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<meta name="robots" content="INDEX,FOLLOW,NOARCHIVE" /><meta name="citation_inbook_title" content="GeneReviews® [Internet]" /><meta name="citation_title" content="NGLY1-Related Congenital Disorder of Deglycosylation" /><meta name="citation_publisher" content="University of Washington, Seattle" /><meta name="citation_date" content="2018/02/08" /><meta name="citation_author" content="Christina Lam" /><meta name="citation_author" content="Lynne Wolfe" /><meta name="citation_author" content="Anna Need" /><meta name="citation_author" content="Vandana Shashi" /><meta name="citation_author" content="Gregory Enns" /><meta name="citation_pmid" content="29419975" /><meta name="citation_fulltext_html_url" content="https://www.ncbi.nlm.nih.gov/books/NBK481554/" /><meta name="citation_keywords" content="NGLY1-CDDG" /><meta name="citation_keywords" content="NGLY1 Deficiency" /><meta name="citation_keywords" content="NGLY1-Related Disorder" /><meta name="citation_keywords" content="NGLY1-CDDG" /><meta name="citation_keywords" content="NGLY1 Deficiency" /><meta name="citation_keywords" content="NGLY1-Related Disorder" /><meta name="citation_keywords" content="Peptide-N(4)-(N-acetyl-beta-glucosaminyl)asparagine amidase" /><meta name="citation_keywords" content="NGLY1" /><meta name="citation_keywords" content="NGLY1-Related Congenital Disorder of Deglycosylation" /><link rel="schema.DC" href="http://purl.org/DC/elements/1.0/" /><meta name="DC.Title" content="NGLY1-Related Congenital Disorder of Deglycosylation" /><meta name="DC.Type" content="Text" /><meta name="DC.Publisher" content="University of Washington, Seattle" /><meta name="DC.Contributor" content="Christina Lam" /><meta name="DC.Contributor" content="Lynne Wolfe" /><meta name="DC.Contributor" content="Anna Need" /><meta name="DC.Contributor" content="Vandana Shashi" /><meta name="DC.Contributor" content="Gregory Enns" /><meta name="DC.Date" content="2018/02/08" /><meta name="DC.Identifier" content="https://www.ncbi.nlm.nih.gov/books/NBK481554/" /><meta name="description" content="Individuals with NGLY1-related congenital disorder of deglycosylation (NGLY1-CDDG) typically display a clinical tetrad of developmental delay / intellectual disability in the mild to profound range, hypo- or alacrima, elevated liver transaminases that may spontaneously resolve in childhood, and a complex hyperkinetic movement disorder that can include choreiform, athetoid, dystonic, myoclonic, action tremor, and dysmetric movements. 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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="#__NBK481554_dtls__">Show details</a><div style="display:none" class="ui-widget" id="__NBK481554_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/nfix-malan/" title="Previous page in this title">< Prev</a><a class="active page_link next" href="/books/n/gene/nkx2-1-dis/" 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="_NBK481554_"><span class="title" itemprop="name"><i>NGLY1</i>-Related Congenital Disorder of Deglycosylation</span></h1><div itemprop="alternativeHeadline" class="subtitle whole_rhythm">Synonyms: NGLY1-CDDG, NGLY1 Deficiency, <i>NGLY1</i>-Related Disorder</div><p class="contrib-group"><span itemprop="author">Christina Lam</span>, MD, FACMG, <span itemprop="author">Lynne Wolfe</span>, MS, CRNP, <span itemprop="author">Anna Need</span>, PhD, <span itemprop="author">Vandana Shashi</span>, MD, and <span itemprop="author">Gregory Enns</span>, MD, FACMG.</p><a data-jig="ncbitoggler" href="#__NBK481554_ai__" style="border:0;text-decoration:none">Author Information and Affiliations</a><div style="display:none" class="ui-widget" id="__NBK481554_ai__"><div class="contrib half_rhythm"><span itemprop="author">Christina Lam</span>, MD, FACMG<div class="affiliation small">University of Washington
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Seattle Children's Hospital
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Seattle, Washington<div><span class="email-label">Email: </span><a href="mailto:dev@null" data-email="ude.wu@2maltc" class="oemail">ude.wu@2maltc</a></div></div></div><div class="contrib half_rhythm"><span itemprop="author">Lynne Wolfe</span>, MS, CRNP<div class="affiliation small">National Institutes of Health
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Bethesda, Maryland<div><span class="email-label">Email: </span><a href="mailto:dev@null" data-email="vog.hin.liam@aleflow" class="oemail">vog.hin.liam@aleflow</a></div></div></div><div class="contrib half_rhythm"><span itemprop="author">Anna Need</span>, PhD<div class="affiliation small">Imperial College London
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London, United Kingdom<div><span class="email-label">Email: </span><a href="mailto:dev@null" data-email="ku.ca.lairepmi@deen.a" class="oemail">ku.ca.lairepmi@deen.a</a></div></div></div><div class="contrib half_rhythm"><span itemprop="author">Vandana Shashi</span>, MD<div class="affiliation small">Duke University
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Durham, North Carolina<div><span class="email-label">Email: </span><a href="mailto:dev@null" data-email="ude.ekud@ihsahs.anadnav" class="oemail">ude.ekud@ihsahs.anadnav</a></div></div></div><div class="contrib half_rhythm"><span itemprop="author">Gregory Enns</span>, MD, FACMG<div class="affiliation small">Stanford University
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Stanford, California<div><span class="email-label">Email: </span><a href="mailto:dev@null" data-email="ude.drofnats@snneg" class="oemail">ude.drofnats@snneg</a></div></div></div></div><p class="small">Initial Posting: <span itemprop="datePublished">February 8, 2018</span>.</p><p><em>Estimated reading time: 23 minutes</em></p></div><div class="jig-ncbiinpagenav body-content whole_rhythm" data-jigconfig="allHeadingLevels: ['h2'],smoothScroll: false" itemprop="text"><div id="ngly1-cddg.Summary" itemprop="description"><h2 id="_ngly1-cddg_Summary_">Summary</h2><div><h4 class="inline">Clinical characteristics.</h4><p>Individuals with <i>NGLY1</i>-related <a class="def" href="/books/n/gene/glossary/def-item/congenital/">congenital</a> disorder of deglycosylation (NGLY1-CDDG) typically display a clinical tetrad of developmental delay / intellectual disability in the mild to profound range, hypo- or alacrima, elevated liver transaminases that may spontaneously resolve in childhood, and a complex hyperkinetic movement disorder that can include choreiform, athetoid, dystonic, myoclonic, action tremor, and dysmetric movements. About half of affected individuals will develop clinical seizures. Other findings may include obstructive and/or central sleep apnea, oral motor defects that affect feeding ability, auditory neuropathy, constipation, scoliosis, and peripheral neuropathy.</p></div><div><h4 class="inline">Diagnosis/testing.</h4><p>The diagnosis of NGLY1-CDDG is established in a <a class="def" href="/books/n/gene/glossary/def-item/proband/">proband</a> by the identification of <a class="def" href="/books/n/gene/glossary/def-item/biallelic/">biallelic</a> pathogenic variants in <i>NGLY1</i> on <a class="def" href="/books/n/gene/glossary/def-item/molecular-genetic-testing/">molecular genetic testing</a>. Typical serum screening tests for <a class="def" href="/books/n/gene/glossary/def-item/congenital/">congenital</a> disorders of glycosylation (i.e., analysis of serum transferrin glycoforms, N and O glycan profiling) will NOT reliably detect NGLY1-CDDG.</p></div><div><h4 class="inline">Management.</h4><p><i>Treatment of manifestations:</i> Lubricating eye drops and/or bland ointments for hypolacrima; feeding therapy and/or supplemental tube feeding for those with oromotor deficits and feeding difficulties; adequate access to water and a cool environment (including a cooling vest for those who live in hot climates) for hypohydrosis; vitamin D supplementation for those with vitamin D deficiency; evaluation by a developmental pediatrician and supportive therapies for developmental and cognitive issues; standard treatment for hearing loss, sleep apnea, constipation, scoliosis, and seizure disorder; consideration of referral to a hematologist for abnormal hematologic studies; consideration of referral to a gastroenterologist for elevated liver transaminases.</p><p><i>Surveillance:</i> Annual follow up by a pediatrician/internist, rehabilitation medicine specialist, ophthalmologist, neurologist, and nutritionist is recommended. Periodic evaluation by a developmental pediatrician, gastroenterologist/hepatologist, and audiologist should be considered.</p><p><i>Agents/circumstances to avoid:</i> Hot environment in those with hypohydrosis.</p></div><div><h4 class="inline">Genetic counseling.</h4><p>NGLY1-CDDG is inherited in an <a class="def" href="/books/n/gene/glossary/def-item/autosomal-recessive/">autosomal recessive</a> manner. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic <a class="def" href="/books/n/gene/glossary/def-item/carrier/">carrier</a>, and a 25% chance of being unaffected and not a carrier. Carrier testing for at-risk relatives, <a class="def" href="/books/n/gene/glossary/def-item/prenatal-testing/">prenatal testing</a> for pregnancies at increased risk, and <a class="def" href="/books/n/gene/glossary/def-item/preimplantation-genetic-testing/">preimplantation genetic testing</a> are possible if the pathogenic variants in the family are known.</p></div></div><div id="ngly1-cddg.Diagnosis"><h2 id="_ngly1-cddg_Diagnosis_">Diagnosis</h2><p>Formal diagnostic criteria have not been established.</p><div id="ngly1-cddg.Suggestive_Findings"><h3>Suggestive Findings</h3><p><i>NGLY1</i>-related <a class="def" href="/books/n/gene/glossary/def-item/congenital/">congenital</a> disorder of deglycosylation (NGLY1-CDDG) <b>should be suspected</b> in individuals with the following clinical features and supportive laboratory findings.</p><p><b>Clinical features</b> include:</p><ul><li class="half_rhythm"><div>Developmental delay / intellectual disability, most often in the severe to profound range</div></li><li class="half_rhythm"><div>Hyperkinetic movement disorder</div></li><li class="half_rhythm"><div>Hypo- or alacrima</div></li></ul><p><b>Supportive laboratory findings</b> include elevated ALT and AST during early childhood that spontaneously normalize.</p><p>Note: Typical serum screening tests for <a class="def" href="/books/n/gene/glossary/def-item/congenital/">congenital</a> disorders of glycosylation (i.e., analysis of serum transferrin glycoforms, N and O glycan profiling) will NOT reliably detect NGLY1-CDDG (see <a href="#ngly1-cddg.Clinical_Description">Clinical Description</a>, <b>Biochemical</b>).</p></div><div id="ngly1-cddg.Establishing_the_Diagnosis"><h3>Establishing the Diagnosis</h3><p>The diagnosis of NGLY1-CDDG <b>is established</b> in a <a class="def" href="/books/n/gene/glossary/def-item/proband/">proband</a> by the identification of <a class="def" href="/books/n/gene/glossary/def-item/biallelic/">biallelic</a> pathogenic variants in <i>NGLY1</i> on <a class="def" href="/books/n/gene/glossary/def-item/molecular-genetic-testing/">molecular genetic testing</a> (see <a href="/books/NBK481554/table/ngly1-cddg.T.molecular_genetic_testing_u/?report=objectonly" target="object" rid-ob="figobngly1cddgTmoleculargenetictestingu">Table 1</a>).