the Mediterranean, Middle East, Transcaucasus, Central Asia, Indian subcontinent, and Far East. It is also relatively common in populations of African descent. The highest incidences are reported in Cyprus (14%), Sardinia (12%), and Southeast Asia (Cao and Galanello, 2010). </p><p>In Lebanon, beta-thalassemia is the predominant genetic defect. Makhoul et al. (2005) investigated the religious and geographic distribution of beta-thalassemia mutations in Lebanon and traced their origins. Sunni Muslims had the highest beta-thalassemia carrier rate and presented the greatest heterogeneity, with 16 different mutations. Shiite Muslims followed closely with 13 mutations, whereas Maronites represented 11.9% of all beta-thalassemic subjects and carried 7 different mutations. RFLP haplotype analysis showed that the observed genetic diversity originated from both new mutational events and gene flow from population migration. </p><p>The estimated number of worldwide annual births of patients with beta-thalassemia major is 22,989; for beta-E-thalassemia, 19,128; and for S-beta thalassemia, 11,074 (Modell and Darlison, 2008 and Weatherall, 2010). </p>
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</span>
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<h4>
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<span class="mim-font">
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<strong>Molecular Genetics</strong>
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</span>
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</h4>
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<span class="mim-text-font">
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<p>For a review of mutations in the HBB gene and the beta-globin gene cluster causing beta-thalassemia, see 141900.</p><p>Uda et al. (2008) found that the C allele of rs11886868 in the BCL11A gene (606557) was associated with an ameliorated phenotype in patients with beta-thalassemia due to increased production of fetal hemoglobin. </p>
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</span>
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>See Also:</strong>
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</span>
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</h4>
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<span class="mim-text-font">
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Cai et al. (1989); Kazazian et al. (1982); Pirastu et al. (1983)
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</span>
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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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<p />
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</div>
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<ol>
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Arlet, J.-B., Ribeil, J.-A., Guillem, F., Negre, O., Hazoume, A., Marcion, G., Beuzard, Y., Dussiot, M., Moura, I. C., Demarest, S., de Beauchene, I. C., Belaid-Choucair, Z., and 12 others.
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<strong>HSP70 sequestration by free alpha-globin promotes ineffective erythropoiesis in beta-thalassaemia.</strong>
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Nature 514: 242-246, 2014.
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[PubMed: 25156257]
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[Full Text: https://doi.org/10.1038/nature13614]
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<p class="mim-text-font">
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Cai, S.-P., Zhang, J.-Z., Doherty, M., Kan, Y. W.
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<strong>A new TATA box mutation detected at prenatal diagnosis for beta-thalassemia.</strong>
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Am. J. Hum. Genet. 45: 112-114, 1989.
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[PubMed: 2741940]
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Camaschella, C., Bertero, M. T., Serra, A., Dall'Acqua, M., Gasparini, P., Trento, M., Vettore, L., Perona, G., Saglio, G., Mazza, U.
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<strong>A benign form of thalassaemia intermedia may be determined by the interaction of triplicated alpha locus and heterozygous beta-thalassaemia.</strong>
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Brit. J. Haemat. 66: 103-107, 1987.
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[PubMed: 3593644]
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[Full Text: https://doi.org/10.1111/j.1365-2141.1987.tb06897.x]
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<p class="mim-text-font">
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Cao, A., Galanello, R.
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<strong>Beta-thalassemia.</strong>
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Genet. Med. 12: 61-76, 2010.
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[PubMed: 20098328]
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Cao, A., Moi, P.
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<strong>Genetic modifying factors in beta-thalassemia.</strong>
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Clin. Chem. Lab. Med. 38: 123-132, 2000.
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Cappellini, M. D., Viprakasit, V., Taher, A. T., Georgiev, P., Kuo, K. H. M., Coates, T., Voskaridou, E., Liew, H.-K., Pazgal-Kobrowski, I., Forni, G. L., Perrotta, S., Khelif, A., and 28 others.
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<strong>A phase 3 trial of luspatercept in patients with transfusion-dependent beta-thalassemia.</strong>
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New Eng. J. Med. 382: 1219-1231, 2020.
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[PubMed: 32212518]
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[Full Text: https://doi.org/10.1056/NEJMoa1910182]
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Cavazzana-Calvo, M., Payen, E., Negre, O., Wang, G., Hehir, K., Fusil, F., Down, J., Denaro, M., Brady, T., Westerman, K., Cavallesco, R., Gillet-Legrand, B., and 26 others.
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<strong>Transfusion independence and HMGA2 activation after gene therapy of human beta-thalassaemia.</strong>
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Nature 467: 318-322, 2010.
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[PubMed: 20844535]
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Ding, C., Chiu, R. W. K., Lau, T. K., Leung, T. N., Chan, L. C., Chan, A. Y. Y., Charoenkwan, P., Ng, I. S. L., Law, H., Ma, E. S. K., Xu, X., Wanapirak, C., Sanguansermsri, T., Liao, C., Ai, M. A. T. J., Chui, D. H. K., Cantor, C. R.
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<strong>MS analysis of single-nucleotide differences in circulating nucleic acids: application to noninvasive prenatal diagnosis.</strong>
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Proc. Nat. Acad. Sci. 101: 10762-10767, 2004.
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[PubMed: 15247415]
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<span class="mim-text-font">
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Ada Hamosh - updated : 05/14/2024<br>Ada Hamosh - updated : 03/08/2021<br>Ada Hamosh - updated : 06/05/2020<br>Ada Hamosh - updated : 05/08/2018<br>Ada Hamosh - updated : 01/26/2015<br>Cassandra L. Kniffin - updated : 2/14/2013<br>Paul J. Converse - updated : 2/13/2012
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Carol A. Bocchini : 5/19/2011
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