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<script type="text/javascript" src="/corehtml/pmc/jatsreader/ptpmc_3.22/js/jr.boots.min.js"> </script><title>Phenylalanine Hydroxylase Deficiency - GeneReviews® - NCBI Bookshelf</title>
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<meta name="citation_inbook_title" content="GeneReviews® [Internet]">
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<meta name="citation_title" content="Phenylalanine Hydroxylase Deficiency">
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<meta name="citation_publisher" content="University of Washington, Seattle">
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<meta name="citation_date" content="2017/01/05">
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<meta name="citation_author" content="Debra S Regier">
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<meta name="citation_author" content="Carol L Greene">
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<meta name="citation_pmid" content="20301677">
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<meta name="citation_fulltext_html_url" content="https://www.ncbi.nlm.nih.gov/books/NBK1504/">
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<meta name="citation_keywords" content="PAH Deficiency">
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<meta name="citation_keywords" content="PAH Deficiency">
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<meta name="citation_keywords" content="Classic PKU">
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<meta name="citation_keywords" content="Phenylalanine-4-hydroxylase">
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<meta name="citation_keywords" content="PAH">
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<meta name="citation_keywords" content="Phenylalanine Hydroxylase Deficiency">
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<meta name="DC.Title" content="Phenylalanine Hydroxylase Deficiency">
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<meta name="DC.Publisher" content="University of Washington, Seattle">
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<meta name="DC.Contributor" content="Debra S Regier">
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<meta name="DC.Contributor" content="Carol L Greene">
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<meta name="DC.Date" content="2017/01/05">
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<meta name="description" content="Phenylalanine hydroxylase (PAH) deficiency results in intolerance to the dietary intake of the essential amino acid phenylalanine and produces a spectrum of disorders. The risk of adverse outcome varies based on the degree of PAH deficiency. Without effective therapy, most individuals with severe PAH deficiency, known as classic PKU, develop profound and irreversible intellectual disability. Affected individuals on an unrestricted diet who have phenylalanine levels above normal but below 1,200 μmol/L (20 mg/dL) are at much lower risk for impaired cognitive development in the absence of treatment.">
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<meta name="og:description" content="Phenylalanine hydroxylase (PAH) deficiency results in intolerance to the dietary intake of the essential amino acid phenylalanine and produces a spectrum of disorders. The risk of adverse outcome varies based on the degree of PAH deficiency. Without effective therapy, most individuals with severe PAH deficiency, known as classic PKU, develop profound and irreversible intellectual disability. Affected individuals on an unrestricted diet who have phenylalanine levels above normal but below 1,200 μmol/L (20 mg/dL) are at much lower risk for impaired cognitive development in the absence of treatment.">
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class="wsprkl btn" title="Jump to next match">▶</a></nav></nav></div><div id="jr-epub-interstitial" class="hidden"></div><div id="jr-content"><article data-type="main"><div class="main-content lit-style" itemscope="itemscope" itemtype="http://schema.org/CreativeWork"><div class="meta-content fm-sec"><div class="fm-sec"><h1 id="_NBK1504_"><span class="title" itemprop="name">Phenylalanine Hydroxylase Deficiency</span></h1><div itemprop="alternativeHeadline" class="subtitle whole_rhythm">Synonym: PAH Deficiency</div><p class="contribs">Regier DS, Greene CL.</p><p class="fm-aai"><a href="#_NBK1504_pubdet_">Publication Details</a></p><p><em>Estimated reading time: 33 minutes</em></p></div></div><div class="jig-ncbiinpagenav body-content whole_rhythm" data-jigconfig="allHeadingLevels: ['h2'],smoothScroll: false" itemprop="text"><div id="pku.Summary" itemprop="description"><h2 id="_pku_Summary_">Summary</h2><div><h4 class="inline">Clinical characteristics.