</p><div id="ngly1-cddg.Recommended_Testing"><h4>Recommended Testing</h4><p><b>A <a class="def" href="/books/n/gene/glossary/def-item/multigene-panel/">multigene panel</a></b> that includes <i>NGLY1</i> and other genes of interest (see <a href="#ngly1-cddg.Differential_Diagnosis">Differential Diagnosis</a>) is recommended (see <a href="/books/NBK481554/table/ngly1-cddg.T.molecular_genetic_testing_u/?report=objectonly" target="object" rid-ob="figobngly1cddgTmoleculargenetictestingu">Table 1</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>; thus, clinicians need to determine which multigene panel 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>. (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="ngly1-cddg.Testing_to_Consider"><h4>Testing to Consider</h4><p><b>Comprehensive <a class="def" href="/books/n/gene/glossary/def-item/genomic/">genomic</a> testing</b> (when available) including <a class="def" href="/books/n/gene/glossary/def-item/exome-sequencing/">exome sequencing</a> and <a class="def" href="/books/n/gene/glossary/def-item/genome-sequencing/">genome sequencing</a> may be considered if the <a class="def" href="/books/n/gene/glossary/def-item/phenotype/">phenotype</a> alone is insufficient to support <a class="def" href="/books/n/gene/glossary/def-item/gene/">gene</a>-targeted testing.</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><p><b>Single-<a class="def" href="/books/n/gene/glossary/def-item/gene/">gene</a> testing.</b> Sequence analysis of <i>NGLY1</i> followed by gene-targeted <a class="def" href="/books/n/gene/glossary/def-item/deletion-duplication-analysis/">deletion/duplication analysis</a> (if no <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a> is found) may be considered in a <a class="def" href="/books/n/gene/glossary/def-item/proband/">proband</a> with features that are highly suggestive of NGLY1-CDDG. However, because many of the clinical features overlap with those of other intellectual disability / developmental delay syndromes, a <a class="def" href="/books/n/gene/glossary/def-item/multigene-panel/">multigene panel</a> or comprehensive <a class="def" href="/books/n/gene/glossary/def-item/genomic/">genomic</a> testing are typically used in lieu of single-gene testing.</p><div id="ngly1-cddg.T.molecular_genetic_testing_u" class="table"><h3><span class="label">Table 1. </span></h3><div class="caption"><p>Molecular Genetic Testing Used in <i>NGLY1</i>-Related Congenital Disorder of Deglycosylation</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK481554/table/ngly1-cddg.T.molecular_genetic_testing_u/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__ngly1-cddg.T.molecular_genetic_testing_u_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_ngly1-cddg.T.molecular_genetic_testing_u_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_ngly1-cddg.T.molecular_genetic_testing_u_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Method</th><th id="hd_h_ngly1-cddg.T.molecular_genetic_testing_u_1_1_1_3" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Proportion of Probands with Pathogenic Variants <sup>2</sup> Detectable by Method</th></tr></thead><tbody><tr><td headers="hd_h_ngly1-cddg.T.molecular_genetic_testing_u_1_1_1_1" rowspan="2" scope="row" colspan="1" style="text-align:left;vertical-align:middle;">
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<i>NGLY1</i>
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</td><td headers="hd_h_ngly1-cddg.T.molecular_genetic_testing_u_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_ngly1-cddg.T.molecular_genetic_testing_u_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">46/46</td></tr><tr><td headers="hd_h_ngly1-cddg.T.molecular_genetic_testing_u_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>4</sup></td><td headers="hd_h_ngly1-cddg.T.molecular_genetic_testing_u_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Unknown <sup>5</sup></td></tr></tbody></table></div><div><div><dl class="temp-labeled-list small"><dt>1. </dt><dd><div id="ngly1-cddg.TF.1.1"><p class="no_margin">See <a href="/books/NBK481554/#ngly1-cddg.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="ngly1-cddg.TF.1.2"><p class="no_margin">See <a href="#ngly1-cddg.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="ngly1-cddg.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="ngly1-cddg.TF.1.4"><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>5. </dt><dd><div id="ngly1-cddg.TF.1.5"><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="ngly1-cddg.Clinical_Characteristics"><h2 id="_ngly1-cddg_Clinical_Characteristics_">Clinical Characteristics</h2><div id="ngly1-cddg.Clinical_Description"><h3>Clinical Description</h3><p><i>NGLY1</i>-related <a class="def" href="/books/n/gene/glossary/def-item/congenital/">congenital</a> disorder of deglycosylation (NGLY1-CDDG) is a multisystemic neurodevelopmental disorder in which individuals most commonly exhibit a tetrad of developmental delay / intellectual disability, hyperkinetic movement disorder, hypolacrima, and elevated transaminases during early childhood [<a class="bk_pop" href="#ngly1-cddg.REF.need.2012.353">Need et al 2012</a>, <a class="bk_pop" href="#ngly1-cddg.REF.enns.2014.751">Enns et al 2014</a>, <a class="bk_pop" href="#ngly1-cddg.REF.heeley.2015.816">Heeley & Shinawi 2015</a>, <a class="bk_pop" href="#ngly1-cddg.REF.caglayan.2015.39">Caglayan et al 2015</a>, <a class="bk_pop" href="#ngly1-cddg.REF.lam.2017.160">Lam et al 2017</a>]. Diagnosis has been achieved at ages ranging from three months to 20 years, mostly through broad molecular testing, such as <a class="def" href="/books/n/gene/glossary/def-item/exome/">exome</a> analysis. While most individuals with NGLY1-CDDG survive into early adulthood, with a relatively stable clinical course [<a class="bk_pop" href="#ngly1-cddg.REF.enns.2014.751">Enns et al 2014</a>, <a class="bk_pop" href="#ngly1-cddg.REF.lam.2017.160">Lam et al 2017</a>], death during infancy from unclear causes has been reported. In addition, an affected child died following an infection complicated by uncontrolled seizure activity [<a class="bk_pop" href="#ngly1-cddg.REF.enns.2014.751">Enns et al 2014</a>], and an affected adolescent died from respiratory failure during a respiratory infection [<a class="bk_pop" href="#ngly1-cddg.REF.caglayan.2015.39">Caglayan et al 2015</a>]. Since so few cases have been identified, understanding of the clinical phenotypic spectrum and natural history continues to evolve.</p><p><b>Growth.</b> In approximately half of individuals with NGLY1-CDDG birth weight is below the tenth centile, while the majority of birth lengths and birth head circumferences are appropriate for gestational age [<a class="bk_pop" href="#ngly1-cddg.REF.lam.2017.160">Lam et al 2017</a>]. Despite a robust appetite, individuals with <i>NGLY1</i>-CDDG develop failure to thrive with weight affected more than length/height. Acquired microcephaly has also been noted in some [<a class="bk_pop" href="#ngly1-cddg.REF.lam.2017.160">Lam et al 2017</a>].</p><p><b>Development.</b> Developmental delay and/or intellectual disability is seen universally in individuals with NGLY1-CDDG. Severity of delay is broad and ranges from individuals having an IQ below average (70s) to individuals with profound intellectual disability. The majority of individuals are nonverbal or can only use single words or phrase speech. Despite lack of verbal communication, they use and benefit from alternate forms of augmentative communication tools, such as switch boards or electronic tablet-based tools. Affected individuals have a consistent developmental profile on the Vineland Adaptive Behavior Scales, Second Edition, in which individuals have relatively strong socialization skills, followed by communication skills, followed by weaknesses in motor skills with fine motor worse than gross motor skills, reflected in low daily living skills [<a class="bk_pop" href="#ngly1-cddg.REF.lam.2017.160">Lam et al 2017</a>].</p><p><b>Neurologic.</b> Approximately half of affected individuals develop clinical seizures. While most develop myoclonic seizures, documented seizure types also include infantile spasms and atonic, tonic, absence, and gelastic seizures. Age of onset ranges from two months to ten years. In some individuals seizures have been intractable, while in others seizures have been controlled with levetiracetam or valproic acid [<a class="bk_pop" href="#ngly1-cddg.REF.lam.2017.160">Lam et al 2017</a>]. Compared to individuals with seizures of different etiologies, those with NGLY1-CDDG have not been more severely affected by any specific antiepileptic medication.</p><p>In addition, individuals with NGLY1-CDDG universally exhibit a complex hyperkinetic movement disorder that can include choreiform, athetoid, dystonic, myoclonic, action tremor, and dysmetric movements [<a class="bk_pop" href="#ngly1-cddg.REF.lam.2017.160">Lam et al 2017</a>].</p><p>Further findings may include the following:</p><ul><li class="half_rhythm"><div>CSF laboratory results typically demonstrate:</div><ul><li class="half_rhythm"><div>Low total protein (from 8 affected individuals, mean protein level was 11 mg/dL, standard error of the mean [SEM] 1) and albumin (from 9 affected individuals, mean 9 mg/dL, SEM 1);</div></li><li class="half_rhythm"><div>Low CSF/serum albumin ratios (from 9 affected individuals, mean ratio was 3, SEM 1);</div></li><li class="half_rhythm"><div>Low CSF 5-hydroxyindolacetic acid, homovanillic acid, and tetrahydrobiopterin levels, especially in older individuals [<a class="bk_pop" href="#ngly1-cddg.REF.enns.2014.751">Enns et al 2014</a>, <a class="bk_pop" href="#ngly1-cddg.REF.lam.2017.160">Lam et al 2017</a>].</div></li></ul></li><li class="half_rhythm"><div>Brain MRI can show:</div><ul><li class="half_rhythm"><div>Delayed myelination during early childhood (ages 0-5), but not in older individuals;</div></li><li class="half_rhythm"><div>Progressive cerebral and occasional cerebellar atrophy, which correlates with worsening function. In 10/11 affected individuals imaged cerebral volume loss was found; in 4/11 cerebellar volume loss was also seen [<a class="bk_pop" href="#ngly1-cddg.REF.lam.2017.160">Lam et al 2017</a>].</div></li></ul></li><li class="half_rhythm"><div>Brain MRS can be significant for:</div><ul><li class="half_rhythm"><div>Lower N-acetylaspartylglutamate and N-acetylaspartate levels compared to normal;</div></li><li class="half_rhythm"><div>Higher choline and myo-inositol levels, becoming more prominent with increasing age, worsening function, and lower brain volume [<a class="bk_pop" href="#ngly1-cddg.REF.lam.2017.160">Lam et al 2017</a>].</div></li></ul></li><li class="half_rhythm"><div>Nerve conduction studies most often demonstrate an axonal sensorimotor polyneuropathy with additional demyelinative features that are length dependent and appear progressive. Neuropathy has been documented in all nerves tested including the median, ulnar, radial, peroneal, tibial, and sural nerves. Individual testing typically reveals more severe neuropathy in the lower (compared to upper) extremities, with lower amplitudes and slower conduction.</div></li><li class="half_rhythm"><div>Needle electromyogram may show neurogenic findings with varying degrees of acute and chronic changes.</div></li><li class="half_rhythm"><div>QSWEAT testing can show absent sweat response, more frequently in the lower extremities than in the forearm, suggesting a length-dependent neuropathy [<a class="bk_pop" href="#ngly1-cddg.REF.lam.2017.160">Lam et al 2017</a>].