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Entry
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- #277460 - ATAXIA WITH VITAMIN E DEFICIENCY; AVED
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- OMIM
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<p>
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<span class="h4">#277460</span>
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<br />
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<strong>Table of Contents</strong>
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<a href="#title"><strong>Title</strong></a>
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<a href="#phenotypeMap"><strong>Phenotype-Gene Relationships</strong></a>
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<a href="/clinicalSynopsis/277460"><strong>Clinical Synopsis</strong></a>
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<a href="#text"><strong>Text</strong></a>
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<a href="#clinicalFeatures">Clinical Features</a>
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<a href="#mapping">Mapping</a>
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<a href="#molecularGenetics">Molecular Genetics</a>
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<a href="#heterogeneity">Heterogeneity</a>
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<a href="#references"><strong>References</strong></a>
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<a href="#contributors"><strong>Contributors</strong></a>
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<a href="#creationDate"><strong>Creation Date</strong></a>
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<a href="#editHistory"><strong>Edit History</strong></a>
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<div style="display: table-cell;">External Links</div>
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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 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=ATAXIA WITH VITAMIN E DEFICIENCY" class="mim-tip-hint" title="A registry of federally and privately supported clinical trials conducted in the United States and around the world." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Clinical Trials', 'domain': 'clinicaltrials.gov'})">Clinical Trials</a></div>
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<div><a href="https://www.orpha.net/consor/cgi-bin/ClinicalLabs_Search_Simple.php?lng=EN&LnkId=149&Typ=Pat" class="mim-tip-hint" title="A list of European laboratories that offer genetic testing." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'EuroGentest', 'domain': 'orpha.net'})">EuroGentest</a></div>
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<div><a href="#mimGeneReviewsFold" id="mimGeneReviewsToggle" data-toggle="collapse" class="mim-tip-hint mimTriangleToggle" title="Expert-authored, peer-reviewed descriptions of inherited disorders including the uses of genetic testing in diagnosis, management, and genetic counseling."><span id="mimGeneReviewsToggleTriangle" class="small" style="margin-left: -0.8em;">►</span>Gene Reviews</div>
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<div id="mimGeneReviewsFold" class="collapse">
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<div style="margin-left: 0.5em;"><a href="https://www.ncbi.nlm.nih.gov/books/NBK1138/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Gene Reviews', 'domain': 'ncbi.nlm.nih.gov'})">Hereditary Ataxia Overview</a></div><div style="margin-left: 0.5em;"><a href="https://www.ncbi.nlm.nih.gov/books/NBK1241/" title="Ataxia with Vitamin E Deficiency" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Gene Reviews', 'domain': 'ncbi.nlm.nih.gov'})">Ataxia with Vitamin E Defi…</a></div>
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</div>
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<div><a href="https://www.diseaseinfosearch.org/x/639" 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/ataxia-with-vitamin-e-deficiency" 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=277460[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="https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=96" class="mim-tip-hint" title="European reference portal for information on rare diseases and orphan drugs." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'OrphaNet', 'domain': 'orpha.net'})">OrphaNet</a></div>
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<div 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 class="panel-body small mim-panel-body">
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<div><a href="https://www.alliancegenome.org/disease/DOID:0090028" 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/277460" 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://omia.org/OMIA002922/" class="mim-tip-hint" title="Online Mendelian Inheritance in Animals (OMIA) is a database of genes, inherited disorders and traits in 191 animal species (other than human and mouse.)" target="_blank">OMIA</a></div>
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<div id="mimCellLinesLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Cell Lines</div>
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<div id="mimCellLinesLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div><a href="https://catalog.coriell.org/Search?q=OmimNum:277460" class="definition" title="Coriell Cell Repositories; cell cultures and DNA derived from cell cultures." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'CCR', 'domain': 'ccr.coriell.org'})">Coriell</a></div>
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<span class="mim-tip-bottom" qtip_title="<strong>Looking for this gene or this phenotype in other resources?</strong>" qtip_text="Select a related resource from the dropdown menu and click for a targeted link to information directly relevant.">
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<a id="title" class="mim-anchor"></a>
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<a href="#" class="mim-tip-icd" qtip_title="<strong>ICD+</strong>" qtip_text="
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<strong>SNOMEDCT:</strong> 702442008<br />
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<strong>ORPHA:</strong> 96<br />
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<strong>DO:</strong> 0090028<br />
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">ICD+</a>
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<span class="h3">
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<span class="mim-font mim-tip-hint" title="Phenotype description, molecular basis known">
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<span class="text-danger"><strong>#</strong></span>
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277460
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</span>
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</span>
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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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ATAXIA WITH VITAMIN E DEFICIENCY; AVED
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</span>
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</h3>
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</div>
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<div>
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<br />
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<div>
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<a id="alternativeTitles" class="mim-anchor"></a>
