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<meta name="robots" content="INDEX,FOLLOW,NOARCHIVE" /><meta name="citation_inbook_title" content="GeneReviews® [Internet]" /><meta name="citation_title" content="Phosphorylase Kinase Deficiency" /><meta name="citation_publisher" content="University of Washington, Seattle" /><meta name="citation_date" content="2018/11/01" /><meta name="citation_author" content="Mrudu Herbert" /><meta name="citation_author" content="Jennifer L Goldstein" /><meta name="citation_author" content="Catherine Rehder" /><meta name="citation_author" content="Stephanie Austin" /><meta name="citation_author" content="Priya S Kishnani" /><meta name="citation_author" content="Deeksha S Bali" /><meta name="citation_pmid" content="21634085" /><meta name="citation_fulltext_html_url" content="https://www.ncbi.nlm.nih.gov/books/NBK55061/" /><meta name="citation_keywords" content="Glycogen Storage Disease Type IX" /><meta name="citation_keywords" content="GSDIX" /><meta name="citation_keywords" content="PhK Deficiency" /><meta name="citation_keywords" content="Phosphorylase b Kinase Deficiency" /><meta name="citation_keywords" content="GSDIX" /><meta name="citation_keywords" content="Phosphorylase b Kinase Deficiency" /><meta name="citation_keywords" content="PhK Deficiency" /><meta name="citation_keywords" content="Glycogen Storage Disease Type IX" /><meta name="citation_keywords" content="Muscle Phosphorylase Kinase Deficiency" /><meta name="citation_keywords" content="Liver Phosphorylase Kinase Deficiency" /><meta name="citation_keywords" content="Phosphorylase b kinase gamma catalytic chain, liver/testis isoform" /><meta name="citation_keywords" content="Phosphorylase b kinase regulatory subunit alpha, liver isoform" /><meta name="citation_keywords" content="Phosphorylase b kinase regulatory subunit alpha, skeletal muscle isoform" /><meta name="citation_keywords" content="Phosphorylase b kinase regulatory subunit beta" /><meta name="citation_keywords" content="PHKA1" /><meta name="citation_keywords" content="PHKA2" /><meta name="citation_keywords" content="PHKB" /><meta name="citation_keywords" content="PHKG2" /><meta name="citation_keywords" content="Phosphorylase Kinase Deficiency" /><link rel="schema.DC" href="http://purl.org/DC/elements/1.0/" /><meta name="DC.Title" content="Phosphorylase Kinase Deficiency" /><meta name="DC.Type" content="Text" /><meta name="DC.Publisher" content="University of Washington, Seattle" /><meta name="DC.Contributor" content="Mrudu Herbert" /><meta name="DC.Contributor" content="Jennifer L Goldstein" /><meta name="DC.Contributor" content="Catherine Rehder" /><meta name="DC.Contributor" content="Stephanie Austin" /><meta name="DC.Contributor" content="Priya S Kishnani" /><meta name="DC.Contributor" content="Deeksha S Bali" /><meta name="DC.Date" content="2018/11/01" /><meta name="DC.Identifier" content="https://www.ncbi.nlm.nih.gov/books/NBK55061/" /><meta name="description" content="Phosphorylase kinase (PhK) deficiency causing glycogen storage disease type IX (GSD IX) results from deficiency of the enzyme phosphorylase b kinase, which has a major regulatory role in the breakdown of glycogen. The two types of PhK deficiency are liver PhK deficiency (characterized by early childhood onset of hepatomegaly and growth restriction, and often, but not always, fasting ketosis and hypoglycemia) and muscle PhK deficiency, which is considerably rarer (characterized by any of the following: exercise intolerance, myalgia, muscle cramps, myoglobinuria, and progressive muscle weakness). While symptoms and biochemical abnormalities of liver PhK deficiency were thought to improve with age, it is becoming evident that affected individuals need to be monitored for long-term complications such as liver fibrosis and cirrhosis." /><meta name="og:title" content="Phosphorylase Kinase Deficiency" /><meta name="og:type" content="book" /><meta name="og:description" content="Phosphorylase kinase (PhK) deficiency causing glycogen storage disease type IX (GSD IX) results from deficiency of the enzyme phosphorylase b kinase, which has a major regulatory role in the breakdown of glycogen. The two types of PhK deficiency are liver PhK deficiency (characterized by early childhood onset of hepatomegaly and growth restriction, and often, but not always, fasting ketosis and hypoglycemia) and muscle PhK deficiency, which is considerably rarer (characterized by any of the following: exercise intolerance, myalgia, muscle cramps, myoglobinuria, and progressive muscle weakness). While symptoms and biochemical abnormalities of liver PhK deficiency were thought to improve with age, it is becoming evident that affected individuals need to be monitored for long-term complications such as liver fibrosis and cirrhosis." /><meta name="og:url" content="https://www.ncbi.nlm.nih.gov/books/NBK55061/" /><meta name="og:site_name" content="NCBI Bookshelf" /><meta name="og:image" content="https://www.ncbi.nlm.nih.gov/corehtml/pmc/pmcgifs/bookshelf/thumbs/th-gene-lrg.png" /><meta name="twitter:card" content="summary" /><meta name="twitter:site" content="@ncbibooks" /><meta name="bk-non-canon-loc" content="/books/n/gene/gsd9/" /><link rel="canonical" href="https://www.ncbi.nlm.nih.gov/books/NBK55061/" /><link rel="stylesheet" href="/corehtml/pmc/css/figpopup.css" type="text/css" media="screen" /><link rel="stylesheet" href="/corehtml/pmc/css/bookshelf/2.26/css/books.min.css" type="text/css" /><link rel="stylesheet" href="/corehtml/pmc/css/bookshelf/2.26/css/books_print.min.css" type="text/css" media="print" /><style type="text/css">p a.figpopup{display:inline !important} .bk_tt {font-family: monospace} .first-line-outdent .bk_ref {display: inline} .body-content h2, .body-content .h2 {border-bottom: 1px solid #97B0C8} .body-content h2.inline {border-bottom: none} a.page-toc-label , .jig-ncbismoothscroll a {text-decoration:none;border:0 !important} .temp-labeled-list .graphic {display:inline-block !important} .temp-labeled-list img{width:100%}</style><script type="text/javascript" src="/corehtml/pmc/js/jquery.hoverIntent.min.js"> </script><script type="text/javascript" src="/corehtml/pmc/js/common.min.js?_=3.18"> </script><script type="text/javascript" src="/corehtml/pmc/js/large-obj-scrollbars.min.js"> </script><script type="text/javascript">window.name="mainwindow";</script><script type="text/javascript" src="/corehtml/pmc/js/bookshelf/2.26/book-toc.min.js"> </script><script type="text/javascript" src="/corehtml/pmc/js/bookshelf/2.26/books.min.js"> </script><script type="text/javascript">if (typeof (jQuery) != 'undefined') { (function ($) { $(function () { var min = Math.ceil(1); var max = Math.floor(100000); var randomNum = Math.floor(Math.random() * (max - min)) + min; var surveyUrl = "/projects/Gene/portal/surveys/seqdbui-survey.js?rando=" + randomNum.toString(); $.getScript(surveyUrl, function () { try { ncbi.seqDbUISurvey.init(); } catch (err) { console.info(err); } }).fail(function (jqxhr, settings, exception) { console.info('Cannot load survey script', jqxhr); });; }); })(jQuery); };</script><meta name="book-collection" content="NONE" />
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<div class="main-content lit-style" itemscope="itemscope" itemtype="http://schema.org/CreativeWork"><div class="meta-content fm-sec"><h1 id="_NBK55061_"><span class="title" itemprop="name">Phosphorylase Kinase Deficiency</span></h1><div itemprop="alternativeHeadline" class="subtitle whole_rhythm">Synonyms: Glycogen Storage Disease Type IX, GSDIX, PhK Deficiency, Phosphorylase b Kinase Deficiency</div><p class="contrib-group"><span itemprop="author">Mrudu Herbert</span>, MD, MPH, <span itemprop="author">Jennifer L Goldstein</span>, PhD, <span itemprop="author">Catherine Rehder</span>, PhD, <span itemprop="author">Stephanie Austin</span>, MS, MA, CGC, <span itemprop="author">Priya S Kishnani</span>, MD, and <span itemprop="author">Deeksha S Bali</span>, PhD.</p><a data-jig="ncbitoggler" href="#__NBK55061_ai__" style="border:0;text-decoration:none">Author Information and Affiliations</a><div style="display:none" class="ui-widget" id="__NBK55061_ai__"><div class="contrib half_rhythm"><span itemprop="author">Mrudu Herbert</span>, MD, MPH<div class="affiliation small">Department of Pediatrics<br />University of Kentucky<br />Lexington, Kentucky<div><span class="email-label">Email: </span><a href="mailto:dev@null" data-email="ude.yku@trebreh.udurm" class="oemail">ude.yku@trebreh.udurm</a></div></div></div><div class="contrib half_rhythm"><span itemprop="author">Jennifer L Goldstein</span>, PhD<div class="affiliation small">Department of Genetics<br />University of North Carolina - Chapel Hill<br />Chapel Hill, North Carolina<div><span class="email-label">Email: </span><a href="mailto:dev@null" data-email="ude.cnu.liame@nejdlog" class="oemail">ude.cnu.liame@nejdlog</a></div></div></div><div class="contrib half_rhythm"><span itemprop="author">Catherine Rehder</span>, PhD<div class="affiliation small">Molecular Genetics Laboratory<br />Duke University Medical Center<br />Durham, North Carolina<div><span class="email-label">Email: </span><a href="mailto:dev@null" data-email="ude.ekud@redher.enirehtac" class="oemail">ude.ekud@redher.enirehtac</a></div></div></div><div class="contrib half_rhythm"><span itemprop="author">Stephanie Austin</span>, MS, MA, CGC<div class="affiliation small">Amicus Therapeutics, Inc<br />Phildelphia, Pennsylvania<div><span class="email-label">Email: </span><a href="mailto:dev@null" data-email="moc.xrsucima@nitsuas" class="oemail">moc.xrsucima@nitsuas</a></div></div></div><div class="contrib half_rhythm"><span itemprop="author">Priya S Kishnani</span>, MD<div class="affiliation small">Clinical Genetics<br />Department of Pediatrics<br />Duke University Medical Center<br />Durham, North Carolina<div><span class="email-label">Email: </span><a href="mailto:dev@null" data-email="ude.ekud@inanhsik.ayirp" class="oemail">ude.ekud@inanhsik.ayirp</a></div></div></div><div class="contrib half_rhythm"><span itemprop="author">Deeksha S Bali</span>, PhD<div class="affiliation small">Biochemical Genetics Laboratory<br />Duke University Medical Center<br />Durham, North Carolina<div><span class="email-label">Email: </span><a href="mailto:dev@null" data-email="ude.ekud@ilabd" class="oemail">ude.ekud@ilabd</a></div></div></div></div><p class="small">Initial Posting: <span itemprop="datePublished">May 31, 2011</span>; Last Update: <span itemprop="dateModified">November 1, 2018</span>.</p><p><em>Estimated reading time: 40 minutes</em></p></div><div class="jig-ncbiinpagenav body-content whole_rhythm" data-jigconfig="allHeadingLevels: ['h2'],smoothScroll: false" itemprop="text"><div id="gsd9.Summary" itemprop="description"><h2 id="_gsd9_Summary_">Summary</h2><div><h4 class="inline">Clinical characteristics.</h4><p>Phosphorylase kinase (PhK) deficiency causing glycogen storage disease type IX (GSD IX) results from deficiency of the enzyme phosphorylase b kinase, which has a major regulatory role in the breakdown of glycogen. The two types of PhK deficiency are <i>liver PhK deficiency</i> (characterized by early childhood onset of hepatomegaly and growth restriction, and often, but not always, fasting ketosis and hypoglycemia) and <i>muscle PhK deficiency</i>, which is considerably rarer (characterized by any of the following: exercise intolerance, myalgia, muscle cramps, myoglobinuria, and progressive muscle weakness). While symptoms and biochemical abnormalities of liver PhK deficiency were thought to improve with age, it is becoming evident that affected individuals need to be monitored for long-term complications such as liver fibrosis and cirrhosis.</p></div><div><h4 class="inline">Diagnosis/testing.</h4><p>The enzyme PhK comprises four copies each of four subunits (α, β, γ, and δ).</p><p>Pathogenic variants in:</p><ul><li class="half_rhythm"><div><i>PHKA1</i>, encoding subunit α, cause the rare <a class="def" href="/books/n/gene/glossary/def-item/x-linked/">X-linked</a> disorder muscle PhK deficiency;</div></li><li class="half_rhythm"><div><i>PHKA2</i>, also encoding subunit α, cause the most common form, liver PhK deficiency (<a class="def" href="/books/n/gene/glossary/def-item/x-linked/">X-linked</a> liver glycogenosis);</div></li><li class="half_rhythm"><div><i>PHKB</i>, encoding subunit β, cause <a class="def" href="/books/n/gene/glossary/def-item/autosomal-recessive/">autosomal recessive</a> PhK deficiency in both liver and muscle;</div></li><li class="half_rhythm"><div><i>PHKG2</i>, encoding subunit γ, cause <a class="def" href="/books/n/gene/glossary/def-item/autosomal-recessive/">autosomal recessive</a> liver PhK deficiency.</div></li></ul><p>The diagnosis of PhK deficiency is established in a <a class="def" href="/books/n/gene/glossary/def-item/proband/">proband</a> with the characteristic clinical findings, a family history of suspected storage disease, and/or a <a class="def" href="/books/n/gene/glossary/def-item/hemizygous/">hemizygous</a> <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a> in <i>PHKA1</i> or <i>PHKA2</i> or <a class="def" href="/books/n/gene/glossary/def-item/biallelic/">biallelic</a> pathogenic variants in <i>PHKB</i> or <i>PHKG2</i> identified by <a class="def" href="/books/n/gene/glossary/def-item/molecular-genetic-testing/">molecular genetic testing</a>.</p></div><div><h4 class="inline">Management.</h4><p>
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<i>Treatment of manifestations:</i>
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</p><ul><li class="half_rhythm"><div><i>Liver PhK deficiency.</i> Hypoglycemia can be prevented with frequent daytime feedings that are high in complex carbohydrates and protein. When hypoglycemia or ketosis is present, Polycose<sup>®</sup> or fruit juice is given orally as tolerated or glucose by IV. Liver manifestations (e.g., cirrhosis, liver failure, portal hypertension) are managed symptomatically.</div></li><li class="half_rhythm"><div><i>Muscle PhK deficiency.</i> Physical therapy based on physical status and function; optimization of blood glucose concentrations by a metabolic nutritionist based on activity.</div></li></ul><p>
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<i>Surveillance:</i>
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</p><ul><li class="half_rhythm"><div><i>Liver PhK deficiency.</i> Regular evaluation by a metabolic physician and a metabolic nutritionist. Monitoring of blood glucose concentration and blood ketones routinely as well as during times of stress (e.g., illness, intense activity, rapid growth, puberty) and reduced food intake. In children younger than age 18 years, liver ultrasound examination should be performed every 12 to 24 months. With increasing age, CT or MRI using intravenous contrast should be considered to evaluate for complications of liver disease. Echocardiogram should be performed at least every two years.</div></li><li class="half_rhythm"><div><i>Muscle PhK deficiency.</i> Regular evaluation by a metabolic physician, a metabolic nutritionist, and a physical therapist.</div></li></ul><p>
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<i>Agents/circumstances to avoid:</i>
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</p><ul><li class="half_rhythm"><div><i>Liver PhK deficiency.</i> Large amounts of simple sugars as they will increase liver storage of glycogen; prolonged fasting; high-impact contact sports if significant hepatomegaly is present; drugs known to cause hypoglycemia such as insulin and insulin secretagogues (the sulfonylureas) or drugs known to mask symptoms of hypoglycemia such as beta-blockers; alcohol (which may predispose to hypoglycemia).</div></li><li class="half_rhythm"><div><i>Muscle PhK deficiency.</i> Vigorous exercise; medications like succinylcholine and statins that can cause rhabdomyolysis.</div></li></ul><p><i>Evaluation of</i>
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<i>relatives at risk:</i> Molecular genetic testing (if the family-specific <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a>[s] are known) and/or evaluation by a metabolic physician (if the family-specific pathogenic variant[s] are not known) allows early diagnosis and treatment for sibs at increased risk for GSD IX.</p><p><i>Pregnancy management:</i> Individualized dietary management is necessary to maintain euglycemia throughout pregnancy.</p></div><div><h4 class="inline">Genetic counseling.</h4><p><i>PHKA2</i>-related liver PhK deficiency and <i>PHKA1</i>-related muscle PhK deficiency are inherited in an <a class="def" href="/books/n/gene/glossary/def-item/x-linked/">X-linked</a> manner. <i>PHKB</i>-related liver and muscle PhK deficiency and <i>PHKG2</i>-related liver PhK deficiency are inherited in an <a class="def" href="/books/n/gene/glossary/def-item/autosomal-recessive/">autosomal recessive</a> manner.</p><ul><li class="half_rhythm"><div><i><a class="def" href="/books/n/gene/glossary/def-item/x-linked/">X-linked</a> inheritance</i>. If the mother of the <a class="def" href="/books/n/gene/glossary/def-item/proband/">proband</a> has a <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a>, the chance of transmitting it in each pregnancy is 50%. Males who inherit the pathogenic variant will be affected; females who inherit the pathogenic variant will be heterozygotes (carriers); the development of symptoms in individuals depends on the pattern of <a class="def" href="/books/n/gene/glossary/def-item/x-chromosome-inactivation/">X-chromosome inactivation</a>. Affected males pass the pathogenic variant to all of their daughters and none of their sons.</div></li><li class="half_rhythm"><div><i>Autosomal recessive inheritance</i>. 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></ul><p>Carrier testing for at-risk relatives, <a class="def" href="/books/n/gene/glossary/def-item/prenatal-testing/">prenatal testing</a> for pregnancies at risk, and <a class="def" href="/books/n/gene/glossary/def-item/preimplantation-genetic-testing/">preimplantation genetic testing</a> are possible if the <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a>(s) in the family have been identified.</p></div></div><div id="gsd9.GeneReview_Scope"><h2 id="_gsd9_GeneReview_Scope_"><i>GeneReview</i> Scope</h2><div id="gsd9.Tc" class="table"><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK55061/table/gsd9.Tc/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__gsd9.Tc_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_gsd9.Tc_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Phosphorylase Kinase Deficiency: Included Phenotypes <sup>1</sup></th></tr></thead><tbody><tr><td headers="hd_h_gsd9.Tc_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Liver phosphorylase kinase deficiency</div></li><li class="half_rhythm"><div>Muscle phosphorylase kinase deficiency</div></li></ul>
