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<meta name="robots" content="INDEX,FOLLOW,NOARCHIVE" /><meta name="citation_inbook_title" content="GeneReviews® [Internet]" /><meta name="citation_title" content="TSEN54 Pontocerebellar Hypoplasia" /><meta name="citation_publisher" content="University of Washington, Seattle" /><meta name="citation_date" content="2020/05/28" /><meta name="citation_author" content="Tessa van Dijk" /><meta name="citation_author" content="Frank Baas" /><meta name="citation_pmid" content="20301773" /><meta name="citation_fulltext_html_url" content="https://www.ncbi.nlm.nih.gov/books/NBK9673/" /><meta name="citation_keywords" content="Pontocerebellar Hypoplasia Type 5 (PCH5)" /><meta name="citation_keywords" content="Pontocerebellar Hypoplasia Type 2 (PCH2)" /><meta name="citation_keywords" content="Pontocerebellar Hypoplasia Type 4 (PCH4)" /><meta name="citation_keywords" content="tRNA-splicing endonuclease subunit Sen54" /><meta name="citation_keywords" content="TSEN54" /><meta name="citation_keywords" content="TSEN54 Pontocerebellar Hypoplasia" /><link rel="schema.DC" href="http://purl.org/DC/elements/1.0/" /><meta name="DC.Title" content="TSEN54 Pontocerebellar Hypoplasia" /><meta name="DC.Type" content="Text" /><meta name="DC.Publisher" content="University of Washington, Seattle" /><meta name="DC.Contributor" content="Tessa van Dijk" /><meta name="DC.Contributor" content="Frank Baas" /><meta name="DC.Date" content="2020/05/28" /><meta name="DC.Identifier" content="https://www.ncbi.nlm.nih.gov/books/NBK9673/" /><meta name="description" content="TSEN54 pontocerebellar hypoplasia (TSEN54-PCH) comprises three PCH phenotypes (PCH2, 4, and 5) that share characteristic neuroradiologic and neurologic findings. The three PCH phenotypes (which differ mainly in life expectancy) were considered to be distinct entities before their molecular basis was known." /><meta name="og:title" content="TSEN54 Pontocerebellar Hypoplasia" /><meta name="og:type" content="book" /><meta name="og:description" content="TSEN54 pontocerebellar hypoplasia (TSEN54-PCH) comprises three PCH phenotypes (PCH2, 4, and 5) that share characteristic neuroradiologic and neurologic findings. The three PCH phenotypes (which differ mainly in life expectancy) were considered to be distinct entities before their molecular basis was known." /><meta name="og:url" content="https://www.ncbi.nlm.nih.gov/books/NBK9673/" /><meta name="og:site_name" content="NCBI Bookshelf" /><meta name="og:image" content="https://www.ncbi.nlm.nih.gov/corehtml/pmc/pmcgifs/bookshelf/thumbs/th-gene-lrg.png" /><meta name="twitter:card" content="summary" /><meta name="twitter:site" content="@ncbibooks" /><meta name="bk-non-canon-loc" content="/books/n/gene/pc-hypo-p/" /><link rel="canonical" href="https://www.ncbi.nlm.nih.gov/books/NBK9673/" /><link rel="stylesheet" href="/corehtml/pmc/css/figpopup.css" type="text/css" media="screen" /><link rel="stylesheet" href="/corehtml/pmc/css/bookshelf/2.26/css/books.min.css" type="text/css" /><link rel="stylesheet" href="/corehtml/pmc/css/bookshelf/2.26/css/books_print.min.css" type="text/css" media="print" /><style type="text/css">p a.figpopup{display:inline !important} .bk_tt {font-family: monospace} .first-line-outdent .bk_ref {display: inline} .body-content h2, .body-content .h2 {border-bottom: 1px solid #97B0C8} .body-content h2.inline {border-bottom: none} a.page-toc-label , .jig-ncbismoothscroll a {text-decoration:none;border:0 !important} .temp-labeled-list .graphic {display:inline-block !important} .temp-labeled-list img{width:100%}</style><script type="text/javascript" src="/corehtml/pmc/js/jquery.hoverIntent.min.js"> </script><script type="text/javascript" src="/corehtml/pmc/js/common.min.js?_=3.18"> </script><script type="text/javascript" src="/corehtml/pmc/js/large-obj-scrollbars.min.js"> </script><script type="text/javascript">window.name="mainwindow";</script><script type="text/javascript" src="/corehtml/pmc/js/bookshelf/2.26/book-toc.min.js"> </script><script type="text/javascript" src="/corehtml/pmc/js/bookshelf/2.26/books.min.js"> </script><script type="text/javascript">if (typeof (jQuery) != 'undefined') { (function ($) { $(function () { var min = Math.ceil(1); var max = Math.floor(100000); var randomNum = Math.floor(Math.random() * (max - min)) + min; var surveyUrl = "/projects/Gene/portal/surveys/seqdbui-survey.js?rando=" + randomNum.toString(); $.getScript(surveyUrl, function () { try { ncbi.seqDbUISurvey.init(); } catch (err) { console.info(err); } }).fail(function (jqxhr, settings, exception) { console.info('Cannot load survey script', jqxhr); });; }); })(jQuery); };</script><meta name="book-collection" content="NONE" />
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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="#__NBK9673_dtls__">Show details</a><div style="display:none" class="ui-widget" id="__NBK9673_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/trpm3-ndd/" title="Previous page in this title">< Prev</a><a class="active page_link next" href="/books/n/gene/tubb4a-leuk/" 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="_NBK9673_"><span class="title" itemprop="name"><i>TSEN54</i> Pontocerebellar Hypoplasia</span></h1><p class="contrib-group"><span itemprop="author">Tessa van Dijk</span>, MD and <span itemprop="author">Frank Baas</span>, MD, PhD.</p><a data-jig="ncbitoggler" href="#__NBK9673_ai__" style="border:0;text-decoration:none">Author Information and Affiliations</a><div style="display:none" class="ui-widget" id="__NBK9673_ai__"><div class="contrib half_rhythm"><span itemprop="author">Tessa van Dijk</span>, MD<div class="affiliation small">Department of Clinical Genetics<br />Leiden University Medical Center<br />Leiden, the Netherlands<div><span class="email-label">Email: </span><a href="mailto:dev@null" data-email="ln.cmul@kjid_nav.t" class="oemail">ln.cmul@kjid_nav.t</a></div></div></div><div class="contrib half_rhythm"><span itemprop="author">Frank Baas</span>, MD, PhD<div class="affiliation small">Department of Clinical Genetics<br />Leiden University Medical Center<br />Leiden, the Netherlands<div><span class="email-label">Email: </span><a href="mailto:dev@null" data-email="ln.cmul@saab.f" class="oemail">ln.cmul@saab.f</a></div></div></div></div><p class="small">Initial Posting: <span itemprop="datePublished">September 8, 2009</span>; Last Update: <span itemprop="dateModified">May 28, 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="pc-hypo-p.Summary" itemprop="description"><h2 id="_pc-hypo-p_Summary_">Summary</h2><div><h4 class="inline">Clinical characteristics.</h4><p><i>TSEN54</i> pontocerebellar hypoplasia (<i>TSEN54</i>-PCH) comprises three PCH phenotypes (PCH2, 4, and 5) that share characteristic neuroradiologic and neurologic findings. The three PCH phenotypes (which differ mainly in life expectancy) were considered to be distinct entities before their molecular basis was known.</p><ul><li class="half_rhythm"><div><b>PCH2.</b> Children usually succumb before age ten years (those with PCH4 and 5 usually succumb as neonates). Children with PCH2 have generalized clonus, uncoordinated sucking and swallowing, impaired cognitive development, lack of voluntary motor development, cortical blindness, and an increased risk for rhabdomyolysis during severe infections. Epilepsy is present in approximately 50%.</div></li><li class="half_rhythm"><div><b>PCH4.</b> Neonates often have seizures, multiple joint contractures ("arthrogryposis"), generalized clonus, and central respiratory impairment.</div></li><li class="half_rhythm"><div><b>PCH5</b> resembles PCH4 and has been described in one family.</div></li></ul></div><div><h4 class="inline">Diagnosis/testing.</h4><p>The diagnosis of <i>TSEN54</i>-PCH is suspected in children with characteristic neuroradiologic and neurologic findings, and is confirmed by the presence of <a class="def" href="/books/n/gene/glossary/def-item/biallelic/">biallelic</a> <i>TSEN54</i> pathogenic variants.</p></div><div><h4 class="inline">Management.</h4><p><i>Treatment of manifestations:</i> PCH2: Treatment of irritability, swallowing incoordination, epilepsy, and central visual impairment is symptomatic. Physiotherapy can be helpful. Adequate hydration during prolonged periods of high fever may help avoid rhabdomyolysis. PCH4 and PCH5: No specific therapy is available.</p><p><i>Surveillance:</i> PCH2: Routine monitoring of respiratory function, feeding, musculoskeletal and neurologic manifestations, developmental milestones, and family needs.</p></div><div><h4 class="inline">Genetic counseling.</h4><p><i>TSEN54</i>-PCH is inherited in an <a class="def" href="/books/n/gene/glossary/def-item/autosomal-recessive/">autosomal recessive</a> manner. If both parents are known to be <a class="def" href="/books/n/gene/glossary/def-item/heterozygous/">heterozygous</a> for a <i>TSEN54</i> <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a>, each sib of an affected individual has at conception a 25% chance of inheriting both pathogenic variants and being affected, a 50% chance of inheriting one pathogenic variant and being an unaffected <a class="def" href="/books/n/gene/glossary/def-item/carrier/">carrier</a>, and a 25% chance of inheriting both normal alleles. Once the <i>TSEN54</i> pathogenic variants have been identified in an affected family member, <a class="def" href="/books/n/gene/glossary/def-item/molecular-genetic-testing/">molecular genetic testing</a> to determine carrier status of 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.</p></div></div><div id="pc-hypo-p.GeneReview_Scope"><h2 id="_pc-hypo-p_GeneReview_Scope_"><i>GeneReview</i> Scope</h2><div id="pc-hypo-p.Td" class="table"><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK9673/table/pc-hypo-p.Td/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__pc-hypo-p.Td_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_pc-hypo-p.Td_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"><i>TSEN54</i> Pontocerebellar Hypoplasia: Included Phenotypes <sup>1</sup></th></tr></thead><tbody><tr><td headers="hd_h_pc-hypo-p.Td_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
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<ul><li class="half_rhythm"><div>Pontocerebellar hypoplasia type 2 (PCH2)</div></li><li class="half_rhythm"><div>Pontocerebellar hypoplasia type 4 (PCH4)</div></li><li class="half_rhythm"><div>Pontocerebellar hypoplasia type 5 (PCH5)</div></li></ul>
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</td></tr></tbody></table></div><div><div><dl class="temp-labeled-list small"><dt></dt><dd><div><p class="no_margin">For synonyms and outdated names see <a href="#pc-hypo-p.Nomenclature">Nomenclature</a>.</p></div></dd><dt>1. </dt><dd><div id="pc-hypo-p.TF.d.1"><p class="no_margin">For other genetic causes of these phenotypes see <a href="#pc-hypo-p.Differential_Diagnosis">Differential Diagnosis</a>.</p></div></dd></dl></div></div></div></div><div id="pc-hypo-p.Diagnosis"><h2 id="_pc-hypo-p_Diagnosis_">Diagnosis</h2><p>The phenotypic spectrum of <i>TSEN54</i> pontocerebellar hypoplasia (<i>TSEN54</i>-PCH) includes three PCH phenotypes (thought to be distinct entities before the molecular basis of PCH was known) based on neuroradiologic and neurologic findings: PCH type 2 (PCH2), PCH type 4 (PCH4), and PCH type 5 (PCH5).</p><div id="pc-hypo-p.Suggestive_Findings"><h3>Suggestive Findings</h3><p><i>TSEN54</i>-PCH <b>should be suspected</b> in children with severe neurologic impairment and the following findings on brain imaging [<a class="bk_pop" href="#pc-hypo-p.REF.barth.2007.373">Barth et al 2007</a>, <a class="bk_pop" href="#pc-hypo-p.REF.steinlin.2007.146">Steinlin et al 2007</a>, <a class="bk_pop" href="#pc-hypo-p.REF.namavar.2011.143">Namavar et al 2011</a>].</p></div><div id="pc-hypo-p.Brain_MRI_Findings"><h3>Brain MRI Findings</h3><p>