</div></li></ul><p><b>Ophthalmologic.</b> Most affected individuals, with the exception of the youngest reported person, have evidence of hypo- or alacrima. Corneal findings include neovascularization, pannus formation, and scarring secondary to hypolacrima. Lagophthalmus, ptosis, exotropia and/or esotropia, optic nerve pallor or atrophy, retinal pigmentary changes including pigmentary granularity and pigmentary retinopathy, and cone dystrophy have been observed in individuals with NGLY1-CDDG [<a class="bk_pop" href="#ngly1-cddg.REF.lam.2017.160">Lam et al 2017</a>].</p><p><b>Audiologic.</b> Tympanometry and behavioral hearing thresholds were normal in the individuals who could tolerate and cooperate with these exams. There is a consistent profile on auditory brain stem evoked response showing dyssynchronous and/or absent transmission through the auditory brain stem and/or eighth nerve in most individuals that appears to worsen with age [<a class="bk_pop" href="#ngly1-cddg.REF.lam.2017.160">Lam et al 2017</a>].</p><p><b>Cardiac.</b> Echocardiogram is normal, and electrocardiogram shows heart rates in the low 100s with a minority of affected individuals with a QTcB >440 ms, but a normal QTcF.</p><p>Note: The QTcB is the standard clinical correction of the QT interval using Bazett's formula, calculated as QT interval divided by square root of the RR interval. The QtcF is the alternative correction based on Fridericia's formula, which is defined as the QT interval divided by the cube root of the RR interval. The QTcB is believed to overestimate the QT prolongation at higher heart rates, and the QTcF may underestimate the QT prolongation at slower heart rates [<a class="bk_pop" href="#ngly1-cddg.REF.fda.2005.61134">FDA 2005</a>].</p><p><b>Sleep.</b> Approximately half of tested individuals with NGLY1-CDDG have also been documented to have mild-to-profound obstructive and/or central sleep apnea [<a class="bk_pop" href="#ngly1-cddg.REF.lam.2017.160">Lam et al 2017</a>].</p><p><b>Feeding.</b> Oral motor defects, including premature spillage, pharyngeal swallow response delays, poor oral bolus formation, weakness of the lips and tongue, dystonic movements of the tongue, and persistent oral reflexes of suckling and suck/swallow are seen in the majority of affected individuals. However, these findings typically do not prohibit oral feeding in the majority of individuals. Enteral feeds have been helpful with nutritional management, although this decision is made on a case-by-case basis [<a class="bk_pop" href="#ngly1-cddg.REF.lam.2017.160">Lam et al 2017</a>].</p><p><b>Gastrointestinal.</b> The majority of affected individuals have some degree of constipation [<a class="bk_pop" href="#ngly1-cddg.REF.enns.2014.751">Enns et al 2014</a>].</p><p>Transaminases (AST and ALT):</p><ul><li class="half_rhythm"><div class="half_rhythm">Are typically elevated and range from just slightly above the upper limit of normal to >1,000 U/L in the first two years of life;</div></li><li class="half_rhythm"><div class="half_rhythm">Usually normalize by age four years without any specific intervention.</div><div class="half_rhythm">Note: In the few liver biopsies performed, findings have been normal or consistent with microvesicular steatosis, ductular proliferation, focal microvacuolation, and micronodular cirrhosis with bands of fibrosis with regenerative nodules.</div></li></ul><p>Total cholesterol, low-density lipoprotein cholesterol, and triglyceride levels are low in about one third of tested individuals, but particle numbers and sizes of HDL, LDL, and VLDL are normal [<a class="bk_pop" href="#ngly1-cddg.REF.lam.2017.160">Lam et al 2017</a>].</p><p>Abdominal ultrasound findings can include splenomegaly, steatosis, coarse or inhomogeneous liver texture, and hepatomegaly.</p><p>Fibroscan scores show evidence of liver fibrosis in a few affected individuals [<a class="bk_pop" href="#ngly1-cddg.REF.lam.2017.160">Lam et al 2017</a>].</p><p><b>Hematologic.</b> Coagulation studies in some individuals can be significant for low protein C, factor II, factor IX, factor XI, and fibrinogen levels. However, significant bleeding or clotting episodes have not yet been reported. Complete blood count is generally unremarkable [<a class="bk_pop" href="#ngly1-cddg.REF.lam.2017.160">Lam et al 2017</a>].</p><p><b>Immunologic.</b> Affected individuals typically are reported to have fewer infections than their peers, with the exception of a few individuals with recurrent, more severe, respiratory infections. Antibody titers indicate that individuals with NGLY1-CDDG appear to respond typically to vaccinations, with the exception of rubella and rubeola vaccinations for which titers exhibited out-of-range elevations or were negative (for rubeola) in a majority of tested individuals [<a class="bk_pop" href="#ngly1-cddg.REF.lam.2017.160">Lam et al 2017</a>].</p><p><b>Musculoskeletal</b> findings include delayed bone age despite a normal endocrine evaluation, low bone density in several individuals with a history of recurrent fractures, joint hypermobility, coxa valga, scoliosis, dislocations or subluxations of the hip or shoulder joints, and sclerosis of the phalanges or tarsal bones [<a class="bk_pop" href="#ngly1-cddg.REF.lam.2017.160">Lam et al 2017</a>]. These findings were present even in affected individuals who were ambulatory.</p><p><b>Biochemical</b> findings include the following:</p><ul><li class="half_rhythm"><div>Carbohydrate-deficient transferrin analysis in blood may show small elevations in mono- and a-oligosaccharides and tri-sialo-oligosaccharides, but not to the levels typically seen in <a href="/books/n/gene/cdg-1a/">PMM2-CDG</a>.</div></li><li class="half_rhythm"><div>O-glycan profiling is normal.</div></li><li class="half_rhythm"><div>Urine quantitative mucopolysaccharides can be elevated, but with a normal pattern.</div></li><li class="half_rhythm"><div>Free and total carnitine, uric acid, white blood cell CoQ<sub>10</sub>, plasma amino acids, and urine organic acids are essentially normal.</div></li><li class="half_rhythm"><div>Lactate was normal in the majority of affected individuals, but can be mild to moderately elevated (~5 mmol/L) especially in younger affected individuals.</div></li><li class="half_rhythm"><div>Lactate to pyruvate ratio is typically normal.</div></li><li class="half_rhythm"><div>Urine amino acids can show generalized aminoaciduria, especially in older individuals [<a class="bk_pop" href="#ngly1-cddg.REF.lam.2017.160">Lam et al 2017</a>].</div></li><li class="half_rhythm"><div>On liver biopsy, abnormal cristae and mitochondrial proliferation was noted in one individual, while depleted cristae and mitochondrial DNA depletion was seen in another individual [<a class="bk_pop" href="#ngly1-cddg.REF.kong.2018.6">Kong et al 2018</a>].</div></li><li class="half_rhythm"><div>On quadriceps muscle biopsy mitochondrial proliferation and mitochondrial DNA proliferation was noted in one affected individual [<a class="bk_pop" href="#ngly1-cddg.REF.kong.2018.6">Kong et al 2018</a>].</div></li></ul></div><div id="ngly1-cddg.GenotypePhenotype_Correlation"><h3>Genotype-Phenotype Correlations</h3><p>The most common <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a> is <a href="/books/NBK481554/table/ngly1-cddg.T.ngly1_pathogenic_variants_d/?report=objectonly" target="object" rid-ob="figobngly1cddgTngly1pathogenicvariantsd">c.1201A>T</a> (p.Arg401Ter), accounting for approximately one third of pathogenic alleles. Affected individuals harboring at least one copy of this pathogenic variant tend to have a more severe clinical course with higher scores on the Nijmegen Pediatric CDG Severity scale [<a class="bk_pop" href="#ngly1-cddg.REF.lam.2017.160">Lam et al 2017</a>].</p><p>A sib pair with the cryptic pathogenic <a href="/books/NBK481554/table/ngly1-cddg.T.ngly1_pathogenic_variants_d/?report=objectonly" target="object" rid-ob="figobngly1cddgTngly1pathogenicvariantsd">c.930C>T</a> <a class="def" href="/books/n/gene/glossary/def-item/splice-site/">splice site</a> variant (predicted as a silent p.Gly310=) and a <a href="/books/NBK481554/table/ngly1-cddg.T.ngly1_pathogenic_variants_d/?report=objectonly" target="object" rid-ob="figobngly1cddgTngly1pathogenicvariantsd">p.Gln208Ter</a> <a class="def" href="/books/n/gene/glossary/def-item/nonsense-variant/">nonsense</a> variant exhibited relatively mild impairment in all domains [<a class="bk_pop" href="#ngly1-cddg.REF.lam.2017.160">Lam et al 2017</a>].</p></div><div id="ngly1-cddg.Nomenclature"><h3>Nomenclature</h3><p>NGLY1-CDDG was previously referred to as <a class="def" href="/books/n/gene/glossary/def-item/congenital/">congenital</a> disorder of glycosylation type Iv (CDG-Iv).</p><p>NGLY1-CDDG is the first primary defect of N-linked <i>deglycosylation</i> shown to cause human disease. Following the established nomenclature for <a class="def" href="/books/n/gene/glossary/def-item/congenital/">congenital</a> disorders of glycosylation, where disorders are formally named with the involved <a class="def" href="/books/n/gene/glossary/def-item/gene/">gene</a> (not italicized) followed by -CDG (e.g., PMM2-CDG) [<a class="bk_pop" href="#ngly1-cddg.REF.jaeken.2009.825">Jaeken et al 2009</a>], the authors propose that this disorder and future disorders of N-linked deglycosylation follow a similar format, except using CDDG instead of CDG.</p></div><div id="ngly1-cddg.Prevalence"><h3>Prevalence</h3><p>A total of 18 individuals from 14 families have been described in the literature [<a class="bk_pop" href="#ngly1-cddg.REF.need.2012.353">Need et al 2012</a>, <a class="bk_pop" href="#ngly1-cddg.REF.enns.2014.751">Enns et al 2014</a>, <a class="bk_pop" href="#ngly1-cddg.REF.caglayan.2015.39">Caglayan et al 2015</a>, <a class="bk_pop" href="#ngly1-cddg.REF.heeley.2015.816">Heeley & Shinawi 2015</a>, <a class="bk_pop" href="#ngly1-cddg.REF.bosch.2016.660">Bosch et al 2016</a>, <a class="bk_pop" href="#ngly1-cddg.REF.lam.2017.160">Lam et al 2017</a>]. However, according to a database maintained by <a href="https://www.ngly1.org/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">NGLY1.org</a>, <a class="def" href="/books/n/gene/glossary/def-item/biallelic/">biallelic</a> pathogenic variants in <i>NGLY1</i> coupled with suggestive clinical <a class="def" href="/books/n/gene/glossary/def-item/phenotype/">phenotype</a> have been identified in 46 individuals worldwide. Most of the reported affected individuals have been of northern European background, but this is likely due to ascertainment bias rather than a true increased prevalence in that population. Although not yet reported in the literature, individuals with African and non-white Hispanic background have been confirmed to have NGLY1-CDDG [Lam & Wolfe, personal observation].</p></div></div><div id="ngly1-cddg.Genetically_Related_Allelic_D"><h2 id="_ngly1-cddg_Genetically_Related_Allelic_D_">Genetically Related (Allelic) Disorders</h2><p>No phenotypes other than those discussed in this <i>GeneReview</i> are known to be associated with pathogenic variants in <i>NGLY1</i>.