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</td></tr></tbody></table></div><div><div><dl class="temp-labeled-list small"><dt></dt><dd><div><p class="no_margin">For synonyms and outdated names see <a href="#gsd9.Nomenclature">Nomenclature</a>.</p></div></dd><dt>1. </dt><dd><div id="gsd9.TF.c.1"><p class="no_margin">For other genetic causes of these phenotypes see <a href="#gsd9.Differential_Diagnosis">Differential Diagnosis</a>.</p></div></dd></dl></div></div></div></div><div id="gsd9.Diagnosis"><h2 id="_gsd9_Diagnosis_">Diagnosis</h2><p>Phosphorylase kinase deficiency causing glycogen storage disease type IX (GSD IX) results from deficiency of the enzyme phosphorylase b kinase (PhK), an enzyme with a key regulatory role in the breakdown of glycogen. Deficiency of this enzyme, which is composed of four copies each of four subunits (α, β, γ, and δ), results in considerable clinical variability [<a class="bk_pop" href="#gsd9.REF.chen.2001">Chen 2001</a>, <a class="bk_pop" href="#gsd9.REF.kishnani.2010">Kishnani & Chen 2010</a>].</p><p>For the purposes of this review, phosphorylase kinase (PhK) deficiency has been divided into liver PhK deficiency and muscle PhK deficiency (see <a class="figpopup" href="/books/NBK55061/figure/gsd9.F1/?report=objectonly" target="object" rid-figpopup="figgsd9F1" rid-ob="figobgsd9F1">Figure 1</a> and <a class="figpopup" href="/books/NBK55061/figure/gsd9.F2/?report=objectonly" target="object" rid-figpopup="figgsd9F2" rid-ob="figobgsd9F2">Figure 2</a>). Liver PhK deficiency is further divided into three subtypes based on the <a class="def" href="/books/n/gene/glossary/def-item/gene/">gene</a> in which pathogenic variants occur (<i>PHKA2</i>, <i>PHKB</i>, and <i>PHKG2</i>) and inheritance pattern. It should be noted that pathogenic variants in <i>PHKB</i> and, rarely, <i>PHKG2</i> result in PhK deficiency both in liver and muscle. However, the symptoms from muscle involvement can be mild or absent; thus, this subtype may be clinically indistinguishable from the liver PhK deficiencies caused by pathogenic variants in <i>PHKA2</i>.</p><div class="iconblock whole_rhythm clearfix ten_col fig" id="figgsd9F1" co-legend-rid="figlgndgsd9F1"><a href="/books/NBK55061/figure/gsd9.F1/?report=objectonly" target="object" title="Figure 1. " class="img_link icnblk_img figpopup" rid-figpopup="figgsd9F1" rid-ob="figobgsd9F1"><img class="small-thumb" src="/books/NBK55061/bin/gsd9-Image001.gif" src-large="/books/NBK55061/bin/gsd9-Image001.jpg" alt="Figure 1. " /></a><div class="icnblk_cntnt" id="figlgndgsd9F1"><h4 id="gsd9.F1"><a href="/books/NBK55061/figure/gsd9.F1/?report=objectonly" target="object" rid-ob="figobgsd9F1">Figure 1. </a></h4><p class="float-caption no_bottom_margin">Phosphorylase kinase subunit expression Note: The CALM genes and <i>PHKG1</i> are not involved in GSD IX.</p></div></div><div class="iconblock whole_rhythm clearfix ten_col fig" id="figgsd9F2" co-legend-rid="figlgndgsd9F2"><a href="/books/NBK55061/figure/gsd9.F2/?report=objectonly" target="object" title="Figure 2. " class="img_link icnblk_img figpopup" rid-figpopup="figgsd9F2" rid-ob="figobgsd9F2"><img class="small-thumb" src="/books/NBK55061/bin/gsd9-Image002.gif" src-large="/books/NBK55061/bin/gsd9-Image002.jpg" alt="Figure 2. " /></a><div class="icnblk_cntnt" id="figlgndgsd9F2"><h4 id="gsd9.F2"><a href="/books/NBK55061/figure/gsd9.F2/?report=objectonly" target="object" rid-ob="figobgsd9F2">Figure 2. </a></h4><p class="float-caption no_bottom_margin">Phosphorylase kinase (PhK) enzyme subunits and genes that encode them </p></div></div><p><i>PHKA2</i>-related PhK deficiency is also known as <a class="def" href="/books/n/gene/glossary/def-item/x-linked/">X-linked</a> liver glycogenosis (XLG) and is divided into two biochemical subtypes, XLG1 and XLG2, depending on enzyme activity in various tissues.</p><p>Muscle PhK deficiency in this review refers to <i>PHKA1</i>-related GSD IX.</p><p><i>PHKG1</i> has not yet been associated with PhK deficiency.</p><p>The delta subunit of PhK, calmodulin, is encoded by three different genes: <i>CALM1</i>, <i>CALM2</i>, and <i>CALM3.</i> To date these have not been associated with PhK deficiency.</p><div id="gsd9.Suggestive_Findings"><h3>Suggestive Findings</h3><p>Liver or muscle phosphorylase kinase (PhK) deficiency resulting in glycogen storage disease type IX (GSD IX) <b>should be suspected</b> in individuals with the phenotypic findings shown in <a href="/books/NBK55061/table/gsd9.T.phk_deficiency_suggestive_phenoty/?report=objectonly" target="object" rid-ob="figobgsd9Tphkdeficiencysuggestivephenoty">Table 1</a>.</p><div id="gsd9.T.phk_deficiency_suggestive_phenoty" class="table"><h3><span class="label">Table 1. </span></h3><div class="caption"><p>PhK Deficiency: Suggestive Phenotypic Findings</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK55061/table/gsd9.T.phk_deficiency_suggestive_phenoty/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__gsd9.T.phk_deficiency_suggestive_phenoty_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_gsd9.T.phk_deficiency_suggestive_phenoty_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">PhK Deficiency Type</th><th id="hd_h_gsd9.T.phk_deficiency_suggestive_phenoty_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Clinical Findings</th><th id="hd_h_gsd9.T.phk_deficiency_suggestive_phenoty_1_1_1_3" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Laboratory Test Results</th></tr></thead><tbody><tr><td headers="hd_h_gsd9.T.phk_deficiency_suggestive_phenoty_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<b>Liver PhK deficiency</b>
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</td><td headers="hd_h_gsd9.T.phk_deficiency_suggestive_phenoty_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Hepatomegaly</div></li><li class="half_rhythm"><div>Growth restriction in many (not all)</div></li><li class="half_rhythm"><div>Fasting ketosis & hypoglycemia – mild to severe</div></li></ul>
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</td><td headers="hd_h_gsd9.T.phk_deficiency_suggestive_phenoty_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>↑ liver transaminases</div></li><li class="half_rhythm"><div>↑ triglycerides & cholesterol [<a class="bk_pop" href="#gsd9.REF.morava.2005.703">Morava et al 2005</a>, <a class="bk_pop" href="#gsd9.REF.roscher.2014.171">Roscher et al 2014</a>, <a class="bk_pop" href="#gsd9.REF.bali.2017.63">Bali et al 2017</a>]</div></li><li class="half_rhythm"><div>Normal uric acid & lactic acid concentrations <sup>1</sup></div></li></ul>
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</td></tr><tr><td headers="hd_h_gsd9.T.phk_deficiency_suggestive_phenoty_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<b>Muscle</b>
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<br />
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<b>PhK</b>
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<br />
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<b>deficiency</b>
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</td><td headers="hd_h_gsd9.T.phk_deficiency_suggestive_phenoty_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Exercise intolerance</div></li><li class="half_rhythm"><div>Myalgia</div></li><li class="half_rhythm"><div>Muscle cramps</div></li><li class="half_rhythm"><div>Myoglobinuria</div></li><li class="half_rhythm"><div>Progressive muscle weakness</div></li></ul>
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See footnote 2.</td><td headers="hd_h_gsd9.T.phk_deficiency_suggestive_phenoty_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Serum concentration of creatine kinase > upper limits of normal in some cases <sup>3</sup></div></li><li class="half_rhythm"><div>Electromyography usually normal</div></li></ul>
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</td></tr></tbody></table></div><div><div><dl class="temp-labeled-list small"><dt>1. </dt><dd><div id="gsd9.TF.1.1"><p class="no_margin">Lactic acid levels may be elevated postprandially [<a class="bk_pop" href="#gsd9.REF.davitspraul.2011.137">Davit-Spraul et al 2011</a>].</p></div></dd><dt>2. </dt><dd><div id="gsd9.TF.1.2"><p class="no_margin">There is considerable variability in the clinical presentation. Some individuals may be virtually asymptomatic.</p></div></dd><dt>3. </dt><dd><div id="gsd9.TF.1.3"><p class="no_margin">Note: Normal ranges tend to be laboratory specific.</p></div></dd></dl></div></div></div></div><div id="gsd9.Establishing_the_Diagnosis"><h3>Establishing the Diagnosis</h3><p>The diagnosis of PhK deficiency <b>is established</b> in a <a class="def" href="/books/n/gene/glossary/def-item/proband/">proband</a> with the characteristic clinical findings (see <a href="#gsd9.Suggestive_Findings">Suggestive Findings</a>), a family history of suspected storage disease, and/or a <a class="def" href="/books/n/gene/glossary/def-item/hemizygous/">hemizygous</a> pathogenic (or <a class="def" href="/books/n/gene/glossary/def-item/likely-pathogenic/">likely pathogenic</a>) variant or <a class="def" href="/books/n/gene/glossary/def-item/biallelic/">biallelic</a> pathogenic (or likely pathogenic) variants in one of the genes listed in <a href="/books/NBK55061/table/gsd9.T.molecular_genetic_testing_used_in/?report=objectonly" target="object" rid-ob="figobgsd9Tmoleculargenetictestingusedin">Table 2</a>. If <a class="def" href="/books/n/gene/glossary/def-item/molecular-genetic-testing/">molecular genetic testing</a> is not diagnostic, PhK activity can be measured in snap-frozen <a href="#gsd9.Liver_Biopsy">liver biopsy</a>, erythrocytes, leukocytes, and frozen <a href="#gsd9.Muscle_Biopsy">muscle biopsy</a> tissue.</p><p>Note: (1) While <a href="#gsd9.Liver_Biopsy">liver biopsy</a> or <a href="#gsd9.Muscle_Biopsy">muscle biopsy</a> was done routinely in previous years to measure PhK activity, the availability of <a class="def" href="/books/n/gene/glossary/def-item/molecular-genetic-testing/">molecular genetic testing</a> has reduced the need for such invasive procedures. (2) Per ACMG/AMP variant interpretation guidelines, the terms "<a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a>" and "<a class="def" href="/books/n/gene/glossary/def-item/likely-pathogenic/">likely pathogenic</a> variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [<a class="bk_pop" href="#gsd9.REF.richards.2015.405">Richards et al 2015</a>]. Reference to "pathogenic variants" in this <i>GeneReview</i> is understood to include any likely pathogenic variants. (3) The identification of variant(s) of <a class="def" href="/books/n/gene/glossary/def-item/uncertain-significance/">uncertain significance</a> cannot be used to confirm or rule out the diagnosis.</p><p>Molecular genetic testing approaches can include a combination of <b><a class="def" href="/books/n/gene/glossary/def-item/gene/">gene</a>-targeted testing</b> (<a class="def" href="/books/n/gene/glossary/def-item/multigene-panel/">multigene panel</a>, single-gene testing) and <b>comprehensive</b>
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<b><a class="def" href="/books/n/gene/glossary/def-item/genomic/">genomic</a> testing</b> (<a class="def" href="/books/n/gene/glossary/def-item/exome-sequencing/">exome sequencing</a>, <a class="def" href="/books/n/gene/glossary/def-item/exome-array/">exome array</a>, <a class="def" href="/books/n/gene/glossary/def-item/genome-sequencing/">genome sequencing</a>) depending on the <a class="def" href="/books/n/gene/glossary/def-item/phenotype/">phenotype</a>.</p><p>Gene-targeted testing requires that the clinician determine which <a class="def" href="/books/n/gene/glossary/def-item/gene/">gene</a>(s) are likely involved, whereas <a class="def" href="/books/n/gene/glossary/def-item/genomic/">genomic</a> testing does not. Because the <a class="def" href="/books/n/gene/glossary/def-item/phenotype/">phenotype</a> of PhK deficiency is broad, individuals with the distinctive findings described in <a href="#gsd9.Suggestive_Findings">Suggestive Findings</a> are likely to be diagnosed using gene-targeted testing (see <a href="#gsd9.Option_1">Option 1</a>), whereas those with a phenotype indistinguishable from many other inherited disorders with hepatomegaly and/or muscle weakness or with atypical phenotypic features are more likely to be diagnosed using genomic testing (see <a href="#gsd9.Option_2">Option 2</a>).</p><div id="gsd9.Option_1"><h4>Option 1</h4><p>When the phenotypic and laboratory findings suggest the diagnosis of PhK deficiency, <a class="def" href="/books/n/gene/glossary/def-item/molecular-genetic-testing/">molecular genetic testing</a> approaches can include use of a <b><a class="def" href="/books/n/gene/glossary/def-item/multigene-panel/">multigene panel</a></b> or <b>single-<a class="def" href="/books/n/gene/glossary/def-item/gene/">gene</a> testing</b>.</p><p><b>A <a class="def" href="/books/n/gene/glossary/def-item/multigene-panel/">multigene panel</a></b> that includes <i>PHKA1</i>, <i>PHKA2</i>, <i>PHKB</i>, <i>PHKG2</i>, and other genes of interest (see <a href="#gsd9.Differential_Diagnosis">Differential Diagnosis</a>) is most likely to identify the genetic cause of the condition while limiting identification of variants of <a class="def" href="/books/n/gene/glossary/def-item/uncertain-significance/">uncertain significance</a> and pathogenic variants in genes that do not explain the underlying <a class="def" href="/books/n/gene/glossary/def-item/phenotype/">phenotype</a>. Note: (1) The genes included in the panel and the diagnostic <a class="def" href="/books/n/gene/glossary/def-item/sensitivity/">sensitivity</a> of the testing used for each <a class="def" href="/books/n/gene/glossary/def-item/gene/">gene</a> vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this <i>GeneReview</i>. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused <a class="def" href="/books/n/gene/glossary/def-item/exome/">exome</a> analysis that includes genes specified by the clinician. (4) Methods used in a panel may include <a class="def" href="/books/n/gene/glossary/def-item/sequence-analysis/">sequence analysis</a>, <a class="def" href="/books/n/gene/glossary/def-item/deletion-duplication-analysis/">deletion/duplication analysis</a>, and/or other non-sequencing-based tests.</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><p><b>Note: Single-<a class="def" href="/books/n/gene/glossary/def-item/gene/">gene</a> testing</b> may be appropriate given the following clinical presentations:</p><ul><li class="half_rhythm"><div>For liver PhK deficiency, perform <a class="def" href="/books/n/gene/glossary/def-item/sequence-analysis/">sequence analysis</a> of <i>PHKA2</i> first, followed by <i>PHKG2</i>, and then <i>PHKB</i>. If only one (in <i>PHKG2</i> or <i>PHKB</i>) or no <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a> (<i>PHKA2</i>, <i>PHKG2</i>, or <i>PHKB</i>) is found, perform <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>.</div></li><li class="half_rhythm"><div>For muscle PhK deficiency, perform <a class="def" href="/books/n/gene/glossary/def-item/sequence-analysis/">sequence analysis</a> of <i>PHKA1</i> first. If no <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a> is found, perform <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>.</div></li><li class="half_rhythm"><div>In a male with a maternal family history of similarly affected males, it is appropriate to perform <a class="def" href="/books/n/gene/glossary/def-item/sequence-analysis/">sequence analysis</a> of <i>PHKA1</i> and <i>PHKA2</i> first depending on muscle/liver symptoms.</div></li></ul></div><div id="gsd9.Option_2"><h4>Option 2</h4><p>When the <a class="def" href="/books/n/gene/glossary/def-item/phenotype/">phenotype</a> is indistinguishable from many other inherited disorders characterized by hepatomegaly and/or muscle weakness, or if an individual has atypical phenotypic features, <b>comprehensive</b>
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<b><a class="def" href="/books/n/gene/glossary/def-item/genomic/">genomic</a> testing</b> (which does not require the clinician to determine which <a class="def" href="/books/n/gene/glossary/def-item/gene/">gene</a>[s] are likely involved) is the best option. <b>Exome sequencing</b> is most commonly used; <b><a class="def" href="/books/n/gene/glossary/def-item/genome-sequencing/">genome sequencing</a></b> is also possible.</p><p><b>Exome array</b> (when clinically available) may be considered if <a class="def" href="/books/n/gene/glossary/def-item/exome-sequencing/">exome sequencing</a> is not diagnostic.</p><p>For an introduction to comprehensive <a class="def" href="/books/n/gene/glossary/def-item/genomic/">genomic</a> testing click <a href="/books/n/gene/app5/#app5.Comprehensive_Genomic_Testing">here</a>. More detailed information for clinicians ordering genomic testing can be found <a href="/books/n/gene/app5/#app5.Comprehensive_Genomic_Testing_1">here</a>.</p><div id="gsd9.T.molecular_genetic_testing_used_in" class="table"><h3><span class="label">Table 2. </span></h3><div class="caption"><p>Molecular Genetic Testing Used in Phosphorylase Kinase Deficiency</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK55061/table/gsd9.T.molecular_genetic_testing_used_in/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__gsd9.T.molecular_genetic_testing_used_in_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_gsd9.T.molecular_genetic_testing_used_in_1_1_1_1" rowspan="2" scope="col" colspan="1" headers="hd_h_gsd9.T.molecular_genetic_testing_used_in_1_1_1_1" style="text-align:left;vertical-align:middle;">Gene <sup>1, 2</sup><br />(MOI)</th><th id="hd_h_gsd9.T.molecular_genetic_testing_used_in_1_1_1_2" rowspan="2" scope="col" colspan="1" headers="hd_h_gsd9.T.molecular_genetic_testing_used_in_1_1_1_2" style="text-align:left;vertical-align:middle;">Proportion of PhK Deficiency Attributed to Pathogenic Variants in Gene</th><th id="hd_h_gsd9.T.molecular_genetic_testing_used_in_1_1_1_3" colspan="2" scope="colgroup" rowspan="1" style="text-align:left;vertical-align:middle;">Proportion of Pathogenic Variants <sup>3</sup> Detectable by Method</th></tr><tr><th headers="hd_h_gsd9.T.molecular_genetic_testing_used_in_1_1_1_3" id="hd_h_gsd9.T.molecular_genetic_testing_used_in_1_1_2_1" colspan="1" scope="colgroup" rowspan="1" style="text-align:left;vertical-align:middle;">Sequence analysis <sup>4</sup></th><th headers="hd_h_gsd9.T.molecular_genetic_testing_used_in_1_1_1_3" id="hd_h_gsd9.T.molecular_genetic_testing_used_in_1_1_2_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Gene-targeted <a class="def" href="/books/n/gene/glossary/def-item/deletion-duplication-analysis/">deletion/duplication analysis</a> <sup>5</sup></th></tr></thead><tbody><tr><td headers="hd_h_gsd9.T.molecular_genetic_testing_used_in_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><i>PHKA1</i> (XL)</td><td headers="hd_h_gsd9.T.molecular_genetic_testing_used_in_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Rare – muscle <a class="def" href="/books/n/gene/glossary/def-item/phenotype/">phenotype</a></td><td headers="hd_h_gsd9.T.molecular_genetic_testing_used_in_1_1_1_3 hd_h_gsd9.T.molecular_genetic_testing_used_in_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">7/7 <sup>6</sup></td><td headers="hd_h_gsd9.T.molecular_genetic_testing_used_in_1_1_1_3 hd_h_gsd9.T.molecular_genetic_testing_used_in_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Unknown <sup>7</sup></td></tr><tr><td headers="hd_h_gsd9.T.molecular_genetic_testing_used_in_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><i>PHKA2</i> (XL)</td><td headers="hd_h_gsd9.T.molecular_genetic_testing_used_in_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">75% of individuals w/liver PhK deficiency</td><td headers="hd_h_gsd9.T.molecular_genetic_testing_used_in_1_1_1_3 hd_h_gsd9.T.molecular_genetic_testing_used_in_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">~94% <sup>8</sup></td><td headers="hd_h_gsd9.T.molecular_genetic_testing_used_in_1_1_1_3 hd_h_gsd9.T.molecular_genetic_testing_used_in_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">~6% <sup>9</sup></td></tr><tr><td headers="hd_h_gsd9.T.molecular_genetic_testing_used_in_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><i>PHKB</i> (AR)</td><td headers="hd_h_gsd9.T.molecular_genetic_testing_used_in_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">~10% of individuals w/liver PhK deficiency</td><td headers="hd_h_gsd9.T.molecular_genetic_testing_used_in_1_1_1_3 hd_h_gsd9.T.molecular_genetic_testing_used_in_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">~96% <sup>10</sup></td><td headers="hd_h_gsd9.T.molecular_genetic_testing_used_in_1_1_1_3 hd_h_gsd9.T.molecular_genetic_testing_used_in_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">~4% <sup>11</sup></td></tr><tr><td headers="hd_h_gsd9.T.molecular_genetic_testing_used_in_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><i>PHKG2</i> (AR)</td><td headers="hd_h_gsd9.T.molecular_genetic_testing_used_in_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">~10% of individuals w/liver PhK deficiency</td><td headers="hd_h_gsd9.T.molecular_genetic_testing_used_in_1_1_1_3 hd_h_gsd9.T.molecular_genetic_testing_used_in_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">~99% <sup>12</sup></td><td headers="hd_h_gsd9.T.molecular_genetic_testing_used_in_1_1_1_3 hd_h_gsd9.T.molecular_genetic_testing_used_in_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Unknown</td></tr></tbody></table></div><div><div><dl class="temp-labeled-list small"><dt></dt><dd><div><p class="no_margin">AR = <a class="def" href="/books/n/gene/glossary/def-item/autosomal-recessive/">autosomal recessive</a>; MOI = <a class="def" href="/books/n/gene/glossary/def-item/mode-of-inheritance/">mode of inheritance</a>; 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="gsd9.TF.2.1"><p class="no_margin">Genes are listed in alphabetic order.