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<meta name="robots" content="INDEX,FOLLOW,NOARCHIVE" /><meta name="citation_inbook_title" content="GeneReviews® [Internet]" /><meta name="citation_title" content="VLDLR Cerebellar Hypoplasia" /><meta name="citation_publisher" content="University of Washington, Seattle" /><meta name="citation_date" content="2020/02/27" /><meta name="citation_author" content="Kym M Boycott" /><meta name="citation_author" content="Stella K MacDonald" /><meta name="citation_author" content="Jillian S Parboosingh" /><meta name="citation_pmid" content="20301729" /><meta name="citation_fulltext_html_url" content="https://www.ncbi.nlm.nih.gov/books/NBK1874/" /><meta name="citation_keywords" content="Cerebellar Ataxia, Mental Retardation, and Dysequilibrium Syndrome 1 (CAMRQ1)" /><meta name="citation_keywords" content="Cerebellar Ataxia, Mental Retardation, and Dysequilibrium Syndrome 1 (CAMRQ1)" /><meta name="citation_keywords" content="Very low-density lipoprotein receptor" /><meta name="citation_keywords" content="VLDLR" /><meta name="citation_keywords" content="VLDLR Cerebellar Hypoplasia" /><link rel="schema.DC" href="http://purl.org/DC/elements/1.0/" /><meta name="DC.Title" content="VLDLR Cerebellar Hypoplasia" /><meta name="DC.Type" content="Text" /><meta name="DC.Publisher" content="University of Washington, Seattle" /><meta name="DC.Contributor" content="Kym M Boycott" /><meta name="DC.Contributor" content="Stella K MacDonald" /><meta name="DC.Contributor" content="Jillian S Parboosingh" /><meta name="DC.Date" content="2020/02/27" /><meta name="DC.Identifier" content="https://www.ncbi.nlm.nih.gov/books/NBK1874/" /><meta name="description" content="VLDLR cerebellar hypoplasia (VLDLR-CH) is characterized by non-progressive congenital ataxia that is predominantly truncal and results in delayed ambulation, moderate-to-profound intellectual disability, dysarthria, strabismus, and seizures. Children either learn to walk very late (often after age 6 years) or never achieve independent ambulation. Brain MRI findings include hypoplasia of the inferior portion of the cerebellar vermis and hemispheres, simplified gyration of the cerebral hemispheres, and small brain stem – particularly the pons." /><meta name="og:title" content="VLDLR Cerebellar Hypoplasia" /><meta name="og:type" content="book" /><meta name="og:description" content="VLDLR cerebellar hypoplasia (VLDLR-CH) is characterized by non-progressive congenital ataxia that is predominantly truncal and results in delayed ambulation, moderate-to-profound intellectual disability, dysarthria, strabismus, and seizures. Children either learn to walk very late (often after age 6 years) or never achieve independent ambulation. 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<div class="pre-content"><div><div class="bk_prnt"><p class="small">NCBI Bookshelf. A service of the National Library of Medicine, National Institutes of Health.</p><p>Adam MP, Feldman J, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2025. </p></div><div class="iconblock clearfix whole_rhythm no_top_margin bk_noprnt"><a class="img_link icnblk_img" title="All GeneReviews" href="/books/n/gene/"><img class="source-thumb" src="/corehtml/pmc/pmcgifs/bookshelf/thumbs/th-gene-lrg.png" alt="Cover of GeneReviews®" height="100px" width="80px" /></a><div class="icnblk_cntnt eight_col"><h2>GeneReviews<sup>®</sup> [Internet].</h2><a data-jig="ncbitoggler" href="#__NBK1874_dtls__">Show details</a><div style="display:none" class="ui-widget" id="__NBK1874_dtls__"><div>Adam MP, Feldman J, Mirzaa GM, et al., editors.</div><div>Seattle (WA): <a href="http://www.washington.edu" ref="pagearea=page-banner&targetsite=external&targetcat=link&targettype=publisher">University of Washington, Seattle</a>; 1993-2025.</div></div><div class="half_rhythm"><ul class="inline_list"><li style="margin-right:1em"><a class="bk_cntns" href="/books/n/gene/">GeneReviews by Title</a></li></ul></div><div class="bk_noprnt"><form method="get" action="/books/n/gene/" id="bk_srch"><div class="bk_search"><label for="bk_term" class="offscreen_noflow">Search term</label><input type="text" title="Search GeneReviews" id="bk_term" name="term" value="" data-jig="ncbiclearbutton" /> <input type="submit" class="jig-ncbibutton" value="Search GeneReviews" submit="false" style="padding: 0.1em 0.4em;" /></div></form><div><ul class="inline_list"><li><a href="/books/n/gene/advanced/">GeneReviews Advanced Search</a></li><li style="margin-left:.5em"><a href="/books/n/gene/helpadvsearch/">Help</a></li></ul></div></div></div><div class="icnblk_cntnt two_col"><div class="pagination bk_noprnt"><a class="active page_link prev" href="/books/n/gene/wagner/" title="Previous page in this title">< Prev</a><a class="active page_link next" href="/books/n/gene/chac/" title="Next page in this title">Next ></a></div></div></div></div></div>
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<div class="main-content lit-style" itemscope="itemscope" itemtype="http://schema.org/CreativeWork"><div class="meta-content fm-sec"><h1 id="_NBK1874_"><span class="title" itemprop="name"><i>VLDLR</i> Cerebellar Hypoplasia</span></h1><div itemprop="alternativeHeadline" class="subtitle whole_rhythm">Synonym: Cerebellar Ataxia, Mental Retardation, and Dysequilibrium Syndrome 1 (CAMRQ1)</div><p class="contrib-group"><span itemprop="author">Kym M Boycott</span>, PhD, MD, <span itemprop="author">Stella K MacDonald</span>, BSc, and <span itemprop="author">Jillian S Parboosingh</span>, PhD.</p><a data-jig="ncbitoggler" href="#__NBK1874_ai__" style="border:0;text-decoration:none">Author Information and Affiliations</a><div style="display:none" class="ui-widget" id="__NBK1874_ai__"><div class="contrib half_rhythm"><span itemprop="author">Kym M Boycott</span>, PhD, MD<div class="affiliation small">Department of Genetics<br />Children's Hospital of Eastern Ontario<br />Professor of Pediatrics<br />University of Ottawa<br />Ottawa, Ontario, Canada<div><span class="email-label">Email: </span><a href="mailto:dev@null" data-email="ac.no.oehc@ttocyobk" class="oemail">ac.no.oehc@ttocyobk</a></div></div></div><div class="contrib half_rhythm"><span itemprop="author">Stella K MacDonald</span>, BSc<div class="affiliation small">Clinical Research Associate, Department of Genetics<br />Children's Hospital of Eastern Ontario<br />Ottawa, Ontario, Canada<div><span class="email-label">Email: </span><a href="mailto:dev@null" data-email="ac.no.oehc@dlanodcams" class="oemail">ac.no.oehc@dlanodcams</a></div></div></div><div class="contrib half_rhythm"><span itemprop="author">Jillian S Parboosingh</span>, PhD<div class="affiliation small">Molecular Diagnostic Laboratory<br />Alberta Children's Hospital<br />Associate Professor of Medical Genetics<br />University of Calgary<br />Calgary, Alberta, Canada<div><span class="email-label">Email: </span><a href="mailto:dev@null" data-email="ac.sbalnoisicerpatrebla@hgnisoobrap.naillij" class="oemail">ac.sbalnoisicerpatrebla@hgnisoobrap.naillij</a></div></div></div></div><p class="small">Initial Posting: <span itemprop="datePublished">August 26, 2008</span>; Last Update: <span itemprop="dateModified">February 27, 2020</span>.</p><p><em>Estimated reading time: 18 minutes</em></p></div><div class="jig-ncbiinpagenav body-content whole_rhythm" data-jigconfig="allHeadingLevels: ['h2'],smoothScroll: false" itemprop="text"><div id="vldlr-ch.Summary" itemprop="description"><h2 id="_vldlr-ch_Summary_">Summary</h2><div><h4 class="inline">Clinical characteristics.</h4><p><i>VLDLR</i> cerebellar hypoplasia (<i>VLDLR</i>-CH) is characterized by non-progressive <a class="def" href="/books/n/gene/glossary/def-item/congenital/">congenital</a> ataxia that is predominantly truncal and results in delayed ambulation, moderate-to-profound intellectual disability, dysarthria, strabismus, and seizures. Children either learn to walk very late (often after age 6 years) or never achieve independent ambulation. Brain MRI findings include hypoplasia of the inferior portion of the cerebellar vermis and hemispheres, simplified gyration of the cerebral hemispheres, and small brain stem – particularly the pons.</p></div><div><h4 class="inline">Diagnosis/testing.</h4><p>The diagnosis of <i>VLDLR</i> cerebellar hypoplasia is established in a <a class="def" href="/books/n/gene/glossary/def-item/proband/">proband</a> with suggestive clinical and brain MRI findings by identification of <a class="def" href="/books/n/gene/glossary/def-item/biallelic/">biallelic</a> pathogenic variants in <i>VLDLR</i> on <a class="def" href="/books/n/gene/glossary/def-item/molecular-genetic-testing/">molecular genetic testing</a>.</p></div><div><h4 class="inline">Management.</h4><p><i>Treatment of manifestations:</i> Seizures and strabismus are treated in the standard manner. Referral to an early intervention program is recommended for access to occupational, physical, and speech therapy, as well as infant mental health services and special educators.</p><p><i>Surveillance:</i> Annual neurologic and rehabilitation evaluations.</p></div><div><h4 class="inline">Genetic counseling.</h4><p><i>VLDLR</i>-CH is inherited in an <a class="def" href="/books/n/gene/glossary/def-item/autosomal-recessive/">autosomal recessive</a> manner. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic <a class="def" href="/books/n/gene/glossary/def-item/carrier/">carrier</a>, and a 25% chance of being unaffected and not a carrier. Carrier testing for at-risk relatives, <a class="def" href="/books/n/gene/glossary/def-item/prenatal-testing/">prenatal testing</a> for a pregnancy at increased risk and <a class="def" href="/books/n/gene/glossary/def-item/preimplantation-genetic-testing/">preimplantation genetic testing</a> are possible when the pathogenic variants in a family are known.</p></div></div><div id="vldlr-ch.Diagnosis"><h2 id="_vldlr-ch_Diagnosis_">Diagnosis</h2><p><i>VLDLR</i> cerebellar hypoplasia (<i>VLDLR</i>-CH) is a subgroup of dysequilibrium syndrome (DES), a spectrum of genetically heterogeneous conditions that combines non-progressive cerebellar ataxia with intellectual disability inherited in an <a class="def" href="/books/n/gene/glossary/def-item/autosomal-recessive/">autosomal recessive</a> manner.</p><div id="vldlr-ch.Suggestive_Findings"><h3>Suggestive Findings</h3><p><i>VLDLR</i> cerebellar hypoplasia <b>should be suspected</b> in individuals with the following major diagnostic features:</p><ul><li class="half_rhythm"><div>Non-progressive <a class="def" href="/books/n/gene/glossary/def-item/congenital/">congenital</a> ataxia that is predominantly truncal and results in delayed ambulation</div></li><li class="half_rhythm"><div>Moderate-to-profound intellectual disability</div></li><li class="half_rhythm"><div>Dysarthria</div></li><li class="half_rhythm"><div>MRI findings (see <a class="figpopup" href="/books/NBK1874/figure/vldlr-ch.F1/?report=objectonly" target="object" rid-figpopup="figvldlrchF1" rid-ob="figobvldlrchF1">Figure 1</a>) that include the following:</div><ul><li class="half_rhythm"><div>Hypoplasia of the inferior portion of the cerebellar vermis and hemispheres</div></li><li class="half_rhythm"><div>Simplified gyration of the cerebral hemispheres with minimally thickened but uniform cortex and lack of clear anteroposterior gradient</div></li><li class="half_rhythm"><div>Small brain stem, particularly the pons</div></li></ul></li></ul><div class="iconblock whole_rhythm clearfix ten_col fig" id="figvldlrchF1" co-legend-rid="figlgndvldlrchF1"><a href="/books/NBK1874/figure/vldlr-ch.F1/?report=objectonly" target="object" title="Figure 1. " class="img_link icnblk_img figpopup" rid-figpopup="figvldlrchF1" rid-ob="figobvldlrchF1"><img class="small-thumb" src="/books/NBK1874/bin/vldlr-ch-Image001.gif" src-large="/books/NBK1874/bin/vldlr-ch-Image001.jpg" alt="Figure 1. " /></a><div class="icnblk_cntnt" id="figlgndvldlrchF1"><h4 id="vldlr-ch.F1"><a href="/books/NBK1874/figure/vldlr-ch.F1/?report=objectonly" target="object" rid-ob="figobvldlrchF1">Figure 1. </a></h4><p class="float-caption no_bottom_margin">MRI of the brain demonstrating typical neuroimaging findings of VLDLR-CH A. Sagittal T<sub>1</sub>-weighted</p></div></div></div><div id="vldlr-ch.Establishing_the_Diagnosis"><h3>Establishing the Diagnosis</h3><p>The diagnosis of <i>VLDLR</i> cerebellar hypoplasia <b>is established</b> in a <a class="def" href="/books/n/gene/glossary/def-item/proband/">proband</a> by identification of <a class="def" href="/books/n/gene/glossary/def-item/biallelic/">biallelic</a> pathogenic (or <a class="def" href="/books/n/gene/glossary/def-item/likely-pathogenic/">likely pathogenic</a>) variants in <i>VLDLR</i> on <a class="def" href="/books/n/gene/glossary/def-item/molecular-genetic-testing/">molecular genetic testing</a> (see <a href="/books/NBK1874/table/vldlr-ch.T.molecular_genetic_testing_use/?report=objectonly" target="object" rid-ob="figobvldlrchTmoleculargenetictestinguse">Table 1</a>).</p><p>Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "<a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a>" and "<a class="def" href="/books/n/gene/glossary/def-item/likely-pathogenic/">likely pathogenic</a> variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [<a class="bk_pop" href="#vldlr-ch.REF.richards.2015.405">Richards et al 2015</a>]. Reference to "pathogenic variants" in this <i>GeneReview</i> is understood to include likely pathogenic variants. (2) Identification of <a class="def" href="/books/n/gene/glossary/def-item/biallelic/">biallelic</a> <i>VLDLR</i> variants of <a class="def" href="/books/n/gene/glossary/def-item/uncertain-significance/">uncertain significance</a> (or of one known <i>VLDLR</i> pathogenic variant and one <i>VLDLR</i> variant of uncertain significance) does not establish or rule out the diagnosis.</p><p>Molecular genetic testing approaches can include a combination of <b><a class="def" href="/books/n/gene/glossary/def-item/gene/">gene</a>-targeted testing</b> (single-gene testing, <a class="def" href="/books/n/gene/glossary/def-item/multigene-panel/">multigene panel</a>) and <b>comprehensive</b>