</h4><p>Phenylalanine hydroxylase (PAH) deficiency results in intolerance to the dietary intake of the essential amino acid phenylalanine and produces a spectrum of disorders. The risk of adverse outcome varies based on the degree of PAH deficiency. Without effective therapy, most individuals with severe PAH deficiency, known as classic PKU, develop profound and irreversible intellectual disability. Affected individuals on an unrestricted diet who have phenylalanine levels above normal but below 1,200 μmol/L (20 mg/dL) are at much lower risk for impaired cognitive development in the absence of treatment.</p></div><div><h4 class="inline">Diagnosis/testing.</h4><p>PAH deficiency can be detected by newborn screening in virtually 100% of cases based on the presence of hyperphenylalaninemia using tandem mass spectrometry on a blood spot obtained from a heel prick. The diagnosis of PAH deficiency is established in a proband with:</p><ul><li class="half_rhythm"><div class="half_rhythm">A plasma phenylalanine concentration persistently above 120 µmol/L (2 mg/dL) and altered ratio of phenylalanine to tyrosine in the untreated state with normal BH4 cofactor metabolism;</div><div class="half_rhythm">and/or</div></li><li class="half_rhythm"><div class="half_rhythm">The finding of biallelic pathogenic variants in <i>PAH</i> by molecular genetic testing.</div></li></ul></div><div><h4 class="inline">Management.</h4><p><i>Treatment of manifestations:</i> Classic PKU: a low-protein diet and use of a Phe-free medical formula as soon as possible after birth to achieve plasma Phe concentrations of 120-360 µmol/L (2-6 mg/dL). A proportion of individuals with PKU benefit from adjuvant therapy with sapropterin. Large neutral amino acid (LNAA) transporters may also decrease the plasma Phe concentration in affected adolescents and adults. Non-classic HPA: individuals with plasma Phe concentrations above 600 μmol/L are treated in most centers. It is debatable whether those with plasma Phe concentrations consistently below 600 µmol/L (10 mg/dL) require dietary treatment. Neuropsychiatric testing may be considered to identify learning differences in affected individuals with referral to developmental services, as indicated.</p><p><i>Surveillance:</i> Regular monitoring of plasma Phe, Tyr, and plasma amino acid concentrations in individuals with classic PKU; regular assessment of growth and micronutrient needs; assessment of developmental progress and screening for mental illness at every visit.</p><p><i>Agents/circumstances to avoid:</i> Aspartame, an artificial sweetener that contains phenylalanine.</p><p><i>Evaluation of relatives at risk:</i> Newborn sibs of an individual with PAH deficiency who have not been tested prenatally should have blood concentration of Phe measured shortly after birth (in addition to newborn screening) to allow earliest possible diagnosis and treatment.</p><p><i>Pregnancy management:</i> To minimize or prevent teratogenic effects of phenylalanine, women with PAH deficiency should follow a Phe-restricted diet for at least several months prior to conception in order to maintain plasma Phe concentrations between 120 and 360 µmol/L (2-6 mg/dL); after conception, continuous nutritional guidance and weekly or biweekly measurement of plasma Phe concentration to assure that target levels are met in addition to adequate energy intake with the proper proportion of protein, fat, and carbohydrates. Evaluation for fetal anomalies using high-resolution ultrasound and fetal echocardiogram.</p></div><div><h4 class="inline">Genetic counseling.</h4><p>PAH deficiency is inherited in an autosomal recessive manner. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Carrier testing for at-risk relatives and prenatal testing for pregnancies at increased risk are possible if the <i>PAH</i> pathogenic variants have been identified in an affected family member.</p></div></div><div id="pku.Diagnosis"><h2 id="_pku_Diagnosis_">Diagnosis</h2><div id="pku.Suggestive_Findings"><h3>Suggestive Findings</h3><p>Phenylalanine hydroxylase (PAH) deficiency <b>should be suspected</b> in an individual with the following newborn screening results, clinical features (by age), neuroimaging, and supportive laboratory findings:</p><p>
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<b>Newborn screening results</b>