</p></div></dd><dt>2. </dt><dd><div id="gsd9.TF.2.2"><p class="no_margin">See <a href="/books/NBK55061/#gsd9.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>3. </dt><dd><div id="gsd9.TF.2.3"><p class="no_margin">See <a href="#gsd9.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>4. </dt><dd><div id="gsd9.TF.2.4"><p class="no_margin">Sequence analysis detects variants that are benign, <a class="def" href="/books/n/gene/glossary/def-item/likely-benign/">likely benign</a>, of <a class="def" href="/books/n/gene/glossary/def-item/uncertain-significance/">uncertain significance</a>, <a class="def" href="/books/n/gene/glossary/def-item/likely-pathogenic/">likely pathogenic</a>, or pathogenic. Variants may include <a class="def" href="/books/n/gene/glossary/def-item/missense/">missense</a>, <a class="def" href="/books/n/gene/glossary/def-item/nonsense-variant/">nonsense</a>, and <a class="def" href="/books/n/gene/glossary/def-item/splice-site/">splice site</a> variants and small intragenic deletions/insertions; typically, <a class="def" href="/books/n/gene/glossary/def-item/exon/">exon</a> or whole-<a class="def" href="/books/n/gene/glossary/def-item/gene/">gene</a> deletions/duplications are not detected. For issues to consider in interpretation of <a class="def" href="/books/n/gene/glossary/def-item/sequence-analysis/">sequence analysis</a> results, click <a href="/books/n/gene/app2/">here</a>.</p></div></dd><dt>5. </dt><dd><div id="gsd9.TF.2.5"><p class="no_margin">Gene-targeted <a class="def" href="/books/n/gene/glossary/def-item/deletion-duplication-analysis/">deletion/duplication analysis</a> detects intragenic deletions or duplications. Methods used may include a range of techniques such as <a class="def" href="/books/n/gene/glossary/def-item/quantitative-pcr/">quantitative PCR</a>, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a <a class="def" href="/books/n/gene/glossary/def-item/gene/">gene</a>-targeted microarray designed to detect single-<a class="def" href="/books/n/gene/glossary/def-item/exon/">exon</a> deletions or duplications.</p></div></dd><dt>6. </dt><dd><div id="gsd9.TF.2.6"><p class="no_margin"><a class="bk_pop" href="#gsd9.REF.wehner.1994.1983">Wehner et al [1994]</a>, <a class="bk_pop" href="#gsd9.REF.bruno.1998.648">Bruno et al [1998]</a>, <a class="bk_pop" href="#gsd9.REF.burwinkel.2003a.516">Burwinkel et al [2003a]</a>, <a class="bk_pop" href="#gsd9.REF.wuyts.2005.82">Wuyts et al [2005]</a>, <a class="bk_pop" href="#gsd9.REF._rngreen.2008.1876">Ørngreen et al [2008]</a>, <a class="bk_pop" href="#gsd9.REF.echanizlaguna.2010.125">Echaniz-Laguna et al [2010]</a>, <a class="bk_pop" href="#gsd9.REF.preisler.2012.265">Preisler et al [2012]</a></p></div></dd><dt>7. </dt><dd><div id="gsd9.TF.2.7"><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><dt>8. </dt><dd><div id="gsd9.TF.2.8"><p class="no_margin"><a class="bk_pop" href="#gsd9.REF.hendrickx.1999.1541">Hendrickx et al [1999]</a>, <a class="bk_pop" href="#gsd9.REF.beauchamp.2007.88">Beauchamp et al [2007]</a>, <a class="bk_pop" href="#gsd9.REF.davitspraul.2011.137">Davit-Spraul et al [2011]</a>, <a class="bk_pop" href="#gsd9.REF.wang.2013.106">Wang et al [2013]</a>, <a class="bk_pop" href="#gsd9.REF.brown.2015.489">Brown et al [2015]</a>, <a class="bk_pop" href="#gsd9.REF.choi.2016.33">Choi et al [2016]</a></p></div></dd><dt>9. </dt><dd><div id="gsd9.TF.2.9"><p class="no_margin"><a class="bk_pop" href="#gsd9.REF.davitspraul.2011.137">Davit-Spraul et al [2011]</a>, <a class="bk_pop" href="#gsd9.REF.wang.2013.106">Wang et al [2013]</a>, <a class="bk_pop" href="#gsd9.REF.brown.2015.489">Brown et al [2015]</a>, <a class="bk_pop" href="#gsd9.REF.choi.2016.33">Choi et al [2016]</a></p></div></dd><dt>10. </dt><dd><div id="gsd9.TF.2.10"><p class="no_margin"><a class="bk_pop" href="#gsd9.REF.burwinkel.1997a.1109">Burwinkel et al [1997a]</a>, <a class="bk_pop" href="#gsd9.REF.burwinkel.1997b.170">Burwinkel et al [1997b]</a>, <a class="bk_pop" href="#gsd9.REF.burwinkel.2003a.516">Burwinkel et al [2003a]</a>, <a class="bk_pop" href="#gsd9.REF.beauchamp.2007.88">Beauchamp et al [2007]</a>, <a class="bk_pop" href="#gsd9.REF.davitspraul.2011.137">Davit-Spraul et al [2011]</a>, <a class="bk_pop" href="#gsd9.REF.brown.2015.489">Brown et al [2015]</a></p></div></dd><dt>11. </dt><dd><div id="gsd9.TF.2.11"><p class="no_margin"><a class="bk_pop" href="#gsd9.REF.burwinkel.1997a.1109">Burwinkel et al [1997a]</a>, <a class="bk_pop" href="#gsd9.REF.alfadhel.2016.126">Alfadhel et al [2016]</a></p></div></dd><dt>12. </dt><dd><div id="gsd9.TF.2.12"><p class="no_margin"><a class="bk_pop" href="#gsd9.REF.burwinkel.1998b.149">Burwinkel et al [1998b]</a>, <a class="bk_pop" href="#gsd9.REF.burwinkel.2003b.834">Burwinkel et al [2003b]</a>, <a class="bk_pop" href="#gsd9.REF.beauchamp.2007.88">Beauchamp et al [2007]</a>, <a class="bk_pop" href="#gsd9.REF.davitspraul.2011.137">Davit-Spraul et al [2011]</a>, <a class="bk_pop" href="#gsd9.REF.bali.2014.309">Bali et al [2014]</a>, <a class="bk_pop" href="#gsd9.REF.brown.2015.489">Brown et al [2015]</a></p></div></dd></dl></div></div></div></div><div id="gsd9.Liver_Biopsy"><h4>Liver Biopsy</h4><p>
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<b>Histology</b>
|
||
</p><ul><li class="half_rhythm"><div>Histology usually shows distended hepatocytes as a result of excess glycogen accumulation. Bridging portal fibrosis, steatosis, and low-grade inflammatory changes may also be seen [<a class="bk_pop" href="#gsd9.REF.johnson.2012.90">Johnson et al 2012</a>, <a class="bk_pop" href="#gsd9.REF.tsilianidis.2013.179">Tsilianidis et al 2013</a>]. Liver cirrhosis and adenomas have been reported.</div></li><li class="half_rhythm"><div>Remarkably elevated glycogen content with normal glycogen structure is found on biochemical testing of snap-frozen liver biopsy tissue.</div></li></ul><p><b>Enzyme testing.</b> Phosphorylase b kinase (PhK) is reduced in liver, erythrocytes, and leukocytes of most (not all) individuals with liver PhK deficiency.</p><ul><li class="half_rhythm"><div>Normal PhK activity in erythrocytes is 1.0 μmol/min/g hemoglobin, and in liver it is 0.1 μmol/min/mg protein.</div></li><li class="half_rhythm"><div>Abnormal range is <10% of normal level in the tissue being tested.</div></li></ul><p>Note: (1) PhK is a labile enzyme that is highly sensitive to handling conditions and temperature exposure; thus, it is recommended that test blood samples be accompanied by a control blood sample drawn at the same time from an unrelated individual. Samples need to be kept cold (4<sup>°</sup>C) at all times including during transport. (2) In a subset of affected individuals, in vitro PhK activity is normal or even elevated in erythrocytes and leukocytes and variable in liver.</p></div><div id="gsd9.Muscle_Biopsy"><h4>Muscle Biopsy</h4><p>
|
||
<b>Histology</b>
|
||
</p><ul><li class="half_rhythm"><div>Excessive amounts of subsarcolemmal glycogen accumulation are found on histology.</div></li><li class="half_rhythm"><div>Elevated glycogen content with normal glycogen structure is found on biochemical testing of muscle.</div></li></ul><p>
|
||
<b>Enzyme testing</b>
|
||
</p><ul><li class="half_rhythm"><div>PhK enzyme activity is markedly reduced in muscle but normal in liver, blood cells, and fibroblasts.</div></li><li class="half_rhythm"><div>Because PhK enzyme activates the enzyme glycogen phosphorylase in muscle and liver, the activity of glycogen myophosphorylase (phosphorylase-a) may be reduced in muscle in individuals with muscle PhK deficiency.</div></li></ul></div></div></div><div id="gsd9.Clinical_Characteristics"><h2 id="_gsd9_Clinical_Characteristics_">Clinical Characteristics</h2><div id="gsd9.Clinical_Description"><h3>Clinical Description</h3><p>Glycogen storage disease type IX (GSD IX) is caused by PhK deficiency affecting primarily liver or muscle.</p><div id="gsd9.Liver_PhK_Deficiency"><h4>Liver PhK Deficiency</h4><p>While liver PhK deficiency has been considered a mild condition, more severe involvement has been documented [<a class="bk_pop" href="#gsd9.REF.johnson.2012.90">Johnson et al 2012</a>, <a class="bk_pop" href="#gsd9.REF.tsilianidis.2013.179">Tsilianidis et al 2013</a>]. The three subtypes, caused by pathogenic variants in three different genes (<i>PHKA2</i>, <i>PHKB</i>, and <i>PHKG2</i>), cannot be distinguished by their clinical features, which can vary significantly in severity. See also <a href="#gsd9.GenotypePhenotype_Correlations">Genotype-Phenotype Correlations</a>.</p><p><b>Presentation.</b> Typically, an affected child presents in the first years of life with hepatomegaly and growth restriction. Hyperketotic hypoglycemia, if present, is usually mild but can be severe and recurrent.</p><p>
|
||
<b>Hepatomegaly</b>
|
||
</p><ul><li class="half_rhythm"><div>Hepatomegaly is one of the most common presentations of liver PhK deficiency. The extent of liver enlargement is variable, ranging from mild to massive [<a class="bk_pop" href="#gsd9.REF.roscher.2014.171">Roscher et al 2014</a>].</div></li><li class="half_rhythm"><div>Liver fibrosis can occur and in some instances progress to cirrhosis, especially in liver PhK deficiency caused by pathogenic variants in <i>PHKG2</i>; it has also been reported in some individuals with pathogenic variants in <i>PHKA2</i> [<a class="bk_pop" href="#gsd9.REF.johnson.2012.90">Johnson et al 2012</a>, <a class="bk_pop" href="#gsd9.REF.tsilianidis.2013.179">Tsilianidis et al 2013</a>]. It has not yet been reported in association with <i>PHKB</i> variants but could occur given the findings in other liver PhK deficiency disorders.</div></li><li class="half_rhythm"><div>Liver adenoma has been reported but appears to be very rare and mostly associated with the <i>PHKG2</i>-related subtype [<a class="bk_pop" href="#gsd9.REF.roscher.2014.171">Roscher et al 2014</a>, <a class="bk_pop" href="#gsd9.REF.bali.2017.63">Bali et al 2017</a>].</div></li><li class="half_rhythm"><div>Hepatomegaly usually decreases with age. Decrease in liver size and normalization of liver enzymes following treatment with cornstarch and high-protein diet is reported [<a class="bk_pop" href="#gsd9.REF.beauchamp.2007.88">Beauchamp et al 2007</a>, <a class="bk_pop" href="#gsd9.REF.roscher.2014.171">Roscher et al 2014</a>].</div></li><li class="half_rhythm"><div>However, as affected individuals live longer and the natural history and long-term complications are better understood, it is becoming clear that individuals can progress to liver cirrhosis after a period of quiescence and what appears to be normalization.</div></li></ul><p><b>Growth restriction</b> is most pronounced in childhood, after which catchup growth and normal sexual development occur; most adults reach normal height [<a class="bk_pop" href="#gsd9.REF.roscher.2014.171">Roscher et al 2014</a>, <a class="bk_pop" href="#gsd9.REF.bali.2017.63">Bali et al 2017</a>].</p><p><b>Hyperketotic hypoglycemia.</b> Hyperketosis, with or without hypoglycemia, can occur following periods of prolonged fasting or decreased nutritional intake, or vomiting and diarrhea during illness. Hyperketonemia is defined as blood 3-β-hydroxybutyrate (βOHB) >1.0 mmol/L (normal <0.3 mmol/L) [<a class="bk_pop" href="#gsd9.REF.clarke.2008.165">Clarke et al 2008</a>].</p><ul><li class="half_rhythm"><div>Ketotic hypoglycemia varies from occasional to recurrent in some cases [<a class="bk_pop" href="#gsd9.REF.brown.2015.489">Brown et al 2015</a>, <a class="bk_pop" href="#gsd9.REF.hodax.2017.247">Hodax et al 2017</a>].</div></li><li class="half_rhythm"><div>Chronic ketosis indicates poor metabolic control and can affect growth and overall health.</div></li></ul><p><b>Muscle</b>
|
||
<b>concerns.</b> Hypotonia and muscle weakness have been observed in some individuals.</p><ul><li class="half_rhythm"><div>Mild delays in gross motor development are often seen in early childhood.</div></li><li class="half_rhythm"><div>Cardiac manifestations are rare; however, asymptomatic interventricular septal hypertrophy was reported in an individual with <i>PHKB</i>-associated liver PhK deficiency [<a class="bk_pop" href="#gsd9.REF.roscher.2014.171">Roscher et al 2014</a>].</div></li></ul><p>
|
||
<b>Genitourinary findings</b>
|
||
</p><ul><li class="half_rhythm"><div>Polycystic ovaries have been noted in females with liver PhK deficiency [<a class="bk_pop" href="#gsd9.REF.lee.1995.462">Lee & Leonard 1995</a>]. While the frequency of fertility issues has not been well studied, dysmenorrhea, menstrual irregularity, and oligomenorrhea have been reported [<a class="bk_pop" href="#gsd9.REF.cho.2013.75">Cho et al 2013</a>].</div></li><li class="half_rhythm"><div>Renal tubular acidosis has been reported in some individuals [<a class="bk_pop" href="#gsd9.REF.burwinkel.1998a.423">Burwinkel et al 1998a</a>, <a class="bk_pop" href="#gsd9.REF.beauchamp.2007.88">Beauchamp et al 2007</a>].</div></li></ul><p><b>Other.</b> Cognitive and/or speech delays that normalized later in life have been reported in a few individuals [<a class="bk_pop" href="#gsd9.REF.beauchamp.2007.88">Beauchamp et al 2007</a>, <a class="bk_pop" href="#gsd9.REF.roscher.2014.171">Roscher et al 2014</a>].</p><p><b>Adulthood.</b> Symptoms and biochemical abnormalities improve with age in most individuals with liver PhK deficiency [<a class="bk_pop" href="#gsd9.REF.zhang.2017.149">Zhang et al 2017</a>].</p><p>Reports of liver cirrhosis and hepatocellular carcinoma show that long-term monitoring is needed in individuals with liver PhK deficiency [<a class="bk_pop" href="#gsd9.REF.tsilianidis.2013.179">Tsilianidis et al 2013</a>, <a class="bk_pop" href="#gsd9.REF.roscher.2014.171">Roscher et al 2014</a>]. Other long-term issues could emerge as affected individuals are followed longitudinally.</p></div><div id="gsd9.Muscle_PhK_Deficiency"><h4>Muscle PhK Deficiency</h4><p>Muscle-specific phosphorylase kinase deficiency is caused by the <i>PHKA1</i> variant. However, muscle PhK deficiency caused by pathogenic variants in <i>PHKB</i> and (rarely) <i>PHKG2</i> is also seen.</p><p><b>Presentation.</b> This <a class="def" href="/books/n/gene/glossary/def-item/phenotype/">phenotype</a> can present anytime from childhood to adulthood with a broad range of symptoms including exercise intolerance, muscle cramps, myalgia, myoglobinuria, and progressive muscle weakness [<a class="bk_pop" href="#gsd9.REF.chen.2001">Chen 2001</a>, <a class="bk_pop" href="#gsd9.REF.kishnani.2010">Kishnani & Chen 2010</a>]. In children, it is primarily manifested as mild gross motor delay [<a class="bk_pop" href="#gsd9.REF.roscher.2014.171">Roscher et al 2014</a>, <a class="bk_pop" href="#gsd9.REF.bali.2017.63">Bali et al 2017</a>].</p><ul><li class="half_rhythm"><div>Minor muscle involvement has been reported in some affected individuals, particularly associated with <i>PHKG2-</i>related muscle PhK deficiency.</div></li><li class="half_rhythm"><div>Interventricular septal hypertrophy has been reported in an individual with pathogenic variants in <i>PHKB</i> [<a class="bk_pop" href="#gsd9.REF.roscher.2014.171">Roscher et al 2014</a>].</div></li></ul><p><b>Muscle concerns</b> can include the following:</p><ul><li class="half_rhythm"><div>Exercise-induced cramps, muscle pain, and fatigue [<a class="bk_pop" href="#gsd9.REF.wuyts.2005.82">Wuyts et al 2005</a>, <a class="bk_pop" href="#gsd9.REF.preisler.2012.265">Preisler et al 2012</a>]</div></li><li class="half_rhythm"><div>Proximal limb-girdle weakness, especially of the pelvic girdle [<a class="bk_pop" href="#gsd9.REF.wuyts.2005.82">Wuyts et al 2005</a>]</div></li><li class="half_rhythm"><div>Progressive muscle weakness leading to muscular atrophy [<a class="bk_pop" href="#gsd9.REF.burwinkel.2000.376">Burwinkel et al 2000</a>]</div></li><li class="half_rhythm"><div>Rhabdomyolysis [<a class="bk_pop" href="#gsd9.REF.burwinkel.2000.376">Burwinkel et al 2000</a>]</div></li><li class="half_rhythm"><div>Asymptomatic elevation of plasma CK in some individuals</div></li></ul><p>
|
||
<b>Other findings</b>
|
||
</p><ul><li class="half_rhythm"><div>Liver involvement</div><ul><li class="half_rhythm"><div>Liver involvement has not been reported in GSD IX caused by pathogenic variants in <i>PHKA1</i>.</div></li><li class="half_rhythm"><div>Hepatomegaly and hypoglycemia are present in some individuals with pathogenic variants in <i>PHKB</i>.</div></li></ul></li><li class="half_rhythm"><div>Interventricular septal hypertrophy has been reported in an individual with a <i>PHKB</i> variant [<a class="bk_pop" href="#gsd9.REF.roscher.2014.171">Roscher et al 2014</a>].</div></li><li class="half_rhythm"><div>One adult male with asymptomatic myopathy and cognitive impairment has been reported, suggesting wide variability in the clinical findings associated with pathogenic variants in <i>PHKA1</i> [<a class="bk_pop" href="#gsd9.REF.echanizlaguna.2010.125">Echaniz-Laguna et al 2010</a>]. However, it is possible that another cause exists for the cognitive impairment in this person.</div></li></ul></div></div><div id="gsd9.GenotypePhenotype_Correlations"><h3>Genotype-Phenotype Correlations</h3><p>Pathogenic variants in <i>PHKA1</i> result in muscle glycogenosis; pathogenic variants in <i>PHKA2</i> and <i>PHKG2</i> cause liver glycogenosis; pathogenic variants in <i>PHKB</i> and, rarely, <i>PHKG2</i> cause liver and muscle glycogenosis (muscle signs are variably present).</p><p>There is no consistent <a class="def" href="/books/n/gene/glossary/def-item/genotype/">genotype</a>-<a class="def" href="/books/n/gene/glossary/def-item/phenotype/">phenotype</a> correlation for pathogenic variants in any of the four genes. Pathogenic variants in <i>PHKG2</i> appear to result in more severe disease with an increased risk of liver fibrosis and cirrhosis, although persons with a milder course have been observed. Progressive liver disease has also been noted in individuals with pathogenic variants in <i>PHKA2</i>.</p></div><div id="gsd9.Nomenclature"><h3>Nomenclature</h3><p><b>Liver PhK deficiency.</b> Historically, the numeric classification of liver PhK deficiency has ranged from GSD type VIa and VIb to GSD VIII to GSD IX.</p><p>Note: (1) Deficiency of the enzyme glycogen phosphorylase that causes GSD V (muscle specific) or GSD VI (liver specific) is distinct from deficiency of the enzyme PhK that causes GSD IX. However, confusion may have arisen in the past reclassification of these types of GSD: because the enzyme PhK activates the enzyme glycogen phosphorylase, PhK deficiency can also result in phosphorylase deficiency. (2) The classification GSD VIII no longer exists: in the past GSD VIII was used to describe some cases of PhK deficiency.</p><p>Liver PhK deficiency has been further subclassified into:</p><ul><li class="half_rhythm"><div>GSD IXa, now known as <i>PHKA2-</i>related glycogen storage disease type IX;</div></li><li class="half_rhythm"><div>GSD IXb, now known as <i>PHKB-</i>related glycogen storage disease type IX;</div></li><li class="half_rhythm"><div>GSD IXc, now known as <i>PHKG2-</i>related glycogen storage disease type IX.</div></li></ul><p><b>Muscle PhK deficiency</b> has been called GSD Vb and GSD IXd.</p></div><div id="gsd9.Prevalence"><h3>Prevalence</h3><p>Liver PhK deficiency is thought to account for about 25% of all GSDs with an estimated prevalence of 1:100,000 [<a class="bk_pop" href="#gsd9.REF.maichele.1996.337">Maichele et al 1996</a>]. However, the disorder may be underdiagnosed as a result of the variable presentation and challenges with diagnostic confirmation.</p><p>Muscle PhK deficiency appears to be rare, but could be underdiagnosed because of the milder and more variable muscle symptoms.</p><p>No populations are known to have an increased prevalence of PhK deficiency.</p></div></div><div id="gsd9.Genetically_Related_Allelic_Disorde"><h2 id="_gsd9_Genetically_Related_Allelic_Disorde_">Genetically Related (Allelic) Disorders</h2><p>No other phenotypes are known to be associated with pathogenic variants in <i>PHKA1</i>, <i>PHKA2</i>, <i>PHKB</i>, or <i>PHKG2.</i></p></div><div id="gsd9.Differential_Diagnosis"><h2 id="_gsd9_Differential_Diagnosis_">Differential Diagnosis</h2><div id="gsd9.T.genetic_disorders_to_consider_in" class="table"><h3><span class="label">Table 3. </span></h3><div class="caption"><p>Genetic Disorders to Consider in the Differential Diagnosis of Phosphorylase Kinase (PhK) Deficiency</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK55061/table/gsd9.T.genetic_disorders_to_consider_in/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__gsd9.T.genetic_disorders_to_consider_in_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_gsd9.T.genetic_disorders_to_consider_in_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">PhK Deficiency<br />Type</th><th id="hd_h_gsd9.T.genetic_disorders_to_consider_in_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Disorder</th><th id="hd_h_gsd9.T.genetic_disorders_to_consider_in_1_1_1_3" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">MOI</th><th id="hd_h_gsd9.T.genetic_disorders_to_consider_in_1_1_1_4" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Overlapping Features</th><th id="hd_h_gsd9.T.genetic_disorders_to_consider_in_1_1_1_5" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Distinguishing Features</th><th id="hd_h_gsd9.T.genetic_disorders_to_consider_in_1_1_1_6" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Gene(s)</th><th id="hd_h_gsd9.T.genetic_disorders_to_consider_in_1_1_1_7" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Enzyme</th></tr></thead><tbody><tr><td headers="hd_h_gsd9.T.genetic_disorders_to_consider_in_1_1_1_1" rowspan="13" scope="row" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Liver PhK</b>