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<b><a class="def" href="/books/n/gene/glossary/def-item/genomic/">genomic</a> testing</b> (<a class="def" href="/books/n/gene/glossary/def-item/chromosomal-microarray/">chromosomal microarray</a> analysis, <a class="def" href="/books/n/gene/glossary/def-item/exome-sequencing/">exome sequencing</a>, <a class="def" href="/books/n/gene/glossary/def-item/exome-array/">exome array</a>, <a class="def" href="/books/n/gene/glossary/def-item/genome-sequencing/">genome sequencing</a>) depending on the <a class="def" href="/books/n/gene/glossary/def-item/phenotype/">phenotype</a>.</p><p>Gene-targeted testing requires that the clinician determine which <a class="def" href="/books/n/gene/glossary/def-item/gene/">gene</a>(s) are likely involved, whereas <a class="def" href="/books/n/gene/glossary/def-item/genomic/">genomic</a> testing does not. Because the <a class="def" href="/books/n/gene/glossary/def-item/phenotype/">phenotype</a> of VLDLR cerebellar hypoplasia is often recognizable, individuals with the distinctive MRI findings described in <a href="#vldlr-ch.Suggestive_Findings">Suggestive Findings</a> can often be diagnosed using gene-targeted testing (see <a href="#vldlr-ch.Option_1">Option 1</a>), whereas those in whom the diagnosis of VLDLR cerebellar hypoplasia has not been considered are more likely to be diagnosed using genomic testing (see <a href="#vldlr-ch.Option_2">Option 2</a>).</p><div id="vldlr-ch.Option_1"><h4>Option 1</h4><p>When the phenotypic and radiographic findings suggest the diagnosis of <i>VLDLR</i> cerebellar hypoplasia, <a class="def" href="/books/n/gene/glossary/def-item/molecular-genetic-testing/">molecular genetic testing</a> approaches can include <b>single-<a class="def" href="/books/n/gene/glossary/def-item/gene/">gene</a> testing</b> or use of a <b><a class="def" href="/books/n/gene/glossary/def-item/multigene-panel/">multigene panel</a></b>:</p><ul><li class="half_rhythm"><div class="half_rhythm"><b>Single-<a class="def" href="/books/n/gene/glossary/def-item/gene/">gene</a> testing.</b> Sequence analysis of <i>VLDLR</i> is performed first to detect <a class="def" href="/books/n/gene/glossary/def-item/missense/">missense</a>, <a class="def" href="/books/n/gene/glossary/def-item/nonsense-variant/">nonsense</a>, and <a class="def" href="/books/n/gene/glossary/def-item/splice-site/">splice site</a> variants and small intragenic deletions/insertions. Note: Depending on the sequencing method used, single-<a class="def" href="/books/n/gene/glossary/def-item/exon/">exon</a>, multiexon, or whole-gene deletions/duplications may not be detected. If no variant is detected by the sequencing method used, the next step is to perform gene-targeted <a class="def" href="/books/n/gene/glossary/def-item/deletion-duplication-analysis/">deletion/duplication analysis</a> to detect exon and whole-gene deletions or duplications.</div><div class="half_rhythm">Note: Targeted analysis for pathogenic variants can be performed first in individuals of Hutterite ancestry. See <a href="/books/NBK1874/table/vldlr-ch.T.notable_vldlr_pathogenic_vari/?report=objectonly" target="object" rid-ob="figobvldlrchTnotablevldlrpathogenicvari">Table 6</a>.</div></li><li class="half_rhythm"><div class="half_rhythm"><b>A <a class="def" href="/books/n/gene/glossary/def-item/multigene-panel/">multigene panel</a></b> that includes <i>VLDLR</i> and other genes of interest (see <a href="#vldlr-ch.Differential_Diagnosis">Differential Diagnosis</a>) is most likely to identify the genetic cause of the condition while limiting identification of variants of <a class="def" href="/books/n/gene/glossary/def-item/uncertain-significance/">uncertain significance</a> and pathogenic variants in genes that do not explain the underlying <a class="def" href="/books/n/gene/glossary/def-item/phenotype/">phenotype</a>. Note: (1) The genes included in the panel and the diagnostic <a class="def" href="/books/n/gene/glossary/def-item/sensitivity/">sensitivity</a> of the testing used for each <a class="def" href="/books/n/gene/glossary/def-item/gene/">gene</a> vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this <i>GeneReview</i>. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused <a class="def" href="/books/n/gene/glossary/def-item/exome/">exome</a> analysis that includes genes specified by the clinician. (4) Methods used in a panel may include <a class="def" href="/books/n/gene/glossary/def-item/sequence-analysis/">sequence analysis</a>, <a class="def" href="/books/n/gene/glossary/def-item/deletion-duplication-analysis/">deletion/duplication analysis</a>, and/or other non-sequencing-based tests. For this disorder a multigene panel that also includes deletion/duplication analysis can be considered if only one or no <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a> is found on sequencing.</div><div class="half_rhythm">For an introduction to multigene panels click <a href="/books/n/gene/app5/#app5.Multigene_Panels">here</a>. More detailed information for clinicians ordering genetic tests can be found <a href="/books/n/gene/app5/#app5.Multigene_Panels_FAQs">here</a>.</div></li></ul></div><div id="vldlr-ch.Option_2"><h4>Option 2</h4><p>When the diagnosis of <i>VLDLR</i> cerebellar hypoplasia is not considered because of its rarity and/or because an individual has atypical phenotypic features, <b>comprehensive</b>
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<b><a class="def" href="/books/n/gene/glossary/def-item/genomic/">genomic</a> testing</b> (which does not require the clinician to determine which <a class="def" href="/books/n/gene/glossary/def-item/gene/">gene</a>[s] are likely involved) is the best option. <b>Exome sequencing</b> is most commonly used; <b><a class="def" href="/books/n/gene/glossary/def-item/genome-sequencing/">genome sequencing</a></b> is also possible.</p><p>If <a class="def" href="/books/n/gene/glossary/def-item/exome-sequencing/">exome sequencing</a> is not diagnostic, <a class="def" href="/books/n/gene/glossary/def-item/exome-array/">exome array</a> (when clinically available) may be considered to detect (multi)<a class="def" href="/books/n/gene/glossary/def-item/exon/">exon</a> deletions or duplications that cannot be detected by <a class="def" href="/books/n/gene/glossary/def-item/sequence-analysis/">sequence analysis</a>.</p><p>For an introduction to comprehensive <a class="def" href="/books/n/gene/glossary/def-item/genomic/">genomic</a> testing click <a href="/books/n/gene/app5/#app5.Comprehensive_Genomic_Testing">here</a>. More detailed information for clinicians ordering genomic testing can be found <a href="/books/n/gene/app5/#app5.Comprehensive_Genomic_Testing_1">here</a>.</p><div id="vldlr-ch.T.molecular_genetic_testing_use" class="table"><h3><span class="label">Table 1. </span></h3><div class="caption"><p>Molecular Genetic Testing Used in <i>VLDLR</i> Cerebellar Hypoplasia</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK1874/table/vldlr-ch.T.molecular_genetic_testing_use/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__vldlr-ch.T.molecular_genetic_testing_use_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_vldlr-ch.T.molecular_genetic_testing_use_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Gene <sup>1</sup></th><th id="hd_h_vldlr-ch.T.molecular_genetic_testing_use_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Method</th><th id="hd_h_vldlr-ch.T.molecular_genetic_testing_use_1_1_1_3" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Proportion of Pathogenic Variants <sup>2</sup> Identified by Method</th></tr></thead><tbody><tr><td headers="hd_h_vldlr-ch.T.molecular_genetic_testing_use_1_1_1_1" rowspan="2" scope="row" colspan="1" style="text-align:left;vertical-align:middle;">
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<i>VLDLR</i>
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</td><td headers="hd_h_vldlr-ch.T.molecular_genetic_testing_use_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Sequence analysis <sup>3</sup></td><td headers="hd_h_vldlr-ch.T.molecular_genetic_testing_use_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">85% <sup>4</sup></td></tr><tr><td headers="hd_h_vldlr-ch.T.molecular_genetic_testing_use_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">Gene-targeted <a class="def" href="/books/n/gene/glossary/def-item/deletion-duplication-analysis/">deletion/duplication analysis</a> <sup>5</sup></td><td headers="hd_h_vldlr-ch.T.molecular_genetic_testing_use_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">15% <sup>4</sup></td></tr></tbody></table></div><div><div><dl class="temp-labeled-list small"><dt>1. </dt><dd><div id="vldlr-ch.TF.1.1"><p class="no_margin">See <a href="/books/NBK1874/#vldlr-ch.molgen.TA">Table A. Genes and Databases</a> for <a class="def" href="/books/n/gene/glossary/def-item/chromosome/">chromosome</a> <a class="def" href="/books/n/gene/glossary/def-item/locus/">locus</a> and protein.</p></div></dd><dt>2. </dt><dd><div id="vldlr-ch.TF.1.2"><p class="no_margin">See <a href="#vldlr-ch.Molecular_Genetics">Molecular Genetics</a> for information on variants detected in this <a class="def" href="/books/n/gene/glossary/def-item/gene/">gene</a>.</p></div></dd><dt>3. </dt><dd><div id="vldlr-ch.TF.1.3"><p class="no_margin">Sequence analysis detects variants that are benign, <a class="def" href="/books/n/gene/glossary/def-item/likely-benign/">likely benign</a>, of <a class="def" href="/books/n/gene/glossary/def-item/uncertain-significance/">uncertain significance</a>, <a class="def" href="/books/n/gene/glossary/def-item/likely-pathogenic/">likely pathogenic</a>, or pathogenic. Variants may include <a class="def" href="/books/n/gene/glossary/def-item/missense/">missense</a>, <a class="def" href="/books/n/gene/glossary/def-item/nonsense-variant/">nonsense</a>, and <a class="def" href="/books/n/gene/glossary/def-item/splice-site/">splice site</a> variants and small intragenic deletions/insertions; typically, <a class="def" href="/books/n/gene/glossary/def-item/exon/">exon</a> or whole-<a class="def" href="/books/n/gene/glossary/def-item/gene/">gene</a> deletions/duplications are not detected. For issues to consider in interpretation of <a class="def" href="/books/n/gene/glossary/def-item/sequence-analysis/">sequence analysis</a> results, click <a href="/books/n/gene/app2/">here</a>.</p></div></dd><dt>4. </dt><dd><div id="vldlr-ch.TF.1.4"><p class="no_margin">Data derived from the subscription-based professional view of Human Gene Mutation Database [<a class="bk_pop" href="#vldlr-ch.REF.stenson.2020.1197">Stenson et al 2020</a>]</p></div></dd><dt>5. </dt><dd><div id="vldlr-ch.TF.1.5"><p class="no_margin">Gene-targeted <a class="def" href="/books/n/gene/glossary/def-item/deletion-duplication-analysis/">deletion/duplication analysis</a> detects intragenic deletions or duplications. Methods used may include a range of techniques such as <a class="def" href="/books/n/gene/glossary/def-item/quantitative-pcr/">quantitative PCR</a>, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a <a class="def" href="/books/n/gene/glossary/def-item/gene/">gene</a>-targeted microarray designed to detect single-<a class="def" href="/books/n/gene/glossary/def-item/exon/">exon</a> deletions or duplications.