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<p>
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<span class="mim-font">
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<em>Alternative titles; symbols</em>
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<div>
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<h4>
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<span class="mim-font">
|
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ATAXIA, FRIEDREICH-LIKE, WITH SELECTIVE VITAMIN E DEFICIENCY<br />
|
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VITAMIN E DEFICIENCY, FAMILIAL ISOLATED; VED<br />
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FRIEDREICH-LIKE ATAXIA
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</span>
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</h4>
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</div>
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<div>
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<br />
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<div>
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<a id="phenotypeMap" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<strong>Phenotype-Gene Relationships</strong>
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</span>
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</h4>
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<div>
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<table class="table table-bordered table-condensed table-hover small mim-table-padding">
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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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8q12.3
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<span class="mim-font">
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Ataxia with isolated vitamin E deficiency
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<span class="mim-font">
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<a href="/entry/277460"> 277460 </a>
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<span class="mim-font">
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<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
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<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
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TTPA
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<a href="/entry/600415"> 600415 </a>
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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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- Spinocerebellar ataxia <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/129609000" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">129609000</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0087012&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0087012</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0007263" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0007263</a>]</span><br /> - Areflexia <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/37280007" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">37280007</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0234146&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0234146</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001284" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001284</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001284" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001284</a>]</span><br /> - Proprioception loss<br />
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- Xanthelasmata<br /> - Tendon xanthomas <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/69880002" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">69880002</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0221253&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0221253</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0010874" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0010874</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0010874" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0010874</a>]</span><br />
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<span class="mim-font">
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- Undetectable serum vitamin E<br /> - High serum cholesterol, triglyceride and beta-lipoprotein<br /> - Defective liver 'tocopherol binding protein'<br />
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<strong> Inheritance </strong>
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- Autosomal recessive <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/258211005" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">258211005</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0441748&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0441748</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000007" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000007</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000007" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000007</a>]</span><br />
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<span class="mim-tip-floating" qtip_title="<strong>Looking For More References?</strong>" qtip_text="Click the 'reference plus' icon <span class='glyphicon glyphicon-plus-sign'></span> at the end of each OMIM text paragraph to see more references related to the content of the preceding paragraph.">
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<strong>TEXT</strong>
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<p>A number sign (#) is used with this entry because of evidence that ataxia with vitamin E deficiency (AVED) is caused by homozygous or compound heterozygous mutation in the TTPA gene (<a href="/entry/600415">600415</a>) on chromosome 8q12.</p>
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<strong>Clinical Features</strong>
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<p><a href="#9" class="mim-tip-reference" title="Harding, A. E., Matthews, S., Jones, S., Ellis, C. J. K., Booth, I. W., Muller, D. P. R. <strong>Spinocerebellar degeneration associated with a selective defect of vitamin E absorption.</strong> New Eng. J. Med. 313: 32-35, 1985.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/4000224/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">4000224</a>] [<a href="https://doi.org/10.1056/NEJM198507043130107" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="4000224">Harding et al. (1985)</a> described a young woman with spinocerebellar degeneration thought to be due to a selective defect in vitamin E absorption. There was no evidence of fat malabsorption. <a href="#4" class="mim-tip-reference" title="Binder, H. J., Solitare, G. B., Spiro, H. M. <strong>Neuromuscular disease in patients with steatorrhoea.</strong> Gut 8: 605-611, 1967.