|
||
<br />
|
||
<b>deficiency</b>
|
||
</td><td headers="hd_h_gsd9.T.genetic_disorders_to_consider_in_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<a href="/books/n/gene/gsd6/">Glycogen storage disease type VI</a>
|
||
</td><td headers="hd_h_gsd9.T.genetic_disorders_to_consider_in_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">AR</td><td headers="hd_h_gsd9.T.genetic_disorders_to_consider_in_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Clinical features can be indistinguishable.</td><td headers="hd_h_gsd9.T.genetic_disorders_to_consider_in_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">In liver PhK deficiency: low liver glycogen phosphorylase activity on in vitro assay <sup>1</sup></td><td headers="hd_h_gsd9.T.genetic_disorders_to_consider_in_1_1_1_6" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<i>PYGL</i>
|
||
</td><td headers="hd_h_gsd9.T.genetic_disorders_to_consider_in_1_1_1_7" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Glycogen phosphorylase, liver form</td></tr><tr><td headers="hd_h_gsd9.T.genetic_disorders_to_consider_in_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;"><a href="/books/n/gene/gsd1/">Glycogen storage disease type I</a><br />(GSD I)</td><td headers="hd_h_gsd9.T.genetic_disorders_to_consider_in_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">AR</td><td headers="hd_h_gsd9.T.genetic_disorders_to_consider_in_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Hepatomegaly</div></li><li class="half_rhythm"><div>Hypoglycemia</div></li></ul>
|
||
</td><td headers="hd_h_gsd9.T.genetic_disorders_to_consider_in_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">In GSD I:
|
||
<ul><li class="half_rhythm"><div>Severe fasting lactic acidosis</div></li><li class="half_rhythm"><div>Hyperuricemia</div></li><li class="half_rhythm"><div>Significant hyperlipidemia</div></li><li class="half_rhythm"><div>Neutropenia</div></li></ul>
|
||
In PhK deficiency: ketosis usually present</td><td headers="hd_h_gsd9.T.genetic_disorders_to_consider_in_1_1_1_6" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><i>G6PC1</i>,<br /><i>SLC37A4</i></td><td headers="hd_h_gsd9.T.genetic_disorders_to_consider_in_1_1_1_7" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Glucose-6-phosphatase</div></li><li class="half_rhythm"><div>Glucose-6-phosphate exchanger SLC37A4</div></li></ul>
|
||
</td></tr><tr><td headers="hd_h_gsd9.T.genetic_disorders_to_consider_in_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;"><a href="/books/n/gene/gsd3/">Glycogen storage disease type III</a><br />(GSD III)</td><td headers="hd_h_gsd9.T.genetic_disorders_to_consider_in_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">AR</td><td headers="hd_h_gsd9.T.genetic_disorders_to_consider_in_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Hepatomegaly</div></li><li class="half_rhythm"><div>Hyperlipidemia</div></li><li class="half_rhythm"><div>Hypoglycemia & ketosis</div></li></ul>
|
||
</td><td headers="hd_h_gsd9.T.genetic_disorders_to_consider_in_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">In GSD III: hypoglycemia more severe & muscle involvement w/↑ CK concentrations</td><td headers="hd_h_gsd9.T.genetic_disorders_to_consider_in_1_1_1_6" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<i>AGL</i>
|
||
</td><td headers="hd_h_gsd9.T.genetic_disorders_to_consider_in_1_1_1_7" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Glycogen-debranching enzyme</td></tr><tr><td headers="hd_h_gsd9.T.genetic_disorders_to_consider_in_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;"><a href="/books/n/gene/gsd4/">Glycogen storage disease type IV</a> (GSD IV)</td><td headers="hd_h_gsd9.T.genetic_disorders_to_consider_in_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">AR</td><td headers="hd_h_gsd9.T.genetic_disorders_to_consider_in_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Hepatomegaly</div></li><li class="half_rhythm"><div>Liver cirrhosis</div></li><li class="half_rhythm"><div>Liver dysfunction</div></li></ul>
|
||
</td><td headers="hd_h_gsd9.T.genetic_disorders_to_consider_in_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">In GSD IV:
|
||
<ul><li class="half_rhythm"><div>Hypoglycemia & ketosis not typically seen</div></li><li class="half_rhythm"><div>No hypoglycemia in initial stages</div></li><li class="half_rhythm"><div>Accumulation of an abnormal glycogen (amylopectin) in liver & other tissues</div></li></ul>
|
||
</td><td headers="hd_h_gsd9.T.genetic_disorders_to_consider_in_1_1_1_6" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<i>GBE1</i>
|
||
</td><td headers="hd_h_gsd9.T.genetic_disorders_to_consider_in_1_1_1_7" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">1,4-alpha-glucan-branching enzyme</td></tr><tr><td headers="hd_h_gsd9.T.genetic_disorders_to_consider_in_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;"><a href="/books/n/gene/fructose1-6-def/">Fructose-1,6-bisphosphatase deficiency</a> (Note: Other disorders of gluconeogenesis can also be considered. <sup>2</sup>)</td><td headers="hd_h_gsd9.T.genetic_disorders_to_consider_in_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">AR</td><td headers="hd_h_gsd9.T.genetic_disorders_to_consider_in_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>↑ uric acid, AST, ALT</div></li><li class="half_rhythm"><div>Fasting hypoglycemia & hyperlacticacidemia</div></li><li class="half_rhythm"><div>Hepatomegaly</div></li></ul>
|
||
</td><td headers="hd_h_gsd9.T.genetic_disorders_to_consider_in_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">In disorders of gluconeogenesis: hypoglycemia after more prolonged (e.g., overnight) fasting or during intercurrent illness w/↓ carbohydrate intake</td><td headers="hd_h_gsd9.T.genetic_disorders_to_consider_in_1_1_1_6" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<i>FBP1</i>
|
||
</td><td headers="hd_h_gsd9.T.genetic_disorders_to_consider_in_1_1_1_7" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Fructose-1,6-bisphosphatase 1</td></tr><tr><td headers="hd_h_gsd9.T.genetic_disorders_to_consider_in_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;"><a href="/books/n/gene/alpha1-a/">Alpha-1 antitrypsin deficiency</a> <sup>3</sup></td><td headers="hd_h_gsd9.T.genetic_disorders_to_consider_in_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">AR</td><td headers="hd_h_gsd9.T.genetic_disorders_to_consider_in_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>↑ AST, ALT</div></li><li class="half_rhythm"><div>Hepatomegaly</div></li></ul>
|
||
</td><td headers="hd_h_gsd9.T.genetic_disorders_to_consider_in_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">In alpha-1-antitrypsin deficiency: lack of fasting hypoglycemia & hyperlacticacidemia</td><td headers="hd_h_gsd9.T.genetic_disorders_to_consider_in_1_1_1_6" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<i>SERPINA1</i>
|
||
</td><td headers="hd_h_gsd9.T.genetic_disorders_to_consider_in_1_1_1_7" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Alpha-1 antitrypsin</td></tr><tr><td headers="hd_h_gsd9.T.genetic_disorders_to_consider_in_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;"><a href="/books/n/gene/dguok-mtddepl/">Deoxyguanosine kinase deficiency</a> (mitochondrial DNA depletion syndrome 3)</td><td headers="hd_h_gsd9.T.genetic_disorders_to_consider_in_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">AR</td><td headers="hd_h_gsd9.T.genetic_disorders_to_consider_in_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Hepatomegaly</div></li><li class="half_rhythm"><div>Hypoglycemia</div></li></ul>
|
||
</td><td headers="hd_h_gsd9.T.genetic_disorders_to_consider_in_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">In deoxyguanosine kinase deficiency:
|
||
<ul><li class="half_rhythm"><div>Neurologic abnormalities</div></li><li class="half_rhythm"><div>Lactic acidosis</div></li></ul>
|
||
</td><td headers="hd_h_gsd9.T.genetic_disorders_to_consider_in_1_1_1_6" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<i>DGUOK</i>
|
||
</td><td headers="hd_h_gsd9.T.genetic_disorders_to_consider_in_1_1_1_7" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Mitochondrial respiratory chain complexes (I, III, IV, V)</td></tr><tr><td headers="hd_h_gsd9.T.genetic_disorders_to_consider_in_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">Mitochondrial complex V (ATP synthase) deficiency (OMIM <a href="https://omim.org/entry/604273" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">604273</a>)</td><td headers="hd_h_gsd9.T.genetic_disorders_to_consider_in_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">AR</td><td headers="hd_h_gsd9.T.genetic_disorders_to_consider_in_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Hepatomegaly</td><td headers="hd_h_gsd9.T.genetic_disorders_to_consider_in_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">In mitochondrial complex V deficiency:
|
||
<ul><li class="half_rhythm"><div>Ataxia</div></li><li class="half_rhythm"><div>Lactic acidosis</div></li></ul>
|
||
</td><td headers="hd_h_gsd9.T.genetic_disorders_to_consider_in_1_1_1_6" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<i>ATPAF2</i>
|
||
</td><td headers="hd_h_gsd9.T.genetic_disorders_to_consider_in_1_1_1_7" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">ATP synthase</td></tr><tr><td headers="hd_h_gsd9.T.genetic_disorders_to_consider_in_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">Glycerol kinase deficiency (OMIM <a href="https://omim.org/entry/307030" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">307030</a>)</td><td headers="hd_h_gsd9.T.genetic_disorders_to_consider_in_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">XL</td><td headers="hd_h_gsd9.T.genetic_disorders_to_consider_in_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Hypoglycemia</td><td headers="hd_h_gsd9.T.genetic_disorders_to_consider_in_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">In glycerol kinase deficiency:
|
||
<ul><li class="half_rhythm"><div>Ketoacidosis</div></li><li class="half_rhythm"><div>Extremely elevated glycerol</div></li></ul>
|
||
</td><td headers="hd_h_gsd9.T.genetic_disorders_to_consider_in_1_1_1_6" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<i>GK</i>
|
||
</td><td headers="hd_h_gsd9.T.genetic_disorders_to_consider_in_1_1_1_7" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Glycerol kinase</td></tr><tr><td headers="hd_h_gsd9.T.genetic_disorders_to_consider_in_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">Niemann-Pick disease type B <sup>4</sup> (See <a href="/books/n/gene/npab/">Acid Sphingomyelinase Deficiency</a>.)</td><td headers="hd_h_gsd9.T.genetic_disorders_to_consider_in_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">AR</td><td headers="hd_h_gsd9.T.genetic_disorders_to_consider_in_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Growth restriction</div></li><li class="half_rhythm"><div>Hepatomegaly</div></li><li class="half_rhythm"><div>Hyperlipidemia</div></li></ul>
|
||
</td><td headers="hd_h_gsd9.T.genetic_disorders_to_consider_in_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">In Niemann-Pick disease type B:
|
||
<ul><li class="half_rhythm"><div>Lack of fasting hypoglycemia</div></li><li class="half_rhythm"><div>Significant splenomegaly</div></li><li class="half_rhythm"><div>Storage cells characteristic of disease</div></li><li class="half_rhythm"><div>Other features incl bone & pulmonary involvement</div></li></ul>
|
||
</td><td headers="hd_h_gsd9.T.genetic_disorders_to_consider_in_1_1_1_6" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<i>SMPD1</i>
|
||
</td><td headers="hd_h_gsd9.T.genetic_disorders_to_consider_in_1_1_1_7" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Sphingomyelin phosphodiesterase</td></tr><tr><td headers="hd_h_gsd9.T.genetic_disorders_to_consider_in_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;"><a href="/books/n/gene/gaucher/">Gaucher disease</a> <sup>4</sup></td><td headers="hd_h_gsd9.T.genetic_disorders_to_consider_in_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">AR</td><td headers="hd_h_gsd9.T.genetic_disorders_to_consider_in_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Hepatomegaly</td><td headers="hd_h_gsd9.T.genetic_disorders_to_consider_in_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">In Gaucher disease:
|
||
<ul><li class="half_rhythm"><div>Lack of fasting hypoglycemia</div></li><li class="half_rhythm"><div>Significant splenomegaly</div></li><li class="half_rhythm"><div>Storage cells characteristic of the disease</div></li><li class="half_rhythm"><div>Other features incl bone involvement</div></li><li class="half_rhythm"><div>Early-onset thrombocytopenia</div></li></ul>
|
||
</td><td headers="hd_h_gsd9.T.genetic_disorders_to_consider_in_1_1_1_6" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<i>GBA</i>
|
||
</td><td headers="hd_h_gsd9.T.genetic_disorders_to_consider_in_1_1_1_7" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Glucosylceramidase</td></tr><tr><td headers="hd_h_gsd9.T.genetic_disorders_to_consider_in_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">Long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) deficiency <sup>5</sup> (See <a href="/books/n/gene/lchad/">Long-Chain Hydroxyacyl-CoA Dehydrogenase Deficiency / Trifunctional Protein Deficiency</a>.)</td><td headers="hd_h_gsd9.T.genetic_disorders_to_consider_in_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">AR</td><td headers="hd_h_gsd9.T.genetic_disorders_to_consider_in_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Hepatomegaly</div></li><li class="half_rhythm"><div>Hypoglycemia</div></li></ul>
|
||
</td><td headers="hd_h_gsd9.T.genetic_disorders_to_consider_in_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">In LCHAD deficiency:
|
||
<ul><li class="half_rhythm"><div>Cardiomyopathy</div></li><li class="half_rhythm"><div>Peripheral neuropathy</div></li><li class="half_rhythm"><div>Retinopathy</div></li></ul>
|
||
</td><td headers="hd_h_gsd9.T.genetic_disorders_to_consider_in_1_1_1_6" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<i>HADHA</i>
|
||
</td><td headers="hd_h_gsd9.T.genetic_disorders_to_consider_in_1_1_1_7" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Trifunctional enzyme subunit alpha, mitochondrial</td></tr><tr><td headers="hd_h_gsd9.T.genetic_disorders_to_consider_in_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">Fanconi-Bickel syndrome (OMIM <a href="https://omim.org/entry/227810" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">227810</a>)</td><td headers="hd_h_gsd9.T.genetic_disorders_to_consider_in_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">AR</td><td headers="hd_h_gsd9.T.genetic_disorders_to_consider_in_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Hepatomegaly</div></li><li class="half_rhythm"><div>Hypoglycemia</div></li></ul>
|
||
</td><td headers="hd_h_gsd9.T.genetic_disorders_to_consider_in_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">In Fanconi-Bickel syndrome:
|
||
<ul><li class="half_rhythm"><div>Splenomegaly</div></li><li class="half_rhythm"><div>Rickets</div></li><li class="half_rhythm"><div>Renal tubular dysfunction</div></li><li class="half_rhythm"><div>Hyperphosphatemia</div></li></ul>
|
||
</td><td headers="hd_h_gsd9.T.genetic_disorders_to_consider_in_1_1_1_6" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<i>SLC2A2</i>
|
||
</td><td headers="hd_h_gsd9.T.genetic_disorders_to_consider_in_1_1_1_7" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Solute carrier family 2, facilitated glucose transporter member 2</td></tr><tr><td headers="hd_h_gsd9.T.genetic_disorders_to_consider_in_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Liver PhK</b>
|
||
<br />
|
||
<b>deficiency &</b>
|
||
<br />
|
||
<b>Muscle PhK</b>
|
||
<br />
|
||
<b>deficiency</b>
|
||
</td><td headers="hd_h_gsd9.T.genetic_disorders_to_consider_in_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<a href="/books/n/gene/vlcad/">VLCAD deficiency</a>
|
||
</td><td headers="hd_h_gsd9.T.genetic_disorders_to_consider_in_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">AR</td><td headers="hd_h_gsd9.T.genetic_disorders_to_consider_in_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Exercise intolerance</div></li><li class="half_rhythm"><div>Hepatomegaly</div></li><li class="half_rhythm"><div>Hypoglycemia</div></li><li class="half_rhythm"><div>Hypotonia</div></li><li class="half_rhythm"><div>Muscle cramps</div></li><li class="half_rhythm"><div>Muscle pain</div></li></ul>
|
||
</td><td headers="hd_h_gsd9.T.genetic_disorders_to_consider_in_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">In early-onset form of VLCAD deficiency:
|
||
<ul><li class="half_rhythm"><div>Hypoketosis</div></li><li class="half_rhythm"><div>Cardiomyopathy</div></li><li class="half_rhythm"><div>Pericardial effusion</div></li></ul>
|
||
Disorders distinguished by enzymatic &<br /><a class="def" href="/books/n/gene/glossary/def-item/molecular-genetic-testing/">molecular genetic testing</a></td><td headers="hd_h_gsd9.T.genetic_disorders_to_consider_in_1_1_1_6" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<i>ACADVL</i>
|
||
</td><td headers="hd_h_gsd9.T.genetic_disorders_to_consider_in_1_1_1_7" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Very long-chain specific acyl-CoA dehydrogenase, mitochondrial</td></tr><tr><td headers="hd_h_gsd9.T.genetic_disorders_to_consider_in_1_1_1_1" rowspan="8" scope="row" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Muscle PhK</b>
|
||
<br />
|
||
<b>deficiency</b>
|
||