</p></div></dd></dl></div></div></div></div></div></div><div id="vldlr-ch.Clinical_Characteristics"><h2 id="_vldlr-ch_Clinical_Characteristics_">Clinical Characteristics</h2><div id="vldlr-ch.Clinical_Description"><h3>Clinical Description</h3><p><i>VLDLR</i> cerebellar hypoplasia is a <a class="def" href="/books/n/gene/glossary/def-item/congenital/">congenital</a> non-progressive disorder characterized by cerebellar ataxia and intellectual disability.</p><p>To date, more than 50 individuals have been identified with a <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a> in <i>VLDLR</i> [<a class="bk_pop" href="#vldlr-ch.REF.boycott.2005.477">Boycott et al 2005</a>, <a class="bk_pop" href="#vldlr-ch.REF.glass.2005.691">Glass et al 2005</a>, <a class="bk_pop" href="#vldlr-ch.REF.moheb.2008.270">Moheb et al 2008</a>, <a class="bk_pop" href="#vldlr-ch.REF.ozcelik.2008.4232">Ozcelik et al 2008</a>, <a class="bk_pop" href="#vldlr-ch.REF.t_rkmen.2008.1070">Türkmen et al 2008</a>, <a class="bk_pop" href="#vldlr-ch.REF.boycott.2009.1310">Boycott et al 2009</a>, <a class="bk_pop" href="#vldlr-ch.REF.kolb.2010.319">Kolb et al 2010</a>, <a class="bk_pop" href="#vldlr-ch.REF.ali.2012.80">Ali et al 2012</a>, <a class="bk_pop" href="#vldlr-ch.REF.azmanov.2013.71">Azmanov et al 2013</a>, <a class="bk_pop" href="#vldlr-ch.REF.kruer.2013.1904">Kruer et al 2013</a>, <a class="bk_pop" href="#vldlr-ch.REF.schlotawa.2013.1678">Schlotawa et al 2013</a>, <a class="bk_pop" href="#vldlr-ch.REF.sonmez.2013.379">Sonmez et al 2013</a>, <a class="bk_pop" href="#vldlr-ch.REF.giorgio.2016.1772">Giorgio et al 2016</a>, <a class="bk_pop" href="#vldlr-ch.REF.micalizzi.2016.191">Micalizzi et al 2016</a>, <a class="bk_pop" href="#vldlr-ch.REF.valence.2016.545">Valence et al 2016</a>, <a class="bk_pop" href="#vldlr-ch.REF.wilker.2019.404">Wilker et al 2019</a>]. The following description of the phenotypic features associated with this condition is based on these reports.</p><div id="vldlr-ch.T.features_of_vldlr_cerebellar" class="table"><h3><span class="label">Table 2. </span></h3><div class="caption"><p>Features of <i>VLDLR</i> Cerebellar Hypoplasia</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK1874/table/vldlr-ch.T.features_of_vldlr_cerebellar/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__vldlr-ch.T.features_of_vldlr_cerebellar_lrgtbl__"><table><thead><tr><th id="hd_h_vldlr-ch.T.features_of_vldlr_cerebellar_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Feature</th><th id="hd_h_vldlr-ch.T.features_of_vldlr_cerebellar_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Number (%) of Persons w/Feature</th><th id="hd_h_vldlr-ch.T.features_of_vldlr_cerebellar_1_1_1_3" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Comment</th></tr></thead><tbody><tr><td headers="hd_h_vldlr-ch.T.features_of_vldlr_cerebellar_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Cerebellar hypoplasia</td><td headers="hd_h_vldlr-ch.T.features_of_vldlr_cerebellar_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">44/44 (100%)</td><td headers="hd_h_vldlr-ch.T.features_of_vldlr_cerebellar_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr><tr><td headers="hd_h_vldlr-ch.T.features_of_vldlr_cerebellar_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Pontine hypoplasia</td><td headers="hd_h_vldlr-ch.T.features_of_vldlr_cerebellar_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">36/44 (81.8%)</td><td headers="hd_h_vldlr-ch.T.features_of_vldlr_cerebellar_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr><tr><td headers="hd_h_vldlr-ch.T.features_of_vldlr_cerebellar_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Simplified cortical gyration</td><td headers="hd_h_vldlr-ch.T.features_of_vldlr_cerebellar_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">43/44 (97.7%)</td><td headers="hd_h_vldlr-ch.T.features_of_vldlr_cerebellar_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr><tr><td headers="hd_h_vldlr-ch.T.features_of_vldlr_cerebellar_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Cerebellar ataxia</td><td headers="hd_h_vldlr-ch.T.features_of_vldlr_cerebellar_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">53/53 (100%)</td><td headers="hd_h_vldlr-ch.T.features_of_vldlr_cerebellar_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Predominantly truncal; peripheral ataxia reported in some</td></tr><tr><td headers="hd_h_vldlr-ch.T.features_of_vldlr_cerebellar_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Hypotonia</td><td headers="hd_h_vldlr-ch.T.features_of_vldlr_cerebellar_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">28/37 (75.7%)</td><td headers="hd_h_vldlr-ch.T.features_of_vldlr_cerebellar_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr><tr><td headers="hd_h_vldlr-ch.T.features_of_vldlr_cerebellar_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Dysarthria</td><td headers="hd_h_vldlr-ch.T.features_of_vldlr_cerebellar_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">34/42 (81.0%)</td><td headers="hd_h_vldlr-ch.T.features_of_vldlr_cerebellar_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr><tr><td headers="hd_h_vldlr-ch.T.features_of_vldlr_cerebellar_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Nystagmus</td><td headers="hd_h_vldlr-ch.T.features_of_vldlr_cerebellar_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">11/47 (23.4%)</td><td headers="hd_h_vldlr-ch.T.features_of_vldlr_cerebellar_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr><tr><td headers="hd_h_vldlr-ch.T.features_of_vldlr_cerebellar_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Strabismus</td><td headers="hd_h_vldlr-ch.T.features_of_vldlr_cerebellar_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">40/51 (78.4%)</td><td headers="hd_h_vldlr-ch.T.features_of_vldlr_cerebellar_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr><tr><td headers="hd_h_vldlr-ch.T.features_of_vldlr_cerebellar_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Cognitive impairment</td><td headers="hd_h_vldlr-ch.T.features_of_vldlr_cerebellar_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">53/53 (100%)</td><td headers="hd_h_vldlr-ch.T.features_of_vldlr_cerebellar_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Moderate to profound</td></tr><tr><td headers="hd_h_vldlr-ch.T.features_of_vldlr_cerebellar_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Developmental delay</td><td headers="hd_h_vldlr-ch.T.features_of_vldlr_cerebellar_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">53/53 (100%)</td><td headers="hd_h_vldlr-ch.T.features_of_vldlr_cerebellar_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr><tr><td headers="hd_h_vldlr-ch.T.features_of_vldlr_cerebellar_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Delayed ambulation</td><td headers="hd_h_vldlr-ch.T.features_of_vldlr_cerebellar_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">53/53 (100%)</td><td headers="hd_h_vldlr-ch.T.features_of_vldlr_cerebellar_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Independent ambulation (if achieved) often in mid-childhood.</td></tr><tr><td headers="hd_h_vldlr-ch.T.features_of_vldlr_cerebellar_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Epilepsy</td><td headers="hd_h_vldlr-ch.T.features_of_vldlr_cerebellar_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">7/53 (13.2%)</td><td headers="hd_h_vldlr-ch.T.features_of_vldlr_cerebellar_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr><tr><td headers="hd_h_vldlr-ch.T.features_of_vldlr_cerebellar_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Brisk reflexes</td><td headers="hd_h_vldlr-ch.T.features_of_vldlr_cerebellar_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">31/40 (77.5%)</td><td headers="hd_h_vldlr-ch.T.features_of_vldlr_cerebellar_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr><tr><td headers="hd_h_vldlr-ch.T.features_of_vldlr_cerebellar_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Microcephaly</td><td headers="hd_h_vldlr-ch.T.features_of_vldlr_cerebellar_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">8/38 (21.1%)</td><td headers="hd_h_vldlr-ch.T.features_of_vldlr_cerebellar_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Head circumference -2SD to -4SD</td></tr><tr><td headers="hd_h_vldlr-ch.T.features_of_vldlr_cerebellar_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Dysmorphism</td><td headers="hd_h_vldlr-ch.T.features_of_vldlr_cerebellar_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">1/53 (1.89%)</td><td headers="hd_h_vldlr-ch.T.features_of_vldlr_cerebellar_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">May not be related to <i>VLDLR</i>-CH</td></tr><tr><td headers="hd_h_vldlr-ch.T.features_of_vldlr_cerebellar_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Short stature</td><td headers="hd_h_vldlr-ch.T.features_of_vldlr_cerebellar_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">19/42 (45.2%)</td><td headers="hd_h_vldlr-ch.T.features_of_vldlr_cerebellar_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr></tbody></table></div></div><p><b>Brain MRI.</b> All affected individuals demonstrate hypoplasia of the inferior portion of the cerebellar vermis and hemispheres. In addition, the majority of affected individuals show a simplified gyration of the cerebral hemispheres with minimally thickened but uniform cortex, lack of clear anteroposterior gradient, and small brain stem (particularly the pons). Some individuals are described as demonstrating neuroimaging features of pontocerebellar hypoplasia.</p><p><b>Cerebellar ataxia.</b> All affected individuals demonstrate significant truncal ataxia. Children either learn to walk very late (often after age 6 years) or never achieve independent ambulation. For those able to ambulate independently, gait is wide based; affected individuals are not able to perform a tandem gait. Affected individuals from Turkey demonstrate quadrupedal locomotion in which the palms of the hands touch the ground and the elbows, back, and knees are straight [<a class="bk_pop" href="#vldlr-ch.REF.ozcelik.2008.4232">Ozcelik et al 2008</a>, <a class="bk_pop" href="#vldlr-ch.REF.t_rkmen.2009.e1000487">Türkmen et al 2009</a>], an interesting behavioral adaptation which likely depends on the presence of special environmental influences during child development [<a class="bk_pop" href="#vldlr-ch.REF.herz.2008.e25">Herz et al 2008</a>, <a class="bk_pop" href="#vldlr-ch.REF.t_rkmen.2009.e1000487">Türkmen et al 2009</a>]. Limb ataxia is present in most individuals but is not severe.</p><p><b>Intellectual disability.</b> All reported affected individuals have intellectual disability, ranging from moderate to profound. Most individuals can follow simple commands. Some can communicate verbally using short phrases or sentences. Adults are unable to live independently.</p><p><b>Dysarthria.</b> Those who are able to communicate verbally demonstrate dysarthria.</p><p><b>Strabismus.</b> The majority of individuals have strabismus.</p><p>
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<b>Other</b>