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/6079812/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">6079812</a>] [<a href="https://doi.org/10.1136/gut.8.6.605" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="6079812">Binder et al. (1967)</a> suggested a relationship between neurologic dysfunction and vitamin E deficiency in patients with chronic steatorrhea. This was subsequently confirmed in patients with abetalipoproteinemia (<a href="/entry/200100">200100</a>), the most severe state of vitamin E deficiency known. When studied at age 23, the proband had no vitamin E in the serum. A progressive neurologic disorder comprising ataxia, areflexia and marked loss of proprioception developed at age 13. She also had increased serum concentrations of cholesterol, triglyceride and beta-lipoprotein and showed xanthelasmata and xanthomas of the Achilles tendon. Improvement in the neurologic disease accompanied administration of vitamin E. The proband's mother had tendinous xanthomas and elevated serum cholesterol. Both parents and 4 brothers had low or low-normal serum vitamin E levels consistent with the heterozygous state of a disorder for which the proband was homozygous. The lipid disturbance in the proband and her mother was thought to be familial hypercholesterolemia. Evidence was cited that the mechanism of absorption of vitamin E may be different from that for the other fat-soluble vitamins. A progressive development of ataxia and areflexia with a 'dying back' of the peripheral nerves, along with spinocerebellar degeneration, are characteristic of vitamin E deficiency. Several patients have been described who, like the patient of <a href="#9" class="mim-tip-reference" title="Harding, A. E., Matthews, S., Jones, S., Ellis, C. J. K., Booth, I. W., Muller, D. P. R. <strong>Spinocerebellar degeneration associated with a selective defect of vitamin E absorption.</strong> New Eng. J. Med. 313: 32-35, 1985.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/4000224/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">4000224</a>] [<a href="https://doi.org/10.1056/NEJM198507043130107" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="4000224">Harding et al. (1985)</a>, had neurologic abnormalities similar to those of vitamin E deficiency but had no evidence of fat malabsorption (<a href="#6" class="mim-tip-reference" title="Burck, U., Goebel, H. H., Kuhlendahl, H. D., Meier, C., Goebel, K. M. <strong>Neuromyopathy and vitamin E deficiency in man.</strong> Neuropediatrics 12: 267-278, 1981.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/6945489/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">6945489</a>] [<a href="https://doi.org/10.1055/s-2008-1059657" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="6945489">Burck et al., 1981</a>; <a href="#11" class="mim-tip-reference" title="Kohlschutter, A., Hubner, C., Jansen, W., Lindner, S. G. <strong>A treatable familial neuromyopathy with vitamin E deficiency, normal absorption, and evidence of increased consumption of vitamin E.</strong> J. Inherit. Metab. Dis. 11: 149-152, 1988.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3141695/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3141695</a>] [<a href="https://doi.org/10.1007/BF01804221" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3141695">Kohlschutter et al., 1988</a>; <a href="#13" class="mim-tip-reference" title="Laplante, P., Vanasse, M., Michaud, J., Geoffroy, G., Brochu, P. <strong>A progressive neurological syndrome associated with an isolated vitamin E deficiency.</strong> Canad. J. Neurol. Sci. 11: 561-564, 1984.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/6509402/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">6509402</a>] [<a href="https://doi.org/10.1017/s0317167100035046" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="6509402">Laplante et al., 1984</a>; <a href="#12" class="mim-tip-reference" title="Krendel, D. A., Gilchrist, J. M., Johnson, A. O., Bossen, E. H. <strong>Isolated deficiency of vitamin E with progressive neurologic deterioration.</strong> Neurology 37: 538-540, 1987.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3822155/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3822155</a>] [<a href="https://doi.org/10.1212/wnl.37.3.538" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3822155">Krendel et al., 1987</a>; <a href="#19" class="mim-tip-reference" title="Yokota, T., Wada, Y., Furukawa, T., Tsukagoshi, H., Uchihara, T., Watabiki, S. <strong>Adult-onset spinocerebellar syndrome with idiopathic vitamin E deficiency.</strong> Ann. Neurol. 22: 84-87, 1987.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3477125/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3477125</a>] [<a href="https://doi.org/10.1002/ana.410220119" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3477125">Yokota et al., 1987</a>; <a href="#17" class="mim-tip-reference" title="Sokol, R. J., Kayden, H. J., Bettis, D. B., Traber, M. G., Neville, H., Ringel, S., Wilson, W. B., Stumpf, D. A. <strong>Isolated vitamin E deficiency in the absence of fat malabsorption--familial and sporadic cases: characterization and investigation of causes.</strong> J. Lab. Clin. Med. 111: 548-559, 1988.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3361234/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3361234</a>]" pmid="3361234">Sokol et al., 1988</a>). <a href="#17" class="mim-tip-reference" title="Sokol, R. J., Kayden, H. J., Bettis, D. B., Traber, M. G., Neville, H., Ringel, S., Wilson, W. B., Stumpf, D. A. <strong>Isolated vitamin E deficiency in the absence of fat malabsorption--familial and sporadic cases: characterization and investigation of causes.</strong> J. Lab. Clin. Med. 111: 548-559, 1988.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3361234/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3361234</a>]" pmid="3361234">Sokol et al. (1988)</a> studied 2 affected sisters, a brother, and an isolated case in another family. No consanguinity was observed, but no other affected persons were demonstrated by studies in these families. These patients all had normal lipid absorption, gastrointestinal, pancreatic, and intestinal function, and lipoproteins, but when consuming a normal diet, they had exquisitely low plasma vitamin E levels and developed neurologic abnormalities characteristic of vitamin E deficiency. With the addition of daily vitamin E supplements (400-1,200 IU) to the diet, normal plasma vitamin E levels could be maintained and in several patients improvement in neurologic function was reported. When vitamin E supplementation was interrupted, plasma tocopherol fell sharply to suboptimal levels. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=3141695+6509402+6079812+6945489+3822155+3361234+4000224+3477125" 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>Selective vitamin E deficiency shows clinical features very similar, and in some cases identical, to those of Friedreich ataxia (FRDA; <a href="/entry/229300">229300</a>). <a href="#3" class="mim-tip-reference" title="Ben Hamida, M., Belal, S., Sirugo, G., Ben Hamida, C., Panayides, K., Ionannou, P., Beckmann, J., Mandel, J. L., Hentati, F., Koenig, M., Middleton, L. <strong>Friedreich's ataxia phenotype not linked to chromosome 9 and associated with selective autosomal recessive vitamin E deficiency in two inbred Tunisian families.</strong> Neurology 43: 2179-2183, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8232925/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8232925</a>] [<a href="https://doi.org/10.1212/wnl.43.11.2179" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8232925">Ben Hamida et al. (1993)</a> pointed out that cardiomyopathy like that in Friedreich ataxia had not been reported in patients with isolated vitamin E deficiency. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8232925" 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>During a search for recombinants between the 9q13-q21 markers and the disease locus in FRDA families, Ben Hamida et al. (<a href="#2" class="mim-tip-reference" title="Ben Hamida, C., Doerflinger, N., Belal, S., Linder, C., Reutenauer, L., Dib, C., Gyapay, G., Vignal, A., Le Paslier, D., Cohen, D., Pandolfo, M., Mokini, V., Novelli, G., Hentati, F., Ben Hamida, M., Mandel, J.