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<b>Common findings</b>
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</p><ul><li class="half_rhythm"><div>Cerebellar hypoplasia and varying degrees of cerebellar atrophy (more severe in PCH4).</div></li><li class="half_rhythm"><div>Ventral pontine atrophy, present in the majority of cases (more severe in PCH4).</div></li><li class="half_rhythm"><div>Cerebellar hemispheres more affected than cerebellar vermis</div></li><li class="half_rhythm"><div>Cerebral cortical atrophy, progressive with age</div></li><li class="half_rhythm"><div>Pericerebral CSF accumulation and delayed neocortical maturation in PCH4</div></li></ul><p><b>Less common findings</b> (not present in all persons) (see <a class="figpopup" href="/books/NBK9673/figure/pc-hypo-p.F1/?report=objectonly" target="object" rid-figpopup="figpchypopF1" rid-ob="figobpchypopF1">Figure 1</a>)</p><div class="iconblock whole_rhythm clearfix ten_col fig" id="figpchypopF1" co-legend-rid="figlgndpchypopF1"><a href="/books/NBK9673/figure/pc-hypo-p.F1/?report=objectonly" target="object" title="Figure 1. " class="img_link icnblk_img figpopup" rid-figpopup="figpchypopF1" rid-ob="figobpchypopF1"><img class="small-thumb" src="/books/NBK9673/bin/pc-hypo-p-Image001.gif" src-large="/books/NBK9673/bin/pc-hypo-p-Image001.jpg" alt="Figure 1. " /></a><div class="icnblk_cntnt" id="figlgndpchypopF1"><h4 id="pc-hypo-p.F1"><a href="/books/NBK9673/figure/pc-hypo-p.F1/?report=objectonly" target="object" rid-ob="figobpchypopF1">Figure 1. </a></h4><p class="float-caption no_bottom_margin">MRI of the brain of an infant age two months with PCH2 a. Midsagittal image showing hypoplastic vermis and flat ventral pons (arrow)</p></div></div><ul><li class="half_rhythm"><div>Striatal hypoplasia or atrophy</div></li><li class="half_rhythm"><div>Delayed myelination of the brain in the first years; no demyelination; gliosis in PCH4</div></li><li class="half_rhythm"><div>Exceptional: cerebellar hemispheric cysts in PCH2</div></li></ul><p><b>Family history consistent with <a class="def" href="/books/n/gene/glossary/def-item/autosomal-recessive/">autosomal recessive</a> inheritance</b> (e.g., affected sibs and/or parental <a class="def" href="/books/n/gene/glossary/def-item/consanguinity/">consanguinity</a>). Absence of a known family history does not preclude the diagnosis.</p></div><div id="pc-hypo-p.Establishing_the_Diagnosis"><h3>Establishing the Diagnosis</h3><p>Diagnosis of <i>TSEN54</i>-PCH <b>is</b>
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<b>established</b> in a <a class="def" href="/books/n/gene/glossary/def-item/proband/">proband</a> with suggestive findings and <a class="def" href="/books/n/gene/glossary/def-item/biallelic/">biallelic</a> <i>TSEN54</i> pathogenic (or <a class="def" href="/books/n/gene/glossary/def-item/likely-pathogenic/">likely pathogenic</a>) variants identified by <a class="def" href="/books/n/gene/glossary/def-item/molecular-genetic-testing/">molecular genetic testing</a> (see <a href="/books/NBK9673/table/pc-hypo-p.T.molecular_genetic_testing_us/?report=objectonly" target="object" rid-ob="figobpchypopTmoleculargenetictestingus">Table 1</a>).</p><p>Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variants" and "<a class="def" href="/books/n/gene/glossary/def-item/likely-pathogenic/">likely pathogenic</a> variants" are synonymous in a clinical setting, meaning that both are considered diagnostic and both can be used for clinical decision making [<a class="bk_pop" href="#pc-hypo-p.REF.richards.2015.405">Richards et al 2015</a>]. Reference to "pathogenic variants" in this section is understood to include any likely pathogenic variants. (2) Identification of <a class="def" href="/books/n/gene/glossary/def-item/biallelic/">biallelic</a> <i>TSEN54</i> variants of <a class="def" href="/books/n/gene/glossary/def-item/uncertain-significance/">uncertain significance</a> (or of one known <i>TSEN54</i> <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a> and one <i>TSEN54</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 or <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/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. Individuals with the distinctive brain imaging findings described in <a href="#pc-hypo-p.Suggestive_Findings">Suggestive Findings</a> are likely to be diagnosed using gene-targeted testing (see <a href="#pc-hypo-p.Option_1">Option 1</a>), whereas those in whom the diagnosis of <i>TSEN54</i>-PCH has not been considered are more likely to be diagnosed using genomic testing (see <a href="#pc-hypo-p.Option_2">Option 2</a>).</p><div id="pc-hypo-p.Option_1"><h4>Option 1</h4><p><b>Single-<a class="def" href="/books/n/gene/glossary/def-item/gene/">gene</a> testing.</b> Sequence analysis of <i>TSEN54</i> is performed first to detect small intragenic deletions/insertions and <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. 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. Typically, if only one or 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; however, to date such variants have not been identified as a cause of this disorder.</p><p>Note: Targeted analysis for the common <a href="/books/NBK9673/table/pc-hypo-p.T.notable_tsen54_pathogenic_va/?report=objectonly" target="object" rid-ob="figobpchypopTnotabletsen54pathogenicva">c.919G>T</a> variant can be performed first, since this is by far the most frequent <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a> in <i>TSEN54</i>.</p><p><b>A cerebellar hypoplasia</b>
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<b><a class="def" href="/books/n/gene/glossary/def-item/multigene-panel/">multigene panel</a></b> that includes <i>TSEN54</i> and other genes of interest (see <a href="#pc-hypo-p.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>. Of note, given the rarity of <i>TSEN54</i> pontocerebellar hypoplasia, some panels for cerebellar hypoplasia may not include this gene. (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.</p><p>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>.</p></div><div id="pc-hypo-p.Option_2"><h4>Option 2</h4><p><b>Comprehensive <a class="def" href="/books/n/gene/glossary/def-item/genomic/">genomic</a> testing</b> does not require the clinician to determine which <a class="def" href="/books/n/gene/glossary/def-item/gene/">gene</a> is likely involved. <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, <b><a class="def" href="/books/n/gene/glossary/def-item/exome-array/">exome array</a></b> (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>; however, to date such variants have not been identified as a cause of <i>TSEN54</i> pontocerebellar hypoplasia.</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="pc-hypo-p.T.molecular_genetic_testing_us" class="table"><h3><span class="label">Table 1. </span></h3><div class="caption"><p>Molecular Genetic Testing Used in <i>TSEN54</i> Pontocerebellar Hypoplasia</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK9673/table/pc-hypo-p.T.molecular_genetic_testing_us/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__pc-hypo-p.T.molecular_genetic_testing_us_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_pc-hypo-p.T.molecular_genetic_testing_us_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_pc-hypo-p.T.molecular_genetic_testing_us_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Method</th><th id="hd_h_pc-hypo-p.T.molecular_genetic_testing_us_1_1_1_3" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Proportion of Pathogenic Variants <sup>2</sup> Detectable by Method</th></tr></thead><tbody><tr><td headers="hd_h_pc-hypo-p.T.molecular_genetic_testing_us_1_1_1_1" rowspan="2" scope="row" colspan="1" style="text-align:left;vertical-align:middle;">
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<i>TSEN54</i>
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</td><td headers="hd_h_pc-hypo-p.T.molecular_genetic_testing_us_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_pc-hypo-p.T.molecular_genetic_testing_us_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">100% <sup>4</sup></td></tr><tr><td headers="hd_h_pc-hypo-p.T.molecular_genetic_testing_us_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_pc-hypo-p.T.molecular_genetic_testing_us_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Unknown <sup>6</sup></td></tr></tbody></table></div><div><div><dl class="temp-labeled-list small"><dt>1. </dt><dd><div id="pc-hypo-p.TF.1.1"><p class="no_margin">See <a href="/books/NBK9673/#pc-hypo-p.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="pc-hypo-p.TF.1.2"><p class="no_margin">See <a href="#pc-hypo-p.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="pc-hypo-p.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 small intragenic deletions/insertions and <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; 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="pc-hypo-p.TF.1.4"><p class="no_margin">Data derived from the subscription-based professional view of the Human Gene Mutation Database [<a class="bk_pop" href="#pc-hypo-p.REF.stenson.2020.1197">Stenson et al 2020</a>]</p></div></dd><dt>5. </dt><dd><div id="pc-hypo-p.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><dt>6. </dt><dd><div id="pc-hypo-p.TF.1.6"><p class="no_margin">No data on detection rate of <a class="def" href="/books/n/gene/glossary/def-item/gene/">gene</a>-targeted <a class="def" href="/books/n/gene/glossary/def-item/deletion-duplication-analysis/">deletion/duplication analysis</a> are available.</p></div></dd></dl></div></div></div></div></div></div><div id="pc-hypo-p.Clinical_Characteristics"><h2 id="_pc-hypo-p_Clinical_Characteristics_">Clinical Characteristics</h2><div id="pc-hypo-p.Clinical_Description"><h3>Clinical Description</h3><p>To date, at least 131 individuals have been identified with <i>TSEN54</i> pontocerebellar hypoplasia (<i>TSEN54</i>-PCH) [<a class="bk_pop" href="#pc-hypo-p.REF.namavar.2011.143">Namavar et al 2011</a>, <a class="bk_pop" href="#pc-hypo-p.REF.s_nchezalbisua.2014.70">Sánchez-Albisua et al 2014</a>].</p><p>The phenotypic spectrum of <i>TSEN54</i>-PCH comprises the three PCH phenotypes (PCH 2, 4, and 5) thought to be distinct entities before their molecular basis was known. The main difference between the three PCH phenotypes is life expectancy: individuals with PCH2 usually survive into childhood, whereas those with PCH4 and PCH5 usually die as neonates.</p><div id="pc-hypo-p.Pontocerebellar_Hypoplasia_Typ"><h4>Pontocerebellar Hypoplasia Type 2</h4><p>The following description of the phenotypic features associated with <i>TSEN54</i>-PCH type 2 is based on <a class="bk_pop" href="#pc-hypo-p.REF.s_nchezalbisua.2014.70">Sánchez-Albisua et al [2014]</a>.</p><div id="pc-hypo-p.T.select_features_of_tsen54_po" class="table"><h3><span class="label">Table 2. </span></h3><div class="caption"><p>Select Features of <i>TSEN54</i> Pontocerebellar Hypoplasia Type 2</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK9673/table/pc-hypo-p.T.select_features_of_tsen54_po/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__pc-hypo-p.T.select_features_of_tsen54_po_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_pc-hypo-p.T.select_features_of_tsen54_po_1_1_1_1" colspan="2" scope="colgroup" rowspan="1" style="text-align:left;vertical-align:middle;">Feature</th><th id="hd_h_pc-hypo-p.T.select_features_of_tsen54_po_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">% of Persons<br />with Feature</th><th id="hd_h_pc-hypo-p.T.select_features_of_tsen54_po_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_pc-hypo-p.T.select_features_of_tsen54_po_1_1_1_1" colspan="2" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Severe developmental delay</b>