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</p><ul><li class="half_rhythm"><div>Nystagmus is reported in some individuals and is described as gaze evoked.</div></li><li class="half_rhythm"><div>Epileptic seizures were reported in 40% of the affected individuals from the Hutterite population [<a class="bk_pop" href="#vldlr-ch.REF.glass.2005.691">Glass et al 2005</a>], and appear to be less frequent in non-Hutterite individuals. The seizures tend to be generalized.</div></li><li class="half_rhythm"><div>Deep tendon reflexes in the lower extremities tend to be brisk.</div></li><li class="half_rhythm"><div>Microcephaly (2-4 SD below the mean) has been reported in a few affected individuals.</div></li><li class="half_rhythm"><div>Short stature (height just below the 2nd centile) is a feature in a few affected individuals.</div></li></ul><p><b>Life span.</b> There has been no formal study of life span in this disorder, but experience from the Hutterite population suggests that life span is not significantly reduced.</p></div><div id="vldlr-ch.GenotypePhenotype_Correlations"><h3>Genotype-Phenotype Correlations</h3><p>No <a class="def" href="/books/n/gene/glossary/def-item/genotype-phenotype-correlations/">genotype-phenotype correlations</a> have been identified.</p></div><div id="vldlr-ch.Nomenclature"><h3>Nomenclature</h3><p><i>VLDLR</i>-CH is a clinically and molecularly well-defined subgroup of dysequilibrium syndrome (DES).</p></div><div id="vldlr-ch.Prevalence"><h3>Prevalence</h3><p>The actual frequency of <i>VLDLR</i>-CH is unknown.</p><p>More than 25 individuals with <i>VLDLR</i>-CH from the Hutterite population in Canada and the US have been followed for many years. This condition is present in all three Hutterite <i>leuts</i> (branches) (i.e., <i>Schmiedeleut</i>, <i>Lehrerleut</i>, and <i>Dariusleut</i>).</p><p>The estimated <a class="def" href="/books/n/gene/glossary/def-item/carrier/">carrier</a> frequency in the Hutterite population is one in 15 [<a class="bk_pop" href="#vldlr-ch.REF.glass.2005.691">Glass et al 2005</a>].</p></div></div><div id="vldlr-ch.Genetically_Related_Allelic_Dis"><h2 id="_vldlr-ch_Genetically_Related_Allelic_Dis_">Genetically Related (Allelic) Disorders</h2><p>No phenotypes other than those discussed in this <i>GeneReview</i> are known to be associated with <a class="def" href="/books/n/gene/glossary/def-item/germline/">germline</a> pathogenic variants in <i>VLDLR</i>.</p></div><div id="vldlr-ch.Differential_Diagnosis"><h2 id="_vldlr-ch_Differential_Diagnosis_">Differential Diagnosis</h2><p>The differential diagnosis of <i>VLDLR</i> cerebellar hypoplasia (<i>VLDLR</i>-CH) includes <a class="def" href="/books/n/gene/glossary/def-item/autosomal-recessive/">autosomal recessive</a> conditions characterized by <a class="def" href="/books/n/gene/glossary/def-item/congenital/">congenital</a> or very early-onset cerebellar ataxia associated with cerebellar hypoplasia. Because cerebellar hypoplasia can be difficult to distinguish from cerebellar atrophy on early imaging, conditions characterized by the latter should also be considered (see <a href="/books/NBK1874/table/vldlr-ch.T.genes_and_disorders_of_intere/?report=objectonly" target="object" rid-ob="figobvldlrchTgenesanddisordersofintere">Table 3</a>).</p><p>Note: Diverse phenotypes associated with childhood- and adult-onset ataxia are to be excluded (see <a href="/books/n/gene/ataxias/#ataxias.T.autosomal_recessive_cerebellar">Hereditary Ataxia Overview, Table 3. Autosomal Recessive Cerebellar Ataxias: Single-Gene Disorders</a>).</p><div id="vldlr-ch.T.genes_and_disorders_of_intere" class="table"><h3><span class="label">Table 3. </span></h3><div class="caption"><p>Genes and Disorders of Interest in the Differential Diagnosis of <i>VLDLR</i> Cerebellar Hypoplasia</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK1874/table/vldlr-ch.T.genes_and_disorders_of_intere/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__vldlr-ch.T.genes_and_disorders_of_intere_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_vldlr-ch.T.genes_and_disorders_of_intere_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Gene(s)</th><th id="hd_h_vldlr-ch.T.genes_and_disorders_of_intere_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Disorder</th><th id="hd_h_vldlr-ch.T.genes_and_disorders_of_intere_1_1_1_3" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Brain Imaging</th><th id="hd_h_vldlr-ch.T.genes_and_disorders_of_intere_1_1_1_4" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Neurologic Findings</th></tr></thead><tbody><tr><td headers="hd_h_vldlr-ch.T.genes_and_disorders_of_intere_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><i>AHI1</i><br /><i>CPLANE1</i><br /><i>CC2D2A</i><br /><i>CEP290</i><br />(~34 genes) <sup>1</sup></td><td headers="hd_h_vldlr-ch.T.genes_and_disorders_of_intere_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><a href="/books/n/gene/joubert/">Joubert syndrome & related disorders</a> <sup>2</sup></td><td headers="hd_h_vldlr-ch.T.genes_and_disorders_of_intere_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">"Molar tooth sign" (hypoplasia of cerebellar vermis & assoc brain stem abnormalities resembling a tooth)</td><td headers="hd_h_vldlr-ch.T.genes_and_disorders_of_intere_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>DD & severe cognitive impairment (in some individuals)</div></li><li class="half_rhythm"><div>Episodic hyperpnea or apnea &/or atypical eye movements</div></li><li class="half_rhythm"><div>Truncal ataxia</div></li></ul>
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</td></tr><tr><td headers="hd_h_vldlr-ch.T.genes_and_disorders_of_intere_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><i>ALG1</i><br /><i>ALG6</i><br /><i>PMM2</i><br />(~42 genes) <sup>3</sup></td><td headers="hd_h_vldlr-ch.T.genes_and_disorders_of_intere_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<a href="/books/n/gene/cdg/">Congenital disorders of glycosylation</a>
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</td><td headers="hd_h_vldlr-ch.T.genes_and_disorders_of_intere_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Cerebellar atrophy</td><td headers="hd_h_vldlr-ch.T.genes_and_disorders_of_intere_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>DD/ID</div></li><li class="half_rhythm"><div>Hypotonia & ataxia</div></li><li class="half_rhythm"><div>Strabismus</div></li></ul>
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</td></tr><tr><td headers="hd_h_vldlr-ch.T.genes_and_disorders_of_intere_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<i>ATCAY</i>
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</td><td headers="hd_h_vldlr-ch.T.genes_and_disorders_of_intere_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Cayman-type cerebellar ataxia (OMIM <a href="http://omim.org/entry/601238" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">601238</a>) <sup>4</sup></td><td headers="hd_h_vldlr-ch.T.genes_and_disorders_of_intere_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">CH</td><td headers="hd_h_vldlr-ch.T.genes_and_disorders_of_intere_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Cerebellar ataxia w/wide-based gait</div></li><li class="half_rhythm"><div>Dysarthria</div></li><li class="half_rhythm"><div>Intention tremor</div></li><li class="half_rhythm"><div>DD/ID</div></li></ul>
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</td></tr><tr><td headers="hd_h_vldlr-ch.T.genes_and_disorders_of_intere_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<i>ATM</i>
|
||
</td><td headers="hd_h_vldlr-ch.T.genes_and_disorders_of_intere_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><a href="/books/n/gene/ataxia-telangiectas/">Ataxia-telangiectasia</a> <sup>5</sup></td><td headers="hd_h_vldlr-ch.T.genes_and_disorders_of_intere_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Cerebellar atrophy (may not be obvious in very young individuals)</td><td headers="hd_h_vldlr-ch.T.genes_and_disorders_of_intere_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Choreoathetosis</div></li><li class="half_rhythm"><div>Oculomotor apraxia</div></li><li class="half_rhythm"><div>Progressive cerebellar ataxia beginning at ages 1-4 yrs</div></li></ul>
|
||
</td></tr><tr><td headers="hd_h_vldlr-ch.T.genes_and_disorders_of_intere_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<i>ATP8A2</i>
|
||
</td><td headers="hd_h_vldlr-ch.T.genes_and_disorders_of_intere_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">CAMRQ4 (OMIM <a href="https://omim.org/entry/615268" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">615268</a>)</td><td headers="hd_h_vldlr-ch.T.genes_and_disorders_of_intere_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Cerebellar atrophy</td><td headers="hd_h_vldlr-ch.T.genes_and_disorders_of_intere_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Congenital cerebellar ataxia</div></li><li class="half_rhythm"><div>ID</div></li></ul>
|
||
</td></tr><tr><td headers="hd_h_vldlr-ch.T.genes_and_disorders_of_intere_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<i>CA8</i>
|
||
</td><td headers="hd_h_vldlr-ch.T.genes_and_disorders_of_intere_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">CAMRQ3 (OMIM <a href="https://omim.org/entry/613227" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">613227</a>)</td><td headers="hd_h_vldlr-ch.T.genes_and_disorders_of_intere_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td><td headers="hd_h_vldlr-ch.T.genes_and_disorders_of_intere_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Congenital cerebellar ataxia</div></li><li class="half_rhythm"><div>ID</div></li></ul>
|
||
</td></tr><tr><td headers="hd_h_vldlr-ch.T.genes_and_disorders_of_intere_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><i>EXOSC3</i><br /><i>RARS2</i><br /><i>SEPSECS</i><br /><i>TSEN2</i><br /><i>TSEN34</i><br /><i>TSEN54</i><br /><i>VRK1</i> <sup>6</sup></td><td headers="hd_h_vldlr-ch.T.genes_and_disorders_of_intere_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">PCH types 1 & 2 (see <a href="/books/n/gene/exosc3-pc-hypo-p/"><i>EXOSC3</i>-PCH</a> & <a href="/books/n/gene/pc-hypo-p/"><i>TSEN54</i>-PCH</a>)</td><td headers="hd_h_vldlr-ch.T.genes_and_disorders_of_intere_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Cerebellar vermis hypoplasia & hypoplasia of the pons (more severe than small pons seen in <i>VLDLR</i>-CH)</td><td headers="hd_h_vldlr-ch.T.genes_and_disorders_of_intere_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Progressive motor degeneration (similar to <a href="/books/n/gene/sma/">spinal muscular atrophy</a>) in PCH1</div></li><li class="half_rhythm"><div>Dyskinesia in PCH2</div></li></ul>
|
||
</td></tr><tr><td headers="hd_h_vldlr-ch.T.genes_and_disorders_of_intere_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<i>RELN</i>
|
||
</td><td headers="hd_h_vldlr-ch.T.genes_and_disorders_of_intere_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><i>RELN</i> lissencephaly w/CH <sup>7</sup> (OMIM <a href="https://omim.org/entry/257320" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">257320</a>)</td><td headers="hd_h_vldlr-ch.T.genes_and_disorders_of_intere_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Cerebellar signs of <i>RELN</i>-LCH that differ from <i>VLDLR</i>-CH:<br />More significant lissencephaly w/anterior>posterior gradient<br />A malformed hippocampus<br />Profound CH w/complete absence of detectable folia</td><td headers="hd_h_vldlr-ch.T.genes_and_disorders_of_intere_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Congenital cerebellar ataxia</div></li><li class="half_rhythm"><div>Hypotonia</div></li><li class="half_rhythm"><div>ID</div></li><li class="half_rhythm"><div>Epilepsy</div></li><li class="half_rhythm"><div>Strabismus</div></li></ul>
|
||
</td></tr><tr><td headers="hd_h_vldlr-ch.T.genes_and_disorders_of_intere_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<i>SACS</i>
|
||
</td><td headers="hd_h_vldlr-ch.T.genes_and_disorders_of_intere_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><a href="/books/n/gene/arsacs/">ARSACS</a> (<i>a</i>utosomal <i>r</i>ecessive <i>s</i>pastic <i>a</i>taxia of <i>C</i>harlevoix-<i>S</i>aguenay)</td><td headers="hd_h_vldlr-ch.T.genes_and_disorders_of_intere_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Atrophy of superior vermis</td><td headers="hd_h_vldlr-ch.T.genes_and_disorders_of_intere_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Distal muscle wasting</div></li><li class="half_rhythm"><div>Distal sensorimotor neuropathy (predominant in legs)</div></li><li class="half_rhythm"><div>Dysarthria</div></li><li class="half_rhythm"><div>Early-onset ataxia</div></li><li class="half_rhythm"><div>Extensor plantar reflexes</div></li><li class="half_rhythm"><div>Horizontal gaze-evoked nystagmus</div></li><li class="half_rhythm"><div>Spasticity</div></li></ul>
|
||
</td></tr><tr><td headers="hd_h_vldlr-ch.T.genes_and_disorders_of_intere_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<i>SIL1</i>
|
||
</td><td headers="hd_h_vldlr-ch.T.genes_and_disorders_of_intere_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><a href="/books/n/gene/mss/">Marinesco-Sjögren syndrome</a> <sup>8</sup></td><td headers="hd_h_vldlr-ch.T.genes_and_disorders_of_intere_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Cerebellar atrophy</td><td headers="hd_h_vldlr-ch.T.genes_and_disorders_of_intere_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Cerebellar ataxia</div></li><li class="half_rhythm"><div>Mild-to-severe cognitive impairment</div></li><li class="half_rhythm"><div>Hypotonia & muscle weakness</div></li></ul>
|
||
</td></tr><tr><td headers="hd_h_vldlr-ch.T.genes_and_disorders_of_intere_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<i>TWNK</i>
|
||
</td><td headers="hd_h_vldlr-ch.T.genes_and_disorders_of_intere_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Infantile-onset spinocerebellar ataxia <sup>9</sup> (OMIM <a href="https://omim.org/entry/271245" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">271245</a>)</td><td headers="hd_h_vldlr-ch.T.genes_and_disorders_of_intere_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Atrophy of cerebellum, brain stem, & spinal cord</td><td headers="hd_h_vldlr-ch.T.genes_and_disorders_of_intere_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Normal development until age 1 yr, followed by onset of ataxia, muscle hypotonia, loss of deep-tendon reflexes, athetosis, ophthalmoplegia, & sensorineural deafness in childhood <sup>10</sup></div></li><li class="half_rhythm"><div>Epilepsy can → serious & often fatal encephalopathy.</div></li></ul>