-L., Koenig, M. <strong>Localization of Friedreich ataxia phenotype with selective vitamin E deficiency to chromosome 8q by homozygosity mapping.</strong> Nature Genet. 5: 195-200, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8252047/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8252047</a>] [<a href="https://doi.org/10.1038/ng1093-195" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8252047">1993</a>, <a href="#3" class="mim-tip-reference" title="Ben Hamida, M., Belal, S., Sirugo, G., Ben Hamida, C., Panayides, K., Ionannou, P., Beckmann, J., Mandel, J. L., Hentati, F., Koenig, M., Middleton, L. <strong>Friedreich's ataxia phenotype not linked to chromosome 9 and associated with selective autosomal recessive vitamin E deficiency in two inbred Tunisian families.</strong> Neurology 43: 2179-2183, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8232925/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8232925</a>] [<a href="https://doi.org/10.1212/wnl.43.11.2179" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8232925">1993</a>) found 5 with apparent recombinations that turned out, in fact, to be segregating a Friedreich-like disease associated with selective vitamin E deficiency. Since 3 such families of Tunisian origin were large and highly inbred, they were used to search for the defective locus by a combination of homozygosity mapping and sib comparisons. Linkage was found to 2 microsatellite markers located about 400 kb apart on proximal 8q. The other 2 families, one Tunisian and one Italian, also showed homozygosity and linkage with these markers, as did a sixth family of Albanese origin for which serum vitamin E levels could not be obtained. By combining all 6 families and by computing the consanguinity loops, a maximum lod score of 17.9 was obtained at theta = 0.0 for a haplotype combining the 2 microsatellite marker loci. The lod-1 confidence interval was 2.4 cM on either side of these markers. <a href="#8" class="mim-tip-reference" title="Doerflinger, N., Linder, C., Ouahchi, K., Gyapay, G., Weissenbach, J., Le Paslier, D., Rigault, P., Belal, S., Ben Hamida, C., Hentati, F., Ben Hamida, M., Pandolfo, M., DiDonato, S., Sokol, R., Kayden, H., Landrieu, P., Durr, A., Brice, A., Goutieres, F., Kohlschutter, A., Sabouraud, P., Benomar, A., Yahyaoui, M., Mandel, J.-L., Koenig, M. <strong>Ataxia with vitamin E deficiency: refinement of genetic localization and analysis of linkage disequilibrium by using new markers in 14 families.</strong> Am. J. Hum. Genet. 56: 1116-1124, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7726167/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7726167</a>]" pmid="7726167">Doerflinger et al. (1995)</a> performed linkage studies in 6 new and 2 previously described families and demonstrated genetic homogeneity despite significant clinical variability. They refined the AVED position to a 1-cM interval on 8q. Haplotype analysis using tightly linked microsatellite markers demonstrated a predominant, although not unique, mutation as responsible for the disorder in North African populations, where this condition is unusually frequent. <a href="#8" class="mim-tip-reference" title="Doerflinger, N., Linder, C., Ouahchi, K., Gyapay, G., Weissenbach, J., Le Paslier, D., Rigault, P., Belal, S., Ben Hamida, C., Hentati, F., Ben Hamida, M., Pandolfo, M., DiDonato, S., Sokol, R., Kayden, H., Landrieu, P., Durr, A., Brice, A., Goutieres, F., Kohlschutter, A., Sabouraud, P., Benomar, A., Yahyaoui, M., Mandel, J.-L., Koenig, M. <strong>Ataxia with vitamin E deficiency: refinement of genetic localization and analysis of linkage disequilibrium by using new markers in 14 families.</strong> Am. J. Hum. Genet. 56: 1116-1124, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7726167/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7726167</a>]" pmid="7726167">Doerflinger et al. (1995)</a> also constructed a YAC contig over this interval to facilitate the search for the AVED gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=8232925+7726167+8252047" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>The tocopherol-binding protein is also known as alpha-tocopherol transfer protein and TTP1. In patients with familial isolated vitamin E deficiency, <a href="#18" class="mim-tip-reference" title="Traber, M. G., Sokol, R. J., Burton, G. W., Ingold, K. U., Papas, A. M., Huffaker, J. E., Kayden, H. J. <strong>Impaired ability of patients with familial isolated vitamin E deficiency to incorporate alpha-tocopherol into lipoproteins secreted by the liver.</strong> J. Clin. Invest. 85: 397-407, 1990.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2298915/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2298915</a>] [<a href="https://doi.org/10.1172/JCI114452" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2298915">Traber et al. (1990)</a> demonstrated a defect in the incorporation of alpha-tocopherol into lipoproteins secreted by the liver. They suggested that these patients are lacking or have a defective liver tocopherol-binding protein that incorporates alpha-tocopherol into nascent very-low-density lipoprotein. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2298915" 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 implication of TTP1 in ataxia with isolated vitamin E deficiency was established by the identification of frameshift mutations in the TTPA gene. A 744delA mutation (<a href="/entry/600415#0001">600415.0001</a>) accounted for 68% of the mutant alleles in 17 families analyzed by <a href="#14" class="mim-tip-reference" title="Ouahchi, K., Arita, M., Kayden, H., Hentati, F., Ben Hamida, M., Sokol, R., Arai, H., Inoue, K., Mandel, J.-L., Koenig, M. <strong>Ataxia with isolated vitamin E deficiency is caused by mutations in the alpha-tocopherol transfer protein.</strong> Nature Genet. 9: 141-145, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7719340/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7719340</a>] [<a href="https://doi.org/10.1038/ng0295-141" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7719340">Ouahchi et al. (1995)</a> and appeared to have spread in North Africa and Italy. Although only the C-terminal tenth of the protein was altered, this mutation correlated with a severe phenotype. Two other mutations were found in single families. <a href="#10" class="mim-tip-reference" title="Hentati, A., Deng, H.-X., Hung, W.-Y., Nayer, M., Ahmed, M. S., He, X., Tim, R., Stumpf, D. A., Siddique, T. <strong>Human alpha-tocopherol transfer protein: gene structure and mutations in familial vitamin E deficiency.</strong> Ann. Neurol. 39: 295-300, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8602747/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8602747</a>] [<a href="https://doi.org/10.1002/ana.410390305" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8602747">Hentati et al. (1996)</a> described the structure of the TTPA gene and identified several TTPA mutations that were associated with familial vitamin E deficiency. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=8602747+7719340" 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="Schuelke, M., Mayatepek, E., Inter, M., Becker, M., Pfeiffer, E., Speer, A., Hubner, C., Finckh, B. <strong>Treatment of ataxia in isolated vitamin E deficiency caused by alpha-tocopherol transfer protein deficiency.</strong> J. Pediat. 