|
||
</td><td headers="hd_h_pc-hypo-p.T.select_features_of_tsen54_po_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">100%</td><td headers="hd_h_pc-hypo-p.T.select_features_of_tsen54_po_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr><tr><td headers="hd_h_pc-hypo-p.T.select_features_of_tsen54_po_1_1_1_1" rowspan="4" scope="row" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Neurologic</b>
|
||
</td><td headers="hd_h_pc-hypo-p.T.select_features_of_tsen54_po_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Choreoathetosis</td><td headers="hd_h_pc-hypo-p.T.select_features_of_tsen54_po_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">88%</td><td headers="hd_h_pc-hypo-p.T.select_features_of_tsen54_po_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">62% w/pyramidal signs</td></tr><tr><td headers="hd_h_pc-hypo-p.T.select_features_of_tsen54_po_1_1_1_1" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">Pure spasticity</td><td headers="hd_h_pc-hypo-p.T.select_features_of_tsen54_po_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">12%</td><td headers="hd_h_pc-hypo-p.T.select_features_of_tsen54_po_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr><tr><td headers="hd_h_pc-hypo-p.T.select_features_of_tsen54_po_1_1_1_1" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">Epileptic seizures</td><td headers="hd_h_pc-hypo-p.T.select_features_of_tsen54_po_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">82%</td><td headers="hd_h_pc-hypo-p.T.select_features_of_tsen54_po_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr><tr><td headers="hd_h_pc-hypo-p.T.select_features_of_tsen54_po_1_1_1_1" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">Dystonic attacks</td><td headers="hd_h_pc-hypo-p.T.select_features_of_tsen54_po_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">33%</td><td headers="hd_h_pc-hypo-p.T.select_features_of_tsen54_po_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr><tr><td headers="hd_h_pc-hypo-p.T.select_features_of_tsen54_po_1_1_1_1" rowspan="2" scope="row" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Gastrointestinal</b>
|
||
</td><td headers="hd_h_pc-hypo-p.T.select_features_of_tsen54_po_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Feeding difficulties</td><td headers="hd_h_pc-hypo-p.T.select_features_of_tsen54_po_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">100%</td><td headers="hd_h_pc-hypo-p.T.select_features_of_tsen54_po_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr><tr><td headers="hd_h_pc-hypo-p.T.select_features_of_tsen54_po_1_1_1_1" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">GERD</td><td headers="hd_h_pc-hypo-p.T.select_features_of_tsen54_po_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">73%</td><td headers="hd_h_pc-hypo-p.T.select_features_of_tsen54_po_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr><tr><td headers="hd_h_pc-hypo-p.T.select_features_of_tsen54_po_1_1_1_1" colspan="2" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Sleep disorder</b>
|
||
</td><td headers="hd_h_pc-hypo-p.T.select_features_of_tsen54_po_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">96%</td><td headers="hd_h_pc-hypo-p.T.select_features_of_tsen54_po_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr><tr><td headers="hd_h_pc-hypo-p.T.select_features_of_tsen54_po_1_1_1_1" colspan="2" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Apnea</b>
|
||
</td><td headers="hd_h_pc-hypo-p.T.select_features_of_tsen54_po_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">67%</td><td headers="hd_h_pc-hypo-p.T.select_features_of_tsen54_po_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr><tr><td headers="hd_h_pc-hypo-p.T.select_features_of_tsen54_po_1_1_1_1" colspan="2" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Recurrent infections</b>
|
||
</td><td headers="hd_h_pc-hypo-p.T.select_features_of_tsen54_po_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">52%</td><td headers="hd_h_pc-hypo-p.T.select_features_of_tsen54_po_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr></tbody></table></div><div><div><dl class="temp-labeled-list small"><dt></dt><dd><div><p class="no_margin">Based on 33 individuals <a class="def" href="/books/n/gene/glossary/def-item/homozygous/">homozygous</a> for the common <a class="def" href="/books/n/gene/glossary/def-item/missense/">missense</a> variant, p.Ala307Ser, from nonconsanguineous parents surviving until age 11 years [<a class="bk_pop" href="#pc-hypo-p.REF.s_nchezalbisua.2014.70">Sánchez-Albisua et al 2014</a>]</p></div></dd><dt></dt><dd><div><p class="no_margin">GERD = gastroesophageal reflux disease</p></div></dd></dl></div></div></div><p><b>Pregnancy</b> is usually unremarkable. Newborns have no external <a class="def" href="/books/n/gene/glossary/def-item/dysmorphic/">dysmorphic</a> features and no visceral abnormalities. Birth is usually at term with normal weight, length, and (though always <50th centile) head circumference. Progressive microcephaly is observed during the first year, with the occipitofrontal circumference dropping below two standard deviations.</p><p>
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<b>Neurologic findings</b>
|
||
</p><ul><li class="half_rhythm"><div>Bucco-pharyngeal incoordination with reduced grasping of the nipple and incoordination of sucking and swallowing</div></li><li class="half_rhythm"><div>Generalized clonus (often described as "jitteriness") present in the majority</div></li><li class="half_rhythm"><div>Impaired motor and cognitive development: lack of voluntary motor development; unsupported sitting or voluntary reaching and grasping rarely achieved</div></li><li class="half_rhythm"><div>Severe chorea often developing during the first six months, usually accompanied by spasticity. Those children who never develop chorea remain tetraspastic.</div></li><li class="half_rhythm"><div>Impaired central vision. Note that primary optic nerve atrophy has not been observed.</div></li><li class="half_rhythm"><div>Epilepsy (in ~50%); usually generalized tonic clonic seizures often provoked by fever, although other types of seizures including infantile spasms have been observed.</div></li></ul><p><b>Other.</b> Subclinical myopathy, associated with elevated creatine kinase, may lead to rhabdomyolysis following severe infections.</p><p><b>Life expectancy.</b> Death is often before age ten years, although survival beyond age 20 years has been reported. Improved care, especially gastrostomy feeding, has probably improved survival. Typical complications are sudden and unexpected death while the child is sleeping (crib death) in infancy and death from hyperthermic crises.</p></div><div id="pc-hypo-p.Pontocerebellar_Hypoplasia_Typ_1"><h4>Pontocerebellar Hypoplasia Type 4</h4><p>Prenatal findings include polyhydramnios in many (but not all) pregnancies.</p><p>Central respiratory impairment (probably the result of brain stem failure) at birth results in prolonged or perpetual dependence on mechanical ventilation. Respiratory complications occur at a later stage when weaning is difficult or plainly impossible.</p><p>Microcephaly is usually present at birth. About 50% of neonates have contractures (arthrogryposis) at birth. Generalized clonus, provoked by handling or noise, may be extreme.</p><p><b>Life expectancy.</b> Infants with PCH4 usually die in the neonatal period from these complications.</p></div><div id="pc-hypo-p.Neuropathology_of_PCH2_and_PCH"><h4>Neuropathology of PCH2 and PCH4</h4><p>[<a class="bk_pop" href="#pc-hypo-p.REF.barth.2007.373">Barth et al 2007</a>]</p><ul><li class="half_rhythm"><div>
|
||
<b>Cerebellum</b>
|
||
</div><ul><li class="half_rhythm"><div>Hypoplasia and reduced branching of the folia; segmental degeneration of the cerebellar cortex and dentate nucleus; variable degeneration of Purkinje cells; relative sparing of the flocculus and vermis</div></li><li class="half_rhythm"><div>PCH4. Denuding of the dorsal part of the cerebellar hemispheric cortex; relative sparing of the flocculus and vermis</div></li></ul></li><li class="half_rhythm"><div><b>Pons.</b> Neuronal death within the ventral pons; relative sparing of the tegmentum</div></li><li class="half_rhythm"><div><b>Cerebral cortex and striatum.</b> Variable neuronal degeneration</div></li><li class="half_rhythm"><div><b>Medulla oblongata.</b> Variable neuronal degeneration; hypoplasia and segmental degeneration of the inferior olivary nuclei; loss of arcuate nuclei</div></li><li class="half_rhythm"><div><b>Myelin.</b> Not involved in PCH2; widespread gliosis variably seen in PCH4</div></li></ul></div><div id="pc-hypo-p.Pontocerebellar_Hypoplasia_Typ_2"><h4>Pontocerebellar Hypoplasia Type 5</h4><p>Described in only one family, findings of PCH5 are similar to those of PCH4 except that the degenerative process occurs in the cerebellar vermis rather than the cerebellar hemispheres [<a class="bk_pop" href="#pc-hypo-p.REF.patel.2006.594">Patel et al 2006</a>]. There is fetal onset of seizure-like activity. Death occurs very shortly after birth.</p></div></div><div id="pc-hypo-p.GenotypePhenotype_Correlations"><h3>Genotype-Phenotype Correlations</h3><p>The following clinical data, supported by pathogenic data, strongly suggest a <a class="def" href="/books/n/gene/glossary/def-item/genotype/">genotype</a>-<a class="def" href="/books/n/gene/glossary/def-item/phenotype/">phenotype</a> correlation.</p><p>The common <a href="/books/NBK9673/table/pc-hypo-p.T.notable_tsen54_pathogenic_va/?report=objectonly" target="object" rid-ob="figobpchypopTnotabletsen54pathogenicva">c.919G>T</a> <a class="def" href="/books/n/gene/glossary/def-item/missense/">missense</a> variant is strongly associated with a dragonfly-like cerebellar pattern on MRI.