|
||
</td></tr><tr><td headers="hd_h_vldlr-ch.T.genes_and_disorders_of_intere_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<i>WDR81</i>
|
||
</td><td headers="hd_h_vldlr-ch.T.genes_and_disorders_of_intere_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">CAMRQ2 (OMIM <a href="https://omim.org/entry/610185" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">610185</a>)</td><td headers="hd_h_vldlr-ch.T.genes_and_disorders_of_intere_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">CH</td><td headers="hd_h_vldlr-ch.T.genes_and_disorders_of_intere_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Congenital cerebellar ataxia</div></li><li class="half_rhythm"><div>ID</div></li></ul>
|
||
</td></tr></tbody></table></div><div><div><dl class="temp-labeled-list small"><dt></dt><dd><div><p class="no_margin">CAMRQ = cerebellar ataxia, mental retardation, and dysequilibrium syndrome; CDG = <a class="def" href="/books/n/gene/glossary/def-item/congenital/">congenital</a> disorder of glycosylation; CH = cerebellar hypoplasia; DD = developmental delay; ID = intellectual disability; LCH = lissencephaly with cerebellar hypoplasia; PCH = pontocerebellar hypoplasia</p></div></dd><dt>1. </dt><dd><div id="vldlr-ch.TF.3.1"><p class="no_margin">To date, pathogenic variants in 34 genes are known to cause Joubert syndrome. <i>AHI1</i>, <i>CPLANE1</i>, <i>CC2D2A</i>, and <i>CEP290</i> are some of the most commonly involved genes.</p></div></dd><dt>2. </dt><dd><div id="vldlr-ch.TF.3.2"><p class="no_margin">Variable features include: retinal dystrophy, renal disease, ocular colobomas, occipital encephalocele, hepatic fibrosis, polydactyly, oral hamartomas, and endocrine abnormalities.</p></div></dd><dt>3. </dt><dd><div id="vldlr-ch.TF.3.3"><p class="no_margin"><i>PMM2-</i>CDG (CDG-Ia), <i>ALG6-</i>CDG (CDG-Ic), and <i>ALG1</i>-CDG (CDG-Ik) represent some of the more frequently identified CDG types. Forty-two different enzymes in the N-linked oligosaccharide synthetic pathway or interactive pathways are currently recognized to be deficient in each of the types of CDG-N-linked or among the multiple-pathway disorders (see <a href="/books/n/gene/cdg/">Congenital Disorders of N-Linked Glycosylation and Multiple Pathway Overview</a>).</p></div></dd><dt>4. </dt><dd><div id="vldlr-ch.TF.3.4"><p class="no_margin">Affected individuals are from a Grand Cayman Island isolate.</p></div></dd><dt>5. </dt><dd><div id="vldlr-ch.TF.3.5"><p class="no_margin">Also characterized by immunodeficiency, frequent infections, telangiectasias of the conjunctivae, and increased risk for malignancy (particularly leukemia and lymphoma)</p></div></dd><dt>6. </dt><dd><div id="vldlr-ch.TF.3.6"><p class="no_margin">About 50% of individuals with pontocerebellar hypoplasia type 1 (PCH1) have pathogenic variants in <i>EXOSC3</i>. See <a href="http://omim.org/phenotypicSeries/PS607596" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">Pontocerebellar hypoplasia: OMIM Phenotypic Series</a> for other genes associated with PCH in OMIM.</p></div></dd><dt>7. </dt><dd><div id="vldlr-ch.TF.3.7"><p class="no_margin">The presentation of lissencephalies with cerebellar hypoplasia (LCH) ranges from the classic pattern of pachygyria/agyria to less severe phenotypes. The cerebellar manifestations range from relatively preserved hemispheres to marked hypoplasia with foliation defects. The malformations seen in VLDLR-CH fall within the LCH spectrum. Forms of LCH other than <i>RELN</i>-LCH are easily distinguished from VLDLR-CH based on the severity of the cortical <a class="def" href="/books/n/gene/glossary/def-item/phenotype/">phenotype</a> or additional features.</p></div></dd><dt>8. </dt><dd><div id="vldlr-ch.TF.3.8"><p class="no_margin">Also characterized by early-onset cataracts</p></div></dd><dt>9. </dt><dd><div id="vldlr-ch.TF.3.9"><p class="no_margin">Infantile-onset spinocerebellar ataxia is well recognized in Finland.</p></div></dd><dt>10. </dt><dd><div id="vldlr-ch.TF.3.10"><p class="no_margin">By adolescence affected individuals are profoundly deaf and no longer ambulatory; sensory axonal neuropathy, optic atrophy, autonomic nervous system dysfunction, and hypergonadotropic hypogonadism in females become evident.</p></div></dd></dl></div></div></div></div><div id="vldlr-ch.Management"><h2 id="_vldlr-ch_Management_">Management</h2><div id="vldlr-ch.Evaluations_Following_Initial_D"><h3>Evaluations Following Initial Diagnosis</h3><p>To establish the extent of disease and needs in an individual diagnosed with <i>VLDLR</i> cerebellar hypoplasia (<i>VLDLR</i>-CH), the evaluations summarized in <a href="/books/NBK1874/table/vldlr-ch.T.recommended_evaluations_follo/?report=objectonly" target="object" rid-ob="figobvldlrchTrecommendedevaluationsfollo">Table 4</a> (if not performed as part of the evaluation that led to the diagnosis) are recommended.</p><div id="vldlr-ch.T.recommended_evaluations_follo" class="table"><h3><span class="label">Table 4. </span></h3><div class="caption"><p>Recommended Evaluations Following Initial Diagnosis in Individuals with <i>VLDLR</i> Cerebellar Hypoplasia</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK1874/table/vldlr-ch.T.recommended_evaluations_follo/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__vldlr-ch.T.recommended_evaluations_follo_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_vldlr-ch.T.recommended_evaluations_follo_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">System/Concern</th><th id="hd_h_vldlr-ch.T.recommended_evaluations_follo_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Evaluation</th><th id="hd_h_vldlr-ch.T.recommended_evaluations_follo_1_1_1_3" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Comment</th></tr></thead><tbody><tr><td headers="hd_h_vldlr-ch.T.recommended_evaluations_follo_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Neurologic</b>
|
||
</td><td headers="hd_h_vldlr-ch.T.recommended_evaluations_follo_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Neurologic eval</td><td headers="hd_h_vldlr-ch.T.recommended_evaluations_follo_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Brain MRI</div></li><li class="half_rhythm"><div>Consider EEG if seizures are a concern.</div></li></ul>
|
||
</td></tr><tr><td headers="hd_h_vldlr-ch.T.recommended_evaluations_follo_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Developmental</b>
|
||
</td><td headers="hd_h_vldlr-ch.T.recommended_evaluations_follo_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Developmental assessment</td><td headers="hd_h_vldlr-ch.T.recommended_evaluations_follo_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Adaptive, cognitive, & speech-language eval</td></tr><tr><td headers="hd_h_vldlr-ch.T.recommended_evaluations_follo_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Musculoskeletal</b>
|
||
</td><td headers="hd_h_vldlr-ch.T.recommended_evaluations_follo_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Orthopedics / physical medicine & rehab / PT & OT eval</td><td headers="hd_h_vldlr-ch.T.recommended_evaluations_follo_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">To incl assessment of:
|
||
<ul><li class="half_rhythm"><div>Mobility, activities of daily living, & need for adaptive devices;</div></li><li class="half_rhythm"><div>Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills);</div></li></ul>
|
||
</td></tr><tr><td headers="hd_h_vldlr-ch.T.recommended_evaluations_follo_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Eyes</b>
|
||
</td><td headers="hd_h_vldlr-ch.T.recommended_evaluations_follo_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Ophthalmologic eval</td><td headers="hd_h_vldlr-ch.T.recommended_evaluations_follo_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">To assess for strabismus</td></tr><tr><td headers="hd_h_vldlr-ch.T.recommended_evaluations_follo_1_1_1_1" rowspan="2" scope="row" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Miscellaneous/</b>
|
||
<br />
|
||
<b>Other</b>
|
||
</td><td headers="hd_h_vldlr-ch.T.recommended_evaluations_follo_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Consultation w/clinical geneticist &/or genetic counselor</td><td headers="hd_h_vldlr-ch.T.recommended_evaluations_follo_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">To incl <a class="def" href="/books/n/gene/glossary/def-item/genetic-counseling/">genetic counseling</a> & reproductive options</td></tr><tr><td headers="hd_h_vldlr-ch.T.recommended_evaluations_follo_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">Family support/resources</td><td headers="hd_h_vldlr-ch.T.recommended_evaluations_follo_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>School support</div></li><li class="half_rhythm"><div>Community support</div></li></ul>
|
||
</td></tr></tbody></table></div><div><div><dl class="temp-labeled-list small"><dt></dt><dd><div><p class="no_margin">OT = occupational therapy; PT = physical therapy</p></div></dd></dl></div></div></div></div><div id="vldlr-ch.Treatment_of_Manifestations"><h3>Treatment of Manifestations</h3><p>Treatment of seizures and strabismus is done in the standard manner.</p><div id="vldlr-ch.Developmental_Delay__Intellectu"><h4>Developmental Delay / Intellectual Disability Management Issues</h4><p>The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country.</p><p><b>Ages 0-3 years.</b> In the US, early intervention is a federally funded program available in all states that provides in-home services to target individual therapy needs.</p><p><b>Ages 3-5 years.</b> In the US, developmental preschool through the local public school district is recommended. Before placement, an evaluation is made to determine needed services and therapies and an individualized education plan (IEP) is developed for those who qualify based on established motor, language, social, or cognitive delay. The early intervention program typically assists with this transition. Developmental preschool is center based; for children too medically unstable to attend, home-based services are provided.</p><p><b>All ages.</b> Consultation with a developmental pediatrician is recommended to ensure the involvement of appropriate community, state, and educational agencies (US) and to support parents in maximizing quality of life. Some issues to consider:</p><ul><li class="half_rhythm"><div>IEP services:</div><ul><li class="half_rhythm"><div>An IEP provides specially designed instruction and related services to children who qualify.</div></li><li class="half_rhythm"><div>IEP services will be reviewed annually to determine whether any changes are needed.</div></li><li class="half_rhythm"><div>As required by special education law, children should be in the least restrictive environment feasible at school and included in general education as much as possible and when appropriate.</div></li><li class="half_rhythm"><div>Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.</div></li><li class="half_rhythm"><div>PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.</div></li><li class="half_rhythm"><div>As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.</div></li></ul></li><li class="half_rhythm"><div>A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.</div></li><li class="half_rhythm"><div>Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.</div></li><li class="half_rhythm"><div>Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.</div></li></ul></div><div id="vldlr-ch.Motor_Dysfunction"><h4>Motor Dysfunction</h4><p>
|
||
<b>Gross motor dysfunction</b>
|
||
</p><ul><li class="half_rhythm"><div>Physical therapy is recommended to maximize mobility and to promote ambulation.</div></li><li class="half_rhythm"><div>Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).</div></li></ul><p><b>Fine motor dysfunction.</b> Occupational therapy is recommended for difficulty with fine motor skills that affect adaptive function such as feeding, grooming, dressing, and writing.</p><p><b>Communication issues.</b> Consider evaluation for alternative means of communication (e.g., <a href="http://www.asha.org/NJC/AAC/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">Augmentative and Alternative Communication</a> [AAC]) for individuals who have expressive language difficulties. An AAC evaluation can be completed by a speech-language pathologist who has expertise in the area. The evaluation will consider cognitive abilities and sensory impairments to determine the most appropriate form of communication. AAC devices can range from low-tech, such as picture exchange communication, to high-tech, such as voice-generating devices. Contrary to popular belief, AAC devices do not hinder verbal development of speech, and in many cases can improve it.</p></div></div><div id="vldlr-ch.Surveillance"><h3>Surveillance</h3><div id="vldlr-ch.T.recommended_surveillance_for" class="table"><h3><span class="label">Table 5. </span></h3><div class="caption"><p>Recommended Surveillance for Individuals with <i>VLDLR</i> Cerebellar Hypoplasia</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK1874/table/vldlr-ch.T.recommended_surveillance_for/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__vldlr-ch.T.recommended_surveillance_for_lrgtbl__"><table><thead><tr><th id="hd_h_vldlr-ch.T.recommended_surveillance_for_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">System/Concern</th><th id="hd_h_vldlr-ch.T.recommended_surveillance_for_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Evaluation</th><th id="hd_h_vldlr-ch.T.recommended_surveillance_for_1_1_1_3" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Frequency</th></tr></thead><tbody><tr><td headers="hd_h_vldlr-ch.T.recommended_surveillance_for_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Seizures</b>