134: 240-244, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9931538/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9931538</a>] [<a href="https://doi.org/10.1016/s0022-3476(99)70424-5" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9931538">Schuelke et al. (1999)</a> described a 14-year-old male with ataxia and mental symptoms who was found to be homozygous for a 552G-A mutation in the TTPA gene (<a href="/entry/600415#0007">600415.0007</a>). After initiation of high-dosage alpha-tocopherol therapy, the organic mental syndrome disappeared and cognitive function improved rapidly. Neurologic recovery, however, was slow and incomplete. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9931538" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#1" class="mim-tip-reference" title="Aoki, K., Washimi, Y., Fujimori, N., Maruyama, K., Yanagisawa, N. <strong>Familial idiopathic vitamin E deficiency associated with cerebellar atrophy.</strong> Rinsho Shinkeigaku 30: 966-971, 1990.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2265507/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2265507</a>]" pmid="2265507">Aoki et al. (1990)</a> reported 2 sibs who had an atypical spinocerebellar syndrome with isolated vitamin E deficiency. On restudy of one of these patients, mutation in the TTPA gene was excluded, suggesting the existence of another gene for familial isolated vitamin E deficiency (<a href="#16" class="mim-tip-reference" title="Shiojiri, T., Yokota, T., Fujimori, N., Mizusawa, H. <strong>Familial ataxia with isolated vitamin E deficiency not due to mutation of alpha-TTP. (Letter)</strong> J. Neurol. 246: 982 only, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10552255/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10552255</a>] [<a href="https://doi.org/10.1007/s004150050499" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10552255">Shiojiri et al., 1999</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=10552255+2265507" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#7" class="mim-tip-reference" title="Cellini, E., Piacentini, S., Nacmias, B., Forleo, P., Tedde, A., Bagnoli, S., Ciantelli, M., Sorbi, S. <strong>A family with spinocerebellar ataxia type 8 expansion and vitamin E deficiency ataxia.</strong> Arch. Neurol. 59: 1952-1953, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12470185/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12470185</a>] [<a href="https://doi.org/10.1001/archneur.59.12.1952" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12470185">Cellini et al. (2002)</a> reported a patient with progressive ataxia from the age of 7 years, becoming wheelchair bound at age 17, as well as cerebellar atrophy and vitamin E deficiency. She had expanded CTA/CAG repeats suggestive of SCA8 (<a href="/entry/608768">608768</a>) and also had compound heterozygosity for mutations in the TTPA gene (<a href="/entry/600415#0004">600415.0004</a> and <a href="/entry/600415#0006">600415.0006</a>), yielding a nonfunctional protein. Supplementation with vitamin E did not improve symptoms. <a href="#7" class="mim-tip-reference" title="Cellini, E., Piacentini, S., Nacmias, B., Forleo, P., Tedde, A., Bagnoli, S., Ciantelli, M., Sorbi, S. <strong>A family with spinocerebellar ataxia type 8 expansion and vitamin E deficiency ataxia.</strong> Arch. Neurol. 59: 1952-1953, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12470185/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12470185</a>] [<a href="https://doi.org/10.1001/archneur.59.12.1952" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12470185">Cellini et al. (2002)</a> suggested that the SCA mutations acted in the neurodegenerative process, worsening the neurologic signs caused by the vitamin E deficit. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12470185" 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="#5" class="mim-tip-reference" title="Bouhlal, Y., Zouari, M., Kefi, M., Ben Hamida, C., Hentati, F., Amouri, R. <strong>Autosomal recessive ataxia caused by three distinct gene defects in a single consanguineous family.</strong> J. Neurogenet. 22: 139-148, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18569450/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18569450</a>] [<a href="https://doi.org/10.1080/01677060802025233" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18569450">Bouhlal et al. (2008)</a> reported an unusual, highly consanguineous Tunisian family in which 11 individuals had autosomal recessive ataxia caused by 3 distinct gene defects. Seven patients who also had low vitamin E levels were all homozygous for the common 744delA mutation in the TTPA gene (<a href="/entry/600415#0001">600415.0001</a>), consistent with a diagnosis of AVED. Two patients with normal vitamin E levels were homozygous for a mutation in the FXN gene (<a href="/entry/606829#0001">606829.0001</a>), consistent with a diagnosis of FRDA (<a href="/entry/229300">229300</a>). The final 2 patients with normal vitamin E levels carried a mutation in the SACS gene (<a href="/entry/604490">604490</a>), consistent with a diagnosis of ARSACS (<a href="/entry/270550">270550</a>). The clinical phenotype was relatively homogeneous, although the 2 patients with SACS mutations had hyperreflexia of the knee. One asymptomatic family member was compound heterozygous for the TTPA and FXN mutations. <a href="#5" class="mim-tip-reference" title="Bouhlal, Y., Zouari, M., Kefi, M., Ben Hamida, C., Hentati, F., Amouri, R. <strong>Autosomal recessive ataxia caused by three distinct gene defects in a single consanguineous family.</strong> J. Neurogenet. 22: 139-148, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18569450/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18569450</a>] [<a href="https://doi.org/10.1080/01677060802025233" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18569450">Bouhlal et al. (2008)</a> emphasized the difficulty of genetic counseling in deeply consanguineous families. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18569450" 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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Aoki, K., Washimi, Y., Fujimori, N., Maruyama, K., Yanagisawa, N.
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<strong>Familial idiopathic vitamin E deficiency associated with cerebellar atrophy.</strong>
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Rinsho Shinkeigaku 30: 966-971, 1990.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2265507/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2265507</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2265507" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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Ben Hamida, C., Doerflinger, N., Belal, S., Linder, C., Reutenauer, L., Dib, C., Gyapay, G., Vignal, A., Le Paslier, D., Cohen, D., Pandolfo, M., Mokini, V., Novelli, G., Hentati, F., Ben Hamida, M., Mandel, J.-L., Koenig, M.
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<strong>Localization of Friedreich ataxia phenotype with selective vitamin E deficiency to chromosome 8q by homozygosity mapping.</strong>
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Nature Genet. 5: 195-200, 1993.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8252047/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8252047</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8252047" 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/ng1093-195" target="_blank">Full Text</a>]
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Ben Hamida, M., Belal, S., Sirugo, G., Ben Hamida, C., Panayides, K., Ionannou, P., Beckmann, J., Mandel, J. L., Hentati, F., Koenig, M., Middleton, L.