</p><p>In general, infants with the PCH4 <a class="def" href="/books/n/gene/glossary/def-item/phenotype/">phenotype</a> who are compound heterozygotes for a pathogenic <a class="def" href="/books/n/gene/glossary/def-item/nonsense-variant/">nonsense</a> or <a class="def" href="/books/n/gene/glossary/def-item/splice-site/">splice site</a> variant and a pathogenic <a class="def" href="/books/n/gene/glossary/def-item/missense/">missense</a> variant have poorer survival than children with the PCH2 phenotype who are <a class="def" href="/books/n/gene/glossary/def-item/homozygous/">homozygous</a> for a missense variant [<a class="bk_pop" href="#pc-hypo-p.REF.budde.2008.1113">Budde et al 2008</a>, <a class="bk_pop" href="#pc-hypo-p.REF.namavar.2011.143">Namavar et al 2011</a>].</p></div><div id="pc-hypo-p.Nomenclature"><h3>Nomenclature</h3><p>Pontocerebellar hypoplasia 2 (PCH2) refers to the <a class="def" href="/books/n/gene/glossary/def-item/phenotype/">phenotype</a>; its subtypes are identified by the <a class="def" href="/books/n/gene/glossary/def-item/gene/">gene</a> in which causative variants occur:</p><ul><li class="half_rhythm"><div>PCH2A (<i>TSEN54</i>)</div></li><li class="half_rhythm"><div>PCH2B (<i>TSEN2</i>)</div></li><li class="half_rhythm"><div>PCH2C (<i>TSEN34</i>)</div></li><li class="half_rhythm"><div>PCH2D (<i>SEPSECS</i>)</div></li></ul></div><div id="pc-hypo-p.Prevalence"><h3>Prevalence</h3><p>The prevalence of <i>TSEN54</i>-PCH is unknown. To date, at least 131 individuals have been identified with <i>TSEN54</i>-PCH.</p><p>The <a class="def" href="/books/n/gene/glossary/def-item/carrier/">carrier</a> frequency of the common <i>TSEN54</i> <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a> <a href="/books/NBK9673/table/pc-hypo-p.T.notable_tsen54_pathogenic_va/?report=objectonly" target="object" rid-ob="figobpchypopTnotabletsen54pathogenicva">c.919G>T</a> (<a href="/books/NBK9673/table/pc-hypo-p.T.notable_tsen54_pathogenic_va/?report=objectonly" target="object" rid-ob="figobpchypopTnotabletsen54pathogenicva">p.Ala307Ser</a>) among 451 Dutch and 279 German individuals was 0.004 [<a class="bk_pop" href="#pc-hypo-p.REF.budde.2008.1113">Budde et al 2008</a>].</p><p>Like many <a class="def" href="/books/n/gene/glossary/def-item/autosomal-recessive/">autosomal recessive</a> disorders, PCH2 has been reported to be more common in isolated populations or populations with a high rate of <a class="def" href="/books/n/gene/glossary/def-item/consanguinity/">consanguinity</a>. PCH2 was originally identified in an isolated population in Volendam, the Netherlands [<a class="bk_pop" href="#pc-hypo-p.REF.barth.1995.311">Barth et al 1995</a>].</p></div></div><div id="pc-hypo-p.Genetically_Related_Allelic_Di"><h2 id="_pc-hypo-p_Genetically_Related_Allelic_Di_">Genetically Related (Allelic) Disorders</h2><p>No phenotypes other than those discussed in this <i>GeneReview</i> have been associated with mutation of <i>TSEN54.</i></p></div><div id="pc-hypo-p.Differential_Diagnosis"><h2 id="_pc-hypo-p_Differential_Diagnosis_">Differential Diagnosis</h2><div id="pc-hypo-p.T.genes_of_interest_in_the_dif" class="table"><h3><span class="label">Table 3. </span></h3><div class="caption"><p>Genes of Interest in the Differential Diagnosis of <i>TSEN54</i> Pontocerebellar Hypoplasia</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK9673/table/pc-hypo-p.T.genes_of_interest_in_the_dif/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__pc-hypo-p.T.genes_of_interest_in_the_dif_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_pc-hypo-p.T.genes_of_interest_in_the_dif_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Gene(s)</th><th id="hd_h_pc-hypo-p.T.genes_of_interest_in_the_dif_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Phenotype/Disorder</th><th id="hd_h_pc-hypo-p.T.genes_of_interest_in_the_dif_1_1_1_3" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">MOI</th><th id="hd_h_pc-hypo-p.T.genes_of_interest_in_the_dif_1_1_1_4" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Brain MRI Findings</th><th id="hd_h_pc-hypo-p.T.genes_of_interest_in_the_dif_1_1_1_5" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Clinical Characteristics</th></tr></thead><tbody><tr><td headers="hd_h_pc-hypo-p.T.genes_of_interest_in_the_dif_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><i>B3GALNT2</i><br /><i>B4GAT1</i><br /><i>DAG1</i><br /><i>FKRP</i><br /><i>FKTN</i><br /><i>GMPPB</i><br /><i>ISPD</i><br /><i>LARGE1</i><br /><i>POMGNT1</i><br /><i>POMGNT2</i><br /><i>POMK</i><br /><i>POMT1</i><br /><i>POMT2</i><br /><i>RXYLT1</i> <sup>1</sup></td><td headers="hd_h_pc-hypo-p.T.genes_of_interest_in_the_dif_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Alpha-dystroglycanopathies</td><td headers="hd_h_pc-hypo-p.T.genes_of_interest_in_the_dif_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">AR</td><td headers="hd_h_pc-hypo-p.T.genes_of_interest_in_the_dif_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Wide spectrum of brain malformations incl cobblestone lissencephaly & hydrocephalus</td><td headers="hd_h_pc-hypo-p.T.genes_of_interest_in_the_dif_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Muscle weakness & ophthalmologic abnormalities</td></tr><tr><td headers="hd_h_pc-hypo-p.T.genes_of_interest_in_the_dif_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<i>CASK</i>
|
||
</td><td headers="hd_h_pc-hypo-p.T.genes_of_interest_in_the_dif_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">ID & microcephaly w/pontine & cerebellar hypoplasia (See <a href="/books/n/gene/cask-dis/"><i>CASK</i> Disorders</a>.)</td><td headers="hd_h_pc-hypo-p.T.genes_of_interest_in_the_dif_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">XL</td><td headers="hd_h_pc-hypo-p.T.genes_of_interest_in_the_dif_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Neocortical dysplasia (simplified gyral pattern, thin brain stem w/flattening of the pons) & severe cerebellar hypoplasia (pontocerebellar hypoplasia)</td><td headers="hd_h_pc-hypo-p.T.genes_of_interest_in_the_dif_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<ul><li class="half_rhythm"><div>Heterozygous females have severe or profound ID & structural brain anomalies incl mild <a class="def" href="/books/n/gene/glossary/def-item/congenital/">congenital</a> microcephaly & severe postnatal microcephaly.</div></li><li class="half_rhythm"><div>Hemizygous males are more severely affected.</div></li></ul>
|
||
</td></tr><tr><td headers="hd_h_pc-hypo-p.T.genes_of_interest_in_the_dif_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<i>CHMP1A</i>
|
||
</td><td headers="hd_h_pc-hypo-p.T.genes_of_interest_in_the_dif_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">PCH8 <sup>2</sup></td><td headers="hd_h_pc-hypo-p.T.genes_of_interest_in_the_dif_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">AR</td><td headers="hd_h_pc-hypo-p.T.genes_of_interest_in_the_dif_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">MRI findings similar to those of PCH2</td><td headers="hd_h_pc-hypo-p.T.genes_of_interest_in_the_dif_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Microcephaly, delayed walking, variable foot deformities, chorea, dystonic posturing, & impaired cognition</td></tr><tr><td headers="hd_h_pc-hypo-p.T.genes_of_interest_in_the_dif_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<i>EXOSC3</i>
|
||
<br />
|
||
<i>EXOSC8</i>
|
||
<br />
|
||
<i>SLC25A46</i>
|
||
<br />
|
||
<i>VRK1</i>
|
||
</td><td headers="hd_h_pc-hypo-p.T.genes_of_interest_in_the_dif_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">PCH1 <sup>2, 3</sup> (See <a href="/books/n/gene/exosc3-pc-hypo-p/"><i>EXOSC3</i>-PCH</a>.)</td><td headers="hd_h_pc-hypo-p.T.genes_of_interest_in_the_dif_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">AR</td><td headers="hd_h_pc-hypo-p.T.genes_of_interest_in_the_dif_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Pontine atrophy may not be present in some individuals.</td><td headers="hd_h_pc-hypo-p.T.genes_of_interest_in_the_dif_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<ul><li class="half_rhythm"><div>Lower motor neuron deficits due to loss of anterior horn cells; manifestations of peripheral denervation incl weakness & muscle hypotonia from birth</div></li><li class="half_rhythm"><div>Mixed central (spastic, dystonic) & peripheral pareses may be present in those w/prolonged survival; some children w/PCH1 die at an early age. <sup>4</sup></div></li></ul>
|
||
</td></tr><tr><td headers="hd_h_pc-hypo-p.T.genes_of_interest_in_the_dif_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">>40 genes (e.g., <i>PMM2</i> <sup>5</sup>)</td><td headers="hd_h_pc-hypo-p.T.genes_of_interest_in_the_dif_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><a href="/books/n/gene/cdg/">Congenital disorders of glycosylation</a> (CDG); see also <a href="/books/n/gene/cdg-1a/">PMM2<i>-</i>CDG<i>
|
||
</i>(<i>CDG-Ia</i>)</a>.</td><td headers="hd_h_pc-hypo-p.T.genes_of_interest_in_the_dif_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">AR<br />(XL)</td><td headers="hd_h_pc-hypo-p.T.genes_of_interest_in_the_dif_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Pontocerebellar hypoplasia w/superimposed atrophy, delayed myelination</td><td headers="hd_h_pc-hypo-p.T.genes_of_interest_in_the_dif_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Dysmorphic features, ataxia, organ failure in neonatal period</td></tr><tr><td headers="hd_h_pc-hypo-p.T.genes_of_interest_in_the_dif_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<i>PCLO</i>
|
||
</td><td headers="hd_h_pc-hypo-p.T.genes_of_interest_in_the_dif_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">PCH3 <sup>2</sup></td><td headers="hd_h_pc-hypo-p.T.genes_of_interest_in_the_dif_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">AR</td><td headers="hd_h_pc-hypo-p.T.genes_of_interest_in_the_dif_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td><td headers="hd_h_pc-hypo-p.T.genes_of_interest_in_the_dif_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr><tr><td headers="hd_h_pc-hypo-p.T.genes_of_interest_in_the_dif_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<i>RARS2</i>
|
||
</td><td headers="hd_h_pc-hypo-p.T.genes_of_interest_in_the_dif_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">PCH6 <sup>2</sup></td><td headers="hd_h_pc-hypo-p.T.genes_of_interest_in_the_dif_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">AR</td><td headers="hd_h_pc-hypo-p.T.genes_of_interest_in_the_dif_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td><td headers="hd_h_pc-hypo-p.T.genes_of_interest_in_the_dif_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Very rare; ↑ CSF lactate concentration</td></tr><tr><td headers="hd_h_pc-hypo-p.T.genes_of_interest_in_the_dif_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_pc-hypo-p.T.genes_of_interest_in_the_dif_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Lissencephaly 2 (OMIM <a href="https://omim.org/entry/257320" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">257320</a>)</td><td headers="hd_h_pc-hypo-p.T.genes_of_interest_in_the_dif_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">AR</td><td headers="hd_h_pc-hypo-p.T.genes_of_interest_in_the_dif_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Classic lissencephaly w/coexistent cerebellar & pontine hypoplasia</td><td headers="hd_h_pc-hypo-p.T.genes_of_interest_in_the_dif_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr><tr><td headers="hd_h_pc-hypo-p.T.genes_of_interest_in_the_dif_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<i>SEPSECS</i>