</p></div><div id="ngly1-cddg.Differential_Diagnosis"><h2 id="_ngly1-cddg_Differential_Diagnosis_">Differential Diagnosis</h2><p>The tetrad of developmental delay / cognitive impairment, hyperkinetic movement disorder, hypo/alacrima, and elevated transaminases during early childhood is pathognomonic of NGLY1-CDDG [<a class="bk_pop" href="#ngly1-cddg.REF.need.2012.353">Need et al 2012</a>, <a class="bk_pop" href="#ngly1-cddg.REF.enns.2014.751">Enns et al 2014</a>, <a class="bk_pop" href="#ngly1-cddg.REF.caglayan.2015.39">Caglayan et al 2015</a>, <a class="bk_pop" href="#ngly1-cddg.REF.heeley.2015.816">Heeley & Shinawi 2015</a>, <a class="bk_pop" href="#ngly1-cddg.REF.lam.2017.160">Lam et al 2017</a>]. However, other multisystemic disorders and conditions that feature variable neurologic phenotypes, including seizures, chorea, athetosis, <a href="/books/n/gene/dystonia-ov/">dystonia</a>, myoclonus, tremors, <a href="/books/n/gene/ataxias/">ataxia</a>, and dysmetria, are in the differential diagnosis.</p><div id="ngly1-cddg.T.disorders_to_consider_in_th" class="table"><h3><span class="label">Table 2. </span></h3><div class="caption"><p>Disorders to Consider in the Differential Diagnosis of <i>NGLY1</i>-Related Congenital Disorder of Deglycosylation</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK481554/table/ngly1-cddg.T.disorders_to_consider_in_th/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__ngly1-cddg.T.disorders_to_consider_in_th_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_ngly1-cddg.T.disorders_to_consider_in_th_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Disorder</th><th id="hd_h_ngly1-cddg.T.disorders_to_consider_in_th_1_1_1_2" rowspan="2" scope="col" colspan="1" headers="hd_h_ngly1-cddg.T.disorders_to_consider_in_th_1_1_1_2" style="text-align:left;vertical-align:middle;">Gene(s)</th><th id="hd_h_ngly1-cddg.T.disorders_to_consider_in_th_1_1_1_3" rowspan="2" scope="col" colspan="1" headers="hd_h_ngly1-cddg.T.disorders_to_consider_in_th_1_1_1_3" style="text-align:left;vertical-align:middle;">MOI</th><th id="hd_h_ngly1-cddg.T.disorders_to_consider_in_th_1_1_1_4" colspan="2" scope="colgroup" rowspan="1" style="text-align:center;vertical-align:middle;">Clinical Features</th></tr><tr><th headers="hd_h_ngly1-cddg.T.disorders_to_consider_in_th_1_1_1_1" id="hd_h_ngly1-cddg.T.disorders_to_consider_in_th_1_1_2_1" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></th><th headers="hd_h_ngly1-cddg.T.disorders_to_consider_in_th_1_1_1_4" id="hd_h_ngly1-cddg.T.disorders_to_consider_in_th_1_1_2_2" colspan="1" scope="colgroup" rowspan="1" style="text-align:left;vertical-align:middle;">Overlapping</th><th headers="hd_h_ngly1-cddg.T.disorders_to_consider_in_th_1_1_1_4" id="hd_h_ngly1-cddg.T.disorders_to_consider_in_th_1_1_2_3" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Distinguishing</th></tr></thead><tbody><tr><td headers="hd_h_ngly1-cddg.T.disorders_to_consider_in_th_1_1_1_1 hd_h_ngly1-cddg.T.disorders_to_consider_in_th_1_1_2_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Congenital disorders of glycosylation (CDGs) (see <a href="/books/n/gene/cdg/">Congenital Disorders of N-Linked Glycosylation and Multiple Pathway Overview</a>.)</td><td headers="hd_h_ngly1-cddg.T.disorders_to_consider_in_th_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">See footnote 1.</td><td headers="hd_h_ngly1-cddg.T.disorders_to_consider_in_th_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">AR<br />XL</td><td headers="hd_h_ngly1-cddg.T.disorders_to_consider_in_th_1_1_1_4 hd_h_ngly1-cddg.T.disorders_to_consider_in_th_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Intrauterine growth restriction</div></li><li class="half_rhythm"><div>DD / cognitive impairment</div></li><li class="half_rhythm"><div>Neurologic dysfunction</div></li><li class="half_rhythm"><div>Liver disease <sup>2</sup></div></li></ul>
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</td><td headers="hd_h_ngly1-cddg.T.disorders_to_consider_in_th_1_1_1_4 hd_h_ngly1-cddg.T.disorders_to_consider_in_th_1_1_2_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">In persons w/NGLY1-CDDG:
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<ul><li class="half_rhythm"><div>No apparent lipodystrophy or significant cardiac manifestations <sup>3</sup></div></li><li class="half_rhythm"><div>Nonspecific brain imaging findings, but usually relatively mild abnormalities <sup>4</sup></div></li></ul>
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</td></tr><tr><td headers="hd_h_ngly1-cddg.T.disorders_to_consider_in_th_1_1_1_1 hd_h_ngly1-cddg.T.disorders_to_consider_in_th_1_1_2_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<a href="/books/n/gene/mt-overview/">Mitochondrial disorders</a>
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</td><td headers="hd_h_ngly1-cddg.T.disorders_to_consider_in_th_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">>250<br />genes <sup>5</sup></td><td headers="hd_h_ngly1-cddg.T.disorders_to_consider_in_th_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">AR<br />AD<br />Maternal</td><td headers="hd_h_ngly1-cddg.T.disorders_to_consider_in_th_1_1_1_4 hd_h_ngly1-cddg.T.disorders_to_consider_in_th_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Multisystem involvement</div></li><li class="half_rhythm"><div>Pigmentary retinopathy <sup>6</sup></div></li></ul>
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In some w/NGLY1-CDDG:
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<ul><li class="half_rhythm"><div>Mild biochemical evidence of mt impairment, especially transient or mildly ↑ blood lactate levels</div></li><li class="half_rhythm"><div>Nonspecific electron transport chain abnormalities in skin fibroblasts, muscle, & liver, & mildly abnormal mt morphology on electron microscopy <sup>3, 6</sup></div></li></ul>
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</td><td headers="hd_h_ngly1-cddg.T.disorders_to_consider_in_th_1_1_1_4 hd_h_ngly1-cddg.T.disorders_to_consider_in_th_1_1_2_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Persons w/NGLY1-CDDG:
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<ul><li class="half_rhythm"><div>Do not typically have episodes of metabolic decompensation or clinical presentations assoc w/classic mt disorder phenotypes.</div></li><li class="half_rhythm"><div>Have normal CSF lactate levels. <sup>6</sup></div></li></ul>
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</td></tr><tr><td headers="hd_h_ngly1-cddg.T.disorders_to_consider_in_th_1_1_1_1 hd_h_ngly1-cddg.T.disorders_to_consider_in_th_1_1_2_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Neurotransmitter disorders (involving metabolic pathways related to monoamine & amino acid metabolism; e.g., <a href="/books/n/gene/drd/">GTPCH1-deficient dopa-responsive dystonia</a>, <a href="/books/n/gene/thdrd/">tyrosine hydroxylase deficiency</a>, <a href="/books/n/gene/aadc-def/">aromatic L-amino acid decarboxylase deficiency</a></td><td headers="hd_h_ngly1-cddg.T.disorders_to_consider_in_th_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">See footnote 8.</td><td headers="hd_h_ngly1-cddg.T.disorders_to_consider_in_th_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">See footnote 8.</td><td headers="hd_h_ngly1-cddg.T.disorders_to_consider_in_th_1_1_1_4 hd_h_ngly1-cddg.T.disorders_to_consider_in_th_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">On CSF analysis:
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<ul><li class="half_rhythm"><div>Various combinations of abnormal levels of HVA, 5-HIAA, & biopterin metabolites in neurotransmitter disorders <sup>9, 10</sup></div></li><li class="half_rhythm"><div>In some cases, ↓ HVA, 5-HIAA, & tetrahydrobiopterin in NGLY1-CDDG; such findings appear to correlate w/degree of brain atrophy. <sup>11</sup></div></li></ul>
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</td><td headers="hd_h_ngly1-cddg.T.disorders_to_consider_in_th_1_1_1_4 hd_h_ngly1-cddg.T.disorders_to_consider_in_th_1_1_2_3" rowspan="2" colspan="1" style="text-align:left;vertical-align:middle;">In persons w/NGLY1-CDDG:
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<ul><li class="half_rhythm"><div>Oculogyric crises not reported</div></li><li class="half_rhythm"><div>No diurnal fluctuation of symptoms</div></li><li class="half_rhythm"><div>Peripheral neuropathy common</div></li></ul>
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In persons w/neurotransmitter disorders:
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<ul><li class="half_rhythm"><div>Alacrima/hypolacrima & liver dysfunction not typically seen</div></li></ul>
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In GTP cyclohydrolase 1-deficient dopa-responsive dystonia:
|
||
<ul><li class="half_rhythm"><div>Intellectual & cognitive function typically normal</div></li></ul>
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</td></tr><tr><td headers="hd_h_ngly1-cddg.T.disorders_to_consider_in_th_1_1_1_1 hd_h_ngly1-cddg.T.disorders_to_consider_in_th_1_1_2_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Secondary abnormalities in neurotransmitter metabolites</td><td headers="hd_h_ngly1-cddg.T.disorders_to_consider_in_th_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">See footnote 8.</td><td headers="hd_h_ngly1-cddg.T.disorders_to_consider_in_th_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">See footnote 8.</td><td headers="hd_h_ngly1-cddg.T.disorders_to_consider_in_th_1_1_1_4 hd_h_ngly1-cddg.T.disorders_to_consider_in_th_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>↓ HVA may be present in hypoxic-ischemic encephalopathy, CNS infections, & some genetic disorders. <sup>10</sup></div></li><li class="half_rhythm"><div>↓ HVA & 5-HIAA may occur in hypoxic-ischemic encephalopathy, <a class="def" href="/books/n/gene/glossary/def-item/congenital/">congenital</a> infections, & some genetic disorders. <sup>12</sup></div></li></ul>
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</td></tr><tr><td headers="hd_h_ngly1-cddg.T.disorders_to_consider_in_th_1_1_1_1 hd_h_ngly1-cddg.T.disorders_to_consider_in_th_1_1_2_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<a href="/books/n/gene/rett/"><i>MECP2</i>-related disorders</a>
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</td><td headers="hd_h_ngly1-cddg.T.disorders_to_consider_in_th_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<i>MECP2</i>
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</td><td headers="hd_h_ngly1-cddg.T.disorders_to_consider_in_th_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">XL</td><td headers="hd_h_ngly1-cddg.T.disorders_to_consider_in_th_1_1_1_4 hd_h_ngly1-cddg.T.disorders_to_consider_in_th_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Cognitive impairment, seizures, ataxia, tremors, & acquired microcephaly:
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<ul><li class="half_rhythm"><div>Are common features in <i>MECP2</i>-related disorders;</div></li><li class="half_rhythm"><div>May also be seen in NGLY1-CDDG.</div></li></ul>
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</td><td headers="hd_h_ngly1-cddg.T.disorders_to_consider_in_th_1_1_1_4 hd_h_ngly1-cddg.T.disorders_to_consider_in_th_1_1_2_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div><i>MECP2</i>-related disorders are classically assoc w/a period of normal development, followed by stagnation & relatively rapid regression in females.</div></li><li class="half_rhythm"><div>Persons w/NGLY1-CDDG have neither a period of normal development nor such rapid developmental regression.</div></li></ul>