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<strong>Friedreich's ataxia phenotype not linked to chromosome 9 and associated with selective autosomal recessive vitamin E deficiency in two inbred Tunisian families.</strong>
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Neurology 43: 2179-2183, 1993.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8232925/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8232925</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8232925" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1212/wnl.43.11.2179" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1136/gut.8.6.605" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1080/01677060802025233" target="_blank">Full Text</a>]
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<strong>Neuromyopathy and vitamin E deficiency in man.</strong>
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[<a href="https://doi.org/10.1055/s-2008-1059657" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1001/archneur.59.12.1952" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1056/NEJM198507043130107" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1002/ana.410390305" target="_blank">Full Text</a>]
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<a id="Kohlschutter1988" class="mim-anchor"></a>
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Kohlschutter, A., Hubner, C., Jansen, W., Lindner, S. G.
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<strong>A treatable familial neuromyopathy with vitamin E deficiency, normal absorption, and evidence of increased consumption of vitamin E.</strong>
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[<a href="https://doi.org/10.1007/BF01804221" target="_blank">Full Text</a>]
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<div class="">
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<strong>Isolated deficiency of vitamin E with progressive neurologic deterioration.</strong>
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[<a href="https://doi.org/10.1212/wnl.37.3.538" target="_blank">Full Text</a>]
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<strong>A progressive neurological syndrome associated with an isolated vitamin E deficiency.</strong>
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[<a href="https://doi.org/10.1017/s0317167100035046" target="_blank">Full Text</a>]
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<a id="Ouahchi1995" class="mim-anchor"></a>
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Ouahchi, K., Arita, M., Kayden, H., Hentati, F., Ben Hamida, M., Sokol, R., Arai, H., Inoue, K., Mandel, J.-L., Koenig, M.
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[<a href="https://doi.org/10.1038/ng0295-141" target="_blank">Full Text</a>]
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<a id="Schuelke1999" class="mim-anchor"></a>
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[<a href="https://doi.org/10.1016/s0022-3476(99)70424-5" target="_blank">Full Text</a>]
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Shiojiri, T., Yokota, T., Fujimori, N., Mizusawa, H.
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<strong>Familial ataxia with isolated vitamin E deficiency not due to mutation of alpha-TTP. (Letter)</strong>
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[<a href="https://doi.org/10.1007/s004150050499" target="_blank">Full Text</a>]
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Traber, M. G., Sokol, R. J., Burton, G. W., Ingold, K. U., Papas, A. M., Huffaker, J. E., Kayden, H. J.
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<strong>Impaired ability of patients with familial isolated vitamin E deficiency to incorporate alpha-tocopherol into lipoproteins secreted by the liver.</strong>
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[<a href="https://doi.org/10.1172/JCI114452" target="_blank">Full Text</a>]
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<a id="Yokota1987" class="mim-anchor"></a>
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Yokota, T., Wada, Y., Furukawa, T., Tsukagoshi, H., Uchihara, T., Watabiki, S.
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<strong>Adult-onset spinocerebellar syndrome with idiopathic vitamin E deficiency.</strong>
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[<a href="https://doi.org/10.1002/ana.410220119" target="_blank">Full Text</a>]
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Cassandra L. Kniffin - updated : 11/25/2013
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Cassandra L. Kniffin - updated : 2/13/2003<br>Victor A. McKusick - updated : 1/21/2000<br>Victor A. McKusick - updated : 3/25/1999<br>Orest Hurko - updated : 5/6/1996<br>Orest Hurko - edited : 5/6/1996
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Victor A. McKusick : 6/4/1986
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joanna : 02/04/2022
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carol : 03/18/2021<br>carol : 06/25/2014<br>carol : 11/27/2013<br>ckniffin : 11/25/2013<br>carol : 7/2/2004<br>carol : 2/24/2003<br>ckniffin : 2/13/2003<br>cwells : 2/22/2001<br>terry : 1/21/2000<br>mgross : 4/2/1999<br>mgross : 3/31/1999<br>terry : 3/25/1999<br>terry : 7/10/1997<br>alopez : 6/11/1997<br>mark : 5/6/1996<br>mark : 5/6/1996<br>mark : 5/6/1996<br>terry : 4/30/1996<br>mark : 11/14/1995<br>carol : 2/16/1995<br>mimadm : 3/12/1994<br>carol : 12/6/1993<br>carol : 10/27/1993<br>carol : 10/13/1993
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<span class="mim-font">
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<strong>#</strong> 277460
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ATAXIA WITH VITAMIN E DEFICIENCY; AVED
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ATAXIA, FRIEDREICH-LIKE, WITH SELECTIVE VITAMIN E DEFICIENCY<br />
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VITAMIN E DEFICIENCY, FAMILIAL ISOLATED; VED<br />
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FRIEDREICH-LIKE ATAXIA
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<strong>SNOMEDCT:</strong> 702442008;
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<strong>ORPHA:</strong> 96;
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<strong>DO:</strong> 0090028;
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<strong>Phenotype-Gene Relationships</strong>
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Location
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Phenotype
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Phenotype <br /> MIM number
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Inheritance
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Phenotype <br /> mapping key
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Gene/Locus
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Gene/Locus <br /> MIM number
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<span class="mim-font">
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8q12.3
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<span class="mim-font">
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Ataxia with isolated vitamin E deficiency
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<span class="mim-font">
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277460
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Autosomal recessive
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<span class="mim-font">
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3
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TTPA
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600415
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<strong>TEXT</strong>
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<p>A number sign (#) is used with this entry because of evidence that ataxia with vitamin E deficiency (AVED) is caused by homozygous or compound heterozygous mutation in the TTPA gene (600415) on chromosome 8q12.</p>
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<strong>Clinical Features</strong>