|
||
</td><td headers="hd_h_pc-hypo-p.T.genes_of_interest_in_the_dif_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">PCH2 <sup>2</sup></td><td headers="hd_h_pc-hypo-p.T.genes_of_interest_in_the_dif_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">AR</td><td headers="hd_h_pc-hypo-p.T.genes_of_interest_in_the_dif_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Progressive cerebello-cerebral atrophy closely resembles mild PCH2.</td><td headers="hd_h_pc-hypo-p.T.genes_of_interest_in_the_dif_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Clinical findings closely resemble mild PCH2.</td></tr><tr><td headers="hd_h_pc-hypo-p.T.genes_of_interest_in_the_dif_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<i>TOE1</i>
|
||
</td><td headers="hd_h_pc-hypo-p.T.genes_of_interest_in_the_dif_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">PCH7 <sup>2</sup></td><td headers="hd_h_pc-hypo-p.T.genes_of_interest_in_the_dif_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">AR</td><td headers="hd_h_pc-hypo-p.T.genes_of_interest_in_the_dif_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">PCH</td><td headers="hd_h_pc-hypo-p.T.genes_of_interest_in_the_dif_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Disorders of sex development</td></tr><tr><td headers="hd_h_pc-hypo-p.T.genes_of_interest_in_the_dif_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<i>VLDLR</i>
|
||
</td><td headers="hd_h_pc-hypo-p.T.genes_of_interest_in_the_dif_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<a href="/books/n/gene/vldlr-ch/"><i>VLDLR</i> cerebellar hypoplasia</a>
|
||
</td><td headers="hd_h_pc-hypo-p.T.genes_of_interest_in_the_dif_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">AR</td><td headers="hd_h_pc-hypo-p.T.genes_of_interest_in_the_dif_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Gross cerebellar hypoplasia, a flat ventral pons, & simplified gyri</td><td headers="hd_h_pc-hypo-p.T.genes_of_interest_in_the_dif_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Ataxia & ID</td></tr></tbody></table></div><div><div><dl class="temp-labeled-list small"><dt></dt><dd><div><p class="no_margin">AR = <a class="def" href="/books/n/gene/glossary/def-item/autosomal-recessive/">autosomal recessive</a>; ID = intellectual disability; MOI = <a class="def" href="/books/n/gene/glossary/def-item/mode-of-inheritance/">mode of inheritance</a>; PCH = pontocerebellar hypoplasia; XL = <a class="def" href="/books/n/gene/glossary/def-item/x-linked/">X-linked</a></p></div></dd><dt>1. </dt><dd><div id="pc-hypo-p.TF.3.1"><p class="no_margin">OMIM <a href="https://omim.org/phenotypicSeries/PS236670" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">Phenotypic Series: Muscular dystrophy-dystroglycanopathy, type A</a></p></div></dd><dt>2. </dt><dd><div id="pc-hypo-p.TF.3.2"><p class="no_margin">
|
||
<a class="bk_pop" href="#pc-hypo-p.REF.van_dijk.2018.92">van Dijk et al [2018]</a>
|
||
</p></div></dd><dt>3. </dt><dd><div id="pc-hypo-p.TF.3.3"><p class="no_margin">OMIM <a href="https://omim.org/phenotypicSeries/PS607596" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">Phenotypic Series: Pontocerebellar hypoplasia</a></p></div></dd><dt>4. </dt><dd><div id="pc-hypo-p.TF.3.4"><p class="no_margin">Children with <i>EXOSC3</i> pathogenic variants other than c.395A>C (p.Asp132Ala) have a more severe <a class="def" href="/books/n/gene/glossary/def-item/phenotype/">phenotype</a> that includes severe pontine and cerebellar hypoplasia, joint contractures, and death in infancy.</p></div></dd><dt>5. </dt><dd><div id="pc-hypo-p.TF.3.5"><p class="no_margin">PMM2-CDG (<i>CDG-Ia</i>) is the most common of a group of disorders of abnormal glycosylation of N-linked oligosaccharides.</p></div></dd></dl></div></div></div><p>
|
||
<b>Other disorders to consider in the differential diagnosis</b>
|
||
</p><ul><li class="half_rhythm"><div>Lissencephalies without known <a class="def" href="/books/n/gene/glossary/def-item/gene/">gene</a> defects exhibiting two-layered cortex, extreme microcephaly, and cerebellar and pontine hypoplasia [<a class="bk_pop" href="#pc-hypo-p.REF.forman.2005.847">Forman et al 2005</a>]</div></li><li class="half_rhythm"><div>Pontocerebellar hypoplasia in extremely premature infants (<28 weeks' gestational age); an acquired phenocopy to be considered [<a class="bk_pop" href="#pc-hypo-p.REF.volpe.2009.1085">Volpe 2009</a>, <a class="bk_pop" href="#pc-hypo-p.REF.pierson.2016.305">Pierson & Al Sufiani 2016</a>]</div></li></ul></div><div id="pc-hypo-p.Management"><h2 id="_pc-hypo-p_Management_">Management</h2><div id="pc-hypo-p.Evaluations_Following_Initial"><h3>Evaluations Following Initial Diagnosis</h3><p>To establish the extent of disease and needs in an individual diagnosed with <i>TSEN54</i> pontocerebellar hypoplasia (<i>TSEN54</i>-PCH), the evaluations summarized in <a href="/books/NBK9673/table/pc-hypo-p.T.recommended_evaluations_foll/?report=objectonly" target="object" rid-ob="figobpchypopTrecommendedevaluationsfoll">Table 4</a> (if not performed as part of the evaluation that led to the diagnosis) are recommended. Note that recommendations are based only on PCH2 caused by homozygosity for the<i>TSEN54</i> <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a> <a href="/books/NBK9673/table/pc-hypo-p.T.notable_tsen54_pathogenic_va/?report=objectonly" target="object" rid-ob="figobpchypopTnotabletsen54pathogenicva">c.919G>T</a>, as all other subtypes are very rare.</p><div id="pc-hypo-p.T.recommended_evaluations_foll" class="table"><h3><span class="label">Table 4. </span></h3><div class="caption"><p>Recommended Evaluations Following Initial Diagnosis of <i>TSEN54</i> Pontocerebellar Hypoplasia Type 2</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK9673/table/pc-hypo-p.T.recommended_evaluations_foll/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__pc-hypo-p.T.recommended_evaluations_foll_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_pc-hypo-p.T.recommended_evaluations_foll_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">System/Concern</th><th id="hd_h_pc-hypo-p.T.recommended_evaluations_foll_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Evaluation</th><th id="hd_h_pc-hypo-p.T.recommended_evaluations_foll_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_pc-hypo-p.T.recommended_evaluations_foll_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Constitutional</b>
|
||
</td><td headers="hd_h_pc-hypo-p.T.recommended_evaluations_foll_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Measure length, weight.</td><td headers="hd_h_pc-hypo-p.T.recommended_evaluations_foll_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">See <b>Gastrointestinal/Feeding</b> recommendations if there is evidence of failure to thrive.</td></tr><tr><td headers="hd_h_pc-hypo-p.T.recommended_evaluations_foll_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Gastrointestinal/</b>
|
||
<br />
|
||
<b>Feeding</b>
|
||
</td><td headers="hd_h_pc-hypo-p.T.recommended_evaluations_foll_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Gastroenterology / nutrition / feeding team eval</td><td headers="hd_h_pc-hypo-p.T.recommended_evaluations_foll_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Assess swallowing & feeding to determine safety of oral vs gastrostomy feeding.</td></tr><tr><td headers="hd_h_pc-hypo-p.T.recommended_evaluations_foll_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Respiratory</b>
|
||
</td><td headers="hd_h_pc-hypo-p.T.recommended_evaluations_foll_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Assess airway & pulmonary function & secretion management.</td><td headers="hd_h_pc-hypo-p.T.recommended_evaluations_foll_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Consult pulmonologist.</td></tr><tr><td headers="hd_h_pc-hypo-p.T.recommended_evaluations_foll_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_pc-hypo-p.T.recommended_evaluations_foll_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Eval by pediatric neurologist</td><td headers="hd_h_pc-hypo-p.T.recommended_evaluations_foll_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Assess for evidence of severe generalized clonus; chorea, spasticity; seizures; impaired central vision.</td></tr><tr><td headers="hd_h_pc-hypo-p.T.recommended_evaluations_foll_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_pc-hypo-p.T.recommended_evaluations_foll_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Multidisciplinary neuromuscular clinic assessment by orthopedist, physical medicine, OT/PT</td><td headers="hd_h_pc-hypo-p.T.recommended_evaluations_foll_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>Contractures, clubfoot, & kyphoscoliosis</div></li><li class="half_rhythm"><div>Need for positioning devices</div></li></ul></td></tr><tr><td headers="hd_h_pc-hypo-p.T.recommended_evaluations_foll_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Palliative care</b>
|
||
</td><td headers="hd_h_pc-hypo-p.T.recommended_evaluations_foll_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Refer to palliative care specialist.</td><td headers="hd_h_pc-hypo-p.T.recommended_evaluations_foll_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">When deemed appropriate by family & care providers</td></tr><tr><td headers="hd_h_pc-hypo-p.T.recommended_evaluations_foll_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Genetic</b>
|
||
<br />
|
||
<b>counseling</b>
|
||
</td><td headers="hd_h_pc-hypo-p.T.recommended_evaluations_foll_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">By genetics professionals <sup>1</sup></td><td headers="hd_h_pc-hypo-p.T.recommended_evaluations_foll_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">To inform affected individuals & their families re nature, MOI, & implications of <i>TSEN54</i>-PCH2 to facilitate medical & personal decision making</td></tr><tr><td headers="hd_h_pc-hypo-p.T.recommended_evaluations_foll_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Family support/</b>
|
||
<br />
|
||
<b>resources</b>
|
||
</td><td headers="hd_h_pc-hypo-p.T.recommended_evaluations_foll_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Assess:
|
||