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</td></tr><tr><td headers="hd_h_ngly1-cddg.T.disorders_to_consider_in_th_1_1_1_1 hd_h_ngly1-cddg.T.disorders_to_consider_in_th_1_1_2_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<a href="/books/n/gene/creatine/">Creatine deficiency syndromes</a>
|
||
</td><td headers="hd_h_ngly1-cddg.T.disorders_to_consider_in_th_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><i>GAMT</i><br /><i>GATM</i><br />SLC6A8</td><td headers="hd_h_ngly1-cddg.T.disorders_to_consider_in_th_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">AR<br />XL</td><td headers="hd_h_ngly1-cddg.T.disorders_to_consider_in_th_1_1_1_4 hd_h_ngly1-cddg.T.disorders_to_consider_in_th_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Like NGLY1-CDDG, disorders of creatine synthesis may be assoc w/DD & cognitive impairment, movement disorders, seizures, & behavior abnormalities.</td><td headers="hd_h_ngly1-cddg.T.disorders_to_consider_in_th_1_1_1_4 hd_h_ngly1-cddg.T.disorders_to_consider_in_th_1_1_2_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Alacrima & liver disease are not seen in disorders of creatine synthesis.</td></tr><tr><td headers="hd_h_ngly1-cddg.T.disorders_to_consider_in_th_1_1_1_1 hd_h_ngly1-cddg.T.disorders_to_consider_in_th_1_1_2_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Triple-A syndrome (OMIM <a href="https://omim.org/entry/231550" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">231550</a>)</td><td headers="hd_h_ngly1-cddg.T.disorders_to_consider_in_th_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<i>AAAS</i>
|
||
</td><td headers="hd_h_ngly1-cddg.T.disorders_to_consider_in_th_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">AR</td><td headers="hd_h_ngly1-cddg.T.disorders_to_consider_in_th_1_1_1_4 hd_h_ngly1-cddg.T.disorders_to_consider_in_th_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Alacrima</div></li><li class="half_rhythm"><div>Mild dementia</div></li><li class="half_rhythm"><div>Cerebellar ataxia <sup>13</sup></div></li></ul>
|
||
</td><td headers="hd_h_ngly1-cddg.T.disorders_to_consider_in_th_1_1_1_4 hd_h_ngly1-cddg.T.disorders_to_consider_in_th_1_1_2_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Triple A syndrome does not feature choreoathetosis.</div></li><li class="half_rhythm"><div>Adrenal insufficiency is not a prominent feature of NGLY1-CDDG.</div></li><li class="half_rhythm"><div>Persons with Triple A syndrome may have anisocoria.</div></li></ul>
|
||
</td></tr><tr><td headers="hd_h_ngly1-cddg.T.disorders_to_consider_in_th_1_1_1_1 hd_h_ngly1-cddg.T.disorders_to_consider_in_th_1_1_2_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Alacrima, achalasia, and mental retardation syndrome (AAMR) (OMIM <a href="https://omim.org/entry/615510" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">615510</a>)</td><td headers="hd_h_ngly1-cddg.T.disorders_to_consider_in_th_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<i>GMPPA</i>
|
||
</td><td headers="hd_h_ngly1-cddg.T.disorders_to_consider_in_th_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">AR</td><td headers="hd_h_ngly1-cddg.T.disorders_to_consider_in_th_1_1_1_4 hd_h_ngly1-cddg.T.disorders_to_consider_in_th_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Alacrima</div></li><li class="half_rhythm"><div>ID</div></li><li class="half_rhythm"><div>Variable hypotonia</div></li><li class="half_rhythm"><div>Ataxia</div></li><li class="half_rhythm"><div>Spasticity</div></li><li class="half_rhythm"><div>Hearing impairment <sup>14</sup></div></li></ul>
|
||
</td><td headers="hd_h_ngly1-cddg.T.disorders_to_consider_in_th_1_1_1_4 hd_h_ngly1-cddg.T.disorders_to_consider_in_th_1_1_2_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">AAMR:
|
||
<ul><li class="half_rhythm"><div>Does not feature choreoathetosis.</div></li><li class="half_rhythm"><div>May feature anisocoria.</div></li></ul>
|
||
</td></tr><tr><td headers="hd_h_ngly1-cddg.T.disorders_to_consider_in_th_1_1_1_1 hd_h_ngly1-cddg.T.disorders_to_consider_in_th_1_1_2_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Hereditary sensory and autonomic neuropathy (HSAN)</td><td headers="hd_h_ngly1-cddg.T.disorders_to_consider_in_th_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">See footnote 15.</td><td headers="hd_h_ngly1-cddg.T.disorders_to_consider_in_th_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">See footnote 16.</td><td headers="hd_h_ngly1-cddg.T.disorders_to_consider_in_th_1_1_1_4 hd_h_ngly1-cddg.T.disorders_to_consider_in_th_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Alacrima may also be present in some forms of HSAN incl <a href="/books/n/gene/fd/">familial dysautonomia</a> (FD) & HSAN type VI (OMIM <a href="https://omim.org/entry/614653" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">614653</a>) <sup>15</sup></td><td headers="hd_h_ngly1-cddg.T.disorders_to_consider_in_th_1_1_1_4 hd_h_ngly1-cddg.T.disorders_to_consider_in_th_1_1_2_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>FD & HSAN type VI do not feature choreoathetosis.</div></li><li class="half_rhythm"><div>Persons w/HSAN usually have normal cognitive function.</div></li></ul>
|
||
</td></tr></tbody></table></div><div><div><dl class="temp-labeled-list small"><dt></dt><dd><div><p class="no_margin">5-HIAA = 5-hydroxyindoleacetic acid; AD = <a class="def" href="/books/n/gene/glossary/def-item/autosomal-dominant/">autosomal dominant</a>; AR = <a class="def" href="/books/n/gene/glossary/def-item/autosomal-recessive/">autosomal recessive</a>; CNS = central nervous system; DD = developmental delay; HVA = homovanillic acid; ID = intellectual disability; MOI = <a class="def" href="/books/n/gene/glossary/def-item/mode-of-inheritance/">mode of inheritance</a>; mt = mitochondrial; 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="ngly1-cddg.TF.2.1"><p class="no_margin">See OMIM Phenotypic Series: <a href="https://omim.org/phenotypicSeries/PS212065" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">Congenital Disorders of Glycosylation, Type I</a> and <a href="https://omim.org/phenotypicSeries/PS212066" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">Congenital Disorders of Glycosylation, Type II</a> to view genes associated with these phenotypes.</p></div></dd><dt>2. </dt><dd><div id="ngly1-cddg.TF.2.2"><p class="no_margin">
|
||
<a class="bk_pop" href="#ngly1-cddg.REF.freeze.2012.453">Freeze et al [2012]</a>
|
||
</p></div></dd><dt>3. </dt><dd><div id="ngly1-cddg.TF.2.3"><p class="no_margin">
|
||
<a class="bk_pop" href="#ngly1-cddg.REF.enns.2014.751">Enns et al [2014]</a>
|
||
</p></div></dd><dt>4. </dt><dd><div id="ngly1-cddg.TF.2.4"><p class="no_margin">Some individuals with <i>NGLY1</i>-CDDG have cerebral and cerebellar atrophy, but the cerebellar atrophy is not typically as severe as in the CDGs [<a class="bk_pop" href="#ngly1-cddg.REF.lam.2017.160">Lam et al 2017</a>].</p></div></dd><dt>5. </dt><dd><div id="ngly1-cddg.TF.2.5"><p class="no_margin">
|
||
<a class="bk_pop" href="#ngly1-cddg.REF.alston.2017.236">Alston et al [2017]</a>
|
||
</p></div></dd><dt>6. </dt><dd><div id="ngly1-cddg.TF.2.6"><p class="no_margin"><a class="bk_pop" href="#ngly1-cddg.REF.lam.2017.160">Lam et al [2017]</a>, <a class="bk_pop" href="#ngly1-cddg.REF.kong.2018.6">Kong et al [2018]</a></p></div></dd><dt>7. </dt><dd><div id="ngly1-cddg.TF.2.7"><p class="no_margin">Neurotransmitter disorders are associated with a wide spectrum of neurologic abnormalities including seizures, choreoathetosis, dystonia, hypotonia, oculogyric crises, and psychiatric disease [<a class="bk_pop" href="#ngly1-cddg.REF.pons.2009.321">Pons 2009</a>, <a class="bk_pop" href="#ngly1-cddg.REF.marecos.2014.619">Marecos et al 2014</a>, <a class="bk_pop" href="#ngly1-cddg.REF.ng.2015.567">Ng et al 2015</a>].</p></div></dd><dt>8. </dt><dd><div id="ngly1-cddg.TF.2.8"><p class="no_margin">For more information, see hyperlinked <i>GeneReviews</i>, OMIM entries, and/or citations.</p></div></dd><dt>9. </dt><dd><div id="ngly1-cddg.TF.2.9"><p class="no_margin"><a class="bk_pop" href="#ngly1-cddg.REF.pons.2009.321">Pons [2009]</a>, <a class="bk_pop" href="#ngly1-cddg.REF.ng.2015.567">Ng et al [2015]</a></p></div></dd><dt>10. </dt><dd><div id="ngly1-cddg.TF.2.10"><p class="no_margin">Genetic disorders that may be associated with low HVA include <a href="/books/n/gene/mt-overview/">mitochondrial disorders</a>, <a href="/books/n/gene/nkh/">glycine encephalopathy</a>, <a href="/books/n/gene/ags/">Aicardi-Goutières syndrome</a>, Rett syndrome (see <a href="/books/n/gene/rett/"><i>MECP2</i> Disorders</a>), <a href="/books/n/gene/myotonic-d/">myotonic dystrophy type 1</a>, and vanishing white matter disease (see <a href="/books/n/gene/cach/">Childhood Ataxia with Central Nervous System Hypomyelination/Vanishing White Matter</a>).</p></div></dd><dt>11. </dt><dd><div id="ngly1-cddg.TF.2.11"><p class="no_margin"><a class="bk_pop" href="#ngly1-cddg.REF.enns.2014.751">Enns et al [2014]</a>, <a class="bk_pop" href="#ngly1-cddg.REF.lam.2017.160">Lam et al [2017]</a></p></div></dd><dt>12. </dt><dd><div id="ngly1-cddg.TF.2.12"><p class="no_margin">Genetic disorders that may be associated with low HVA and 5-HIAA include <a href="/books/n/gene/mt-overview/">mitochondrial disease</a>, <a href="/books/n/gene/npc/">Niemann-Pick disease type C</a>, <a href="/books/n/gene/alexander/">Alexander disease</a>, <a href="/books/n/gene/nkh/">glycine encephalopathy</a>, pontocerebellar hypoplasia type 2 (see <a href="/books/n/gene/pc-hypo-p/"><i>TSEN54</i>-Related Pontocerebellar Hypoplasia</a>), Rett syndrome (see <a href="/books/n/gene/rett/"><i>MECP2</i> Disorders</a>), <a href="/books/n/gene/slo/">Smith-Lemli-Opitz syndrome</a>, <a href="/books/n/gene/ucd-overview/">urea cycle disorders</a> [<a class="bk_pop" href="#ngly1-cddg.REF.moleroluis.2013.559">Molero-Luis et al 2013</a>, <a class="bk_pop" href="#ngly1-cddg.REF.ng.2015.567">Ng et al 2015</a>].</p></div></dd><dt>13. </dt><dd><div id="ngly1-cddg.TF.2.13"><p class="no_margin"><a class="bk_pop" href="#ngly1-cddg.REF.tulliopelet.2000.332">Tullio-Pelet et al [2000]</a>, <a class="bk_pop" href="#ngly1-cddg.REF.handschug.2001.283">Handschug et al [2001]</a></p></div></dd><dt>14. </dt><dd><div id="ngly1-cddg.TF.2.14"><p class="no_margin">
|
||
<a class="bk_pop" href="#ngly1-cddg.REF.koehler.2013.727">Koehler et al [2013]</a>
|
||
</p></div></dd><dt>15. </dt><dd><div id="ngly1-cddg.TF.2.15"><p class="no_margin"><a class="bk_pop" href="#ngly1-cddg.REF.anderson.2001.753">Anderson et al [2001]</a>, <a class="bk_pop" href="#ngly1-cddg.REF.edvardson.2012.569">Edvardson et al [2012]</a></p></div></dd><dt>16. </dt><dd><div id="ngly1-cddg.TF.2.16"><p class="no_margin">See OMIM Phenotypic Series: <a href="https://omim.org/phenotypicSeries/PS162400" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">Hereditary Sensory and Autonomic Neuropathy</a> to view genes and modes of inheritance associated with these phenotypes.</p></div></dd></dl></div></div></div></div><div id="ngly1-cddg.Management"><h2 id="_ngly1-cddg_Management_">Management</h2><div id="ngly1-cddg.Evaluations_Following_Initial"><h3>Evaluations Following Initial Diagnosis</h3><p>To establish the extent of disease and needs in an individual diagnosed with <i>NGLY1</i>-related <a class="def" href="/books/n/gene/glossary/def-item/congenital/">congenital</a> disorder of deglycosylation (NGLY1-CDDG), the evaluations summarized in <a href="/books/NBK481554/table/ngly1-cddg.T.recommended_evaluations_fol/?report=objectonly" target="object" rid-ob="figobngly1cddgTrecommendedevaluationsfol">Table 3</a> (if not performed as part of the initial evaluation that led to diagnosis) are recommended.</p><div id="ngly1-cddg.T.recommended_evaluations_fol" class="table"><h3><span class="label">Table 3. </span></h3><div class="caption"><p>Recommended Evaluations Following Initial Diagnosis of NGLY1-CDDG</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK481554/table/ngly1-cddg.T.recommended_evaluations_fol/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__ngly1-cddg.T.recommended_evaluations_fol_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_ngly1-cddg.T.recommended_evaluations_fol_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">System/Concern</th><th id="hd_h_ngly1-cddg.T.recommended_evaluations_fol_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Evaluation</th><th id="hd_h_ngly1-cddg.T.recommended_evaluations_fol_1_1_1_3" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Comment</th></tr></thead><tbody><tr><td headers="hd_h_ngly1-cddg.T.recommended_evaluations_fol_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Eyes</b>