|
||
</td><td headers="hd_h_vldlr-ch.T.recommended_surveillance_for_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Neurologic evaluation</td><td headers="hd_h_vldlr-ch.T.recommended_surveillance_for_1_1_1_3" rowspan="2" colspan="1" style="text-align:left;vertical-align:middle;">Annually</td></tr><tr><td headers="hd_h_vldlr-ch.T.recommended_surveillance_for_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Cerebellar ataxia</b>
|
||
</td><td headers="hd_h_vldlr-ch.T.recommended_surveillance_for_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Rehabilitation evaluation</td></tr></tbody></table></div></div></div><div id="vldlr-ch.Evaluation_of_Relatives_at_Risk"><h3>Evaluation of Relatives at Risk</h3><p>See <a href="#vldlr-ch.Related_Genetic_Counseling_Issu">Genetic Counseling</a> for issues related to testing of at-risk relatives for <a class="def" href="/books/n/gene/glossary/def-item/genetic-counseling/">genetic counseling</a> purposes.</p></div><div id="vldlr-ch.Therapies_Under_Investigation"><h3>Therapies Under Investigation</h3><p>Search <a href="https://clinicaltrials.gov/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">ClinicalTrials.gov</a> in the US and <a href="https://www.clinicaltrialsregister.eu/ctr-search/search" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">EU Clinical Trials Register</a> in Europe for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.</p></div></div><div id="vldlr-ch.Genetic_Counseling"><h2 id="_vldlr-ch_Genetic_Counseling_">Genetic Counseling</h2><p>
|
||
<i>Genetic counseling is the process of providing individuals and families with
|
||
information on the nature, mode(s) of inheritance, and implications of genetic disorders to help them
|
||
make informed medical and personal decisions. The following section deals with genetic
|
||
risk assessment and the use of family history and genetic testing to clarify genetic
|
||
status for family members; it is not meant to address all personal, cultural, or
|
||
ethical issues that may arise or to substitute for consultation with a genetics
|
||
professional</i>. —ED.</p><div id="vldlr-ch.Mode_of_Inheritance"><h3>Mode of Inheritance</h3><p><i>VLDLR</i> cerebellar hypoplasia (<i>VLDLR</i>-CH) is inherited in an <a class="def" href="/books/n/gene/glossary/def-item/autosomal-recessive/">autosomal recessive</a> manner.</p></div><div id="vldlr-ch.Risk_to_Family_Members"><h3>Risk to Family Members</h3><p>
|
||
<b>Parents of a <a class="def" href="/books/n/gene/glossary/def-item/proband/">proband</a></b>
|
||
</p><ul><li class="half_rhythm"><div>The parents of an affected child are obligate heterozygotes (i.e., carriers of one <i>VLDLR</i> <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a>).</div></li><li class="half_rhythm"><div>Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.</div></li></ul><p>
|
||
<b>Sibs of a <a class="def" href="/books/n/gene/glossary/def-item/proband/">proband</a></b>
|
||
</p><ul><li class="half_rhythm"><div>At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic <a class="def" href="/books/n/gene/glossary/def-item/carrier/">carrier</a>, and a 25% chance of being unaffected and not a carrier.</div></li><li class="half_rhythm"><div>Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.</div></li></ul><p><b>Offspring of a <a class="def" href="/books/n/gene/glossary/def-item/proband/">proband</a>.</b> To date, individuals with <i>VLDLR</i>-CH are not known to reproduce.</p><p><b>Other family members.</b> Each sib of the <a class="def" href="/books/n/gene/glossary/def-item/proband/">proband</a>'s parents is at a 50% risk of being a <a class="def" href="/books/n/gene/glossary/def-item/carrier/">carrier</a> of a <i>VLDLR</i> <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a>.</p></div><div id="vldlr-ch.Carrier_Detection"><h3>Carrier Detection</h3><p>Carrier testing for at-risk relatives requires prior identification of the <i>VLDLR</i> pathogenic variants in the family.</p></div><div id="vldlr-ch.Related_Genetic_Counseling_Issu"><h3>Related Genetic Counseling Issues</h3><p>
|
||
<b>Family planning</b>
|
||
</p><ul><li class="half_rhythm"><div>The optimal time for determination of genetic risk, clarification of <a class="def" href="/books/n/gene/glossary/def-item/carrier/">carrier</a> status, and discussion of the availability of prenatal/<a class="def" href="/books/n/gene/glossary/def-item/preimplantation-genetic-testing/">preimplantation genetic testing</a> is before pregnancy.</div></li><li class="half_rhythm"><div>It is appropriate to offer <a class="def" href="/books/n/gene/glossary/def-item/genetic-counseling/">genetic counseling</a> (including discussion of potential risks to offspring and reproductive options) to young adults who are carriers or are at risk of being carriers.</div></li></ul><p><b>Population screening.</b> In the Hutterite population, the high <a class="def" href="/books/n/gene/glossary/def-item/carrier/">carrier</a> frequency (~1:15) could warrant population screening for reproductive purposes [<a class="bk_pop" href="#vldlr-ch.REF.glass.2005.691">Glass et al 2005</a>]. Carrier testing for the Hutterite population involves targeted analysis for the founder <a class="def" href="/books/n/gene/glossary/def-item/deletion/">deletion</a> [<a class="bk_pop" href="#vldlr-ch.REF.boycott.2005.477">Boycott et al 2005</a>].</p><p><b>DNA banking.</b> Because it is likely that testing methodology and our understanding of genes, pathogenic mechanisms, and diseases will improve in the future, consideration should be given to banking DNA from probands in whom a molecular diagnosis has not been confirmed (i.e., the causative pathogenic mechanism is unknown). For more information, see <a class="bk_pop" href="#vldlr-ch.REF.huang.2022.389">Huang et al [2022]</a>.</p></div><div id="vldlr-ch.Prenatal_Testing_and_Preimplant"><h3>Prenatal Testing and Preimplantation Genetic Testing</h3><p>Once the <i>VLDLR</i> pathogenic variants have been identified in an affected family member, prenatal and <a class="def" href="/books/n/gene/glossary/def-item/preimplantation-genetic-testing/">preimplantation genetic testing</a> for <i>VLDLR</i>-CH are possible.</p><p>Differences in perspective may exist among medical professionals and within families regarding the use of <a class="def" href="/books/n/gene/glossary/def-item/prenatal-testing/">prenatal testing</a>. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.</p></div></div><div id="vldlr-ch.Resources"><h2 id="_vldlr-ch_Resources_">Resources</h2><p>
|
||
<i>GeneReviews staff has selected the following disease-specific and/or umbrella
|
||
support organizations and/or registries for the benefit of individuals with this disorder
|
||
and their families. GeneReviews is not responsible for the information provided by other
|
||
organizations. For information on selection criteria, click <a href="/books/n/gene/app4/">here</a>.</i></p>
|
||
<ul><li class="half_rhythm"><div>
|
||
<b>National Institute of Neurological Disorders and Stroke (NINDS)</b>
|
||
</div><div>PO Box 5801</div><div>Bethesda MD 20824</div><div><b>Phone:</b> 800-352-9424 (toll-free); 301-496-5751; 301-468-5981 (TTY)</div><div>
|
||
<a href="https://www.ninds.nih.gov/Disorders/All-Disorders/Cerebellar-Hypoplasia-Information-Page" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">Cerebellar Hypoplasia Information Page</a>
|
||
</div></li><li class="half_rhythm"><div>
|
||
<b>American Association on Intellectual and Developmental Disabilities (AAIDD)</b>
|
||
</div><div><b>Phone:</b> 202-387-1968</div><div>
|
||
<a href="https://www.aaidd.org" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">aaidd.org</a>
|
||
</div></li><li class="half_rhythm"><div>
|
||
<b>CDC - Child Development</b>
|
||
</div><div><b>Phone:</b> 800-232-4636</div><div>
|
||
<a href="https://www.cdc.gov/child-development/about/developmental-disability-basics.html" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">Developmental Disability Basics</a>
|
||
</div></li><li class="half_rhythm"><div>
|
||
<b>National Ataxia Foundation</b>
|
||
</div><div><b>Phone:</b> 763-553-0020</div><div><b>Email:</b> naf@ataxia.org</div><div>
|
||
<a href="https://www.ataxia.org" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">ataxia.org</a>
|
||
</div></li></ul>
|
||
</div><div id="vldlr-ch.Molecular_Genetics"><h2 id="_vldlr-ch_Molecular_Genetics_">Molecular Genetics</h2><p><i>Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —</i>ED.</p><div id="vldlr-ch.molgen.TA" class="table"><h3><span class="label">Table A.</span></h3><div class="caption"><p>VLDLR Cerebellar Hypoplasia: Genes and Databases</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK1874/table/vldlr-ch.molgen.TA/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__vldlr-ch.molgen.TA_lrgtbl__"><table class="no_bottom_margin"><tbody><tr><th id="hd_b_vldlr-ch.molgen.TA_1_1_1_1" rowspan="1" colspan="1" style="vertical-align:top;">Gene</th><th id="hd_b_vldlr-ch.molgen.TA_1_1_1_2" rowspan="1" colspan="1" style="vertical-align:top;">Chromosome Locus</th><th id="hd_b_vldlr-ch.molgen.TA_1_1_1_3" rowspan="1" colspan="1" style="vertical-align:top;">Protein</th><th id="hd_b_vldlr-ch.molgen.TA_1_1_1_4" rowspan="1" colspan="1" style="vertical-align:top;">Locus-Specific Databases</th><th id="hd_b_vldlr-ch.molgen.TA_1_1_1_5" rowspan="1" colspan="1" style="vertical-align:top;">HGMD</th><th id="hd_b_vldlr-ch.molgen.TA_1_1_1_6" rowspan="1" colspan="1" style="vertical-align:top;">ClinVar</th></tr><tr><td headers="hd_b_vldlr-ch.molgen.TA_1_1_1_1" rowspan="1" colspan="1" style="vertical-align:top;">
|
||
<a href="/gene/7436" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=gene">
|
||
<i>VLDLR</i>
|
||
</a>
|
||
</td><td headers="hd_b_vldlr-ch.molgen.TA_1_1_1_2" rowspan="1" colspan="1" style="vertical-align:top;">
|
||
<a href="https://www.ncbi.nlm.nih.gov/genome/gdv/?context=gene&acc=7436" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">9p24<wbr style="display:inline-block"></wbr>.2</a>
|
||
</td><td headers="hd_b_vldlr-ch.molgen.TA_1_1_1_3" rowspan="1" colspan="1" style="vertical-align:top;">
|
||
<a href="http://www.uniprot.org/uniprot/P98155" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">Very low-density lipoprotein receptor</a>
|
||
</td><td headers="hd_b_vldlr-ch.molgen.TA_1_1_1_4" rowspan="1" colspan="1" style="vertical-align:top;">
|
||
<a href="http://databases.lovd.nl/shared/genes/VLDLR" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">VLDLR database</a>
|
||
</td><td headers="hd_b_vldlr-ch.molgen.TA_1_1_1_5" rowspan="1" colspan="1" style="vertical-align:top;">
|
||
<a href="http://www.hgmd.cf.ac.uk/ac/gene.php?gene=VLDLR" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">VLDLR</a>
|
||
</td><td headers="hd_b_vldlr-ch.molgen.TA_1_1_1_6" rowspan="1" colspan="1" style="vertical-align:top;">
|
||
<a href="https://www.ncbi.nlm.nih.gov/clinvar/?term=VLDLR[gene]" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">VLDLR</a>
|
||
</td></tr></tbody></table></div><div><div><dl class="temp-labeled-list small"><dt></dt><dd><div id="vldlr-ch.TFA.1"><p class="no_margin">Data are compiled from the following standard references: <a class="def" href="/books/n/gene/glossary/def-item/gene/">gene</a> from
|
||
<a href="http://www.genenames.org/index.html" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">HGNC</a>;
|
||
<a class="def" href="/books/n/gene/glossary/def-item/chromosome/">chromosome</a> <a class="def" href="/books/n/gene/glossary/def-item/locus/">locus</a> from
|
||
<a href="http://www.omim.org/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">OMIM</a>;
|
||
protein from <a href="http://www.uniprot.org/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">UniProt</a>.