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<p>Harding et al. (1985) described a young woman with spinocerebellar degeneration thought to be due to a selective defect in vitamin E absorption. There was no evidence of fat malabsorption. Binder et al. (1967) suggested a relationship between neurologic dysfunction and vitamin E deficiency in patients with chronic steatorrhea. This was subsequently confirmed in patients with abetalipoproteinemia (200100), the most severe state of vitamin E deficiency known. When studied at age 23, the proband had no vitamin E in the serum. A progressive neurologic disorder comprising ataxia, areflexia and marked loss of proprioception developed at age 13. She also had increased serum concentrations of cholesterol, triglyceride and beta-lipoprotein and showed xanthelasmata and xanthomas of the Achilles tendon. Improvement in the neurologic disease accompanied administration of vitamin E. The proband's mother had tendinous xanthomas and elevated serum cholesterol. Both parents and 4 brothers had low or low-normal serum vitamin E levels consistent with the heterozygous state of a disorder for which the proband was homozygous. The lipid disturbance in the proband and her mother was thought to be familial hypercholesterolemia. Evidence was cited that the mechanism of absorption of vitamin E may be different from that for the other fat-soluble vitamins. A progressive development of ataxia and areflexia with a 'dying back' of the peripheral nerves, along with spinocerebellar degeneration, are characteristic of vitamin E deficiency. Several patients have been described who, like the patient of Harding et al. (1985), had neurologic abnormalities similar to those of vitamin E deficiency but had no evidence of fat malabsorption (Burck et al., 1981; Kohlschutter et al., 1988; Laplante et al., 1984; Krendel et al., 1987; Yokota et al., 1987; Sokol et al., 1988). Sokol et al. (1988) studied 2 affected sisters, a brother, and an isolated case in another family. No consanguinity was observed, but no other affected persons were demonstrated by studies in these families. These patients all had normal lipid absorption, gastrointestinal, pancreatic, and intestinal function, and lipoproteins, but when consuming a normal diet, they had exquisitely low plasma vitamin E levels and developed neurologic abnormalities characteristic of vitamin E deficiency. With the addition of daily vitamin E supplements (400-1,200 IU) to the diet, normal plasma vitamin E levels could be maintained and in several patients improvement in neurologic function was reported. When vitamin E supplementation was interrupted, plasma tocopherol fell sharply to suboptimal levels. </p><p>Selective vitamin E deficiency shows clinical features very similar, and in some cases identical, to those of Friedreich ataxia (FRDA; 229300). Ben Hamida et al. (1993) pointed out that cardiomyopathy like that in Friedreich ataxia had not been reported in patients with isolated vitamin E deficiency. </p>
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<strong>Mapping</strong>
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<span class="mim-text-font">
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<p>During a search for recombinants between the 9q13-q21 markers and the disease locus in FRDA families, Ben Hamida et al. (1993, 1993) found 5 with apparent recombinations that turned out, in fact, to be segregating a Friedreich-like disease associated with selective vitamin E deficiency. Since 3 such families of Tunisian origin were large and highly inbred, they were used to search for the defective locus by a combination of homozygosity mapping and sib comparisons. Linkage was found to 2 microsatellite markers located about 400 kb apart on proximal 8q. The other 2 families, one Tunisian and one Italian, also showed homozygosity and linkage with these markers, as did a sixth family of Albanese origin for which serum vitamin E levels could not be obtained. By combining all 6 families and by computing the consanguinity loops, a maximum lod score of 17.9 was obtained at theta = 0.0 for a haplotype combining the 2 microsatellite marker loci. The lod-1 confidence interval was 2.4 cM on either side of these markers. Doerflinger et al. (1995) performed linkage studies in 6 new and 2 previously described families and demonstrated genetic homogeneity despite significant clinical variability. They refined the AVED position to a 1-cM interval on 8q. Haplotype analysis using tightly linked microsatellite markers demonstrated a predominant, although not unique, mutation as responsible for the disorder in North African populations, where this condition is unusually frequent. Doerflinger et al. (1995) also constructed a YAC contig over this interval to facilitate the search for the AVED gene. </p>
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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 class="mim-text-font">
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<p>The tocopherol-binding protein is also known as alpha-tocopherol transfer protein and TTP1. In patients with familial isolated vitamin E deficiency, Traber et al. (1990) demonstrated a defect in the incorporation of alpha-tocopherol into lipoproteins secreted by the liver. They suggested that these patients are lacking or have a defective liver tocopherol-binding protein that incorporates alpha-tocopherol into nascent very-low-density lipoprotein. </p><p>The implication of TTP1 in ataxia with isolated vitamin E deficiency was established by the identification of frameshift mutations in the TTPA gene. A 744delA mutation (600415.0001) accounted for 68% of the mutant alleles in 17 families analyzed by Ouahchi et al. (1995) and appeared to have spread in North Africa and Italy. Although only the C-terminal tenth of the protein was altered, this mutation correlated with a severe phenotype. Two other mutations were found in single families. Hentati et al. (1996) described the structure of the TTPA gene and identified several TTPA mutations that were associated with familial vitamin E deficiency. </p><p>Schuelke et al. (1999) described a 14-year-old male with ataxia and mental symptoms who was found to be homozygous for a 552G-A mutation in the TTPA gene (600415.0007). After initiation of high-dosage alpha-tocopherol therapy, the organic mental syndrome disappeared and cognitive function improved rapidly. Neurologic recovery, however, was slow and incomplete. </p><p>Aoki et al. (1990) reported 2 sibs who had an atypical spinocerebellar syndrome with isolated vitamin E deficiency. On restudy of one of these patients, mutation in the TTPA gene was excluded, suggesting the existence of another gene for familial isolated vitamin E deficiency (Shiojiri et al., 1999). </p><p>Cellini et al. (2002) reported a patient with progressive ataxia from the age of 7 years, becoming wheelchair bound at age 17, as well as cerebellar atrophy and vitamin E deficiency. She had expanded CTA/CAG repeats suggestive of SCA8 (608768) and also had compound heterozygosity for mutations in the TTPA gene (600415.0004 and 600415.0006), yielding a nonfunctional protein. Supplementation with vitamin E did not improve symptoms. Cellini et al. (2002) suggested that the SCA mutations acted in the neurodegenerative process, worsening the neurologic signs caused by the vitamin E deficit. </p>
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<h4>
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<span class="mim-font">
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<strong>Heterogeneity</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>Bouhlal et al. (2008) reported an unusual, highly consanguineous Tunisian family in which 11 individuals had autosomal recessive ataxia caused by 3 distinct gene defects. Seven patients who also had low vitamin E levels were all homozygous for the common 744delA mutation in the TTPA gene (600415.0001), consistent with a diagnosis of AVED. Two patients with normal vitamin E levels were homozygous for a mutation in the FXN gene (606829.0001), consistent with a diagnosis of FRDA (229300). The final 2 patients with normal vitamin E levels carried a mutation in the SACS gene (604490), consistent with a diagnosis of ARSACS (270550). The clinical phenotype was relatively homogeneous, although the 2 patients with SACS mutations had hyperreflexia of the knee. One asymptomatic family member was compound heterozygous for the TTPA and FXN mutations. Bouhlal et al. (2008) emphasized the difficulty of genetic counseling in deeply consanguineous families. </p>
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<h4>
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<span class="mim-font">
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<strong>REFERENCES</strong>
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</span>
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</h4>
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<p />
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</div>
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<ol>
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<p class="mim-text-font">
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Aoki, K., Washimi, Y., Fujimori, N., Maruyama, K., Yanagisawa, N.