|
||
</td><td headers="hd_h_ngly1-cddg.T.recommended_evaluations_fol_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Ophthalmologic eval for hypolacrima & retinal disease</td><td headers="hd_h_ngly1-cddg.T.recommended_evaluations_fol_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr><tr><td headers="hd_h_ngly1-cddg.T.recommended_evaluations_fol_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>ENT/Mouth</b>
|
||
</td><td headers="hd_h_ngly1-cddg.T.recommended_evaluations_fol_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Auditory brain stem evoked potentials</td><td headers="hd_h_ngly1-cddg.T.recommended_evaluations_fol_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr><tr><td headers="hd_h_ngly1-cddg.T.recommended_evaluations_fol_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_ngly1-cddg.T.recommended_evaluations_fol_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Sleep study</td><td headers="hd_h_ngly1-cddg.T.recommended_evaluations_fol_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">If review of systems reveals snoring or symptoms concerning for sleep apnea</td></tr><tr><td headers="hd_h_ngly1-cddg.T.recommended_evaluations_fol_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_ngly1-cddg.T.recommended_evaluations_fol_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Nutrition eval to optimize intake</td><td headers="hd_h_ngly1-cddg.T.recommended_evaluations_fol_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Feeding & swallowing eval if indicated</td></tr><tr><td headers="hd_h_ngly1-cddg.T.recommended_evaluations_fol_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Transaminase levels</div></li><li class="half_rhythm"><div>Eval for constipation</div></li></ul>
|
||
</td><td headers="hd_h_ngly1-cddg.T.recommended_evaluations_fol_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Consultation w/gastroenterologist or hepatologist as needed</td></tr><tr><td headers="hd_h_ngly1-cddg.T.recommended_evaluations_fol_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_ngly1-cddg.T.recommended_evaluations_fol_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Radiologic & orthopedic assessment incl DXA scan</td><td headers="hd_h_ngly1-cddg.T.recommended_evaluations_fol_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">To evaluate bone health & help manage scoliosis, coxa valga, &/or contractures</td></tr><tr><td headers="hd_h_ngly1-cddg.T.recommended_evaluations_fol_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Skin</b>
|
||
</td><td headers="hd_h_ngly1-cddg.T.recommended_evaluations_fol_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">QSWEAT analysis to evaluate for hypohydrosis</td><td headers="hd_h_ngly1-cddg.T.recommended_evaluations_fol_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr><tr><td headers="hd_h_ngly1-cddg.T.recommended_evaluations_fol_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_ngly1-cddg.T.recommended_evaluations_fol_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Neurologic & neurodevelopmental eval of cognitive abilities</div></li><li class="half_rhythm"><div>Nerve conduction study</div></li></ul>
|
||
</td><td headers="hd_h_ngly1-cddg.T.recommended_evaluations_fol_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr><tr><td headers="hd_h_ngly1-cddg.T.recommended_evaluations_fol_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Endocrinologic</b>
|
||
</td><td headers="hd_h_ngly1-cddg.T.recommended_evaluations_fol_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Vitamin D level</td><td headers="hd_h_ngly1-cddg.T.recommended_evaluations_fol_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">To assess for vitamin D deficiency</td></tr><tr><td headers="hd_h_ngly1-cddg.T.recommended_evaluations_fol_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Hematologic/</b>
|
||
<br />
|
||
<b>Lymphatic</b>
|
||
</td><td headers="hd_h_ngly1-cddg.T.recommended_evaluations_fol_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Protein C; factor II, IX, XI; fibrinogen levels</td><td headers="hd_h_ngly1-cddg.T.recommended_evaluations_fol_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Consultation w/hematologist if abnormal</td></tr><tr><td headers="hd_h_ngly1-cddg.T.recommended_evaluations_fol_1_1_1_1" rowspan="3" scope="row" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Miscellaneous/</b>
|
||
<br />
|
||
<b>Other</b>
|
||
</td><td headers="hd_h_ngly1-cddg.T.recommended_evaluations_fol_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Speech & language eval</td><td headers="hd_h_ngly1-cddg.T.recommended_evaluations_fol_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Referral to speech therapist if indicated</td></tr><tr><td headers="hd_h_ngly1-cddg.T.recommended_evaluations_fol_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">Rehabilitation team eval</td><td headers="hd_h_ngly1-cddg.T.recommended_evaluations_fol_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Referral for OT &/or PT if indicated</td></tr><tr><td headers="hd_h_ngly1-cddg.T.recommended_evaluations_fol_1_1_1_2" colspan="1" scope="col" rowspan="1" style="text-align:left;vertical-align:middle;">Consultation w/clinical geneticist &/or genetic counselor</td><td headers="hd_h_ngly1-cddg.T.recommended_evaluations_fol_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">DXA = dual-energy x-ray absorptiometry; OT = occupational therapy; PT = physical therapy</p></div></dd></dl></div></div></div></div><div id="ngly1-cddg.Treatment_of_Manifestations"><h3>Treatment of Manifestations</h3><p>Treatment and quality of life can be optimized when care is provided by specialists in biochemical genetics, neurology, developmental pediatrics, ophthalmology, gastroenterology, orthopedics, and rehabilitation medicine who are knowledgeable about NGLY1-CDDG.</p><div id="ngly1-cddg.T.treatment_of_manifestations" class="table"><h3><span class="label">Table 4. </span></h3><div class="caption"><p>Treatment of Manifestations in Individuals with NGLY1-CDDG</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK481554/table/ngly1-cddg.T.treatment_of_manifestations/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__ngly1-cddg.T.treatment_of_manifestations_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_ngly1-cddg.T.treatment_of_manifestations_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Manifestation/Concern</th><th id="hd_h_ngly1-cddg.T.treatment_of_manifestations_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Treatment</th><th id="hd_h_ngly1-cddg.T.treatment_of_manifestations_1_1_1_3" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Considerations/Other</th></tr></thead><tbody><tr><td headers="hd_h_ngly1-cddg.T.treatment_of_manifestations_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Hypolacrima</b>
|
||
</td><td headers="hd_h_ngly1-cddg.T.treatment_of_manifestations_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Lubricating eye drops &/or bland ointments</td><td headers="hd_h_ngly1-cddg.T.treatment_of_manifestations_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr><tr><td headers="hd_h_ngly1-cddg.T.treatment_of_manifestations_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Hearing loss</b>
|
||
</td><td headers="hd_h_ngly1-cddg.T.treatment_of_manifestations_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Standard treatment</td><td headers="hd_h_ngly1-cddg.T.treatment_of_manifestations_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">See <a href="/books/n/gene/deafness-overview/">Hereditary Hearing Loss and Deafness Overview</a>.</td></tr><tr><td headers="hd_h_ngly1-cddg.T.treatment_of_manifestations_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Sleep apnea</b>
|
||
</td><td headers="hd_h_ngly1-cddg.T.treatment_of_manifestations_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Routine management</td><td headers="hd_h_ngly1-cddg.T.treatment_of_manifestations_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr><tr><td headers="hd_h_ngly1-cddg.T.treatment_of_manifestations_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Oromotor deficits leading to feeding problems</b>
|
||
</td><td headers="hd_h_ngly1-cddg.T.treatment_of_manifestations_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Feeding therapy; supplemental tube feeding if indicated</td><td headers="hd_h_ngly1-cddg.T.treatment_of_manifestations_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Referral to gastroenterologist</td></tr><tr><td headers="hd_h_ngly1-cddg.T.treatment_of_manifestations_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Constipation</b>
|
||
</td><td headers="hd_h_ngly1-cddg.T.treatment_of_manifestations_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Standard management</td><td headers="hd_h_ngly1-cddg.T.treatment_of_manifestations_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Referral to gastroenterologist if refractory to typical medical management</td></tr><tr><td headers="hd_h_ngly1-cddg.T.treatment_of_manifestations_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Abnormal hematologic &/or gastroenterologic labs</b>
|
||
</td><td headers="hd_h_ngly1-cddg.T.treatment_of_manifestations_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Follow up w/hematologist & gastroenterologist</td><td headers="hd_h_ngly1-cddg.T.treatment_of_manifestations_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr><tr><td headers="hd_h_ngly1-cddg.T.treatment_of_manifestations_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Scoliosis & osteopenia</b>
|
||
</td><td headers="hd_h_ngly1-cddg.T.treatment_of_manifestations_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Routine management</td><td headers="hd_h_ngly1-cddg.T.treatment_of_manifestations_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr><tr><td headers="hd_h_ngly1-cddg.T.treatment_of_manifestations_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Hypohydrosis</b>
|
||