</td><td headers="hd_h_gsd9.T.genetic_disorders_to_consider_in_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><a href="/books/n/gene/gsd5/">Glycogen storage disease type V</a><br />(GSD V) <sup>6</sup></td><td headers="hd_h_gsd9.T.genetic_disorders_to_consider_in_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">AR</td><td headers="hd_h_gsd9.T.genetic_disorders_to_consider_in_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Cramps</div></li><li class="half_rhythm"><div>Exercise intolerance</div></li><li class="half_rhythm"><div>Fatigue</div></li><li class="half_rhythm"><div>Muscle weakness</div></li><li class="half_rhythm"><div>Myalgia</div></li><li class="half_rhythm"><div>Myoglobinuria</div></li><li class="half_rhythm"><div>Poor endurance</div></li></ul>
|
||
</td><td headers="hd_h_gsd9.T.genetic_disorders_to_consider_in_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">In GSD V: "second-wind" phenomenon</td><td headers="hd_h_gsd9.T.genetic_disorders_to_consider_in_1_1_1_6" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<i>PYGM</i>
|
||
</td><td headers="hd_h_gsd9.T.genetic_disorders_to_consider_in_1_1_1_7" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Glycogen phosphorylase, muscle form</td></tr><tr><td headers="hd_h_gsd9.T.genetic_disorders_to_consider_in_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">Glycogen storage disease type VII (GSDVII) <sup>7</sup><br />(OMIM <a href="https://omim.org/entry/232800" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">232800</a>)</td><td headers="hd_h_gsd9.T.genetic_disorders_to_consider_in_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">AR</td><td headers="hd_h_gsd9.T.genetic_disorders_to_consider_in_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Exercise intolerance</div></li><li class="half_rhythm"><div>Fatigue</div></li><li class="half_rhythm"><div>Muscle cramps</div></li></ul>
|
||
</td><td headers="hd_h_gsd9.T.genetic_disorders_to_consider_in_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">In GSD VII:
|
||
<ul><li class="half_rhythm"><div>Compensated hemolysis</div></li><li class="half_rhythm"><div>Hyperuricemia</div></li></ul>
|
||
</td><td headers="hd_h_gsd9.T.genetic_disorders_to_consider_in_1_1_1_6" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<i>PFKM</i>
|
||
</td><td headers="hd_h_gsd9.T.genetic_disorders_to_consider_in_1_1_1_7" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">ATP-dependent 6-phosphofructokinase, muscle type</td></tr><tr><td headers="hd_h_gsd9.T.genetic_disorders_to_consider_in_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">Mitochondrial myopathy</td><td headers="hd_h_gsd9.T.genetic_disorders_to_consider_in_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">See<br />footnote<br />8.</td><td headers="hd_h_gsd9.T.genetic_disorders_to_consider_in_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Hypoglycemia</div></li><li class="half_rhythm"><div>Muscle weakness</div></li><li class="half_rhythm"><div>Exercise intolerance</div></li></ul>
|
||
</td><td headers="hd_h_gsd9.T.genetic_disorders_to_consider_in_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">In mitochondrial myopathy:
|
||
<ul><li class="half_rhythm"><div>Ragged red fibers</div></li><li class="half_rhythm"><div>Multisystem involvement incl: abnormal eye movements, ptosis, optic neuropathy; epilepsy; sensorineural hearing loss; lactic acidemia</div></li></ul>
|
||
</td><td headers="hd_h_gsd9.T.genetic_disorders_to_consider_in_1_1_1_6" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">See footnote 8.</td><td headers="hd_h_gsd9.T.genetic_disorders_to_consider_in_1_1_1_7" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">See footnote 8.</td></tr><tr><td headers="hd_h_gsd9.T.genetic_disorders_to_consider_in_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">Myoadenylate deaminase deficiency (OMIM <a href="https://omim.org/entry/615511" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">615511</a>)</td><td headers="hd_h_gsd9.T.genetic_disorders_to_consider_in_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">AR</td><td headers="hd_h_gsd9.T.genetic_disorders_to_consider_in_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Exercise-induced myalgia, rhabdomyolysis, &/or ↑ serum CK</td><td headers="hd_h_gsd9.T.genetic_disorders_to_consider_in_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Disorders distinguished by enzymatic &<br /><a class="def" href="/books/n/gene/glossary/def-item/molecular-genetic-testing/">molecular genetic testing</a></td><td headers="hd_h_gsd9.T.genetic_disorders_to_consider_in_1_1_1_6" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<i>AMPD1</i>
|
||
</td><td headers="hd_h_gsd9.T.genetic_disorders_to_consider_in_1_1_1_7" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">AMP deaminase 1</td></tr><tr><td headers="hd_h_gsd9.T.genetic_disorders_to_consider_in_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">
|
||
<a href="/books/n/gene/cpt2/">Carnitine palmitoyltransferase II deficiency</a>
|
||
</td><td headers="hd_h_gsd9.T.genetic_disorders_to_consider_in_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">AR</td><td headers="hd_h_gsd9.T.genetic_disorders_to_consider_in_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>↑ hepatic transaminases</div></li><li class="half_rhythm"><div>Hepatomegaly</div></li><li class="half_rhythm"><div>Hypoglycemia</div></li><li class="half_rhythm"><div>Myalgia</div></li><li class="half_rhythm"><div>Myoglobinuria</div></li></ul>
|
||
</td><td headers="hd_h_gsd9.T.genetic_disorders_to_consider_in_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">In CPT II deficiency:
|
||
<ul><li class="half_rhythm"><div>Hypoketosis</div></li><li class="half_rhythm"><div>Cardiomyopathy</div></li><li class="half_rhythm"><div>Arrhythmia</div></li></ul>
|
||
</td><td headers="hd_h_gsd9.T.genetic_disorders_to_consider_in_1_1_1_6" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<i>CPT2</i>
|
||
</td><td headers="hd_h_gsd9.T.genetic_disorders_to_consider_in_1_1_1_7" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Carnitine O-palmitoyltransferase 2, mitochondrial</td></tr><tr><td headers="hd_h_gsd9.T.genetic_disorders_to_consider_in_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">Phosphoglycerate kinase 1 deficiency (PGK1) (OMIM <a href="https://omim.org/entry/300653" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">300653</a>)</td><td headers="hd_h_gsd9.T.genetic_disorders_to_consider_in_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">XL</td><td headers="hd_h_gsd9.T.genetic_disorders_to_consider_in_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Cramping, particularly w/exercise</div></li><li class="half_rhythm"><div>Exercise-induced myalgia</div></li><li class="half_rhythm"><div>Pain</div></li><li class="half_rhythm"><div>Progressive weakness</div></li><li class="half_rhythm"><div>Rhabdomyolysis &/or ↑ serum CK</div></li></ul>
|
||
</td><td headers="hd_h_gsd9.T.genetic_disorders_to_consider_in_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">In PGK1 deficiency:
|
||
<ul><li class="half_rhythm"><div>Hemolytic anemia</div></li><li class="half_rhythm"><div>Intellectual disability</div></li></ul>
|
||
</td><td headers="hd_h_gsd9.T.genetic_disorders_to_consider_in_1_1_1_6" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<i>PGK1</i>
|
||
</td><td headers="hd_h_gsd9.T.genetic_disorders_to_consider_in_1_1_1_7" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Phosphoglycerate kinase 1</td></tr><tr><td headers="hd_h_gsd9.T.genetic_disorders_to_consider_in_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">Phosphoglycerate mutase deficiency (GSDX) (OMIM <a href="https://omim.org/entry/261670" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">261670</a>)</td><td headers="hd_h_gsd9.T.genetic_disorders_to_consider_in_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">AR</td><td headers="hd_h_gsd9.T.genetic_disorders_to_consider_in_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>↑ rhabdomyolysis &/or ↑ serum CK</div></li><li class="half_rhythm"><div>Exercise-induced myalgia</div></li><li class="half_rhythm"><div>Myoglobinuria</div></li></ul>
|
||
</td><td headers="hd_h_gsd9.T.genetic_disorders_to_consider_in_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Disorders distinguished by enzymatic &<br /><a class="def" href="/books/n/gene/glossary/def-item/molecular-genetic-testing/">molecular genetic testing</a></td><td headers="hd_h_gsd9.T.genetic_disorders_to_consider_in_1_1_1_6" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<i>PGAM2</i>
|
||
</td><td headers="hd_h_gsd9.T.genetic_disorders_to_consider_in_1_1_1_7" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Phosphoglycerate mutase 2</td></tr><tr><td headers="hd_h_gsd9.T.genetic_disorders_to_consider_in_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">Lactate dehydrogenase deficiency (GSDXI) (OMIM <a href="https://omim.org/entry/612933" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">612933</a>)</td><td headers="hd_h_gsd9.T.genetic_disorders_to_consider_in_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">AR</td><td headers="hd_h_gsd9.T.genetic_disorders_to_consider_in_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Exercise-induced myalgia</div></li><li class="half_rhythm"><div>Exercise intolerance</div></li><li class="half_rhythm"><div>Fatigue</div></li><li class="half_rhythm"><div>Muscle cramps</div></li><li class="half_rhythm"><div>Rhabdomyolysis</div></li></ul>
|
||
</td><td headers="hd_h_gsd9.T.genetic_disorders_to_consider_in_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Disorders distinguished by enzymatic &<br /><a class="def" href="/books/n/gene/glossary/def-item/molecular-genetic-testing/">molecular genetic testing</a></td><td headers="hd_h_gsd9.T.genetic_disorders_to_consider_in_1_1_1_6" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<i>LDHA</i>
|
||
</td><td headers="hd_h_gsd9.T.genetic_disorders_to_consider_in_1_1_1_7" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">L-lactate dehydrogenase A chain</td></tr></tbody></table></div><div><div><dl class="temp-labeled-list small"><dt></dt><dd><div><p class="no_margin">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>, MOI = <a class="def" href="/books/n/gene/glossary/def-item/mode-of-inheritance/">mode of inheritance</a>, 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="gsd9.TF.3.1"><p class="no_margin">Liver glycogen phosphorylase is activated by liver phosphorylase b kinase (PhK).</p></div></dd><dt>2. </dt><dd><div id="gsd9.TF.3.2"><p class="no_margin">Disorders of gluconeogenesis include: fructose-1,6-bisphosphatase deficiency, <a href="/books/n/gene/pdhc-def-ov/">pyruvate dehydrogenase complex deficiency</a>, and glycogen storage disease type I.</p></div></dd><dt>3. </dt><dd><div id="gsd9.TF.3.3"><p class="no_margin">Other causes of non-genetic primary liver disease (e.g., hepatitis) can also be considered.</p></div></dd><dt>4. </dt><dd><div id="gsd9.TF.3.4"><p class="no_margin">Other storage (metabolic) diseases can also be considered.</p></div></dd><dt>5. </dt><dd><div id="gsd9.TF.3.5"><p class="no_margin">LCHAD may also be referred to as mitochondrial trifunctional protein deficiency.</p></div></dd><dt>6. </dt><dd><div id="gsd9.TF.3.6"><p class="no_margin">Glycogen storage disease type V may also be referred to as McArdle disease.</p></div></dd><dt>7. </dt><dd><div id="gsd9.TF.3.7"><p class="no_margin">Glycogen storage disease type VII may also be referred to as Tarui disease or phosphofructokinase deficiency.</p></div></dd><dt>8. </dt><dd><div id="gsd9.TF.3.8"><p class="no_margin">See <a href="/books/n/gene/mt-overview/">Mitochondrial Disorders Overview</a>.</p></div></dd></dl></div></div></div></div><div id="gsd9.Management"><h2 id="_gsd9_Management_">Management</h2><div id="gsd9.Evaluations_Following_Initial_Diagn"><h3>Evaluations Following Initial Diagnosis</h3><p>To establish the extent of disease and needs of an individual diagnosed with <b>liver PhK deficiency</b>, the following evaluations are recommended if they have not already been completed:</p><ul><li class="half_rhythm"><div class="half_rhythm">Measurement of blood glucose concentration (normal >70 mg/dL) for two to three days:</div><ul><li class="half_rhythm"><div>Upon waking in the morning;</div></li><li class="half_rhythm"><div>Prior to meals and nighttime supplementation with oral cornstarch; and</div></li><li class="half_rhythm"><div>After activity</div></li></ul></li><li class="half_rhythm"><div class="half_rhythm">Measurement of blood ketone levels for two to three days:</div><ul><li class="half_rhythm"><div>Upon waking in the morning;</div></li><li class="half_rhythm"><div>Prior to meals and nighttime supplementation with oral cornstarch; and</div></li><li class="half_rhythm"><div>After activity.</div></li></ul><div class="half_rhythm">Elevated blood ketones (beta-hydroxybutyrate >1.0 mmol/L) could be an indicator of suboptimal metabolic control and pending hypoglycemia.</div></li><li class="half_rhythm"><div class="half_rhythm">Liver imaging, if not performed in the past year. The type of liver imaging (ultrasound, MRI, or CT) is determined by factors such as age and underlying liver status (e.g., liver cirrhosis).</div></li><li class="half_rhythm"><div class="half_rhythm">Basic metabolic panel including liver enzymes (AST, ALT, and alkaline phosphatase)</div></li><li class="half_rhythm"><div class="half_rhythm">Prothrombin time</div></li><li class="half_rhythm"><div class="half_rhythm">Lipid panel (cholesterol and triglyceride concentrations)</div></li><li class="half_rhythm"><div class="half_rhythm">Serum creatine kinase measurement (Some individuals with liver PhK deficiency have muscle involvement.)</div></li><li class="half_rhythm"><div class="half_rhythm">Baseline echocardiogram (Baseline echocardiogram may be done as a precaution as interventricular septal hypertrophy was found in an individual with GSD IX caused by pathogenic variants in <i>PHKB</i> [<a class="bk_pop" href="#gsd9.REF.roscher.2014.171">Roscher et al 2014</a>].)</div></li></ul><p>To establish the extent of disease and needs of an individual diagnosed with <b>muscle PhK deficiency</b>, the following evaluations are suggested:</p><ul><li class="half_rhythm"><div>Physical therapy evaluation</div></li><li class="half_rhythm"><div>Serum creatine kinase measurement</div></li></ul><p>Consultation with a clinical geneticist and/or genetic counselor is recommended for <b>both PhK phenotypes</b>.</p></div><div id="gsd9.Treatment_of_Manifestations"><h3>Treatment of Manifestations</h3><div id="gsd9.Liver_PhK_Deficiency_1"><h4>Liver PhK Deficiency</h4><p>Goal of treatment is to keep blood glucose between 70 and 100 mg/dL. The target range for blood βOHB is 0.0-0.2 mmol/L.</p><p><b>Hypoglycemia</b>
|
||
<b>can be prevented</b> with frequent daytime feedings that are high in complex carbohydrates and protein.</p><ul><li class="half_rhythm"><div>The dose of cornstarch can range from 0.6 to 2.5 g/kg every six hours based on clinical symptoms. A waxy maize extended-release cornstarch, Glycosade<sup>®</sup>, allows sustained release of glucose, especially overnight in some cases.</div></li><li class="half_rhythm"><div>Protein should be given as 15% to 25% of total calories, 2-3 g protein/kg body weight/day (tailored to the individual's age) as long as renal function is normal. Protein provides an alternative source of glucose via intact gluconeogenesis.</div></li><li class="half_rhythm"><div>Fats should provide ~30% of total calories. Saturated fats should be restricted to <10% of total calories and cholesterol to <300 mg/day.</div></li><li class="half_rhythm"><div>Overtreatment with cornstarch should be avoided as it can cause diarrhea, weight gain, and insulin resistance.</div></li></ul><p><b>For signs of</b>
|
||
<b>hypoglycemia or ketosis,</b> Polycose<sup>®</sup> or fruit juice should be given orally (if oral intake is tolerated) followed by a snack high in complex carbohydrates and protein. Blood glucose and ketone concentrations should be monitored periodically to ensure that they return to normal. If oral intake is not tolerated, an IV should be started.</p><p>When intravenous dextrose support is required, a concentration of 10% dextrose should be used at a rate that is 1-1.25x the maintenance rate with appropriate electrolytes. The rate can be increased based on blood glucose levels. Fluids with less concentrated dextrose (i.e., 5% dextrose) could result in fluid overload at the rate required to maintain blood glucose above 70 mg/dL and prevent ketosis.</p><p>Symptomatic management of liver manifestations such as cirrhosis, liver failure, and portal hypertension is appropriate.</p></div><div id="gsd9.Muscle_PhK_Deficiency_1"><h4>Muscle PhK Deficiency</h4><p>Signs and symptoms should be managed as with other muscle GSDs, such as <a href="/books/n/gene/gsd3/">GSD III</a> [<a class="bk_pop" href="#gsd9.REF.kishnani.2010.446">Kishnani et al 2010</a>]:</p><ul><li class="half_rhythm"><div>Physical therapy evaluation and intervention based on physical status and function</div></li><li class="half_rhythm"><div>Coordination with a metabolic nutritionist regarding monitoring and optimizing of blood glucose concentrations based on levels of exercise and activity</div></li></ul></div></div><div id="gsd9.Prevention_of_Secondary_Complicatio"><h3>Prevention of Secondary Complications</h3><div id="gsd9.Liver_PhK_Deficiency_2"><h4>Liver PhK Deficiency</h4><p><b>General medical care.</b> During childhood, <b>routine immunizations</b> should be given on the recommended schedule. Any immunizations that may prevent illness, such as influenza leading to hypoglycemia, should be offered.</p><p><b>Surgery/anesthesia.</b> If prolonged fasting is required in preparation for surgery, the individual should be admitted overnight for IV dextrose support to maintain blood glucose concentration >70 mg/dL and to prevent ketosis.</p><p>Perioperative care for elective procedures should include IV dextrose infusion preoperatively, which should start as soon as the individual is made NPO with a goal of maintaining blood glucose levels >70 mg/dL and to prevent ketosis. A concentration of 10% dextrose should be used at 1.25-1.5x the maintenance rate. Using a lower concentration of dextrose such as 5% dextrose can result in fluid overload. Blood glucose and βOHB levels should be measured upon arrival and hourly. Continue with intraoperative and postoperative IV dextrose infusion to prevent hypoglycemia. IV dextrose should be tapered off gradually over two to three hours as the individual tolerates the usual diet. Abrupt discontinuation of fluids could result in hypoglycemia.</p><p>In individuals with liver fibrosis or cirrhosis, anesthetic agents with hepatic side effects should be avoided.</p><p>If general anesthesia is required, <b>malignant hyperthermia precautions</b> should be taken as individuals with liver PhK deficiency may have increased CK levels and myopathy [Author, personal experience] (see <a href="/books/n/gene/mhs/">Malignant Hyperthermia Susceptibility</a>).</p><p><b>Physical activity.</b> Contact sports should be avoided in individuals with hepatomegaly. Blood glucose and ketones should be monitored during and after exercise, based on the needs of the individual. This is because of the extreme clinical heterogeneity in those with GSD IX.</p></div><div id="gsd9.Muscle_PhK_Deficiency_2"><h4>Muscle PhK Deficiency</h4><p>Lipid-lowering drugs (e.g., statins) that can worsen or unmask myopathy should be used cautiously due to the risk of rhabdomyolysis.</p><p>If general anesthesia is required, <b>malignant hyperthermia precautions</b> should be taken as individuals with muscle PhK deficiency have increased CK levels and myopathy (see <a href="/books/n/gene/mhs/">Malignant Hyperthermia Susceptibility</a>).</p><p>During childhood, <b>routine immunizations</b> should be given on the recommended schedule. Hepatitis B vaccine should be administered when liver enzymes of the individual are within normal limits.</p></div></div><div id="gsd9.Surveillance"><h3>Surveillance</h3><p>
|
||
<b>Liver PhK deficiency</b>