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<strong>Familial idiopathic vitamin E deficiency associated with cerebellar atrophy.</strong>
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Rinsho Shinkeigaku 30: 966-971, 1990.
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[PubMed: 2265507]
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Ben Hamida, C., Doerflinger, N., Belal, S., Linder, C., Reutenauer, L., Dib, C., Gyapay, G., Vignal, A., Le Paslier, D., Cohen, D., Pandolfo, M., Mokini, V., Novelli, G., Hentati, F., Ben Hamida, M., Mandel, J.-L., Koenig, M.
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<strong>Localization of Friedreich ataxia phenotype with selective vitamin E deficiency to chromosome 8q by homozygosity mapping.</strong>
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Nature Genet. 5: 195-200, 1993.
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[PubMed: 8252047]
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[Full Text: https://doi.org/10.1038/ng1093-195]
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</li>
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<li>
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<p class="mim-text-font">
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Ben Hamida, M., Belal, S., Sirugo, G., Ben Hamida, C., Panayides, K., Ionannou, P., Beckmann, J., Mandel, J. L., Hentati, F., Koenig, M., Middleton, L.
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<strong>Friedreich's ataxia phenotype not linked to chromosome 9 and associated with selective autosomal recessive vitamin E deficiency in two inbred Tunisian families.</strong>
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Neurology 43: 2179-2183, 1993.
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[PubMed: 8232925]
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[Full Text: https://doi.org/10.1212/wnl.43.11.2179]
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</li>
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<li>
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<p class="mim-text-font">
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Binder, H. J., Solitare, G. B., Spiro, H. M.
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<strong>Neuromuscular disease in patients with steatorrhoea.</strong>
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Gut 8: 605-611, 1967.
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[PubMed: 6079812]
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[Full Text: https://doi.org/10.1136/gut.8.6.605]
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</li>
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<li>
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<p class="mim-text-font">
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Bouhlal, Y., Zouari, M., Kefi, M., Ben Hamida, C., Hentati, F., Amouri, R.
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<strong>Autosomal recessive ataxia caused by three distinct gene defects in a single consanguineous family.</strong>
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J. Neurogenet. 22: 139-148, 2008.
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[PubMed: 18569450]
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[Full Text: https://doi.org/10.1080/01677060802025233]
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<li>
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<p class="mim-text-font">
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Burck, U., Goebel, H. H., Kuhlendahl, H. D., Meier, C., Goebel, K. M.
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<strong>Neuromyopathy and vitamin E deficiency in man.</strong>
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Neuropediatrics 12: 267-278, 1981.
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[PubMed: 6945489]
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[Full Text: https://doi.org/10.1055/s-2008-1059657]
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<li>
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<p class="mim-text-font">
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Cellini, E., Piacentini, S., Nacmias, B., Forleo, P., Tedde, A., Bagnoli, S., Ciantelli, M., Sorbi, S.
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<strong>A family with spinocerebellar ataxia type 8 expansion and vitamin E deficiency ataxia.</strong>
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Arch. Neurol. 59: 1952-1953, 2002.
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[PubMed: 12470185]
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[Full Text: https://doi.org/10.1001/archneur.59.12.1952]
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<li>
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Canad. J. Neurol. Sci. 11: 561-564, 1984.
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<strong>Ataxia with isolated vitamin E deficiency is caused by mutations in the alpha-tocopherol transfer protein.</strong>
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Sokol, R. J., Kayden, H. J., Bettis, D. B., Traber, M. G., Neville, H., Ringel, S., Wilson, W. B., Stumpf, D. A.
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<strong>Impaired ability of patients with familial isolated vitamin E deficiency to incorporate alpha-tocopherol into lipoproteins secreted by the liver.</strong>
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Yokota, T., Wada, Y., Furukawa, T., Tsukagoshi, H., Uchihara, T., Watabiki, S.
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<strong>Adult-onset spinocerebellar syndrome with idiopathic vitamin E deficiency.</strong>
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Cassandra L. Kniffin - updated : 11/25/2013<br>Cassandra L. Kniffin - updated : 2/13/2003<br>Victor A. McKusick - updated : 1/21/2000<br>Victor A. McKusick - updated : 3/25/1999<br>Orest Hurko - updated : 5/6/1996<br>Orest Hurko - edited : 5/6/1996
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