<ul><li class="half_rhythm"><div>Use of community or <a href="#pc-hypo-p.Resources">online resources</a> such as <a href="https://www.p2pusa.org/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">Parent to Parent</a>;</div></li><li class="half_rhythm"><div>Need for social work involvement for parental support;</div></li><li class="half_rhythm"><div>Need for home nursing referral.</div></li></ul></td><td headers="hd_h_pc-hypo-p.T.recommended_evaluations_foll_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr></tbody></table></div><div><div><dl class="temp-labeled-list small"><dt></dt><dd><div><p class="no_margin">MOI = <a class="def" href="/books/n/gene/glossary/def-item/mode-of-inheritance/">mode of inheritance</a>; OT = occupational therapist; PT = physical therapist</p></div></dd><dt>1. </dt><dd><div id="pc-hypo-p.TF.4.1"><p class="no_margin">Medical geneticist, certified genetic counselor, certified advanced genetic nurse</p></div></dd></dl></div></div></div></div><div id="pc-hypo-p.Treatment_of_Manifestations"><h3>Treatment of Manifestations</h3><p><b>PCH4</b> and <b>PCH5.</b> No specific therapy is available. Respiratory support is usually given for a limited time. Weaning from respiratory support may be possible for only short periods.</p><p><b>PCH2.</b> Although there is no specific treatment, the goals are to maximize function and reduce complications. Ideally each affected individual is managed by a multidisciplinary team of relevant specialists such as developmental pediatricians, neurologists, occupational therapists (OT), physical therapists (PT), physiatrists, orthopedists, nutritionists, pulmonologists, and psychologists depending on the clinical manifestations (see <a href="/books/NBK9673/table/pc-hypo-p.T.treatment_of_manifestations/?report=objectonly" target="object" rid-ob="figobpchypopTtreatmentofmanifestations">Table 5</a>).</p><p>Of note, adequate hydration during prolonged periods of high fever may help avoid rhabdomyolysis.</p><div id="pc-hypo-p.T.treatment_of_manifestations" class="table"><h3><span class="label">Table 5. </span></h3><div class="caption"><p>Treatment of Manifestations in Individuals with <i>TSEN54</i> Pontocerebellar Hypoplasia Type 2</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK9673/table/pc-hypo-p.T.treatment_of_manifestations/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__pc-hypo-p.T.treatment_of_manifestations_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_pc-hypo-p.T.treatment_of_manifestations_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Manifestation/Concern</th><th id="hd_h_pc-hypo-p.T.treatment_of_manifestations_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Treatment</th><th id="hd_h_pc-hypo-p.T.treatment_of_manifestations_1_1_1_3" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Considerations/Other</th></tr></thead><tbody><tr><td headers="hd_h_pc-hypo-p.T.treatment_of_manifestations_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_pc-hypo-p.T.treatment_of_manifestations_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Per standard practice</td><td headers="hd_h_pc-hypo-p.T.treatment_of_manifestations_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">By neurologist experienced in epilepsy management</td></tr><tr><td headers="hd_h_pc-hypo-p.T.treatment_of_manifestations_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Irritability</b>
|
||
</td><td headers="hd_h_pc-hypo-p.T.treatment_of_manifestations_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">None</td><td headers="hd_h_pc-hypo-p.T.treatment_of_manifestations_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Often related to chorea (involuntary movements)</td></tr><tr><td headers="hd_h_pc-hypo-p.T.treatment_of_manifestations_1_1_1_1" rowspan="2" scope="row" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Musculoskeletal</b>
|
||
</td><td headers="hd_h_pc-hypo-p.T.treatment_of_manifestations_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Multidisciplinary neuromuscular clinic physical medicine, OT/PT</td><td headers="hd_h_pc-hypo-p.T.treatment_of_manifestations_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<ul><li class="half_rhythm"><div>Maximize gross motor & fine motor skills through PT/OT & use of adaptive devices.</div></li><li class="half_rhythm"><div>Alternative casting/splinting & stretching</div></li></ul>
|
||
</td></tr><tr><td headers="hd_h_pc-hypo-p.T.treatment_of_manifestations_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">Orthopedics</td><td headers="hd_h_pc-hypo-p.T.treatment_of_manifestations_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Manage contractures, clubfoot, & scoliosis w/bracing &/or surgical intervention.</td></tr><tr><td headers="hd_h_pc-hypo-p.T.treatment_of_manifestations_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Feeding/</b>
|
||
<br />
|
||
<b>Dysphagia</b>
|
||
</td><td headers="hd_h_pc-hypo-p.T.treatment_of_manifestations_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Gastroenterology / nutrition / feeding team</td><td headers="hd_h_pc-hypo-p.T.treatment_of_manifestations_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Modify food consistency to ↓ aspiration risk &/or consider NG feeding & gastrostomy.</td></tr><tr><td headers="hd_h_pc-hypo-p.T.treatment_of_manifestations_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Speech</b>
|
||
</td><td headers="hd_h_pc-hypo-p.T.treatment_of_manifestations_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Speech/language eval</td><td headers="hd_h_pc-hypo-p.T.treatment_of_manifestations_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Consider involving speech therapist & OT to improve communication skills.</td></tr><tr><td headers="hd_h_pc-hypo-p.T.treatment_of_manifestations_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Respiratory</b>
|
||
</td><td headers="hd_h_pc-hypo-p.T.treatment_of_manifestations_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Manage pulmonary complications; treatment of respiratory infections</td><td headers="hd_h_pc-hypo-p.T.treatment_of_manifestations_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Per treating pulmonologist</td></tr><tr><td headers="hd_h_pc-hypo-p.T.treatment_of_manifestations_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Neurodevelopmental</b>
|
||
</td><td headers="hd_h_pc-hypo-p.T.treatment_of_manifestations_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Early intervention / individual education program based on needs</td><td headers="hd_h_pc-hypo-p.T.treatment_of_manifestations_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">See <a href="#pc-hypo-p.Developmental_Delay__Intellect">Developmental Delay / Intellectual Disability Management Issues</a>.</td></tr></tbody></table></div><div><div><dl class="temp-labeled-list small"><dt></dt><dd><div><p class="no_margin">NG = nasogastric, OT = occupational therapy, PT = physical therapy</p></div></dd></dl></div></div></div><div id="pc-hypo-p.Developmental_Delay__Intellect"><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> Referral to an early intervention program is recommended for access to occupational, physical, speech, and feeding therapy as well as infant mental health services, special educators, and sensory impairment specialists. 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>Individualized education plan (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>Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.</div></li><li class="half_rhythm"><div>A vision consultant 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><div id="pc-hypo-p.Surveillance"><h3>Surveillance</h3><div id="pc-hypo-p.T.recommended_surveillance_for" class="table"><h3><span class="label">Table 6. </span></h3><div class="caption"><p>Recommended Surveillance for Individuals with <i>TSEN54</i> Pontocerebellar Hypoplasia Type 2</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK9673/table/pc-hypo-p.T.recommended_surveillance_for/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__pc-hypo-p.T.recommended_surveillance_for_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_pc-hypo-p.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_pc-hypo-p.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_pc-hypo-p.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_pc-hypo-p.T.recommended_surveillance_for_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Respiratory</b>
|
||
</td><td headers="hd_h_pc-hypo-p.T.recommended_surveillance_for_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Assess airway & pulmonary function & secretion management.</td><td headers="hd_h_pc-hypo-p.T.recommended_surveillance_for_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Monitoring of respiratory function may be needed to detect sleep apnea.</td></tr><tr><td headers="hd_h_pc-hypo-p.T.recommended_surveillance_for_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Gastrointestinal/</b>
|
||
<br />
|
||
<b>Feeding</b>
|
||
</td><td headers="hd_h_pc-hypo-p.T.recommended_surveillance_for_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<ul><li class="half_rhythm"><div>Aspiration risk & nutritional status</div></li><li class="half_rhythm"><div>Monitor for constipation.</div></li></ul>
|
||
</td><td headers="hd_h_pc-hypo-p.T.recommended_surveillance_for_1_1_1_3" rowspan="5" colspan="1" style="text-align:left;vertical-align:middle;">Annually; more frequently if needed</td></tr><tr><td headers="hd_h_pc-hypo-p.T.recommended_surveillance_for_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_pc-hypo-p.T.recommended_surveillance_for_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<ul><li class="half_rhythm"><div>PT/OT eval</div></li><li class="half_rhythm"><div>Assessment for contractures, scoliosis, & foot deformities.</div></li><li class="half_rhythm"><div>Hip/spine x-rays</div></li></ul>
|
||
</td></tr><tr><td headers="hd_h_pc-hypo-p.T.recommended_surveillance_for_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_pc-hypo-p.T.recommended_surveillance_for_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<ul><li class="half_rhythm"><div>Monitor those w/seizures as clinically indicated.</div></li><li class="half_rhythm"><div>Monitor for dystonia & choreic movements.</div></li></ul>
|
||
</td></tr><tr><td headers="hd_h_pc-hypo-p.T.recommended_surveillance_for_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Development</b>
|
||
</td><td headers="hd_h_pc-hypo-p.T.recommended_surveillance_for_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Monitor developmental milestones.</td></tr><tr><td headers="hd_h_pc-hypo-p.T.recommended_surveillance_for_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Family support</b>
|
||
<br />
|
||
<b>& resources</b>
|
||