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</p><ul><li class="half_rhythm"><div>Positive newborn screen by tandem mass spectrometry (MS/MS) using dried blood spots collected after 24 hours of age. This method is used in most if not all states in the USA for newborn screening.</div></li><li class="half_rhythm"><div>The ability of current tests to accurately measure Phe concentrations in infants before age 24 hours is a concern, since hyperphenylalaninemia (HPA) manifests itself as a time-dependent increase of Phe concentration in the blood. However, recognition of an altered ratio of phenylalanine and tyrosine may still identify the affected newborn.</div></li></ul><p><b>Postnatal clinical findings in a newborn.</b> No physical signs of hyperphenylalaninemia (HPA)</p><p>
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<b>Clinical findings in an untreated, older individual (infancy to adulthood)</b>
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</p><ul><li class="half_rhythm"><div>Epilepsy</div></li><li class="half_rhythm"><div>Any level of intellectual disability and behavior problems, including autistic features</div></li><li class="half_rhythm"><div>Parkinson-like features (particularly in an adult)</div></li><li class="half_rhythm"><div>Musty body odor</div></li><li class="half_rhythm"><div>Eczema</div></li><li class="half_rhythm"><div>Decreased skin and hair pigmentation</div></li><li class="half_rhythm"><div>Female with no prior normal offspring who has a history of recurrent pregnancy loss and/or offspring with malformations including any combination of small size, microcephaly / brain malformations, congenital heart defect, limb malformations, and/or tracheoesophageal fistula</div></li></ul><p><b>Neuroimaging.</b> Progressive white matter disease on brain MRI; observed in 90% of individuals with PAH deficiency even without evidence of neurologic deterioration</p><ul><li class="half_rhythm"><div>Advanced-age affected individuals off diet or with poor compliance and those who are untreated have the most severe MRI findings.</div></li><li class="half_rhythm"><div>It is proposed that in untreated affected individuals, Phe prevents myelination and in early-treated affected individuals, myelin is normally made but may be functionally impaired [<a class="bibr" href="#pku.REF.anderson.2010.s3" rid="pku.REF.anderson.2010.s3">Anderson & Leuzzi 2010</a>].</div></li></ul><p>
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<b>Supportive laboratory findings</b>
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</p><ul><li class="half_rhythm"><div><b>Plasma amino acid analysis.</b> In the untreated state, an elevated plasma phenylalanine (Phe) concentration persistently higher than 120 µmol/L (2 mg/dL) with phenylalanine levels higher than tyrosine (Tyr) levels</div><ul><li class="half_rhythm"><div>A normal Phe:Tyr ratio is typically <1; a ratio of >3 is considered useful in the diagnosis of PAH deficiency [<a class="bibr" href="#pku.REF.vockley.2014" rid="pku.REF.vockley.2014">Vockley et al 2014</a>].</div></li><li class="half_rhythm"><div>Most severely affected individuals with complete enzyme loss (also called "classic PKU") have untreated levels of phenylalanine (Phe) of >1,200 µmol/L. If diagnosed early and if treatment is begun in the first or second week of life, most severely affected individuals do not attain Phe levels this high.</div></li></ul></li><li class="half_rhythm"><div>
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<b>BH4 (tetrahydrobiopterin) cofactor analysis and/or challenge</b>
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</div><ul><li class="half_rhythm"><div>Normal urine or dried blood spot pterins (neopterin and biopterins) studies using liquid chromatography</div></li><li class="half_rhythm"><div>Normal dihydropterine reductase measurement in erythrocytes, typically from a dried blood spot</div></li></ul></li></ul></div><div id="pku.Establishing_the_Diagnosis"><h3>Establishing the Diagnosis</h3><p>The diagnosis of PAH deficiency <b>is established</b> in a proband with a plasma phenylalanine concentration persistently above 120 µmol/L (2 mg/dL) and altered ratio of phenylalanine to tyrosine in the untreated state, with normal BH<sub>4</sub> cofactor metabolism; and/or the finding of biallelic pathogenic variants in <i>PAH</i> by molecular genetic testing (see <a href="/books/NBK1504/table/pku.T.molecular_genetic_testing_used_in/?report=objectonly" target="object" rid-ob="figobpkuTmoleculargenetictestingusedin">Table 1</a>).</p><p>Note: (1) It is important that a low phenylalanine diet be initiated prior to receiving the results of the pterins or molecular genetic studies. (2) See <a href="#pku.GenotypePhenotype_Correlations">Genotype-Phenotype Correlations</a> for information on the clinical utility of a molecular diagnosis.</p><p>Molecular testing approaches can include <b>single-gene testing</b> or use of a <b>multigene panel</b>:</p><ul><li class="half_rhythm"><div class="half_rhythm"><b>Single-gene testing.