|
||
For a description of databases (Locus Specific, HGMD, ClinVar) to which links are provided, click
|
||
<a href="/books/n/gene/app1/">here</a>.</p></div></dd></dl></div></div></div><div id="vldlr-ch.molgen.TB" class="table"><h3><span class="label">Table B.</span></h3><div class="caption"><p>OMIM Entries for VLDLR Cerebellar Hypoplasia (<a href="/omim/192977,224050" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=omim">View All in OMIM</a>) </p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK1874/table/vldlr-ch.molgen.TB/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__vldlr-ch.molgen.TB_lrgtbl__"><table><tbody><tr><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
||
<a href="/omim/192977" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=omim">192977</a></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">VERY LOW DENSITY LIPOPROTEIN RECEPTOR; VLDLR</td></tr><tr><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
||
<a href="/omim/224050" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=omim">224050</a></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">CEREBELLAR ATAXIA, IMPAIRED INTELLECTUAL DEVELOPMENT, AND DYSEQUILIBRIUM SYNDROME 1; CAMRQ1</td></tr></tbody></table></div></div><div id="vldlr-ch.Molecular_Pathogenesis"><h3>Molecular Pathogenesis</h3><p><i>VLDLR</i> encodes a protein of 873 amino acids and is expressed abundantly in the heart, skeletal muscle, kidney, and brain. VLDLR protein is part of the reelin signaling pathway, which guides neuroblast migration in the developing cerebral cortex and cerebellum [<a class="bk_pop" href="#vldlr-ch.REF.tissir.2003.496">Tissir & Goffinet 2003</a>]. In an evolutionarily conserved pathway, reelin engages two lipoprotein receptors, VLDLR and apolipoprotein E receptor-2 (Apoer2), resulting in phosphorylation of disabled-1 (Dab1) and activation of an intracellular signaling cascade that allows neuroblasts to complete migration.</p><p>VLDLR belongs to a subset of cell surface receptors called the LDL receptor protein family. Family members share a number of domains arranged in a similar pattern: ligand-binding repeat <a class="def" href="/books/n/gene/glossary/def-item/domain/">domain</a>, EGF repeat, YWTD domain, O-linked sugar domain, transmembrane domain, and a cytoplasmic domain containing a NPXY motif. VLDLR was initially identified to function in the receptor-mediated endocytosis of apoE-containing lipoproteins.</p><p><b>Mechanism of disease causation.</b> All of the reported pathogenic variants to date are predicted to result in loss of function of the VLDLR protein. In the absence of this receptor, neuroblasts are unable to complete migration and adopt their ultimate position in the developing central nervous system.</p><div id="vldlr-ch.T.notable_vldlr_pathogenic_vari" class="table"><h3><span class="label">Table 6. </span></h3><div class="caption"><p>Notable <i>VLDLR</i> Pathogenic Variants</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK1874/table/vldlr-ch.T.notable_vldlr_pathogenic_vari/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__vldlr-ch.T.notable_vldlr_pathogenic_vari_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_vldlr-ch.T.notable_vldlr_pathogenic_vari_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Reference Sequences</th><th id="hd_h_vldlr-ch.T.notable_vldlr_pathogenic_vari_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">DNA Nucleotide Change</th><th id="hd_h_vldlr-ch.T.notable_vldlr_pathogenic_vari_1_1_1_3" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Predicted Protein Change</th><th id="hd_h_vldlr-ch.T.notable_vldlr_pathogenic_vari_1_1_1_4" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Comment [Reference]</th></tr></thead><tbody><tr><td headers="hd_h_vldlr-ch.T.notable_vldlr_pathogenic_vari_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<a href="https://www.ncbi.nlm.nih.gov/nuccore/NC_000009" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">NC<wbr style="display:inline-block"></wbr>_000009</a>
|
||
</td><td headers="hd_h_vldlr-ch.T.notable_vldlr_pathogenic_vari_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">g.2479657_2678818del</td><td headers="hd_h_vldlr-ch.T.notable_vldlr_pathogenic_vari_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Entire <a class="def" href="/books/n/gene/glossary/def-item/gene/">gene</a> <a class="def" href="/books/n/gene/glossary/def-item/deletion/">deletion</a></td><td headers="hd_h_vldlr-ch.T.notable_vldlr_pathogenic_vari_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Hutterite <a class="def" href="/books/n/gene/glossary/def-item/founder-variant/">founder variant</a> [<a class="bk_pop" href="#vldlr-ch.REF.boycott.2005.477">Boycott et al 2005</a>]</td></tr><tr><td headers="hd_h_vldlr-ch.T.notable_vldlr_pathogenic_vari_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<a href="https://www.ncbi.nlm.nih.gov/nuccore/NM_003383" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">NM<wbr style="display:inline-block"></wbr>_003383</a>
|
||
<br />
|
||
<a href="https://www.ncbi.nlm.nih.gov/protein/NP_003374.3" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">NP_003374<wbr style="display:inline-block"></wbr>.3</a>
|
||
</td><td headers="hd_h_vldlr-ch.T.notable_vldlr_pathogenic_vari_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">c.1256G>A</td><td headers="hd_h_vldlr-ch.T.notable_vldlr_pathogenic_vari_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">p.Cys419Tyr</td><td headers="hd_h_vldlr-ch.T.notable_vldlr_pathogenic_vari_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Person reported w/less severe <a class="def" href="/books/n/gene/glossary/def-item/phenotype/">phenotype</a>, predicted due to <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a> in a less essential <a class="def" href="/books/n/gene/glossary/def-item/domain/">domain</a> (EGF-B) [<a class="bk_pop" href="#vldlr-ch.REF.micalizzi.2016.191">Micalizzi et al 2016</a>]</td></tr></tbody></table></div><div><div><dl class="temp-labeled-list small"><dt></dt><dd><div><p class="no_margin">Variants listed in the table have been provided by the authors. <i>GeneReviews</i> staff have not independently verified the classification of variants.</p></div></dd><dt></dt><dd><div><p class="no_margin"><i>GeneReviews</i> follows the standard naming conventions of the Human Genome Variation Society (<a href="https://varnomen.hgvs.org/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">varnomen<wbr style="display:inline-block"></wbr>.hgvs.org</a>). See <a href="/books/n/gene/app3/">Quick Reference</a> for an explanation of nomenclature.</p></div></dd></dl></div></div></div></div></div><div id="vldlr-ch.Chapter_Notes"><h2 id="_vldlr-ch_Chapter_Notes_">Chapter Notes</h2><div id="vldlr-ch.Revision_History"><h3>Revision History</h3><ul><li class="half_rhythm"><div>27 February 2020 (ha) Comprehensive update posted live</div></li><li class="half_rhythm"><div>8 August 2013 (me) Comprehensive update posted live</div></li><li class="half_rhythm"><div>26 August 2008 (cg) Review posted live</div></li><li class="half_rhythm"><div>7 July 2008 (kmb) Original submission</div></li></ul></div></div><div id="vldlr-ch.References"><h2 id="_vldlr-ch_References_">References</h2><div id="vldlr-ch.Literature_Cited"><h3>Literature Cited</h3><ul class="simple-list"><li class="half_rhythm"><div class="bk_ref" id="vldlr-ch.REF.ali.2012.80">Ali
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contact: <a href="mailto:dev@null" data-email="ude.wu@tssamda" class="oemail">ude.wu@tssamda</a>.</p></div><div class="small"><span class="label">Bookshelf ID: NBK1874</span><span class="label">PMID: <a href="https://pubmed.ncbi.nlm.nih.gov/20301729" title="PubMed record of this page" ref="pagearea=meta&targetsite=entrez&targetcat=link&targettype=pubmed">20301729</a></span></div><div style="margin-top:2em" class="bk_noprnt"><a class="bk_cntns" href="/books/n/gene/">GeneReviews by Title</a><div class="pagination bk_noprnt"><a class="active page_link prev" href="/books/n/gene/wagner/" title="Previous page in this title">< Prev</a><a class="active page_link next" href="/books/n/gene/chac/" title="Next page in this title">Next ></a></div></div></div></div>
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<div id="ncbi_share_book"><a href="#" class="ncbi_share" data-ncbi_share_config="popup:false,shorten:true" ref="id=NBK1874&db=books">Share</a></div>
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<div xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"></div><div class="portlet"><div class="portlet_head"><div class="portlet_title"><h3><span>Views</span></h3></div><a name="Shutter" sid="1" href="#" class="portlet_shutter" title="Show/hide content" remembercollapsed="true" pgsec_name="PDF_download" id="Shutter"></a></div><div class="portlet_content"><ul xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="simple-list"><li><a href="/books/NBK1874/?report=reader">PubReader</a></li><li><a href="/books/NBK1874/?report=printable">Print View</a></li><li><a data-jig="ncbidialog" href="#_ncbi_dlg_citbx_NBK1874" data-jigconfig="width:400,modal:true">Cite this Page</a><div id="_ncbi_dlg_citbx_NBK1874" style="display:none" title="Cite this Page"><div class="bk_tt">Boycott KM, MacDonald SK, Parboosingh JS. VLDLR Cerebellar Hypoplasia. 