|
||
</p><ul><li class="half_rhythm"><div class="half_rhythm">Regular evaluation by a <b>metabolic physician</b> familiar with liver PhK deficiency to monitor medical issues and a <b>metabolic nutritionist</b> to give dietary recommendations and monitor cornstarch requirement</div></li><li class="half_rhythm"><div class="half_rhythm">Regular monitoring of blood glucose concentration and ketones, as recommended by a metabolic physician and nutritionist. Blood glucose concentrations and ketones should also be measured during times of stress including illness, intense activity, rapid growth, puberty, and pregnancy; and at any time in which intake of food is reduced, or meal and/or cornstarch dose or scheduling is altered.</div><div class="half_rhythm">Note: It is possible that blood glucose concentrations may be normal when moderate to large ketosis in liver PhK deficiency results from increased fatty acid oxidation and upregulated gluconeogenesis. The role of ketone monitoring in this setting as a marker of metabolic control requires further systematic investigation.</div></li><li class="half_rhythm"><div class="half_rhythm"><b>Liver imaging.</b> In children younger than age 18 years, liver ultrasound examination every 12 to 24 months. With increasing age, consideration of CT or MRI using intravenous contrast to evaluate for complications of liver disease such as liver adenomas and cirrhosis</div></li><li class="half_rhythm"><div class="half_rhythm"><b>Follow-up echocardiogram.</b> No guidelines established; follow up approximately every two years or earlier if symptoms are present</div></li></ul><p>
|
||
<b>Muscle PhK deficiency</b>
|
||
</p><ul><li class="half_rhythm"><div>Regular evaluation by a <b>metabolic physician</b> familiar with liver PhK deficiency to monitor medical issues and a <b>metabolic nutritionist</b> to give dietary recommendations and monitor cornstarch requirement</div></li><li class="half_rhythm"><div>Regular evaluation by a <b>physical therapist</b> to look for progression in symptoms and to guide exercise program</div></li></ul></div><div id="gsd9.AgentsCircumstances_to_Avoid"><h3>Agents/Circumstances to Avoid</h3><p><b>Liver PhK deficiency.</b> Affected Individuals should avoid the following:</p><ul><li class="half_rhythm"><div>Large amounts of simple sugars, as they will increase liver storage of glycogen and may result in rapid fluctuations in levels of blood glucose and insulin</div></li><li class="half_rhythm"><div>Prolonged fasting</div></li><li class="half_rhythm"><div>High-impact contact sports if significant (moderate to massive) hepatomegaly is present. The final decision is based on clinician judgment.</div></li><li class="half_rhythm"><div>Drugs known to:</div><ul><li class="half_rhythm"><div>Cause hypoglycemia, such as insulin and insulin secretagogues (the sulfonylureas)</div></li><li class="half_rhythm"><div>Mask symptoms of hypoglycemia, such as beta-blockers</div></li></ul></li><li class="half_rhythm"><div>Alcohol, as this may predispose to hypoglycemia</div></li><li class="half_rhythm"><div>Glucagon, as glycogenolysis is defective</div></li><li class="half_rhythm"><div>Augmentin<sup>®</sup>, as it can cause malabsorption and contains clavulanic acid, which is associated with <a class="def" href="/books/n/gene/glossary/def-item/idiopathic/">idiopathic</a> liver disease</div></li><li class="half_rhythm"><div>Growth hormone therapy unless there is proven growth hormone deficiency, as it can promote ketosis and development of liver adenomas</div></li></ul><p>Hypoglycemic events in adults with liver PhK deficiency are relatively uncommon; however, caution should be used with drugs causing potential hypoglycemia, particularly in persons with impaired liver function.</p><p><b>Muscle PhK deficiency.</b> Affected individuals should avoid the following:</p><ul><li class="half_rhythm"><div>Vigorous exercise</div></li><li class="half_rhythm"><div>Medications that can cause rhabdomyolysis (e.g., succinylcholine)</div></li><li class="half_rhythm"><div>Statins (to be used with caution, as they can cause rhabdomyolysis)</div></li></ul></div><div id="gsd9.Evaluation_of_Relatives_at_Risk"><h3>Evaluation of Relatives at Risk</h3><p>Molecular genetic testing (if the family-specific variant[s] are known) and/or evaluation by a metabolic physician during the first year of life (if the family-specific variant[s] are not known) allows for early diagnosis and treatment for sibs at increased risk for GSD IX.</p><p>See <a href="#gsd9.Related_Genetic_Counseling_Issues">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="gsd9.ObstetricGynecologic_Care"><h3>Obstetric/Gynecologic Care</h3><p>Females with GSD IX should be evaluated for symptoms for polycystic ovary syndrome.</p></div><div id="gsd9.Pregnancy_Management"><h3>Pregnancy Management</h3><p>Ideally, females with PhK deficiency should consult with their health care team and maintain optimal metabolic control before conception.</p><p>It is extremely important that euglycemia be maintained throughout pregnancy to avoid upregulation of counter-regulatory hormones, which would result in lipolysis and ketosis, with risk of fetal demise. The appropriate diet during pregnancy is unique to each individual. For some, this may only require following a regular healthy diet, but for many it may mean increasing snacks to include more complex carbohydrates and protein and/or adding or increasing the amount of cornstarch. Blood glucose concentrations and ketones should also be measured during pregnancy on a regular basis to ensure euglycemia. Adequate amounts of protein are necessary to provide an alternate source of glucose via gluconeogenesis.</p></div><div id="gsd9.Therapies_under_Investigation"><h3>Therapies under Investigation</h3><p>Search <a href="https://clinicaltrials.gov/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">ClinicalTrials.gov</a> in the US and <a href="https://www.clinicaltrialsregister.eu/ctr-search/search" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">EU Clinical Trials Register</a> in Europe for information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.</p></div></div><div id="gsd9.Genetic_Counseling"><h2 id="_gsd9_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="gsd9.Mode_of_Inheritance"><h3>Mode of Inheritance</h3><p><i>PHKA2</i>-related liver PhK deficiency and <i>PHKA1</i>-related muscle PhK deficiency are inherited in an <a class="def" href="/books/n/gene/glossary/def-item/x-linked/">X-linked</a> manner.</p><p><i>PHKB</i>-related liver and muscle PhK deficiency and <i>PHKG2</i>-related liver PhK deficiency are inherited in an <a class="def" href="/books/n/gene/glossary/def-item/autosomal-recessive/">autosomal recessive</a> manner.</p></div><div id="gsd9.XLinked_Inheritance__Risk_To_Family"><h3>X-Linked Inheritance – Risk To Family Members</h3><p>
|
||
<b>Parents of a male <a class="def" href="/books/n/gene/glossary/def-item/proband/">proband</a></b>
|
||
</p><ul><li class="half_rhythm"><div>The father of an affected male will not have the disorder nor will he be <a class="def" href="/books/n/gene/glossary/def-item/hemizygous/">hemizygous</a> for a <i>PHKA1</i> or <i>PHKA2</i> <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a>.</div></li><li class="half_rhythm"><div>In a family with more than one affected individual, the mother of an affected male is an <a class="def" href="/books/n/gene/glossary/def-item/obligate-heterozygote/">obligate heterozygote</a> (<a class="def" href="/books/n/gene/glossary/def-item/carrier/">carrier</a>). If a woman has more than one affected child and no other affected relatives, and if the <i>PHKA1</i> or <i>PHKA2</i> <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a> cannot be detected in her leukocyte DNA, she most likely has <a class="def" href="/books/n/gene/glossary/def-item/germline-mosaicism/">germline mosaicism</a> (maternal germline mosaicism has been reported in <i>PHKA2</i>-related liver PhK deficiency) [<a class="bk_pop" href="#gsd9.REF.qin.2016.446">Qin et a 2016</a>].</div></li><li class="half_rhythm"><div>If a male is the only affected family member (i.e., a <a class="def" href="/books/n/gene/glossary/def-item/simplex/">simplex</a> case), the mother may be a <a class="def" href="/books/n/gene/glossary/def-item/heterozygote/">heterozygote</a> (<a class="def" href="/books/n/gene/glossary/def-item/carrier/">carrier</a>), or the affected male may have a <a class="def" href="/books/n/gene/glossary/def-item/de-novo/"><i>de novo</i></a> <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a>, in which case the mother is not a carrier. To date, <i>PHKA2</i>-related liver PhK deficiency caused by a <i>de novo</i> pathogenic variant has been documented in one individual [<a class="bk_pop" href="#gsd9.REF.rodr_guezjim_nez.2017.52">Rodríguez-Jiménez et al 2017</a>]. The overall frequency of <i>de novo</i> pathogenic variants in <i>PHKA1</i> and <i>PHKA2</i> is unknown.</div></li></ul><p><b>Sibs of a male <a class="def" href="/books/n/gene/glossary/def-item/proband/">proband</a>.</b> The risk to sibs depends on the genetic status of the mother:</p><ul><li class="half_rhythm"><div>If the mother of the <a class="def" href="/books/n/gene/glossary/def-item/proband/">proband</a> has a <i>PHKA1</i> or <i>PHKA2</i> <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a>, the chance of transmitting it in each pregnancy is 50%. Males who inherit the pathogenic variant will be affected; females who inherit the variant will be heterozygotes (carriers).</div><ul><li class="half_rhythm"><div><i>PHKA1</i>. No symptoms have been reported in females who are <a class="def" href="/books/n/gene/glossary/def-item/heterozygous/">heterozygous</a> for a <i>PHKA1</i> <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a>, although development of symptoms may occur, in theory, if skewed <a class="def" href="/books/n/gene/glossary/def-item/x-chromosome-inactivation/">X-chromosome inactivation</a> is present.</div></li><li class="half_rhythm"><div><i>PHKA2</i>. Females who are <a class="def" href="/books/n/gene/glossary/def-item/heterozygous/">heterozygous</a> for a <i>PHKA2</i> <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a> may be unaffected, have mild hepatomegaly, or (rarely) have more severe symptoms depending on the pattern of <a class="def" href="/books/n/gene/glossary/def-item/x-chromosome-inactivation/">X-chromosome inactivation</a> [Author, personal observation].</div></li></ul></li><li class="half_rhythm"><div>If the affected male represents a <a class="def" href="/books/n/gene/glossary/def-item/simplex/">simplex</a> case (i.e., a single occurrence in a family) and if the <i>PHKA1</i> or <i>PHKA2</i> <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a> cannot be detected in the leukocyte DNA of the mother, the risk to sibs is slightly greater than that of the general population (though still <1%) because of the theoretic possibility of maternal <a class="def" href="/books/n/gene/glossary/def-item/germline-mosaicism/">germline mosaicism</a>.</div></li></ul><p><b>Offspring of a male <a class="def" href="/books/n/gene/glossary/def-item/proband/">proband</a>.</b> Affected males transmit the <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a> to all of their daughters and none of their sons.</p><p><b>Other family members.</b> An affected male's maternal aunts may be at risk of being carriers, and the aunts' offspring, depending on their sex, may be at risk of being carriers or of being affected.</p><p>Note: Molecular genetic testing may be able to identify the family member in whom a <a class="def" href="/books/n/gene/glossary/def-item/de-novo/"><i>de novo</i></a> <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a> arose, information that could help determine genetic risk status of the extended family.</p><p><b>Heterozygote detection.</b> Molecular genetic testing of at-risk female relatives to determine their genetic status is most informative if the <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a> in the family has been identified in the <a class="def" href="/books/n/gene/glossary/def-item/proband/">proband</a>.</p><p>Note: (1) Identification of female carriers requires either (a) prior identification of the <i>PHKA1</i> or <i>PHKA2</i> <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a> in the family or, (b) if an affected male is not available for testing, <a class="def" href="/books/n/gene/glossary/def-item/molecular-genetic-testing/">molecular genetic testing</a> first by <a class="def" href="/books/n/gene/glossary/def-item/sequence-analysis/">sequence analysis</a>, and then, if no variant is identified, using <a class="def" href="/books/n/gene/glossary/def-item/deletion-duplication-analysis/">deletion/duplication analysis</a> if available. (2) Enzyme-based <a class="def" href="/books/n/gene/glossary/def-item/carrier-testing/">carrier testing</a> is not recommended for determining carrier status. (3) Female carriers are heterozygotes for these <a class="def" href="/books/n/gene/glossary/def-item/x-linked/">X-linked</a> disorders. Females who are <a class="def" href="/books/n/gene/glossary/def-item/heterozygous/">heterozygous</a> for a <i>PHKA2</i> pathogenic variant may develop mild hepatomegaly, short stature in childhood, and biochemical abnormalities [<a class="bk_pop" href="#gsd9.REF.willems.1990.268">Willems et al 1990</a>, <a class="bk_pop" href="#gsd9.REF.morava.2005.703">Morava et al 2005</a>], and theoretically more severe symptoms (including hypoglycemia) resulting from skewed <a class="def" href="/books/n/gene/glossary/def-item/x-chromosome-inactivation/">X-chromosome inactivation</a>. No symptoms have been reported in females who are heterozygous for a pathogenic variant in <i>PHKA1</i> [<a class="bk_pop" href="#gsd9.REF.bak.2001.286">Bak et al 2001</a>], but it is possible that they, too, could exhibit symptoms as a result of skewed X-chromosome inactivation.</p></div><div id="gsd9.Autosomal_Recessive_Inheritance__Ri"><h3>Autosomal Recessive Inheritance – 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>PHKB</i> or <i>PHKG2</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 PhK deficiency.</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 PhK deficiency.</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 <a class="def" href="/books/n/gene/glossary/def-item/autosomal-recessive/">autosomal recessive</a> PhK deficiency are obligate heterozygotes (carriers) for a <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a> in <i>PHKB</i> or <i>PHKG2</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>.</p><p><b>Carrier detection.</b> Carrier testing for relatives at risk for the two subtypes of <a class="def" href="/books/n/gene/glossary/def-item/autosomal-recessive/">autosomal recessive</a> PhK deficiency (caused by pathogenic variants in <i>PHKB</i> or <i>PHKG2</i>) requires prior identification of the pathogenic variants in the family<i>.</i></p><p>Enzyme-based <a class="def" href="/books/n/gene/glossary/def-item/carrier-testing/">carrier testing</a> is not recommended for determining carrier status.</p></div><div id="gsd9.Related_Genetic_Counseling_Issues"><h3>Related Genetic Counseling Issues</h3><p>See Management, <a href="#gsd9.Evaluation_of_Relatives_at_Risk">Evaluation of Relatives at Risk</a> for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.</p><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 affected or at risk of being carriers or of being affected.</div></li></ul><p><b>DNA banking.</b> Because it is likely that testing methodology and our understanding of genes, pathogenic mechanisms, and diseases will improve in the future, consideration should be given to banking DNA from probands in whom a molecular diagnosis has not been confirmed (i.e., the causative pathogenic mechanism is unknown). For more information, see <a class="bk_pop" href="#gsd9.REF.huang.2022.389">Huang et al [2022]</a>.</p></div><div id="gsd9.Prenatal_Testing_and_Preimplantatio"><h3>Prenatal Testing and Preimplantation Genetic Testing</h3><p><b>Molecular genetic testing.</b> Once the <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a>(s) have been identified in an affected family member, prenatal and <a class="def" href="/books/n/gene/glossary/def-item/preimplantation-genetic-testing/">preimplantation genetic testing</a> for PhK deficiency are possible. Molecular testing is the preferred method for <a class="def" href="/books/n/gene/glossary/def-item/prenatal-testing/">prenatal testing</a>.</p><p><b>Biochemical testing.</b> Prenatal testing based on PK enzyme testing is not available and not recommended. PK is a very labile kinase enzyme so that any <a class="def" href="/books/n/gene/glossary/def-item/prenatal-testing/">prenatal testing</a> or <a class="def" href="/books/n/gene/glossary/def-item/carrier-testing/">carrier testing</a> results may not be reliable.</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 use of prenatal testing is a personal decision, discussion of these issues may be helpful.</p></div></div><div id="gsd9.Resources"><h2 id="_gsd9_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>Association for Glycogen Storage Disease</b>
|
||
</div><div>
|
||
<a href="http://www.agsdus.org" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">www.agsdus.org</a>
|
||
</div></li><li class="half_rhythm"><div>
|
||
<b>Metabolic Support UK</b>
|
||
</div><div>United Kingdom</div><div><b>Phone:</b> 0845 241 2173</div><div>
|
||
<a href="https://metabolicsupportuk.org/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">metabolicsupportuk.org</a>
|
||
</div></li></ul>
|
||
</div><div id="gsd9.Molecular_Genetics"><h2 id="_gsd9_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="gsd9.molgen.TA" class="table"><h3><span class="label">Table A.</span></h3><div class="caption"><p>Phosphorylase Kinase Deficiency: Genes and Databases</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK55061/table/gsd9.molgen.TA/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__gsd9.molgen.TA_lrgtbl__"><table class="no_bottom_margin"><tbody><tr><th id="hd_b_gsd9.molgen.TA_1_1_1_1" rowspan="1" colspan="1" style="vertical-align:top;">Gene</th><th id="hd_b_gsd9.molgen.TA_1_1_1_2" rowspan="1" colspan="1" style="vertical-align:top;">Chromosome Locus</th><th id="hd_b_gsd9.molgen.TA_1_1_1_3" rowspan="1" colspan="1" style="vertical-align:top;">Protein</th><th id="hd_b_gsd9.molgen.TA_1_1_1_4" rowspan="1" colspan="1" style="vertical-align:top;">Locus-Specific Databases</th><th id="hd_b_gsd9.molgen.TA_1_1_1_5" rowspan="1" colspan="1" style="vertical-align:top;">HGMD</th><th id="hd_b_gsd9.molgen.TA_1_1_1_6" rowspan="1" colspan="1" style="vertical-align:top;">ClinVar</th></tr><tr><td headers="hd_b_gsd9.molgen.TA_1_1_1_1" rowspan="1" colspan="1" style="vertical-align:top;">
|
||
<a href="/gene/5255" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=gene">
|
||
<i>PHKA1</i>
|
||
</a>
|
||
</td><td headers="hd_b_gsd9.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=5255" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">Xq13<wbr style="display:inline-block"></wbr>.1</a>
|
||
</td><td headers="hd_b_gsd9.molgen.TA_1_1_1_3" rowspan="1" colspan="1" style="vertical-align:top;">
|
||
<a href="http://www.uniprot.org/uniprot/P46020" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">Phosphorylase b kinase regulatory subunit alpha, skeletal muscle isoform</a>
|
||
</td><td headers="hd_b_gsd9.molgen.TA_1_1_1_4" rowspan="1" colspan="1" style="vertical-align:top;">
|
||
<a href="http://www.LOVD.nl/PHKA1" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">PHKA1 @ LOVD</a>
|
||
</td><td headers="hd_b_gsd9.molgen.TA_1_1_1_5" rowspan="1" colspan="1" style="vertical-align:top;">
|
||
<a href="http://www.hgmd.cf.ac.uk/ac/gene.php?gene=PHKA1" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">PHKA1</a>
|
||
</td><td headers="hd_b_gsd9.molgen.TA_1_1_1_6" rowspan="1" colspan="1" style="vertical-align:top;">
|
||
<a href="https://www.ncbi.nlm.nih.gov/clinvar/?term=PHKA1[gene]" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">PHKA1</a>