</b> Sequence analysis of <i>PAH</i> is performed first followed by gene-targeted deletion/duplication analysis if only one or no pathogenic variant is found.</div><div class="half_rhythm">Targeted analysis for common pan ethnic pathogenic variants (see <a href="/books/NBK1504/table/pku.T.common_pathogenic_changes_in_pah_a/?report=objectonly" target="object" rid-ob="figobpkuTcommonpathogenicchangesinpaha">Table 2</a>), as well as targeted analysis for founder pathogenic variants, may be performed. Note that founder variants in specific populations may be the same as those found in pan ethnic populations.</div></li><li class="half_rhythm"><div class="half_rhythm"><b>A multigene panel</b> that includes <i>PAH</i> and other genes of interest (see <a href="#pku.Differential_Diagnosis">Differential Diagnosis</a>) may also be considered. Note: The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time.</div><div class="half_rhythm">For an introduction to multigene panels click <a href="/books/n/gene/app5/?report=reader#app5.Multigene_Panels">here</a>. More detailed information for clinicians ordering genetic tests can be found <a href="/books/n/gene/app5/?report=reader#app5.Multigene_Panels_FAQs">here</a>.</div></li></ul><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figpkuTmoleculargenetictestingusedin"><a href="/books/NBK1504/table/pku.T.molecular_genetic_testing_used_in/?report=objectonly" target="object" title="Table 1. " class="img_link icnblk_img" rid-ob="figobpkuTmoleculargenetictestingusedin"><img class="small-thumb" src="/corehtml/pmc/css/bookshelf/2.26/img/table-icon.gif" alt="Table Icon" /></a><div class="icnblk_cntnt"><h4 id="pku.T.molecular_genetic_testing_used_in"><a href="/books/NBK1504/table/pku.T.molecular_genetic_testing_used_in/?report=objectonly" target="object" rid-ob="figobpkuTmoleculargenetictestingusedin">Table 1. </a></h4><p class="float-caption no_bottom_margin">Molecular Genetic Testing Used in Phenylalanine Hydroxylase Deficiency </p></div></div><p><b>Enzyme analysis</b> is not usually indicated in the diagnosis of PAH deficiency because PAH is a hepatic enzyme and accurate, less invasive methods of diagnosis are available.</p></div></div><div id="pku.Clinical_Characteristics"><h2 id="_pku_Clinical_Characteristics_">Clinical Characteristics</h2><div id="pku.Clinical_Description"><h3>Clinical Description</h3><p>Phenylalanine hydroxylase (PAH) deficiency results in intolerance to the dietary intake of the essential amino acid phenylalanine and produces a spectrum of disorders [<a class="bibr" href="#pku.REF.vockley.2014" rid="pku.REF.vockley.2014">Vockley et al 2014</a>]. Many terms have been used to describe the various clinical phenotypes that result from PAH deficiency (see <a href="#pku.Nomenclature">Nomenclature</a>). This <i>GeneReview</i> will follow the American College of Medical Genetics and Genomics (ACMGG) recommended convention.</p><p>The risk of adverse outcome varies based on the degree of PAH deficiency. Without effective therapy, most individuals with severe PAH deficiency, known as classic PKU, develop profound and irreversible intellectual disability. Affected individuals on an unrestricted diet who have phenylalanine levels above normal but below 1,200 μmol/L (20 mg/dL) are at much lower risk for impaired cognitive development in the absence of treatment. However, current understanding of these issues is not complete.</p><div id="pku.Untreated_Individuals_with_Persisten"><h4>Untreated Individuals with Persistent Severe Hyperphenylalaninemia (i.e., Classic PKU)</h4><p>Affected individuals almost always show impaired brain development. Signs and symptoms include nearly invariable severe intellectual disability and behavior problems with a high frequency of seizures and variable microcephaly.</p><p>The excretion of excessive phenylalanine and its metabolites can create a musty body odor and skin conditions such as eczema.</p><p>The associated inhibition of tyrosinase and low tyrosine levels are responsible for decreased skin and hair pigmentation.</p><p>Affected individuals also have decreased myelin formation, leading eventually to white matter changes on head MRI.</p><p>Significantly elevated Phe levels decrease dopamine, norepinephrine, and serotonin production and can be reflected in electroencephalographic changes, which are reversible if the Phe level is reduced.</p></div><div id="pku.Individuals_with_Classic_PKU_Identif"><h4>Individuals with Classic PKU Identified and Treated from Birth</h4><p><b>Intelligence.</b> The correlation between early elevated Phe levels and long-term decreases in IQ has been well studied. The benefit of normalized Phe levels on IQ throughout life has also been shown in studies of affected adults.