</td><td headers="hd_h_pc-hypo-p.T.recommended_surveillance_for_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Family needs</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="pc-hypo-p.AgentsCircumstances_to_Avoid"><h3>Agents/Circumstances to Avoid</h3><p>Although hyperthermic episodes have been documented in individuals with PCH2, no special risk appears to be associated with generalized anesthesia.</p></div><div id="pc-hypo-p.Evaluation_of_Relatives_at_Ris"><h3>Evaluation of Relatives at Risk</h3><p>See <a href="#pc-hypo-p.Related_Genetic_Counseling_Iss">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="pc-hypo-p.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="pc-hypo-p.Genetic_Counseling"><h2 id="_pc-hypo-p_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="pc-hypo-p.Mode_of_Inheritance"><h3>Mode of Inheritance</h3><p><i>TSEN54</i> pontocerebellar hypoplasia (<i>TSEN54</i>-PCH) is inherited in an <a class="def" href="/books/n/gene/glossary/def-item/autosomal-recessive/">autosomal recessive</a> manner.</p></div><div id="pc-hypo-p.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., presumed to be carriers of one <i>TSEN54</i> <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a> based on family history).</div></li><li class="half_rhythm"><div>Molecular genetic testing is recommended for the parents of a <a class="def" href="/books/n/gene/glossary/def-item/proband/">proband</a> to confirm that both parents are <a class="def" href="/books/n/gene/glossary/def-item/heterozygous/">heterozygous</a> for a <i>TSEN54</i> <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a> and allow reliable <a class="def" href="/books/n/gene/glossary/def-item/recurrence-risk/">recurrence risk</a> assessment. (Although a <a class="def" href="/books/n/gene/glossary/def-item/de-novo/"><i>de novo</i></a> pathogenic variant has not been reported in <i>TSEN54</i>-PCH to date, <i>de novo</i> variants are known to occur at a low but appreciable rate in <a class="def" href="/books/n/gene/glossary/def-item/autosomal-recessive/">autosomal recessive</a> disorders [<a class="bk_pop" href="#pc-hypo-p.REF.j_nsson.2017.519">Jónsson et al 2017</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>If both parents are known to be <a class="def" href="/books/n/gene/glossary/def-item/heterozygous/">heterozygous</a> for a <i>TSEN54</i> <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a>, each sib of an affected individual has at conception 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> Individuals with <i>TSEN54</i>-PCH are not likely to have offspring because of severe intellectual disability and the likelihood of death before the age of fertility.</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>TSEN54</i> <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a>.</p></div><div id="pc-hypo-p.Carrier_Detection"><h3>Carrier Detection</h3><p>Carrier testing for at-risk relatives requires prior identification of the <i>TSEN54</i> pathogenic variants in the family.</p></div><div id="pc-hypo-p.Related_Genetic_Counseling_Iss"><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>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="#pc-hypo-p.REF.huang.2022.389">Huang et al [2022]</a>.</p></div><div id="pc-hypo-p.Prenatal_Testing_and_Preimplan"><h3>Prenatal Testing and Preimplantation Genetic Testing</h3><p>Once the <i>TSEN54</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> 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="pc-hypo-p.Resources"><h2 id="_pc-hypo-p_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 Library of Medicine Genetics Home Reference</b>
|
||
</div><div>
|
||
<a href="http://ghr.nlm.nih.gov/condition/pontocerebellar-hypoplasia" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">Pontocerebellar hypoplasia</a>
|
||
</div></li></ul>
|
||
</div><div id="pc-hypo-p.Molecular_Genetics"><h2 id="_pc-hypo-p_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="pc-hypo-p.molgen.TA" class="table"><h3><span class="label">Table A.</span></h3><div class="caption"><p>TSEN54 Pontocerebellar Hypoplasia: Genes and Databases</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK9673/table/pc-hypo-p.molgen.TA/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__pc-hypo-p.molgen.TA_lrgtbl__"><table class="no_bottom_margin"><tbody><tr><th id="hd_b_pc-hypo-p.molgen.TA_1_1_1_1" rowspan="1" colspan="1" style="vertical-align:top;">Gene</th><th id="hd_b_pc-hypo-p.molgen.TA_1_1_1_2" rowspan="1" colspan="1" style="vertical-align:top;">Chromosome Locus</th><th id="hd_b_pc-hypo-p.molgen.TA_1_1_1_3" rowspan="1" colspan="1" style="vertical-align:top;">Protein</th><th id="hd_b_pc-hypo-p.molgen.TA_1_1_1_4" rowspan="1" colspan="1" style="vertical-align:top;">Locus-Specific Databases</th><th id="hd_b_pc-hypo-p.molgen.TA_1_1_1_5" rowspan="1" colspan="1" style="vertical-align:top;">HGMD</th><th id="hd_b_pc-hypo-p.molgen.TA_1_1_1_6" rowspan="1" colspan="1" style="vertical-align:top;">ClinVar</th></tr><tr><td headers="hd_b_pc-hypo-p.molgen.TA_1_1_1_1" rowspan="1" colspan="1" style="vertical-align:top;">
|
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<a href="/gene/283989" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=gene">
|
||
<i>TSEN54</i>
|
||
</a>
|
||
</td><td headers="hd_b_pc-hypo-p.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=283989" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">17q25<wbr style="display:inline-block"></wbr>.1</a>
|
||
</td><td headers="hd_b_pc-hypo-p.molgen.TA_1_1_1_3" rowspan="1" colspan="1" style="vertical-align:top;">
|
||
<a href="http://www.uniprot.org/uniprot/Q7Z6J9" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">tRNA-splicing endonuclease subunit Sen54</a>
|
||
</td><td headers="hd_b_pc-hypo-p.molgen.TA_1_1_1_4" rowspan="1" colspan="1" style="vertical-align:top;">
|
||
<a href="http://databases.lovd.nl/shared/genes/TSEN54" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">TSEN54 database</a>
|
||
</td><td headers="hd_b_pc-hypo-p.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=TSEN54" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">TSEN54</a>
|
||
</td><td headers="hd_b_pc-hypo-p.molgen.TA_1_1_1_6" rowspan="1" colspan="1" style="vertical-align:top;">
|
||
<a href="https://www.ncbi.nlm.nih.gov/clinvar/?term=TSEN54[gene]" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">TSEN54</a>
|
||
</td></tr></tbody></table></div><div><div><dl class="temp-labeled-list small"><dt></dt><dd><div id="pc-hypo-p.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="pc-hypo-p.molgen.TB" class="table"><h3><span class="label">Table B.</span></h3><div class="caption"><p>OMIM Entries for TSEN54 Pontocerebellar Hypoplasia (<a href="/omim/225753,277470,608755,610204" 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/NBK9673/table/pc-hypo-p.molgen.TB/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__pc-hypo-p.molgen.TB_lrgtbl__"><table><tbody><tr><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
||
<a href="/omim/225753" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=omim">225753</a></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">PONTOCEREBELLAR HYPOPLASIA, TYPE 4; PCH4</td></tr><tr><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
||
<a href="/omim/277470" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=omim">277470</a></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">PONTOCEREBELLAR HYPOPLASIA, TYPE 2A; PCH2A</td></tr><tr><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
||
<a href="/omim/608755" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=omim">608755</a></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">tRNA SPLICING ENDONUCLEASE, SUBUNIT 54; TSEN54</td></tr><tr><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
||
<a href="/omim/610204" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=omim">610204</a></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">PONTOCEREBELLAR HYPOPLASIA, TYPE 5; PCH5</td></tr></tbody></table></div></div><div id="pc-hypo-p.Molecular_Pathogenesis"><h3>Molecular Pathogenesis</h3><p>The genes of the TSEN complex encode subunits of tRNA <a class="def" href="/books/n/gene/glossary/def-item/splicing/">splicing</a> endonuclease. The tRNA splicing endonuclease (TSEN) complex has a role in RNA processing [<a class="bk_pop" href="#pc-hypo-p.REF.paushkin.2004.311">Paushkin et al 2004</a>, <a class="bk_pop" href="#pc-hypo-p.REF.trotta.2006.375">Trotta et al 2006</a>]:</p><ul><li class="half_rhythm"><div>It is involved in tRNA maturation; 6% of human tRNAs carry an <a class="def" href="/books/n/gene/glossary/def-item/intron/">intron</a> in a premature state that is spliced out by the TSEN.</div></li><li class="half_rhythm"><div>The TSEN complex is also involved in <a class="def" href="/books/n/gene/glossary/def-item/mrna/">mRNA</a> 3' end formation. The precise role of the TSEN complex in this process remains elusive; however, it is known that in vitro knockdown of TSEN2 protein leads to impaired mRNA 3' end formation.</div></li></ul><p>The TSEN complex comprises four different subunits: two catalytic subunits encoded by <i>TSEN2</i> and <i>TSEN34</i>; and two structural subunits encoded by<i>TSEN15</i> and <i>TSEN54</i>.</p><p><b>Mechanism of disease causation.</b> Because individuals with <a class="def" href="/books/n/gene/glossary/def-item/nonsense-variant/">nonsense</a> variants are more seriously affected than those with <a class="def" href="/books/n/gene/glossary/def-item/missense/">missense</a> variants, the authors suggest that pathogenic variants lead to loss of function or reduced function of <i>TSEN54</i>.</p><div id="pc-hypo-p.T.notable_tsen54_pathogenic_va" class="table"><h3><span class="label">Table 7. </span></h3><div class="caption"><p>Notable <i>TSEN54</i> Pathogenic Variants</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK9673/table/pc-hypo-p.T.notable_tsen54_pathogenic_va/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__pc-hypo-p.T.notable_tsen54_pathogenic_va_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_pc-hypo-p.T.notable_tsen54_pathogenic_va_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Reference Sequences</th><th id="hd_h_pc-hypo-p.T.notable_tsen54_pathogenic_va_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_pc-hypo-p.T.notable_tsen54_pathogenic_va_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_pc-hypo-p.T.notable_tsen54_pathogenic_va_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_pc-hypo-p.T.notable_tsen54_pathogenic_va_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_207346.2" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">NM_207346<wbr style="display:inline-block"></wbr>.2</a>
|
||
<br />
|
||
<a href="https://www.ncbi.nlm.nih.gov/protein/NP_997229.2" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">NP_997229<wbr style="display:inline-block"></wbr>.2</a>
|
||
</td><td headers="hd_h_pc-hypo-p.T.notable_tsen54_pathogenic_va_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">c.919G>T</td><td headers="hd_h_pc-hypo-p.T.notable_tsen54_pathogenic_va_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">p.Ala307Ser</td><td headers="hd_h_pc-hypo-p.T.notable_tsen54_pathogenic_va_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Accounts for ~88% of PCH2 [<a class="bk_pop" href="#pc-hypo-p.REF.budde.2008.1113">Budde et al 2008</a>, <a class="bk_pop" href="#pc-hypo-p.REF.namavar.2011.143">Namavar et al 2011</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="pc-hypo-p.Chapter_Notes"><h2 id="_pc-hypo-p_Chapter_Notes_">Chapter Notes</h2><div id="pc-hypo-p.Author_History"><h3>Author History</h3><p>Frank Baas, MD, PhD (2009-present)<br />Peter G Barth, MD, PhD; University of Amsterdam (2009-2020)<br />Veerle RC Eggens, MSc; University of Amsterdam (2009-2020)<br />Yasmin Namavar, MSc; University of Amsterdam (2009-2020)<br />Tessa van Dijk, MD (2020-present)</p></div><div id="pc-hypo-p.Revision_History"><h3>Revision History</h3><ul><li class="half_rhythm"><div>28 May 2020 (bp) Comprehensive update posted live</div></li><li class="half_rhythm"><div>14 July 2016 (pgb) Revision: clarification of muscle problem in PCH2</div></li><li class="half_rhythm"><div>18 February 2016 (pgb) Revision: Agents/Circumstances to Avoid</div></li><li class="half_rhythm"><div>24 October 2013 (me) Comprehensive update posted live</div></li><li class="half_rhythm"><div>22 September 2009 (cd) Revision: <a class="def" href="/books/n/gene/glossary/def-item/sequence-analysis/">sequence analysis</a> and <a class="def" href="/books/n/gene/glossary/def-item/prenatal-testing/">prenatal testing</a> is available clinically for <i>TSEN2</i> and <i>TSEN34</i> pathogenic variants.