</td><td headers="hd_h_ngly1-cddg.T.treatment_of_manifestations_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Adequate access to water & cool environment (AC, wet T-shirt, &/or spray bottle of water)</td><td headers="hd_h_ngly1-cddg.T.treatment_of_manifestations_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Cooling vests may be helpful in hot climates.</td></tr><tr><td headers="hd_h_ngly1-cddg.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_ngly1-cddg.T.treatment_of_manifestations_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Standard treatment</td><td headers="hd_h_ngly1-cddg.T.treatment_of_manifestations_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Referral to neurologist for those w/refractory or severe seizures</td></tr><tr><td headers="hd_h_ngly1-cddg.T.treatment_of_manifestations_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Vitamin D deficiency</b>
|
||
</td><td headers="hd_h_ngly1-cddg.T.treatment_of_manifestations_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Supplemental vitamin D</td><td headers="hd_h_ngly1-cddg.T.treatment_of_manifestations_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr><tr><td headers="hd_h_ngly1-cddg.T.treatment_of_manifestations_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Any condition requiring surgical intervention</b>
|
||
</td><td headers="hd_h_ngly1-cddg.T.treatment_of_manifestations_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Surgery best performed in centers w/surgeons & anesthesiologists experienced in care of those w/metabolic disorders & special needs</td><td headers="hd_h_ngly1-cddg.T.treatment_of_manifestations_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">AC = air conditioning</p></div></dd></dl></div></div></div><div id="ngly1-cddg.Developmental_Delay__Intellec"><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. In the US, early intervention is a federally funded program available in all states.</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.</p><p>
|
||
<b>Ages 5-21 years</b>
|
||
</p><ul><li class="half_rhythm"><div>In the US, an IEP based on the individual's level of function should be developed by the local public school district. Affected children are permitted to remain in the public school district until age 21.</div></li><li class="half_rhythm"><div>Discussion about transition plans including financial, vocation/employment, and medical arrangements should begin at age 12 years. Developmental pediatricians can provide assistance with transition to adulthood.</div></li></ul><p><b>All ages.</b> Consultation with a developmental pediatrician is recommended to ensure the involvement of appropriate community, state, and educational agencies and to support parents in maximizing quality of life.</p><p>Consideration of private supportive therapies based on the affected individual's needs is recommended. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.</p><p>In the US:</p><ul><li class="half_rhythm"><div>Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.</div></li><li class="half_rhythm"><div>Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.</div></li></ul></div><div id="ngly1-cddg.Motor_Dysfunction"><h4>Motor Dysfunction</h4><p>
|
||
<b>Gross motor dysfunction</b>
|
||
</p><ul><li class="half_rhythm"><div>Physical therapy is recommended to maximize mobility.</div></li><li class="half_rhythm"><div>Consider use of durable medical equipment as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).</div></li><li class="half_rhythm"><div>For muscle tone abnormalities including dystonia, consider involving appropriate specialists to aid in management of baclofen, Botox<sup>®</sup>, anti-parkinsonian medications, or orthopedic procedures.</div></li></ul><p><b>Fine motor dysfunction.</b> Occupational therapy is recommended for difficulty with fine motor skills that affect adaptive function such as feeding, grooming, dressing, and writing.</p><p><b>Oral motor dysfunction.</b> Assuming that the individual is safe to eat by mouth, feeding therapy (typically from an occupational or speech therapist) is recommended for affected individuals who have difficulty feeding due to poor oral motor control.</p><p><b>Communication issues.</b> Consider evaluation for alternative means of communication (e.g., <a href="http://www.asha.org/NJC/AAC/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">augmentative and alternative communication</a> [AAC]) for individuals who have expressive language difficulties.</p></div></div><div id="ngly1-cddg.Surveillance"><h3>Surveillance</h3><p>In the absence of formal surveillance guidelines, the authors recommend the following:</p><ul><li class="half_rhythm"><div>Annual follow up by:</div><ul><li class="half_rhythm"><div>Pediatrician or internist</div></li><li class="half_rhythm"><div>Physical medicine and rehabilitation medicine</div></li><li class="half_rhythm"><div>Ophthalmology</div></li><li class="half_rhythm"><div>Neurology</div></li><li class="half_rhythm"><div>Nutrition</div></li></ul></li><li class="half_rhythm"><div>Follow up as recommended by:</div><ul><li class="half_rhythm"><div>Developmental pediatrician</div></li><li class="half_rhythm"><div>Gastroenterologist/hepatologist</div></li><li class="half_rhythm"><div>Audiologist</div></li><li class="half_rhythm"><div>Clinical or biochemical geneticist</div></li></ul></li></ul></div><div id="ngly1-cddg.AgentsCircumstances_to_Avoid"><h3>Agents/Circumstances to Avoid</h3><p>Hot environment should be avoided by those with hypohydrosis.</p></div><div id="ngly1-cddg.Evaluation_of_Relatives_at_Ri"><h3>Evaluation of Relatives at Risk</h3><p>See <a href="#ngly1-cddg.Related_Genetic_Counseling_Is">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="ngly1-cddg.Therapies_Under_Investigation"><h3>Therapies Under Investigation</h3><p>No FDA-approved treatments for NGLY1-CDDG exist.</p><p>Enzyme replacement therapy is currently being evaluated in the pre-clinical arena.</p><p>Pre-clinical screens for endo-beta-N-acetylglucosaminidase (ENGase) inhibitors are underway [<a class="bk_pop" href="#ngly1-cddg.REF.bi.2017.2962">Bi et al 2017</a>].</p><p>Large-scale compound screens on model organisms and cell lines are being evaluated.</p><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 information on clinical studies for a wide range of diseases and conditions.</p></div></div><div id="ngly1-cddg.Genetic_Counseling"><h2 id="_ngly1-cddg_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="ngly1-cddg.Mode_of_Inheritance"><h3>Mode of Inheritance</h3><p><i>NGLY1</i>-related <a class="def" href="/books/n/gene/glossary/def-item/congenital/">congenital</a> disorder of deglycosylation (NGLY1-CDDG) is inherited in an <a class="def" href="/books/n/gene/glossary/def-item/autosomal-recessive/">autosomal recessive</a> manner.</p></div><div id="ngly1-cddg.Risk_to_Family_Members"><h3>Risk to Family Members</h3><p>
|
||
<b>Parents of a <a class="def" href="/books/n/gene/glossary/def-item/proband/">proband</a></b>
|
||
</p><ul><li class="half_rhythm"><div>The parents of an affected child are obligate heterozygotes (i.e., carriers of one <i>NGLY1</i> <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a>).</div></li><li class="half_rhythm"><div>Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.</div></li></ul><p>
|
||
<b>Sibs of a <a class="def" href="/books/n/gene/glossary/def-item/proband/">proband</a></b>
|
||
</p><ul><li class="half_rhythm"><div>At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic <a class="def" href="/books/n/gene/glossary/def-item/carrier/">carrier</a>, and a 25% chance of being unaffected and not a carrier.</div></li><li class="half_rhythm"><div>Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.</div></li></ul><p><b>Offspring of a <a class="def" href="/books/n/gene/glossary/def-item/proband/">proband</a>.</b> The offspring of an individual with NGLY1-CDDG are obligate heterozygotes (carriers) for a <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a> in <i>NGLY1</i>.</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>NGLY1</i> <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a>.</p></div><div id="ngly1-cddg.Carrier_Detection"><h3>Carrier Detection</h3><p>Carrier testing for at-risk relatives requires prior identification of the <i>NGLY1</i> pathogenic variants in the family.</p></div><div id="ngly1-cddg.Related_Genetic_Counseling_Is"><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).</p></div><div id="ngly1-cddg.Prenatal_Testing_and_Preimpla"><h3>Prenatal Testing and Preimplantation Genetic Testing</h3><p>Once the <i>NGLY1</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="ngly1-cddg.Resources"><h2 id="_ngly1-cddg_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>Grace Science Foundation</b>
|
||
</div><div><b>Phone:</b> 650-746-4591</div><div><b>Email:</b> info@gracescience.org</div><div>
|
||
<a href="https://gracescience.org/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">www.gracescience.org</a>
|
||
</div></li><li class="half_rhythm"><div>
|
||
<b>CDG CARE (Community Alliance and Resource Exchange)</b>
|
||
</div><div><b>Email:</b> info@cdgcare.com</div><div>
|
||
<a href="https://cdgcare.org/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">cdgcare.org</a>
|
||
</div></li></ul>
|
||
</div><div id="ngly1-cddg.Molecular_Genetics"><h2 id="_ngly1-cddg_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="ngly1-cddg.molgen.TA" class="table"><h3><span class="label">Table A.</span></h3><div class="caption"><p>NGLY1-Related Congenital Disorder of Deglycosylation: Genes and Databases</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK481554/table/ngly1-cddg.molgen.TA/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__ngly1-cddg.molgen.TA_lrgtbl__"><table class="no_bottom_margin"><tbody><tr><th id="hd_b_ngly1-cddg.molgen.TA_1_1_1_1" rowspan="1" colspan="1" style="vertical-align:top;">Gene</th><th id="hd_b_ngly1-cddg.molgen.TA_1_1_1_2" rowspan="1" colspan="1" style="vertical-align:top;">Chromosome Locus</th><th id="hd_b_ngly1-cddg.molgen.TA_1_1_1_3" rowspan="1" colspan="1" style="vertical-align:top;">Protein</th><th id="hd_b_ngly1-cddg.molgen.TA_1_1_1_4" rowspan="1" colspan="1" style="vertical-align:top;">HGMD</th><th id="hd_b_ngly1-cddg.molgen.TA_1_1_1_5" rowspan="1" colspan="1" style="vertical-align:top;">ClinVar</th></tr><tr><td headers="hd_b_ngly1-cddg.molgen.TA_1_1_1_1" rowspan="1" colspan="1" style="vertical-align:top;">
|
||
<a href="/gene/55768" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=gene">
|
||
<i>NGLY1</i>
|
||
</a>
|
||
</td><td headers="hd_b_ngly1-cddg.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=55768" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">3p24<wbr style="display:inline-block"></wbr>.2</a>
|
||
</td><td headers="hd_b_ngly1-cddg.molgen.TA_1_1_1_3" rowspan="1" colspan="1" style="vertical-align:top;">
|
||
<a href="http://www.uniprot.org/uniprot/Q96IV0" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">Peptide-N(4)-(N-acetyl-beta-glucosaminyl)asparagine amidase</a>
|
||
</td><td headers="hd_b_ngly1-cddg.molgen.TA_1_1_1_4" rowspan="1" colspan="1" style="vertical-align:top;">
|
||
<a href="http://www.hgmd.cf.ac.uk/ac/gene.php?gene=NGLY1" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">NGLY1</a>
|
||
</td><td headers="hd_b_ngly1-cddg.molgen.TA_1_1_1_5" rowspan="1" colspan="1" style="vertical-align:top;">
|
||
<a href="https://www.ncbi.nlm.nih.gov/clinvar/?term=NGLY1[gene]" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">NGLY1</a>
|
||
</td></tr></tbody></table></div><div><div><dl class="temp-labeled-list small"><dt></dt><dd><div id="ngly1-cddg.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="ngly1-cddg.molgen.TB" class="table"><h3><span class="label">Table B.</span></h3><div class="caption"><p>OMIM Entries for NGLY1-Related Congenital Disorder of Deglycosylation (<a href="/omim/610661,615273" 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/NBK481554/table/ngly1-cddg.molgen.TB/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__ngly1-cddg.molgen.TB_lrgtbl__"><table><tbody><tr><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