</p><ul><li class="half_rhythm"><div>Those who decrease their adherence to a Phe-restricted diet in adulthood have a small drop in IQ, further supporting the current advice of "diet for life" (see <a href="#pku.Management">Management</a>) [<a class="bibr" href="#pku.REF.brumm.2010.s18" rid="pku.REF.brumm.2010.s18">Brumm & Grant 2010</a>, <a class="bibr" href="#pku.REF.vockley.2014" rid="pku.REF.vockley.2014">Vockley et al 2014</a>, <a class="bibr" href="#pku.REF.jahja.2016.355" rid="pku.REF.jahja.2016.355">Jahja et al 2016</a>].</div></li><li class="half_rhythm"><div>However, even with strict adherence to a low phenylalanine (Phe) diet, adults may still have some underlying sequelae and suboptimal cognitive outcomes affecting language skills, memory, learning skills, and executive function [<a class="bibr" href="#pku.REF.moyle.2007.91" rid="pku.REF.moyle.2007.91">Moyle et al 2007</a>, <a class="bibr" href="#pku.REF.waisbren.2007.63" rid="pku.REF.waisbren.2007.63">Waisbren et al 2007</a>, <a class="bibr" href="#pku.REF.antshel.2010.s52" rid="pku.REF.antshel.2010.s52">Antshel 2010</a>, <a class="bibr" href="#pku.REF.burton.2013.8" rid="pku.REF.burton.2013.8">Burton et al 2013</a>].</div></li></ul><p><b>Neuropsychological issues.</b> In treated individuals, certain psychological problems are increased – as compared to unaffected sibs or children with other chronic diseases [<a class="bibr" href="#pku.REF.brumm.2010.s59" rid="pku.REF.brumm.2010.s59">Brumm et al 2010</a>, <a class="bibr" href="#pku.REF.bilder.2013.155" rid="pku.REF.bilder.2013.155">Bilder et al 2013</a>].</p><ul><li class="half_rhythm"><div>Adults who have increased Phe levels typically due to relaxed Phe-restricted diet tend to have a reduced attention span, slow information-processing abilities, and slow motor reaction time [<a class="bibr" href="#pku.REF.channon.2007.213" rid="pku.REF.channon.2007.213">Channon et al 2007</a>, <a class="bibr" href="#pku.REF.moyle.2007.91" rid="pku.REF.moyle.2007.91">Moyle et al 2007</a>]. These findings appear to be related to both current and historical phenylalanine levels [<a class="bibr" href="#pku.REF.huijbregts.2002.419" rid="pku.REF.huijbregts.2002.419">Huijbregts et al 2002</a>, <a class="bibr" href="#pku.REF.fonnesbeck.2013.757" rid="pku.REF.fonnesbeck.2013.757">Fonnesbeck et al 2013</a>].</div></li><li class="half_rhythm"><div>There is also a higher incidence of anxiety, depression, phobias, and panic attacks in early-treated individuals who discontinued therapy in the second decade of life [<a class="bibr" href="#pku.REF.koch.2002.333" rid="pku.REF.koch.2002.333">Koch et al 2002</a>].</div></li></ul><p><b>Neurologic.</b> Early-treated adults who discontinue diet are also at risk for minor neurologic abnormalities such as tremor and brisk reflexes [<a class="bibr" href="#pku.REF.pietz.1998.824" rid="pku.REF.pietz.1998.824">Pietz et al 1998</a>] and, in some cases, more severe neurologic dysfunction, including paralysis. Return to diet often resolves these neurologic symptoms [<a class="bibr" href="#pku.REF.camp.2014.87" rid="pku.REF.camp.2014.87">Camp et al 2014</a>].</p></div><div id="pku.PAH_with_Milder_Biochemical_and_Clin"><h4>PAH with Milder Biochemical and Clinical Phenotypes</h4><p>Individuals with PAH deficiency and <b>plasma Phe between 600 and 1,200 μmol/L (10-20 mg/dL)</b> on an unrestricted diet have not been extensively studied. However, it is well documented that individuals with classic PKU who have levels in this range have both acute and chronic neuropsychological problems. Therefore, treatment with a Phe-restricted diet is recommended for individuals with Phe levels in this range.</p><p>Individuals with PAH deficiency who have plasma <b>Phe concentrations consistently below 600 µmol/L (10 mg/dL)</b> on an unrestricted diet are considered by many experts not to be at higher risk of developing intellectual, neurologic, and neuropsychological impairment than are individuals without PAH deficiency. However, since evidence suggests that individuals with classic PKU have demonstrable neurophysiologic changes when Phe levels are between 360 and 600 μmol/L (6 to 10 mg/dL), other experts recommend Phe restriction for any individual who has Phe levels >360 μmol/L (6 mg/dL) on an unrestricted diet. A very small number of programs begin therapy for individuals with Phe levels >240 μmol/L (4 mg/dL). As Phe is an essential amino acid, having inadequate phenylalanine leads to growth restriction, microcephaly, and developmental problems. The safety of dietary restriction of Phe for individuals with the milder PAH deficiency has not been systematically studied. Practices vary around the world [<a class="bibr" href="#pku.REF.blau.2010.109" rid="pku.REF.blau.2010.109">Blau et al 2010</a>].