|
||
</td></tr><tr><td headers="hd_b_gsd9.molgen.TA_1_1_1_1" rowspan="1" colspan="1" style="vertical-align:top;">
|
||
<a href="/gene/5256" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=gene">
|
||
<i>PHKA2</i>
|
||
</a>
|
||
</td><td headers="hd_b_gsd9.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=5256" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">Xp22<wbr style="display:inline-block"></wbr>.13</a>
|
||
</td><td headers="hd_b_gsd9.molgen.TA_1_1_1_3" rowspan="1" colspan="1" style="vertical-align:top;">
|
||
<a href="http://www.uniprot.org/uniprot/P46019" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">Phosphorylase b kinase regulatory subunit alpha, liver isoform</a>
|
||
</td><td headers="hd_b_gsd9.molgen.TA_1_1_1_4" rowspan="1" colspan="1" style="vertical-align:top;">
|
||
<a href="http://www.LOVD.nl/PHKA2" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">PHKA2 @ LOVD</a>
|
||
</td><td headers="hd_b_gsd9.molgen.TA_1_1_1_5" rowspan="1" colspan="1" style="vertical-align:top;">
|
||
<a href="http://www.hgmd.cf.ac.uk/ac/gene.php?gene=PHKA2" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">PHKA2</a>
|
||
</td><td headers="hd_b_gsd9.molgen.TA_1_1_1_6" rowspan="1" colspan="1" style="vertical-align:top;">
|
||
<a href="https://www.ncbi.nlm.nih.gov/clinvar/?term=PHKA2[gene]" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">PHKA2</a>
|
||
</td></tr><tr><td headers="hd_b_gsd9.molgen.TA_1_1_1_1" rowspan="1" colspan="1" style="vertical-align:top;">
|
||
<a href="/gene/5257" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=gene">
|
||
<i>PHKB</i>
|
||
</a>
|
||
</td><td headers="hd_b_gsd9.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=5257" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">16q12<wbr style="display:inline-block"></wbr>.1</a>
|
||
</td><td headers="hd_b_gsd9.molgen.TA_1_1_1_3" rowspan="1" colspan="1" style="vertical-align:top;">
|
||
<a href="http://www.uniprot.org/uniprot/Q93100" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">Phosphorylase b kinase regulatory subunit beta</a>
|
||
</td><td headers="hd_b_gsd9.molgen.TA_1_1_1_4" rowspan="1" colspan="1" style="vertical-align:top;">
|
||
<a href="http://databases.lovd.nl/shared/genes/PHKB" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">PHKB database</a>
|
||
</td><td headers="hd_b_gsd9.molgen.TA_1_1_1_5" rowspan="1" colspan="1" style="vertical-align:top;">
|
||
<a href="http://www.hgmd.cf.ac.uk/ac/gene.php?gene=PHKB" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">PHKB</a>
|
||
</td><td headers="hd_b_gsd9.molgen.TA_1_1_1_6" rowspan="1" colspan="1" style="vertical-align:top;">
|
||
<a href="https://www.ncbi.nlm.nih.gov/clinvar/?term=PHKB[gene]" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">PHKB</a>
|
||
</td></tr><tr><td headers="hd_b_gsd9.molgen.TA_1_1_1_1" rowspan="1" colspan="1" style="vertical-align:top;">
|
||
<a href="/gene/5261" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=gene">
|
||
<i>PHKG2</i>
|
||
</a>
|
||
</td><td headers="hd_b_gsd9.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=5261" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">16p11<wbr style="display:inline-block"></wbr>.2</a>
|
||
</td><td headers="hd_b_gsd9.molgen.TA_1_1_1_3" rowspan="1" colspan="1" style="vertical-align:top;">
|
||
<a href="http://www.uniprot.org/uniprot/P15735" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">Phosphorylase b kinase gamma catalytic chain, liver/testis isoform</a>
|
||
</td><td headers="hd_b_gsd9.molgen.TA_1_1_1_4" rowspan="1" colspan="1" style="vertical-align:top;">
|
||
<a href="http://databases.lovd.nl/shared/genes/PHKG2" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">PHKG2 database</a>
|
||
</td><td headers="hd_b_gsd9.molgen.TA_1_1_1_5" rowspan="1" colspan="1" style="vertical-align:top;">
|
||
<a href="http://www.hgmd.cf.ac.uk/ac/gene.php?gene=PHKG2" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">PHKG2</a>
|
||
</td><td headers="hd_b_gsd9.molgen.TA_1_1_1_6" rowspan="1" colspan="1" style="vertical-align:top;">
|
||
<a href="https://www.ncbi.nlm.nih.gov/clinvar/?term=PHKG2[gene]" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">PHKG2</a>
|
||
</td></tr></tbody></table></div><div><div><dl class="temp-labeled-list small"><dt></dt><dd><div id="gsd9.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="gsd9.molgen.TB" class="table"><h3><span class="label">Table B.</span></h3><div class="caption"><p>OMIM Entries for Phosphorylase Kinase Deficiency (<a href="/omim/172471,172490,261750,300559,300798,306000,311870,613027" 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/NBK55061/table/gsd9.molgen.TB/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__gsd9.molgen.TB_lrgtbl__"><table><tbody><tr><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
||
<a href="/omim/172471" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=omim">172471</a></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">PHOSPHORYLASE KINASE, TESTIS/LIVER, GAMMA-2; PHKG2</td></tr><tr><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
||
<a href="/omim/172490" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=omim">172490</a></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">PHOSPHORYLASE KINASE, BETA SUBUNIT; PHKB</td></tr><tr><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
||
<a href="/omim/261750" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=omim">261750</a></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">GLYCOGEN STORAGE DISEASE IXb; GSD9B</td></tr><tr><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
||
<a href="/omim/300559" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=omim">300559</a></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">GLYCOGEN STORAGE DISEASE IXd; GSD9D</td></tr><tr><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
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||
<a href="/omim/300798" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=omim">300798</a></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">PHOSPHORYLASE KINASE, LIVER, ALPHA-2 SUBUNIT; PHKA2</td></tr><tr><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
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||
<a href="/omim/306000" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=omim">306000</a></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">GLYCOGEN STORAGE DISEASE IXa1; GSD9A1</td></tr><tr><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
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||
<a href="/omim/311870" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=omim">311870</a></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">PHOSPHORYLASE KINASE, MUSCLE, ALPHA-1 SUBUNIT; PHKA1</td></tr><tr><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
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<a href="/omim/613027" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=omim">613027</a></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">GLYCOGEN STORAGE DISEASE IXc; GSD9C</td></tr></tbody></table></div></div><div id="gsd9.Molecular_Pathogenesis"><h3>Molecular Pathogenesis</h3><p>The enzyme phosphorylase kinase (PhK) activates liver glycogen phosphorylase and muscle glycogen phosphorylase in response to neuronal and hormonal stimuli and thus is a key regulatory enzyme in glycogen breakdown. In liver PhK deficiency, the inability to break down glycogen results in risk for hypoglycemia and glycogen accumulation in the liver, which in turn causes hepatomegaly and liver damage.</p><p>PhK is a multi-subunit enzyme composed of four copies each of four subunits (α, β, γ, and δ). The gamma (γ) subunit contains the catalytic activity and is regulated by the alpha (α), beta (β), and delta (δ) subunits. The inhibitory effect of the alpha and beta subunits is modulated by phosphorylation (phosphorylation removes the inhibitory effect); calcium levels modulate the regulatory effect of the delta subunit (calmodulin).</p><p>Each PhK subunit is encoded by at least one <a class="def" href="/books/n/gene/glossary/def-item/gene/">gene</a>: <i>PHKA1</i> and <i>PHKA2</i> encode the muscle and liver <a class="def" href="/books/n/gene/glossary/def-item/isoforms/">isoforms</a> of the α-subunit, respectively; <i>PHKB</i> encodes the liver and muscle β-subunits; <i>PHKG1</i> and <i>PHKG2</i> encode the muscle and liver isoforms of the γ-subunit, respectively; and the δ-subunit, calmodulin, is encoded by three genes: <i>CALM1</i>, <i>CALM2</i>, and <i>CALM3</i>. Expression of these genes is tissue dependent (<a class="figpopup" href="/books/NBK55061/figure/gsd9.F1/?report=objectonly" target="object" rid-figpopup="figgsd9F1" rid-ob="figobgsd9F1">Figure 1</a>). Further complexity is introduced by tissue-specific alternative <a class="def" href="/books/n/gene/glossary/def-item/splicing/">splicing</a>. The complexity of the enzyme PhK explains to some degree the clinical and biochemical heterogeneity of PhK deficiency.</p><p>Of these eight genes, four are known to contain pathogenic variants that cause PhK enzyme deficiency (<a class="figpopup" href="/books/NBK55061/figure/gsd9.F2/?report=objectonly" target="object" rid-figpopup="figgsd9F2" rid-ob="figobgsd9F2">Figure 2</a>).</p><p>The two <a class="def" href="/books/n/gene/glossary/def-item/x-linked/">X-linked</a> genes are:</p><ul><li class="half_rhythm"><div><i>PHKA1</i>, which causes the rare disorder <a class="def" href="/books/n/gene/glossary/def-item/x-linked/">X-linked</a> muscle PhK deficiency; and</div></li><li class="half_rhythm"><div><i>PHKA2</i>, which causes the most common form of liver PhK deficiency, also known as <a class="def" href="/books/n/gene/glossary/def-item/x-linked/">X-linked</a> liver glycogenosis (XLG).</div></li></ul><p>The two <a class="def" href="/books/n/gene/glossary/def-item/autosomal/">autosomal</a> genes are:</p><ul><li class="half_rhythm"><div><i>PHKB</i>, which causes PhK deficiency in both liver and muscle but manifests primarily with liver symptoms with or without muscle involvement; and</div></li><li class="half_rhythm"><div><i>PHKG2</i>, which causes PhK deficiency in liver.</div></li></ul><p>Muscle PhK activity is normal in individuals with pathogenic variants in either <i>PHKA2</i> or <i>PHKG2</i> and can be deficient in those with pathogenic variants in <i>PHKB</i>.</p><div id="gsd9.PHKA1"><h4>
|
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<i>PHKA1</i>
|
||
</h4><p><b>Gene structure.</b> Alternatively spliced transcript variants encoding different <a class="def" href="/books/n/gene/glossary/def-item/isoforms/">isoforms</a> have been identified in this <a class="def" href="/books/n/gene/glossary/def-item/gene/">gene</a>. The longest transcript (<a href="https://www.ncbi.nlm.nih.gov/nuccore/NM_002637.3" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">NM_002637.3</a>) consists of 32 exons and is transcribed into a 6-kb <a class="def" href="/books/n/gene/glossary/def-item/cdna/">cDNA</a>. <i>PHKA1</i> spans approximately 133 kb of <a class="def" href="/books/n/gene/glossary/def-item/genomic/">genomic</a> DNA. A <a class="def" href="/books/n/gene/glossary/def-item/pseudogene/">pseudogene</a>, <i>PHKA1P1</i>, has been found on <a class="def" href="/books/n/gene/glossary/def-item/chromosome/">chromosome</a> 1p22.2. For a detailed summary of gene and protein information, see <a href="/books/NBK55061/#gsd9.molgen.TA">Table A</a>, <b>Gene</b>.</p><p><b>Pathogenic variants.</b> To date, seven pathogenic variants have been reported in <i>PHKA1</i>, each of which was found in only one or two individuals. Pathogenic variants include <a class="def" href="/books/n/gene/glossary/def-item/missense/">missense</a> (3), frameshift (2), <a class="def" href="/books/n/gene/glossary/def-item/nonsense-variant/">nonsense</a>(1), and <a class="def" href="/books/n/gene/glossary/def-item/splice-site/">splice site</a> changes (1) [<a class="bk_pop" href="#gsd9.REF.wehner.1994.1983">Wehner et al 1994</a>, <a class="bk_pop" href="#gsd9.REF.bruno.1998.648">Bruno et al 1998</a>, <a class="bk_pop" href="#gsd9.REF.burwinkel.2003a.516">Burwinkel et al 2003a</a>, <a class="bk_pop" href="#gsd9.REF.wuyts.2005.82">Wuyts et al 2005</a>, <a class="bk_pop" href="#gsd9.REF._rngreen.2008.1876">Ørngreen et al 2008</a>, <a class="bk_pop" href="#gsd9.REF.echanizlaguna.2010.125">Echaniz-Laguna et al 2010</a>].</p><p>A <a class="def" href="/books/n/gene/glossary/def-item/frameshift-variant/">frameshift variant</a> in mouse ortholog <i>Phka1</i> causes PhK deficiency in the I-strain mouse [<a class="bk_pop" href="#gsd9.REF.schneider.1993.381">Schneider et al 1993</a>].</p><p><b>Normal <a class="def" href="/books/n/gene/glossary/def-item/gene-product/">gene product</a>.</b>
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<i>PHKA1</i> encodes the muscle isoform of the alpha subunit of PhK, a 1,223-amino-acid protein (<a href="https://www.ncbi.nlm.nih.gov/protein/NP_002628.2" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">NP_002628.2</a>).</p><p>Two alternatively spliced transcript variants encoding different <a class="def" href="/books/n/gene/glossary/def-item/isoforms/">isoforms</a> have been identified [<a class="bk_pop" href="#gsd9.REF.harmann.1991.15631">Harmann et al 1991</a>]; alpha-FM is the predominant form in fast-twitch skeletal muscle and is also expressed in brain, while alpha-prime is the predominant form in slow-twitch skeletal muscle. Alpha-prime has an internal <a class="def" href="/books/n/gene/glossary/def-item/deletion/">deletion</a> of 59 amino acids (amino acids 654-712) when compared to alpha-FM.</p><p>The degree of phosphorylation of the alpha subunit regulates the activity of PhK; the greater the phosphorylation, the less the inhibitory effect.</p><p><b>Abnormal <a class="def" href="/books/n/gene/glossary/def-item/gene-product/">gene product</a>.</b> Muscle PhK deficiency due to pathogenic variants in <i>PHKA1</i> appears to cause myopathy through a defect in glycogen availability during submaximal exercise (oxidative metabolism; e.g., cycle test) presumably because PhK is required to activate glycogen phosphorylase under these conditions. Interestingly, anaerobic glycogenolysis is normal, suggesting that other regulatory factors are involved in phosphorylase activation in this situation [<a class="bk_pop" href="#gsd9.REF._rngreen.2008.1876">Ørngreen et al 2008</a>].</p><p>Complete lack of PHKA1 protein is predicted to affect formation or stability of PhK holoenzyme. Production of an altered PHKA1 protein, resulting from <a class="def" href="/books/n/gene/glossary/def-item/missense/">missense</a> variants, may affect its ability to interact with other subunits or to activate PhK activity.</p></div><div id="gsd9.PHKA2"><h4>
|
||
<i>PHKA2</i>
|
||
</h4><p><b>Gene structure.</b> The <a class="def" href="/books/n/gene/glossary/def-item/gene/">gene</a> contains 33 exons [<a class="bk_pop" href="#gsd9.REF.hendrickx.1999.1541">Hendrickx et al 1999</a>] and spans 91.3 kb of DNA. Alternatively spliced transcript variants have been reported, but the full-length nature of these variants has not been determined. For a detailed summary of gene and protein information, see <a href="/books/NBK55061/#gsd9.molgen.TA">Table A</a>, <b>Gene</b>.</p><p><b>Pathogenic variants.</b> More than 100 different pathogenic variants have been reported in <i>PHKA2</i>. Most of them are <a class="def" href="/books/n/gene/glossary/def-item/missense/">missense</a> or <a class="def" href="/books/n/gene/glossary/def-item/nonsense-variant/">nonsense</a> variants or small deletions causing frameshifts. Only seven gross deletions/duplications have been reported. The pathogenic variants are distributed throughout the <a class="def" href="/books/n/gene/glossary/def-item/gene/">gene</a>.</p><div id="gsd9.T.phka2_pathogenic_variants_discuss" class="table"><h3><span class="label">Table 4. </span></h3><div class="caption"><p><i>PHKA2</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/NBK55061/table/gsd9.T.phka2_pathogenic_variants_discuss/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__gsd9.T.phka2_pathogenic_variants_discuss_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_gsd9.T.phka2_pathogenic_variants_discuss_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_gsd9.T.phka2_pathogenic_variants_discuss_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_gsd9.T.phka2_pathogenic_variants_discuss_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_gsd9.T.phka2_pathogenic_variants_discuss_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">c.884G>A</td><td headers="hd_h_gsd9.T.phka2_pathogenic_variants_discuss_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">p.Arg295His</td><td headers="hd_h_gsd9.T.phka2_pathogenic_variants_discuss_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<a href="https://www.ncbi.nlm.nih.gov/entrez/viewer.fcgi?val=NM_000292.2" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">NM_000292<wbr style="display:inline-block"></wbr>.2</a>
|
||
<br />
|
||
<a href="https://www.ncbi.nlm.nih.gov/protein/NP_000283.1" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">NP_000283<wbr style="display:inline-block"></wbr>.1</a>
|
||
</td></tr></tbody></table></div><div><div><dl class="temp-labeled-list small"><dt></dt><dd><div><p class="no_margin">Variants listed in the table have been provided by the authors. <i>GeneReviews</i> staff have not independently verified the classification of variants.</p></div></dd><dt></dt><dd><div><p class="no_margin"><i>GeneReviews</i> follows the standard naming conventions of the Human Genome Variation Society (<a href="https://varnomen.hgvs.org/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">varnomen<wbr style="display:inline-block"></wbr>.hgvs.org</a>). See <a href="/books/n/gene/app3/">Quick Reference</a> for an explanation of nomenclature.</p></div></dd></dl></div></div></div><p><b>Normal <a class="def" href="/books/n/gene/glossary/def-item/gene-product/">gene product</a>.</b>
|
||