||
<a href="/omim/610661" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=omim">610661</a></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">N-GLYCANASE 1; NGLY1</td></tr><tr><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
||
<a href="/omim/615273" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=omim">615273</a></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">CONGENITAL DISORDER OF DEGLYCOSYLATION 1; CDDG1</td></tr></tbody></table></div></div><p><b>Gene structure.</b>
|
||
<i>NGLY1</i> is located on <a class="def" href="/books/n/gene/glossary/def-item/chromosome/">chromosome</a> 3:25,718,944-25,790,039 on the reverse strand (GRCh38/hg19). The canonic transcript of <i>NGLY1</i>, <a href="https://www.ncbi.nlm.nih.gov/nuccore/NM_018297.3" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">NM_018297.3</a> (ENST00000280700.9), has 12 exons, spans 2,473 bp, and encodes 654 amino acids. There are three protein coding transcript variants; the clinical relevance of these variants is unknown [<a class="bk_pop" href="#ngly1-cddg.REF.suzuki.2016.89">Suzuki 2016</a>]. See <a href="/books/NBK481554/#ngly1-cddg.molgen.TA">Table A</a>, <b>Gene</b> for a detailed summary of <a class="def" href="/books/n/gene/glossary/def-item/gene/">gene</a> and protein information.</p><p><b>Pathogenic variants.</b> A number of <a class="def" href="/books/n/gene/glossary/def-item/loss-of-function/">loss-of-function</a> pathogenic variants in <i>NGLY1</i> have been reported, including <a class="def" href="/books/n/gene/glossary/def-item/nonsense-variant/">nonsense</a>, <a class="def" href="/books/n/gene/glossary/def-item/missense/">missense</a>, frameshift, and <a class="def" href="/books/n/gene/glossary/def-item/splice-site/">splice site</a> variants. These occur all through the <a class="def" href="/books/n/gene/glossary/def-item/gene/">gene</a>, with no obvious hot spots. The p.Arg401Ter nonsense variant is the most common, and since most of the individuals diagnosed with NGLY1-CDDG are of northern European background, this variant may have originated in northern Europe [<a class="bk_pop" href="#ngly1-cddg.REF.enns.2014.751">Enns et al 2014</a>].</p><div id="ngly1-cddg.T.ngly1_pathogenic_variants_d" class="table"><h3><span class="label">Table 5. </span></h3><div class="caption"><p><i>NGLY1</i> Pathogenic Variants Discussed in This <i>GeneReview</i></p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK481554/table/ngly1-cddg.T.ngly1_pathogenic_variants_d/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__ngly1-cddg.T.ngly1_pathogenic_variants_d_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_ngly1-cddg.T.ngly1_pathogenic_variants_d_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">DNA Nucleotide Change</th><th id="hd_h_ngly1-cddg.T.ngly1_pathogenic_variants_d_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Predicted Protein Change</th><th id="hd_h_ngly1-cddg.T.ngly1_pathogenic_variants_d_1_1_1_3" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Reference Sequences</th></tr></thead><tbody><tr><td headers="hd_h_ngly1-cddg.T.ngly1_pathogenic_variants_d_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">c.622C>T</td><td headers="hd_h_ngly1-cddg.T.ngly1_pathogenic_variants_d_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">p.Gln208Ter</td><td headers="hd_h_ngly1-cddg.T.ngly1_pathogenic_variants_d_1_1_1_3" rowspan="3" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<a href="https://www.ncbi.nlm.nih.gov/nuccore/NM_018297.3" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">NM_018297<wbr style="display:inline-block"></wbr>.3</a>
|
||
<br />
|
||
<a href="https://www.ncbi.nlm.nih.gov/protein/NP_060767.2" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">NP_060767<wbr style="display:inline-block"></wbr>.2</a>
|
||
</td></tr><tr><td headers="hd_h_ngly1-cddg.T.ngly1_pathogenic_variants_d_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">c.930C>T</td><td headers="hd_h_ngly1-cddg.T.ngly1_pathogenic_variants_d_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">p.Gly310= (<a class="def" href="/books/n/gene/glossary/def-item/splice-site/">splice site</a>)</td></tr><tr><td headers="hd_h_ngly1-cddg.T.ngly1_pathogenic_variants_d_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">c.1201A>T</td><td headers="hd_h_ngly1-cddg.T.ngly1_pathogenic_variants_d_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">p.Arg401Ter</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><p><b>Normal <a class="def" href="/books/n/gene/glossary/def-item/gene-product/">gene product</a>.</b> N-glycanase contains 654 amino acids. Functional domains include:</p><ul><li class="half_rhythm"><div>Amino acids 26-102: peptide:N-glycanase/UBA or UBX-containing proteins (PUB) <a class="def" href="/books/n/gene/glossary/def-item/domain/">domain</a></div></li><li class="half_rhythm"><div>Amino acids 269-354: catalytic transglutaminase <a class="def" href="/books/n/gene/glossary/def-item/domain/">domain</a></div></li><li class="half_rhythm"><div>Amino acids 457-651: PAW (present in PNGase and other worm proteins) <a class="def" href="/books/n/gene/glossary/def-item/domain/">domain</a></div></li></ul><p>N-glycanase catalyzes the deglycosylation of misfolded glycoproteins as part of the endoplasmic reticulum-associated degradation (ERAD) process [<a class="bk_pop" href="#ngly1-cddg.REF.suzuki.2016.89">Suzuki 2016</a>]. This enzyme is highly conserved in eukaryotes down to yeast, although the yeast homolog is expressed in both the cytoplasm and nucleus [<a class="bk_pop" href="#ngly1-cddg.REF.suzuki.2000.1039">Suzuki et al 2000</a>].</p><p><b>Abnormal <a class="def" href="/books/n/gene/glossary/def-item/gene-product/">gene product</a>.</b> The exact pathogenesis of the NGLY1-CDDG is unclear. Loss of N-glycanase is associated with dysregulation of the ERAD process [<a class="bk_pop" href="#ngly1-cddg.REF.enns.2014.751">Enns et al 2014</a>]. One hypothesis is that loss of N-glycanase and ERAD dysregulation results in endo-beta-N-acetylglucosaminidase (ENGase) to act on the unfolded glycoproteins, resulting in N-GlcNAc protein aggregation in the cytoplasm.</p><p>If the formation/aggregation of N-GlcNAc proteins is shown to be related to the symptoms/signs of NGLY1-CDDG, inhibition of ENGase activity may be a therapeutic target [<a class="bk_pop" href="#ngly1-cddg.REF.huang.2015.1398">Huang et al 2015</a>]. Additionally, deglycosylation of certain glycoproteins may be necessary for their activation and may contribute to the pathogenesis of NGLY1-CDDG [<a class="bk_pop" href="#ngly1-cddg.REF.lehrbach.2016.e17721">Lehrbach & Ruvkun 2016</a>].</p></div><div id="ngly1-cddg.References"><h2 id="_ngly1-cddg_References_">References</h2><div id="ngly1-cddg.Literature_Cited"><h3>Literature Cited</h3><ul class="simple-list"><li class="half_rhythm"><div class="bk_ref" id="ngly1-cddg.REF.alston.2017.236">Alston
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Nat Rev Neurol.
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[<a href="https://pubmed.ncbi.nlm.nih.gov/11062474" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 11062474</span></a>]</div></li></ul></div></div><div id="ngly1-cddg.Chapter_Notes"><h2 id="_ngly1-cddg_Chapter_Notes_">Chapter Notes</h2><div id="ngly1-cddg.Author_Notes"><h3>Author Notes</h3><p>The Medical Genetics Branch of the National Human Genome Research Institute continues to study the natural history of patients with NGLY1-CDDG. Careful phenotyping facilitates the characterization of disease progression necessary to evaluate the efficacy of therapeutic interventions.</p></div><div id="ngly1-cddg.Acknowledgments"><h3>Acknowledgments</h3><p>Dr Matthew Might and Mrs Cristina Might (<a href="https://www.ngly1.org" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">www.ngly1.org</a>) provided prevalence and <a class="def" href="/books/n/gene/glossary/def-item/genotype/">genotype</a> information included in this <i>GeneReview</i>.</p></div><div id="ngly1-cddg.Revision_History"><h3>Revision History</h3><ul><li class="half_rhythm"><div>8 February 2018 (ma) Review posted live</div></li><li class="half_rhythm"><div>29 November 2016 (cl) Original submission</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/NBK481554/?report=reader">PubReader</a></li><li><a href="/books/NBK481554/?report=printable">Print View</a></li><li><a data-jig="ncbidialog" href="#_ncbi_dlg_citbx_NBK481554" data-jigconfig="width:400,modal:true">Cite this Page</a><div id="_ncbi_dlg_citbx_NBK481554" style="display:none" title="Cite this Page"><div class="bk_tt">Lam C, Wolfe L, Need A, et al. NGLY1-Related Congenital Disorder of Deglycosylation. 2018 Feb 8. 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offscreen_noflow"><span xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="invert">Review</span> Citrullinemia Type I.<div class="brieflinkpopdesc"><em xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="author">Quinonez SC, Lee KN. </em><em xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="cit">GeneReviews(®). 1993</em></div></div></li><li class="brieflinkpopper two_line"><a class="brieflinkpopperctrl" href="/pubmed/20301656" ref="ordinalpos=1&linkpos=4&log$=relatedreviews&logdbfrom=pubmed"><span xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="invert">Review</span> Adenosine Deaminase Deficiency.</a><span class="source">[GeneReviews(®). 1993]</span><div class="brieflinkpop offscreen_noflow"><span xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="invert">Review</span> Adenosine Deaminase Deficiency.<div class="brieflinkpopdesc"><em xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="author">Hershfield M, Tarrant T. </em><em xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="cit">GeneReviews(®). 1993</em></div></div></li><li class="brieflinkpopper two_line"><a class="brieflinkpopperctrl" href="/pubmed/25032271" ref="ordinalpos=1&linkpos=5&log$=relatedreviews&logdbfrom=pubmed"><span xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="invert">Review</span> Dihydrolipoamide Dehydrogenase Deficiency.</a><span class="source">[GeneReviews(®). 1993]</span><div class="brieflinkpop offscreen_noflow"><span xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="invert">Review</span> Dihydrolipoamide Dehydrogenase Deficiency.<div class="brieflinkpopdesc"><em xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="author">Quinonez SC, Thoene JG. </em><em xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="cit">GeneReviews(®). 1993</em></div></div></li></ul><a class="seemore" href="/sites/entrez?db=pubmed&cmd=link&linkname=pubmed_pubmed_reviews&uid=29419975" ref="ordinalpos=1&log$=relatedreviews_seeall&logdbfrom=pubmed">See reviews...</a><a class="seemore" href="/sites/entrez?db=pubmed&cmd=link&linkname=pubmed_pubmed&uid=29419975" ref="ordinalpos=1&log$=relatedarticles_seeall&logdbfrom=pubmed">See all...</a></div></div><div class="portlet"><div class="portlet_head"><div class="portlet_title"><h3><span>Recent Activity</span></h3></div><a name="Shutter" sid="1" href="#" class="portlet_shutter" title="Show/hide content" 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