</p><p>In a few case reports untreated individuals with mild PAH deficiency who had normal intelligence were diagnosed in adulthood as a result of sudden and severe psychiatric deterioration [<a class="bibr" href="#pku.REF.weglage.2000.83" rid="pku.REF.weglage.2000.83">Weglage et al 2000</a>, <a class="bibr" href="#pku.REF.camp.2014.87" rid="pku.REF.camp.2014.87">Camp et al 2014</a>].</p></div><div id="pku.Other"><h4>Other</h4><p><b>Osteopenia.</b> While numerous studies indicate that individuals with PAH deficiency have a high incidence of osteopenia (as measured by DXA, dual-energy x-ray absorptiometry) [<a class="bibr" href="#pku.REF.zeman.1999.1348" rid="pku.REF.zeman.1999.1348">Zeman et al 1999</a>, <a class="bibr" href="#pku.REF.p_rezdue_as.2002.899" rid="pku.REF.p_rezdue_as.2002.899">Pérez-Dueñas et al 2002</a>, <a class="bibr" href="#pku.REF.modanmoses.2007.202" rid="pku.REF.modanmoses.2007.202">Modan-Moses et al 2007</a>], a recent meta-analysis showed that the combined data do not support a high risk based on World Health Organization and International Society for Clinical Densitometry measurement guidelines [<a class="bibr" href="#pku.REF.demirdas.2015.17" rid="pku.REF.demirdas.2015.17">Demirdas et al 2015</a>]. Studies to explore the mechanism of low bone density and clinical significance are under way. Until additional studies are performed, it is important to continue to closely monitor the bone health of individuals with PAH deficiency. A recent study of individuals with PAH deficiency by <a class="bibr" href="#pku.REF.coakley.2016.363" rid="pku.REF.coakley.2016.363">Coakley et al [2016]</a> identified risk factors for lower Z-scores, with the highest significance for dietary prescription compliance in an adult population.</p><p><b>Vitamin B<sub>12</sub> deficiency</b> can occur when individuals with PKU relax their diet in adolescence [<a class="bibr" href="#pku.REF.robinson.2000.545" rid="pku.REF.robinson.2000.545">Robinson et al 2000</a>]. This vitamin is found in natural animal protein; when affected individuals decrease their amino acid supplementation, they often still choose low-protein foods and are therefore at risk for vitamin B<sub>12</sub> deficiency.</p></div><div id="pku.Children_Born_to_Women_with_PAH_Defi"><h4>Children Born to Women with PAH Deficiency</h4><p>The abnormalities that result from exposure of a fetus to high maternal plasma Phe concentration are the result of maternal PAH deficiency. Risks include the following [<a class="bibr" href="#pku.REF.vockley.2014" rid="pku.REF.vockley.2014">Vockley et al 2014</a>]:</p><ul><li class="half_rhythm"><div><b>Intellectual disability</b> (>90%).The threshold for this finding is a maternal Phe concentration consistently above 360 µmol/L during pregnancy with an inverse relationship between cognitive function and maternal Phe level above 360 µmol/L.</div></li><li class="half_rhythm"><div>
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<b>Poor behavioral outcomes</b>
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</div></li><li class="half_rhythm"><div><b>Microcephaly.</b> The risk is 5%-18% in pregnancies in which the maternal Phe level is optimized prior to ten weeks' gestation and increases to 67% if appropriate Phe levels are not achieved by 30 weeks' gestation.</div></li><li class="half_rhythm"><div><b>Congenital heart defect and other malformations.</b> Due to the early formation of the heart, consistently elevated maternal Phe concentrations (>600 µmol/L) during early gestation leads to an approximately 8%-12% risk of cardiac malformations. Minor dysmorphic features and other birth defects have also been reported in infants born to women with maternal PKU, including tracheoesophageal fistula.</div></li><li class="half_rhythm"><div><b>Intrauterine growth restriction (IUGR).</b> Frequency is not different from that in the general population if maternal Phe levels are controlled by week ten of gestation; the risk of IUGR increases if the Phe concentration is optimized later in pregnancy.</div></li></ul></div></div><div id="pku.GenotypePhenotype_Correlations"><h3>Genotype-Phenotype Correlations</h3><p>More than 900 pathogenic variants have been described in <i>PAH</i> (see <a href="http://www.biopku.org/home/pah.asp" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">www.biopku.org</a>). While both genetic (particular pathogenic variant) and environmental (dietary consumption) components contribute to an affected individual's total plasma Phe level, knowledge of the specific genetic cause can offer insight helpful for long-term management [<a class="bibr" href="#pku.REF.zschocke.2000.s154" rid="pku.REF.zschocke.2000.s154">Zschocke & Hoffmann 2000</a>, <a class="bibr" href="#pku.REF.national_institutes_of_health_consensus_development_panel.2001.972" rid="pku.REF.national_institutes_of_health_consensus_development_panel.2001.972">National Institutes of Health Consensus Development Panel 2001</a>, <a class="bibr" href="#pku.REF.g_ttler.2006" rid="pku.REF.g_ttler.2006">Güttler & Guldberg 2006</a>, <a class="bibr" href="#pku.REF.santos.2010.1" rid="pku.REF.santos.2010.1">Santos et al 2010</a>].