2008 Aug 26 [Updated 2020 Feb 27]. In: Adam MP, Feldman J, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2025. <span class="bk_cite_avail"></span></div></div></li><li><a href="/books/NBK1874/pdf/Bookshelf_NBK1874.pdf">PDF version of this page</a> (617K)</li><li><a href="#" class="toggle-glossary-link" title="Enable/disable links to the glossary">Disable Glossary Links</a></li></ul></div></div><div class="portlet"><div class="portlet_head"><div class="portlet_title"><h3><span>In this GeneReview</span></h3></div><a name="Shutter" sid="1" href="#" class="portlet_shutter" title="Show/hide content" remembercollapsed="true" pgsec_name="page-toc" id="Shutter"></a></div><div class="portlet_content"><ul xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="simple-list"><li><a href="#vldlr-ch.Summary" ref="log$=inpage&link_id=inpage">Summary</a></li><li><a href="#vldlr-ch.Diagnosis" ref="log$=inpage&link_id=inpage">Diagnosis</a></li><li><a href="#vldlr-ch.Clinical_Characteristics" ref="log$=inpage&link_id=inpage">Clinical Characteristics</a></li><li><a href="#vldlr-ch.Genetically_Related_Allelic_Dis" ref="log$=inpage&link_id=inpage">Genetically Related (Allelic) Disorders</a></li><li><a href="#vldlr-ch.Differential_Diagnosis" ref="log$=inpage&link_id=inpage">Differential Diagnosis</a></li><li><a href="#vldlr-ch.Management" ref="log$=inpage&link_id=inpage">Management</a></li><li><a href="#vldlr-ch.Genetic_Counseling" ref="log$=inpage&link_id=inpage">Genetic Counseling</a></li><li><a href="#vldlr-ch.Resources" ref="log$=inpage&link_id=inpage">Resources</a></li><li><a href="#vldlr-ch.Molecular_Genetics" ref="log$=inpage&link_id=inpage">Molecular Genetics</a></li><li><a href="#vldlr-ch.Chapter_Notes" ref="log$=inpage&link_id=inpage">Chapter Notes</a></li><li><a href="#vldlr-ch.References" ref="log$=inpage&link_id=inpage">References</a></li></ul></div></div><div class="portlet"><div class="portlet_head"><div class="portlet_title"><h3><span>Bulk Download</span></h3></div><a name="Shutter" sid="1" href="#" class="portlet_shutter" title="Show/hide content" remembercollapsed="true" pgsec_name="source-links" id="Shutter"></a></div><div class="portlet_content"><ul xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="simple-list"><li><a href="https://ftp.ncbi.nlm.nih.gov/pub/litarch/ca/84/" ref="pagearea=source-links&targetsite=external&targetcat=link&targettype=uri">Bulk download GeneReviews data from FTP</a></li></ul></div></div><div class="portlet"><div class="portlet_head"><div class="portlet_title"><h3><span>GeneReviews Links</span></h3></div><a name="Shutter" sid="1" href="#" class="portlet_shutter" title="Show/hide content" remembercollapsed="true" pgsec_name="source-links" id="Shutter"></a></div><div class="portlet_content"><ul xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="simple-list"><li><a href="/books/n/gene/advanced/"><i>GeneReviews</i> Advanced Search</a></li><li><a href="/books/n/gene/glossary/"><i>GeneReviews</i> Glossary</a></li><li><a href="/books/n/gene/resource_mats/">Resource Materials</a> <span class="bk_hlight1">NEW FEATURE</span></li><li><a href="/books/n/gene/updates/">New in <i>GeneReviews</i></a></li><li><a href="/books/n/gene/authors/">Author List</a></li><li><a href="/books/n/gene/prospective_authors/">For Current/Prospective Authors</a></li><li><a href="/books/n/gene/GRpersonnel/"><i>GeneReviews</i> Personnel</a></li><li><a href="/books/n/gene/howto_linkin/">Download/Link to <i>GeneReviews</i></a></li><li><a href="/books/n/gene/contact_us/">Contact Us</a></li></ul></div></div><div class="portlet"><div class="portlet_head"><div class="portlet_title"><h3><span>Tests in GTR by Gene</span></h3></div><a name="Shutter" sid="1" href="#" class="portlet_shutter" title="Show/hide content" remembercollapsed="true" pgsec_name="document-links" id="Shutter"></a></div><div class="portlet_content"><ul xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="simple-list"><li>
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<a href="https://www.ncbi.nlm.nih.gov/gtr/tests/?term=7436[geneid]" ref="pagearea=document-links&targetsite=external&targetcat=link&targettype=uri&link_id=tests_in_gtr_by_gene">VLDLR</a>
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</li></ul></div></div><div class="portlet"><div class="portlet_head"><div class="portlet_title"><h3><span>Variations in ClinVar</span></h3></div><a name="Shutter" sid="1" href="#" class="portlet_shutter" title="Show/hide content" remembercollapsed="true" pgsec_name="document-links" id="Shutter"></a></div><div class="portlet_content"><ul xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="simple-list"><li>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar/?term=NBK1874+AND+genereviews[submitter]" ref="pagearea=document-links&targetsite=external&targetcat=link&targettype=uri">Variations from this GeneReview in ClinVar</a>
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</li></ul></div></div><div class="portlet"><div class="portlet_head"><div class="portlet_title"><h3><span>Related information</span></h3></div><a name="Shutter" sid="1" href="#" class="portlet_shutter" title="Show/hide content" remembercollapsed="true" pgsec_name="discovery_db_links" id="Shutter"></a></div><div class="portlet_content"><ul><li class="brieflinkpopper"><a class="brieflinkpopperctrl" href="/books/?Db=omim&DbFrom=books&Cmd=Link&LinkName=books_omim&IdsFromResult=1483868" ref="log$=recordlinks">OMIM</a><div class="brieflinkpop offscreen_noflow">Related OMIM records</div></li><li class="brieflinkpopper"><a class="brieflinkpopperctrl" href="/books/?Db=pmc&DbFrom=books&Cmd=Link&LinkName=books_pmc_refs&IdsFromResult=1483868" ref="log$=recordlinks">PMC</a><div class="brieflinkpop offscreen_noflow">PubMed Central citations</div></li><li class="brieflinkpopper"><a class="brieflinkpopperctrl" href="/books/?Db=pubmed&DbFrom=books&Cmd=Link&LinkName=books_pubmed_refs&IdsFromResult=1483868" ref="log$=recordlinks">PubMed</a><div class="brieflinkpop offscreen_noflow">Links to PubMed</div></li><li class="brieflinkpopper"><a class="brieflinkpopperctrl" href="/books/?Db=gene&DbFrom=books&Cmd=Link&LinkName=books_gene&IdsFromResult=1483868" ref="log$=recordlinks">Gene</a><div class="brieflinkpop offscreen_noflow">Locus Links</div></li></ul></div></div><div class="portlet"><div class="portlet_head"><div class="portlet_title"><h3><span>Similar articles in PubMed</span></h3></div><a name="Shutter" sid="1" href="#" class="portlet_shutter" title="Show/hide content" remembercollapsed="true" pgsec_name="PBooksDiscovery_RA" id="Shutter"></a></div><div class="portlet_content"><ul><li class="brieflinkpopper two_line"><a class="brieflinkpopperctrl" href="/pubmed/20301790" ref="ordinalpos=1&linkpos=1&log$=relatedreviews&logdbfrom=pubmed"><span xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="invert">Review</span> Ataxia-Telangiectasia.</a><span class="source">[GeneReviews(®). 1993]</span><div class="brieflinkpop offscreen_noflow"><span xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="invert">Review</span> Ataxia-Telangiectasia.<div class="brieflinkpopdesc"><em xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="author">Veenhuis S, van Os N, Weemaes C, Kamsteeg EJ, Willemsen M. </em><em xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="cit">GeneReviews(®). 1993</em></div></div></li><li class="brieflinkpopper two_line"><a class="brieflinkpopperctrl" href="/pubmed/20301656" ref="ordinalpos=1&linkpos=2&log$=relatedreviews&logdbfrom=pubmed"><span xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="invert">Review</span> Adenosine Deaminase Deficiency.</a><span class="source">[GeneReviews(®). 1993]</span><div class="brieflinkpop offscreen_noflow"><span xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="invert">Review</span> Adenosine Deaminase Deficiency.<div class="brieflinkpopdesc"><em xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="author">Hershfield M, Tarrant T. </em><em xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="cit">GeneReviews(®). 1993</em></div></div></li><li class="brieflinkpopper two_line"><a class="brieflinkpopperctrl" href="/pubmed/20301551" ref="ordinalpos=1&linkpos=3&log$=relatedreviews&logdbfrom=pubmed"><span xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="invert">Review</span> Sickle Cell Disease.</a><span class="source">[GeneReviews(®). 1993]</span><div class="brieflinkpop offscreen_noflow"><span xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="invert">Review</span> Sickle Cell Disease.<div class="brieflinkpopdesc"><em xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="author">Bender MA, Carlberg K. </em><em xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="cit">GeneReviews(®). 1993</em></div></div></li><li class="brieflinkpopper two_line"><a class="brieflinkpopperctrl" href="/pubmed/20301570" ref="ordinalpos=1&linkpos=4&log$=relatedreviews&logdbfrom=pubmed"><span xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="invert">Review</span> Alpha-Mannosidosis.</a><span class="source">[GeneReviews(®). 1993]</span><div class="brieflinkpop offscreen_noflow"><span xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="invert">Review</span> Alpha-Mannosidosis.<div class="brieflinkpopdesc"><em xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="author">Ficicioglu C, Stepien KM. </em><em xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="cit">GeneReviews(®). 1993</em></div></div></li><li class="brieflinkpopper two_line"><a class="brieflinkpopperctrl" href="/pubmed/20301432" ref="ordinalpos=1&linkpos=5&log$=relatedreviews&logdbfrom=pubmed"><span xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="invert">Review</span> ARSACS.</a><span class="source">[GeneReviews(®). 1993]</span><div class="brieflinkpop offscreen_noflow"><span xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="invert">Review</span> ARSACS.<div class="brieflinkpopdesc"><em xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="author">Vermeer S, van de Warrenburg BP, Kamsteeg EJ, Brais B, Synofzik M. </em><em xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="cit">GeneReviews(®). 1993</em></div></div></li></ul><a class="seemore" href="/sites/entrez?db=pubmed&cmd=link&linkname=pubmed_pubmed_reviews&uid=20301729" ref="ordinalpos=1&log$=relatedreviews_seeall&logdbfrom=pubmed">See reviews...</a><a class="seemore" href="/sites/entrez?db=pubmed&cmd=link&linkname=pubmed_pubmed&uid=20301729" ref="ordinalpos=1&log$=relatedarticles_seeall&logdbfrom=pubmed">See all...</a></div></div><div class="portlet"><div class="portlet_head"><div class="portlet_title"><h3><span>Recent Activity</span></h3></div><a name="Shutter" sid="1" href="#" class="portlet_shutter" title="Show/hide content" remembercollapsed="true" pgsec_name="recent_activity" id="Shutter"></a></div><div class="portlet_content"><div xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" id="HTDisplay" class=""><div class="action"><a href="javascript:historyDisplayState('ClearHT')">Clear</a><a href="javascript:historyDisplayState('HTOff')" class="HTOn">Turn Off</a><a href="javascript:historyDisplayState('HTOn')" class="HTOff">Turn On</a></div><ul id="activity"><li class="ra_rcd ralinkpopper two_line"><a class="htb ralinkpopperctrl" ref="log$=activity&linkpos=1" href="/portal/utils/pageresolver.fcgi?recordid=67d2b13df4a390645e5a1cf8">VLDLR Cerebellar Hypoplasia - GeneReviews®</a><div class="ralinkpop offscreen_noflow">VLDLR Cerebellar Hypoplasia - GeneReviews®<div class="brieflinkpopdesc"></div></div><div class="tertiary"></div></li><li class="ra_rcd 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