<i>PHKA2</i> encodes the liver alpha subunit of PhK. A 5,325-bp <a class="def" href="/books/n/gene/glossary/def-item/mrna/">mRNA</a> is translated into a 1,235-amino-acid protein with high expression in liver and brain, but not in muscle [<a class="bk_pop" href="#gsd9.REF.hendrickx.1993.583">Hendrickx et al 1993</a>]. <i>PHKA2</i> is highly homologous to <i>PHKA1</i> and <i>PHKB</i>.</p><p><b>Abnormal <a class="def" href="/books/n/gene/glossary/def-item/gene-product/">gene product</a>.</b> Two biochemical subtypes of <a class="def" href="/books/n/gene/glossary/def-item/x-linked/">X-linked</a> glycogenosis (XLG) are caused by pathogenic variants in <i>PHKA2</i> [<a class="bk_pop" href="#gsd9.REF.hendrickx.1994.620">Hendrickx et al 1994</a>, <a class="bk_pop" href="#gsd9.REF.burwinkel.1996.653">Burwinkel et al 1996</a>, <a class="bk_pop" href="#gsd9.REF.hendrickx.1996.649">Hendrickx et al 1996</a>, <a class="bk_pop" href="#gsd9.REF.burwinkel.1998a.423">Burwinkel et al 1998a</a>, <a class="bk_pop" href="#gsd9.REF.hendrickx.1999.1541">Hendrickx et al 1999</a>]:</p><ul><li class="half_rhythm"><div>XLG1, the more common form, in which in vitro PhK activity is deficient in peripheral blood cells and liver</div></li><li class="half_rhythm"><div>XLG2, in which in vitro PhK activity in peripheral blood cells is normal or even elevated and activity in liver is variable</div></li></ul><p>While not yet fully understood, there are various theories as to how different pathogenic variants in <i>PHKA2</i> could result in these different biochemical subtypes.</p><p>Regarding correlation between <a class="def" href="/books/n/gene/glossary/def-item/genotype/">genotype</a> and biochemical <a class="def" href="/books/n/gene/glossary/def-item/phenotype/">phenotype</a>, <a class="bk_pop" href="#gsd9.REF.hendrickx.1999.1541">Hendrickx et al [1999]</a> suggested the following:</p><ul><li class="half_rhythm"><div><i>PHKA2</i> variants resulting in reduced amounts of alpha subunit protein (e.g., <a class="def" href="/books/n/gene/glossary/def-item/nonsense-variant/">nonsense</a> and frameshift variants or <a class="def" href="/books/n/gene/glossary/def-item/missense/">missense</a> variants that destabilize the protein) cause detectable PhK deficiency in vitro (XLG1 biochemical subtype).</div></li><li class="half_rhythm"><div><i>PHKA2</i> variants that disrupt activation of PhK enzyme activity (e.g., <a class="def" href="/books/n/gene/glossary/def-item/missense/">missense</a> variants or small <a class="def" href="/books/n/gene/glossary/def-item/in-frame/">in-frame</a> insertions or deletions affecting regulatory sites of the enzyme) can result in the normal PhK activity that is observed in vitro in some affected persons (XLG2 biochemical subtype).</div></li></ul><p>These subtle changes may allow normal amounts of PhK to be made but affect enzyme function [<a class="bk_pop" href="#gsd9.REF.maire.1991.169">Maire et al 1991</a>, <a class="bk_pop" href="#gsd9.REF.hendrickx.1994.620">Hendrickx et al 1994</a>, <a class="bk_pop" href="#gsd9.REF.burwinkel.1996.653">Burwinkel et al 1996</a>, <a class="bk_pop" href="#gsd9.REF.hendrickx.1996.649">Hendrickx et al 1996</a>, <a class="bk_pop" href="#gsd9.REF.burwinkel.1997b.170">Burwinkel et al 1997b</a>, <a class="bk_pop" href="#gsd9.REF.burwinkel.1998a.423">Burwinkel et al 1998a</a>, <a class="bk_pop" href="#gsd9.REF.hendrickx.1998.919">Hendrickx et al 1998</a>].</p><p><a class="bk_pop" href="#gsd9.REF.carri_re.2008.664">Carrière et al [2008]</a> showed that <i>PHKA2</i> <a class="def" href="/books/n/gene/glossary/def-item/missense/">missense</a> variants and small <a class="def" href="/books/n/gene/glossary/def-item/in-frame/">in-frame</a> deletions/insertions are concentrated into two domains of the protein, the N-terminal glucoamylase <a class="def" href="/books/n/gene/glossary/def-item/domain/">domain</a> (principally leading to XLG2) and the C-terminal calcineurin B-like domain (domain D; principally leading to XLG1).</p><p>Further studies are needed to determine the molecular basis of the XLG1 and XLG2 biochemical subtypes. Of note, the same <i>PHKA2</i> variant (p.Arg295His) has been associated with normal and deficient PhK activity in vitro, suggesting that other factors, such as handling of the specimen and laboratory methodologies, can also affect the biochemical <a class="def" href="/books/n/gene/glossary/def-item/phenotype/">phenotype</a> [<a class="bk_pop" href="#gsd9.REF.hendrickx.1999.1541">Hendrickx et al 1999</a>].</p></div><div id="gsd9.PHKB"><h4>
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||
<i>PHKB</i>
|
||
</h4><p><b>Gene structure.</b> Alternatively spliced transcript variants encoding different <a class="def" href="/books/n/gene/glossary/def-item/isoforms/">isoforms</a> have been identified in this <a class="def" href="/books/n/gene/glossary/def-item/gene/">gene</a>. The longer transcript variant, <a href="https://www.ncbi.nlm.nih.gov/nuccore/NM_000293.2" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">NM_000293.2</a>, is composed of 33 exons spanning 239 kb of <a class="def" href="/books/n/gene/glossary/def-item/genomic/">genomic</a> DNA. Exons 26 and 27 are two homologous, mutually exclusively spliced exons that encode muscle and non-muscle PHKB, respectively; <a class="def" href="/books/n/gene/glossary/def-item/exon/">exon</a> 2 is a facultatively used cassette exon encoding an alternative N-terminus [<a class="bk_pop" href="#gsd9.REF.w_llrichschmoll.1996.374">Wüllrich-Schmoll & Kilimann 1996</a>]. For a detailed summary of gene and protein information, see <a href="/books/NBK55061/#gsd9.molgen.TA">Table A</a>, <b>Gene</b>.</p><p>Two processed pseudogenes have been identified: <i>PHKBP1</i> on <a class="def" href="/books/n/gene/glossary/def-item/chromosome/">chromosome</a> 20p12.3-20p12.2 and <i>PHKBP2</i> on chromosome 14q13.3 [<a class="bk_pop" href="#gsd9.REF.w_llrichschmoll.1996.374">Wüllrich-Schmoll & Kilimann 1996</a>].</p><p><b>Pathogenic variants.</b> More than 20 variants suspected or known to be pathogenic have been reported in <i>PHKB</i>. These include <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>, <a class="def" href="/books/n/gene/glossary/def-item/splice-site/">splice site</a>, frameshift, and gross <a class="def" href="/books/n/gene/glossary/def-item/deletion/">deletion</a> changes [<a class="bk_pop" href="#gsd9.REF.burwinkel.1997b.170">Burwinkel et al 1997b</a>, <a class="bk_pop" href="#gsd9.REF.van_den_berg.1997.539">van den Berg et al 1997</a>, <a class="bk_pop" href="#gsd9.REF.burwinkel.2003a.516">Burwinkel et al 2003a</a>, <a class="bk_pop" href="#gsd9.REF.beauchamp.2007.88">Beauchamp et al 2007</a>]. Two of the missense changes, p.Met185Ile and p.Gln657Lys, were identified in heterozygotes in whom no other <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a> was identified, and thus their significance is unknown [<a class="bk_pop" href="#gsd9.REF.burwinkel.1997a.1109">Burwinkel et al 1997a</a>, <a class="bk_pop" href="#gsd9.REF.burwinkel.2003a.516">Burwinkel et al 2003a</a>, <a class="bk_pop" href="#gsd9.REF.beauchamp.2007.88">Beauchamp et al 2007</a>].</p><div id="gsd9.T.phkb_pathogenic_variants_discusse" class="table"><h3><span class="label">Table 5. </span></h3><div class="caption"><p><i>PHKB</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/NBK55061/table/gsd9.T.phkb_pathogenic_variants_discusse/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__gsd9.T.phkb_pathogenic_variants_discusse_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_gsd9.T.phkb_pathogenic_variants_discusse_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_gsd9.T.phkb_pathogenic_variants_discusse_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_gsd9.T.phkb_pathogenic_variants_discusse_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_gsd9.T.phkb_pathogenic_variants_discusse_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">c.555G>T</td><td headers="hd_h_gsd9.T.phkb_pathogenic_variants_discusse_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">p.Met185Ile</td><td headers="hd_h_gsd9.T.phkb_pathogenic_variants_discusse_1_1_1_3" rowspan="2" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<a href="https://www.ncbi.nlm.nih.gov/nuccore/NM_000253.3" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">NM_000293<wbr style="display:inline-block"></wbr>.2</a>
|
||
</td></tr><tr><td headers="hd_h_gsd9.T.phkb_pathogenic_variants_discusse_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">c.1969C>A</td><td headers="hd_h_gsd9.T.phkb_pathogenic_variants_discusse_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">p.Gln657Lys</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 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>
|
||
<i>PHKB</i> encodes the beta subunit of liver or muscle PhK. The degree of phosphorylation of the beta subunit determines the activity of the enzyme PhK.</p><p><b>Abnormal <a class="def" href="/books/n/gene/glossary/def-item/gene-product/">gene product</a>.</b> It is not known exactly how <i>PHKB</i> pathogenic variants result in PhK deficiency. Lack of PHKB protein would affect formation of the normal PhK holoenzyme, and an abnormal PHKB protein would presumably affect its interaction with other PhK subunits and its regulatory function. Biochemical evidence suggests that an alpha-gamma-delta complex may form in the absence of the beta subunit, explaining the residual enzyme activity seen in some individuals and the mild clinical features [<a class="bk_pop" href="#gsd9.REF.burwinkel.1997a.1109">Burwinkel et al 1997a</a>, <a class="bk_pop" href="#gsd9.REF.brushia.1999.d618">Brushia & Walsh 1999</a>].</p></div><div id="gsd9.PHKG2"><h4>
|
||
<i>PHKG2</i>
|
||
</h4><p><b>Gene structure.</b> Alternatively spliced transcript variants encoding different <a class="def" href="/books/n/gene/glossary/def-item/isoforms/">isoforms</a> have been identified in this <a class="def" href="/books/n/gene/glossary/def-item/gene/">gene</a>. The <i>PHKG2</i> longer transcript isoform <a href="https://www.ncbi.nlm.nih.gov/nuccore/NM_000294.2" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">NM_000294.2</a> comprises ten exons spanning 9 kb of <a class="def" href="/books/n/gene/glossary/def-item/genomic/">genomic</a> DNA. A complex <a class="def" href="/books/n/gene/glossary/def-item/microsatellite/">microsatellite</a> repeat has been identified at the beginning of <a class="def" href="/books/n/gene/glossary/def-item/intron/">intron</a> 2 [<a class="bk_pop" href="#gsd9.REF.burwinkel.1998b.149">Burwinkel et al 1998b</a>]. For a detailed summary of gene and protein information, see <a href="/books/NBK55061/#gsd9.molgen.TA">Table A</a>, <b>Gene</b>.</p><p><b>Pathogenic variants.</b> More than 30 pathogenic variants have been reported in <i>PHKG2</i> including <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>, <a class="def" href="/books/n/gene/glossary/def-item/splice-site/">splice site</a>, and frameshift changes [<a class="bk_pop" href="#gsd9.REF.maichele.1996.337">Maichele et al 1996</a>, <a class="bk_pop" href="#gsd9.REF.van_beurden.1997.544">van Beurden et al 1997</a>, <a class="bk_pop" href="#gsd9.REF.burwinkel.1998b.149">Burwinkel et al 1998b</a>, <a class="bk_pop" href="#gsd9.REF.burwinkel.2000.376">Burwinkel et al 2000</a>, <a class="bk_pop" href="#gsd9.REF.burwinkel.2003b.834">Burwinkel et al 2003b</a>, <a class="bk_pop" href="#gsd9.REF.beauchamp.2007.88">Beauchamp et al 2007</a>].</p><p><b>Normal <a class="def" href="/books/n/gene/glossary/def-item/gene-product/">gene product</a>.</b>
|
||
<i>PHKG2</i> encodes the catalytic gamma subunit of liver PhK, a 406-amino-acid protein, <a href="https://www.ncbi.nlm.nih.gov/protein/NP_000285.1" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">NP_000285.1</a>. Alternative <a class="def" href="/books/n/gene/glossary/def-item/splicing/">splicing</a> creates a variant of 374 amino acids with a different C-terminus.</p><p><b>Abnormal <a class="def" href="/books/n/gene/glossary/def-item/gene-product/">gene product</a>.</b> Pathogenic variants in <i>PHKG2</i> are expected to affect the catalytic ability of the gamma subunit either by resulting in production of no protein or affecting the stability or confirmation of the protein.</p></div></div></div><div id="gsd9.Chapter_Notes"><h2 id="_gsd9_Chapter_Notes_">Chapter Notes</h2><div id="gsd9.Acknowledgments"><h3>Acknowledgments</h3><p>We would like to thank Dr YT Chen, Denise Petersen, and Keri Fredrickson for their useful discussions and professional contributions to increasing the understanding and knowledge of this complicated disorder.</p></div><div id="gsd9.Revision_History"><h3>Revision History</h3><ul><li class="half_rhythm"><div>1 November 2018 (ha) Comprehensive update posted live</div></li><li class="half_rhythm"><div>31 May 2011 (me) Review posted live</div></li><li class="half_rhythm"><div>7 September 2010 (db) Original submission</div></li></ul></div></div><div id="gsd9.References"><h2 id="_gsd9_References_">References</h2><div id="gsd9.Literature_Cited"><h3>Literature Cited</h3><ul class="simple-list"><li class="half_rhythm"><div class="bk_ref" id="gsd9.REF.alfadhel.2016.126">Alfadhel
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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/NBK55061/?report=reader">PubReader</a></li><li><a href="/books/NBK55061/?report=printable">Print View</a></li><li><a data-jig="ncbidialog" href="#_ncbi_dlg_citbx_NBK55061" data-jigconfig="width:400,modal:true">Cite this Page</a><div id="_ncbi_dlg_citbx_NBK55061" style="display:none" title="Cite this Page"><div class="bk_tt">Herbert M, Goldstein JL, Rehder C, et al. Phosphorylase Kinase Deficiency. 2011 May 31 [Updated 2018 Nov 1]. In: Adam MP, Feldman J, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2025. <span class="bk_cite_avail"></span></div></div></li><li><a href="/books/NBK55061/pdf/Bookshelf_NBK55061.pdf">PDF version of this page</a> (749K)</li><li><a href="#" class="toggle-glossary-link" title="Enable/disable links to the glossary">Disable Glossary Links</a></li></ul></div></div><div class="portlet"><div class="portlet_head"><div class="portlet_title"><h3><span>In this GeneReview</span></h3></div><a name="Shutter" sid="1" href="#" class="portlet_shutter" title="Show/hide content" remembercollapsed="true" pgsec_name="page-toc" id="Shutter"></a></div><div class="portlet_content"><ul xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="simple-list"><li><a href="#gsd9.Summary" ref="log$=inpage&link_id=inpage">Summary</a></li><li><a href="#gsd9.GeneReview_Scope" ref="log$=inpage&link_id=inpage"><i>GeneReview</i> Scope</a></li><li><a href="#gsd9.Diagnosis" ref="log$=inpage&link_id=inpage">Diagnosis</a></li><li><a href="#gsd9.Clinical_Characteristics" ref="log$=inpage&link_id=inpage">Clinical Characteristics</a></li><li><a href="#gsd9.Genetically_Related_Allelic_Disorde" ref="log$=inpage&link_id=inpage">Genetically Related (Allelic) Disorders</a></li><li><a href="#gsd9.Differential_Diagnosis" ref="log$=inpage&link_id=inpage">Differential Diagnosis</a></li><li><a href="#gsd9.Management" ref="log$=inpage&link_id=inpage">Management</a></li><li><a href="#gsd9.Genetic_Counseling" ref="log$=inpage&link_id=inpage">Genetic Counseling</a></li><li><a href="#gsd9.Resources" ref="log$=inpage&link_id=inpage">Resources</a></li><li><a href="#gsd9.Molecular_Genetics" ref="log$=inpage&link_id=inpage">Molecular Genetics</a></li><li><a href="#gsd9.Chapter_Notes" ref="log$=inpage&link_id=inpage">Chapter Notes</a></li><li><a href="#gsd9.References" ref="log$=inpage&link_id=inpage">References</a></li></ul></div></div><div class="portlet"><div class="portlet_head"><div class="portlet_title"><h3><span>Bulk Download</span></h3></div><a name="Shutter" sid="1" href="#" class="portlet_shutter" title="Show/hide content" remembercollapsed="true" pgsec_name="source-links" id="Shutter"></a></div><div class="portlet_content"><ul xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="simple-list"><li><a href="https://ftp.ncbi.nlm.nih.gov/pub/litarch/ca/84/" ref="pagearea=source-links&targetsite=external&targetcat=link&targettype=uri">Bulk download GeneReviews data from FTP</a></li></ul></div></div><div class="portlet"><div class="portlet_head"><div class="portlet_title"><h3><span>GeneReviews Links</span></h3></div><a name="Shutter" sid="1" href="#" class="portlet_shutter" title="Show/hide content" remembercollapsed="true" pgsec_name="source-links" id="Shutter"></a></div><div class="portlet_content"><ul xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="simple-list"><li><a href="/books/n/gene/advanced/"><i>GeneReviews</i> Advanced Search</a></li><li><a href="/books/n/gene/glossary/"><i>GeneReviews</i> Glossary</a></li><li><a href="/books/n/gene/resource_mats/">Resource Materials</a> <span class="bk_hlight1">NEW FEATURE</span></li><li><a href="/books/n/gene/updates/">New in <i>GeneReviews</i></a></li><li><a href="/books/n/gene/authors/">Author List</a></li><li><a href="/books/n/gene/prospective_authors/">For Current/Prospective Authors</a></li><li><a href="/books/n/gene/GRpersonnel/"><i>GeneReviews</i> Personnel</a></li><li><a href="/books/n/gene/howto_linkin/">Download/Link to <i>GeneReviews</i></a></li><li><a href="/books/n/gene/contact_us/">Contact Us</a></li></ul></div></div><div class="portlet"><div class="portlet_head"><div class="portlet_title"><h3><span>Tests in GTR by Gene</span></h3></div><a name="Shutter" sid="1" href="#" class="portlet_shutter" title="Show/hide content" remembercollapsed="true" pgsec_name="document-links" id="Shutter"></a></div><div class="portlet_content"><ul xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="simple-list"><li>
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href="/books/?Db=pmc&DbFrom=books&Cmd=Link&LinkName=books_pmc_refs&IdsFromResult=2476030" ref="log$=recordlinks">PMC</a><div class="brieflinkpop offscreen_noflow">PubMed Central citations</div></li><li class="brieflinkpopper"><a class="brieflinkpopperctrl" href="/books/?Db=pubmed&DbFrom=books&Cmd=Link&LinkName=books_pubmed_refs&IdsFromResult=2476030" ref="log$=recordlinks">PubMed</a><div class="brieflinkpop offscreen_noflow">Links to PubMed</div></li><li class="brieflinkpopper"><a class="brieflinkpopperctrl" href="/books/?Db=gene&DbFrom=books&Cmd=Link&LinkName=books_gene&IdsFromResult=2476030" ref="log$=recordlinks">Gene</a><div class="brieflinkpop offscreen_noflow">Locus Links</div></li></ul></div></div><div class="portlet"><div class="portlet_head"><div class="portlet_title"><h3><span>Similar articles in PubMed</span></h3></div><a name="Shutter" sid="1" href="#" class="portlet_shutter" title="Show/hide content" remembercollapsed="true" pgsec_name="PBooksDiscovery_RA" id="Shutter"></a></div><div class="portlet_content"><ul><li class="brieflinkpopper two_line"><a class="brieflinkpopperctrl" href="/pubmed/20301788" ref="ordinalpos=1&linkpos=1&log$=relatedreviews&logdbfrom=pubmed"><span xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="invert">Review</span> Glycogen Storage Disease Type III.</a><span class="source">[GeneReviews(®). 1993]</span><div class="brieflinkpop offscreen_noflow"><span xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="invert">Review</span> Glycogen Storage Disease Type III.<div class="brieflinkpopdesc"><em xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="author">Schreuder AB, Rossi A, Grünert SC, Derks TGJ. </em><em xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="cit">GeneReviews(®). 1993</em></div></div></li><li class="brieflinkpopper two_line"><a class="brieflinkpopperctrl" href="/pubmed/24006547" ref="ordinalpos=1&linkpos=2&log$=relatedreviews&logdbfrom=pubmed"><span xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="invert">Review</span> Ornithine Transcarbamylase 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> Ornithine Transcarbamylase Deficiency.<div class="brieflinkpopdesc"><em xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="author">Lichter-Konecki U, Caldovic L, Morizono H, Simpson K, Ah Mew N, MacLeod E. </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/20301668" ref="ordinalpos=1&linkpos=3&log$=relatedreviews&logdbfrom=pubmed"><span xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="invert">Review</span> Hemophilia B.</a><span class="source">[GeneReviews(®). 1993]</span><div class="brieflinkpop offscreen_noflow"><span xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="invert">Review</span> Hemophilia B.<div class="brieflinkpopdesc"><em xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="author">Konkle BA, Nakaya Fletcher S. </em><em xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="cit">GeneReviews(®). 1993</em></div></div></li><li class="brieflinkpopper two_line"><a class="brieflinkpopperctrl" href="/pubmed/20301575" ref="ordinalpos=1&linkpos=4&log$=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> Fanconi Anemia.</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> Fanconi Anemia.<div class="brieflinkpopdesc"><em xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="author">Mehta PA, Ebens C. </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/20301489" ref="ordinalpos=1&linkpos=5&log$=relatedreviews&logdbfrom=pubmed"><span xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="invert">Review</span> Glycogen Storage Disease Type I.</a><span class="source">[GeneReviews(®). 1993]</span><div class="brieflinkpop offscreen_noflow"><span xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="invert">Review</span> Glycogen Storage Disease Type I.<div class="brieflinkpopdesc"><em xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="author">Bali DS, El-Gharbawy A, Austin S, Pendyal S, Kishnani PS. </em><em xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="cit">GeneReviews(®). 1993</em></div></div></li></ul><a class="seemore" href="/sites/entrez?db=pubmed&cmd=link&linkname=pubmed_pubmed_reviews&uid=21634085" ref="ordinalpos=1&log$=relatedreviews_seeall&logdbfrom=pubmed">See reviews...</a><a 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