</p><p>In compound heterozygotes with functional hemizygosity (null/missense paired alleles), the less severe of the two <i>PAH</i> pathogenic variants determines disease severity. However, when two pathogenic variants associated with similar severity are present, the phenotype may be milder than predicted by either allele [<a class="bibr" href="#pku.REF.kayaalp.1997.1309" rid="pku.REF.kayaalp.1997.1309">Kayaalp et al 1997</a>, <a class="bibr" href="#pku.REF.guldberg.1998.71" rid="pku.REF.guldberg.1998.71">Guldberg et al 1998</a>, <a class="bibr" href="#pku.REF.waters.1998.4" rid="pku.REF.waters.1998.4">Waters et al 1998</a>].</p><p>In general, affected individuals with milder <i>PAH</i> pathogenic variants have a better response to sapropterin (B6BH4, Kuvan™) (see <a href="#pku.Management">Management</a>). The current guidelines recommend that all affected individuals (except those with two pathogenic null variants <i>in</i>
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<i>trans</i>) be offered a trial with sapropterin (B6BH4, Kuvan™) because of the difficulty of predicting the phenotype from the genotype [<a class="bibr" href="#pku.REF.vockley.2014" rid="pku.REF.vockley.2014">Vockley et al 2014</a>]. See <a href="#pku.Molecular_Genetics">Molecular Genetics</a> for more information on common pathogenic variants in <i>PAH</i> and their reported responsiveness to sapropterin therapy.</p><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figpkuTcommonpathogenicchangesinpaha"><a href="/books/NBK1504/table/pku.T.common_pathogenic_changes_in_pah_a/?report=objectonly" target="object" title="Table 2. " class="img_link icnblk_img" rid-ob="figobpkuTcommonpathogenicchangesinpaha"><img class="small-thumb" src="/corehtml/pmc/css/bookshelf/2.26/img/table-icon.gif" alt="Table Icon" /></a><div class="icnblk_cntnt"><h4 id="pku.T.common_pathogenic_changes_in_pah_a"><a href="/books/NBK1504/table/pku.T.common_pathogenic_changes_in_pah_a/?report=objectonly" target="object" rid-ob="figobpkuTcommonpathogenicchangesinpaha">Table 2. </a></h4><p class="float-caption no_bottom_margin">Common Pathogenic Changes in <i>PAH</i> and Their Responsiveness to Sapropterin </p></div></div><p>However, genotype-phenotype correlation becomes more complex when clinical outcomes are also taken into account. While <a class="bibr" href="#pku.REF.disilvestre.1991.1014" rid="pku.REF.disilvestre.1991.1014">DiSilvestre et al [1991]</a> found that genotype does predict biochemical phenotype (i.e., by Phe loading tests), it does not always predict clinical phenotype (i.e., occurrence of intellectual disability). Some untreated individuals with PAH deficiency and biallelic <i>PAH</i> pathogenic variants that usually result in classic PKU have elevated plasma Phe concentration but normal intelligence. In other instances, sibs with the same genotype have different clinical and metabolic phenotypes. While mechanisms that cause dissimilarities in pathogenesis at the level of the brain in spite of comparable plasma Phe concentrations are not fully understood [<a class="bibr" href="#pku.REF.scriver.1999.267" rid="pku.REF.scriver.1999.267">Scriver & Waters 1999</a>], there is evidence that variation in transport of Phe across the blood-brain barrier is at least one relevant factor [<a class="bibr" href="#pku.REF.weglage.2002.431" rid="pku.REF.weglage.2002.431">Weglage et al 2002</a>].</p></div><div id="pku.Nomenclature"><h3>Nomenclature</h3><p>The 2014 American College of Medical Genetics and Genomics guidelines on the diagnosis and management of PAH (PKU) recommends the term "phenylalanine hydroxylase (PAH) deficiency" to describe all affected individuals, in order to best recognize that there is a spectrum of PAH deficiency. The guideline recognizes that the most severe expression of that spectrum will continue to be termed "classic PKU." They also recognized that other classification schema in historical use suggested the use of the term "hyperphenylalaninemia" (hyperPhe or HPA) for those who have Phe levels on an unrestricted diet that are above normal but below 1,200 μmol/L (20 mg/dL) [<a class="bibr" href="#pku.REF.vockley.2014" rid="pku.REF.vockley.2014">Vockley et al 2014</a>].