</div></li><li class="half_rhythm"><div>8 September 2009 (me) Review posted live</div></li><li class="half_rhythm"><div>1 May 2009 (fb) Original submission</div></li></ul></div></div><div id="pc-hypo-p.References"><h2 id="_pc-hypo-p_References_">References</h2><div id="pc-hypo-p.Literature_Cited"><h3>Literature Cited</h3><ul class="simple-list"><li class="half_rhythm"><div class="bk_ref" id="pc-hypo-p.REF.barth.2007.373">Barth PG, Aronica E, de Vries L, Nikkels PG, Scheper W, Hoozemans JJ, Poll-The BT, Troost D. Pontocerebellar hypoplasia type 2: a neuropathological update. <span><span class="ref-journal">Acta Neuropathol (Berl). </span>2007;<span class="ref-vol">114</span>:373–86.</span> [<a href="/pmc/articles/PMC2039791/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC2039791</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/17641900" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 17641900</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="pc-hypo-p.REF.barth.1995.311">Barth PG, Blennow G, Lenard HG, Begeer JH, van der Kley JM, Hanefeld F, Peters ACB, Valk J. The syndrome of autosomal recessive pontocerebellar hypoplasia, microcephaly and extrapyramidal dyskinesia (pontocerebellar hypoplasia type 2): compiled data from ten pedigrees. <span><span class="ref-journal">Neurology. </span>1995;<span class="ref-vol">45</span>:311–7.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/7854532" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 7854532</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="pc-hypo-p.REF.budde.2008.1113">Budde BS, Namavar Y, Barth PG, Poll-The BT, Nürnberg G, Becker C, van Ruissen F, Weterman MA, Fluiter K, te Beek ET, Aronica E, van der Knaap MS, Höhne W, Toliat MR, Crow YJ, Steinling M, Voit T, Roelenso F, Brussel W, Brockmann K, Kyllerman M, Boltshauser E, Hammersen G, Willemsen M, Basel-Vanagaite L, Krägeloh-Mann I, de Vries LS, Sztriha L, Muntoni F, Ferrie CD, Battini R, Hennekam RC, Grillo E, Beemer FA, Stoets LM, Wollnik B, Nürnberg P, Baas F. tRNA splicing endonuclease mutations cause pontocerebellar hypoplasia. <span><span class="ref-journal">Nat Genet. </span>2008;<span class="ref-vol">40</span>:1113–8.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/18711368" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 18711368</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="pc-hypo-p.REF.forman.2005.847">Forman MS, Squier W, Dobyns WB, Golden JA. Genotypically defined lissencephalies show distinct pathologies. <span><span class="ref-journal">J Neuropathol Exp Neurol. </span>2005;<span class="ref-vol">64</span>:847–57.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/16215456" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 16215456</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="pc-hypo-p.REF.huang.2022.389">Huang SJ, Amendola LM, Sternen DL. Variation among DNA banking consent forms: points for clinicians to bank on. <span><span class="ref-journal">J Community Genet. </span>2022;<span class="ref-vol">13</span>:389–97.</span> [<a href="/pmc/articles/PMC9314484/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC9314484</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/35834113" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 35834113</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="pc-hypo-p.REF.j_nsson.2017.519">Jónsson H, Sulem P, Kehr B, Kristmundsdottir S, Zink F, Hjartarson E, Hardarson MT, Hjorleifsson KE, Eggertsson HP, Gudjonsson SA, Ward LD, Arnadottir GA, Helgason EA, Helgason H, Gylfason A, Jonasdottir A, Jonasdottir A, Rafnar T, Frigge M, Stacey SN, Th Magnusson O, Thorsteinsdottir U, Masson G, Kong A, Halldorsson BV, Helgason A, Gudbjartsson DF, Stefansson K. Parental influence on human germline de novo mutations in 1,548 trios from Iceland. <span><span class="ref-journal">Nature. </span>2017;<span class="ref-vol">549</span>:519–22.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/28959963" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 28959963</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="pc-hypo-p.REF.namavar.2011.143">Namavar Y, Barth PG, Kasher PR, van Ruissen F, Brockmann K, Bernert G, Writzl K, Ventura K, Cheng EY, Ferriero DM, Basel-Vanagaite L, Eggens VR, Krägeloh-Mann I, De Meirleir L, King M, Graham JM Jr, von Moers A, Knoers N, Sztriha L, Korinthenberg R, Consortium PCH, Dobyns WB, Baas F, Poll-The BT. Clinical, neuroradiological and genetic findings in pontocerebellar hypoplasia. <span><span class="ref-journal">Brain. </span>2011;<span class="ref-vol">134</span>:143–56.</span> [<a href="/pmc/articles/PMC9136852/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC9136852</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/20952379" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 20952379</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="pc-hypo-p.REF.patel.2006.594">Patel MS, Becker LE, Toi A, Armstrong DL, Chitayat D. Severe, fetal-onset form of olivopontocerebellar hypoplasia in three sibs: PCH type 5? <span><span class="ref-journal">Am J Med Genet A. </span>2006;<span class="ref-vol">140</span>:594–603.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/16470708" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 16470708</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="pc-hypo-p.REF.paushkin.2004.311">Paushkin SV, Patel M, Furia BS, Peltz SW, Trotta CR. Identification of a human endonuclease complex reveals a link between tRNA splicing and pre-mRNA 3’end formation. <span><span class="ref-journal">Cell. </span>2004;<span class="ref-vol">117</span>:311–21.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/15109492" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 15109492</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="pc-hypo-p.REF.pierson.2016.305">Pierson CR, Al Sufiani F. Preterm birth and cerebellar neuropathology. <span><span class="ref-journal">Semin Fetal Neonatal Med. </span>2016;<span class="ref-vol">21</span>:305–11.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/27161081" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 27161081</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="pc-hypo-p.REF.richards.2015.405">Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. <span><span class="ref-journal">Genet Med. </span>2015;<span class="ref-vol">17</span>:405–24.</span> [<a href="/pmc/articles/PMC4544753/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC4544753</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/25741868" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 25741868</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="pc-hypo-p.REF.s_nchezalbisua.2014.70">Sánchez-Albisua I, Frölich S, Barth PG, Steinlin M, Krägeloh-Mann I. Natural course of pontocerebellar hypoplasia type 2A. <span><span class="ref-journal">Orphanet J Rare Dis. </span>2014;<span class="ref-vol">9</span>:70.</span> [<a href="/pmc/articles/PMC4019562/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC4019562</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/24886362" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 24886362</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="pc-hypo-p.REF.steinlin.2007.146">Steinlin M, Klein A, Haas-Lude K, Zafeiriou D, Strozzi S, Müller T, Gubser-Mercati D, Schmitt Mechelke T, Krägeloh-Mann I, Boltshauser E. Pontocerebellar hypoplasia type 2: variability in clinical and imaging findings. <span><span class="ref-journal">Eur J Paediatr Neurol. </span>2007;<span class="ref-vol">11</span>:146–52.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/17320436" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 17320436</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="pc-hypo-p.REF.stenson.2020.1197">Stenson PD, Mort M, Ball EV, Chapman M, Evans K, Azevedo L, Hayden M, Heywood S, Millar DS, Phillips AD, Cooper DN. The Human Gene Mutation Database (HGMD®): optimizing its use in a clinical diagnostic or research setting. <span><span class="ref-journal">Hum Genet. </span>2020;<span class="ref-vol">139</span>:1197–207.</span> [<a href="/pmc/articles/PMC7497289/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC7497289</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/32596782" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 32596782</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="pc-hypo-p.REF.trotta.2006.375">Trotta CR, Paushkin SV, Patel M, Li H, Peltz SW. Cleavage of pre-tRNAs by the splicing endonuclease requires a composite active site. <span><span class="ref-journal">Nature. </span>2006;<span class="ref-vol">441</span>:375–7.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/16710424" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 16710424</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="pc-hypo-p.REF.van_dijk.2018.92">van Dijk T, Baas F, Barth PG, Poll-The BT. What's new in pontocerebellar hypoplasia? An update on genes and subtypes. <span><span class="ref-journal">Orphanet J Rare Dis. </span>2018;<span class="ref-vol">13</span>:92.</span> [<a href="/pmc/articles/PMC6003036/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC6003036</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/29903031" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 29903031</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="pc-hypo-p.REF.volpe.2009.1085">Volpe JJ. Cerebellum of the premature infant: rapidly developing, vulnerable, clinically important. <span><span class="ref-journal">J Child Neurol. </span>2009;<span class="ref-vol">24</span>:1085–104.</span> [<a href="/pmc/articles/PMC2799249/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC2799249</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/19745085" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 19745085</span></a>]</div></li></ul></div></div><div id="bk_toc_contnr"></div></div></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/NBK9673/?report=reader">PubReader</a></li><li><a href="/books/NBK9673/?report=printable">Print View</a></li><li><a data-jig="ncbidialog" href="#_ncbi_dlg_citbx_NBK9673" data-jigconfig="width:400,modal:true">Cite this Page</a><div id="_ncbi_dlg_citbx_NBK9673" style="display:none" title="Cite this Page"><div class="bk_tt">van Dijk T, Baas F. TSEN54 Pontocerebellar Hypoplasia. 2009 Sep 8 [Updated 2020 May 28]. 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<a href="https://www.ncbi.nlm.nih.gov/gtr/tests/?term=283989[geneid]" ref="pagearea=document-links&targetsite=external&targetcat=link&targettype=uri&link_id=tests_in_gtr_by_gene">TSEN54</a>
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<a href="https://www.ncbi.nlm.nih.gov/gtr/tests/?term=80746[geneid]" ref="pagearea=document-links&targetsite=external&targetcat=link&targettype=uri&link_id=tests_in_gtr_by_gene">TSEN2</a>
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</li><li>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar/?term=NBK9673+AND+genereviews[submitter]" ref="pagearea=document-links&targetsite=external&targetcat=link&targettype=uri">Variations from this GeneReview in ClinVar</a>
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