</p><div id="pku.Alternative_Nomenclature_Systems"><h4>Alternative Nomenclature Systems</h4><p>In the early literature there was no universal system of nomenclature; thus, it was necessary to understand how terms were used in a given report to interpret the significance of the observations regarding PAH activity. In response to this difficulty, various systems of nomenclature have been proposed.</p><p><a class="bibr" href="#pku.REF.camp.2014.87" rid="pku.REF.camp.2014.87">Camp et al [2014]</a> provide, as part of an NIH systematic review of PKU, a recommendation for terminology of PAH deficiency (from most to least severe) of "classic PKU," "moderate PKU," "mild PKU," "mild HPA-gray zone," and "mild HPA-NT" (no treatment), and a table mapping the various terms to the level of blood Phe when untreated, to the dietary tolerance of Phe, and to the observed or expected level of PAH activity. This table of nomenclature will be of particular value to those wishing to understand the relationship between the various historical systems of nomenclature. See Table 2 in <a class="bibr" href="#pku.REF.camp.2014.87" rid="pku.REF.camp.2014.87">Camp et al [2014]</a>.</p><p>An early classification scheme proposed by <a class="bibr" href="#pku.REF.kayaalp.1997.1309" rid="pku.REF.kayaalp.1997.1309">Kayaalp et al [1997]</a> was intended to simplify the nomenclature. In this system:</p><ul><li class="half_rhythm"><div><b>Phenylketonuria (PKU)</b> is the most severe of the three types and in an untreated state is associated with plasma Phe concentrations >1,000 µmol/L and a dietary Phe tolerance of <500 mg/day. PKU is associated with a high risk of severely impaired cognitive development.</div></li><li class="half_rhythm"><div><b>Non-PKU hyperphenylalaninemia (non-PKU HPA)</b> is associated with plasma Phe concentrations consistently above normal (i.e., >120 µmol/L) but lower than 1,000 µmol/L when an individual is on a normal diet. Individuals with non-PKU HPA are at a much lower risk for impaired cognitive development in the absence of treatment.</div></li><li class="half_rhythm"><div><b>Variant PKU</b> includes those individuals who do not fit the description for either PKU or non-PKU HPA.</div></li></ul><p>A classification scheme proposed by <a class="bibr" href="#pku.REF.guldberg.1998.71" rid="pku.REF.guldberg.1998.71">Guldberg et al [1998]</a> subdivides PAH deficiency into the following four categories:</p><ul><li class="half_rhythm"><div><b>Classic PKU</b> is caused by a complete or near-complete deficiency of PAH activity. Affected individuals tolerate less than 250-350 mg of dietary phenylalanine per day to keep plasma concentration of Phe at a safe level of ≤300 µmol/L (5 mg/dL). Without dietary treatment most individuals develop profound, irreversible intellectual disability.</div></li><li class="half_rhythm"><div><b>Moderate PKU.</b> Affected individuals tolerate 350-400 mg of dietary phenylalanine per day.</div></li><li class="half_rhythm"><div><b>Mild PKU.</b> Affected individuals tolerate 400-600 mg of dietary phenylalanine per day.</div></li><li class="half_rhythm"><div><b>Mild hyperphenylalaninemia (MHP).</b> Affected infants have plasma Phe concentrations <600 µmol/L (10 mg/dL) on a normal diet.</div></li></ul></div></div><div id="pku.Prevalence"><h3>Prevalence</h3><p>PAH deficiency varies in frequency from more than 1:5,000 (Turkey, Ireland) to approximately 1:10,000 in those of northern European and East Asian origin (lower in Finland and Japan). Classic PKU was once the most common identifiable etiology of severe intellectual disability in institutions for the developmentally disabled in Europe and North America, but since the adoption of universal newborn screening in many countries, symptomatic classic PKU is less frequently seen. The predicted incidence of severe intellectual disability resulting from PKU in screened populations – fewer than one in a million live births – reflects those children not detected by newborn screening. See <a href="/books/NBK1504/table/pku.T.prevalence_of_pah_deficiency_by_po/?report=objectonly" target="object" rid-ob="figobpkuTprevalenceofpahdeficiencybypo">Table 3</a>.</p><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figpkuTprevalenceofpahdeficiencybypo"><a href="/books/NBK1504/table/pku.T.prevalence_of_pah_deficiency_by_po/?report=objectonly" target="object" title="Table 3. " class="img_link icnblk_img" rid-ob="figobpkuTprevalenceofpahdeficiencybypo"><img class="small-thumb" src="/corehtml/pmc/css/bookshelf/2.26/img/table-icon.gif" alt="Table Icon" /></a><div class="icnblk_cntnt"><h4 id="pku.T.prevalence_of_pah_deficiency_by_po"><a href="/books/NBK1504/table/pku.T.prevalence_of_pah_deficiency_by_po/?report=objectonly" target="object" rid-ob="figobpkuTprevalenceofpahdeficiencybypo">Table 3. </a></h4><p class="float-caption no_bottom_margin">Prevalence of PAH Deficiency by Population </p></div></div><p>Click <a href="/books/NBK1504/bin/pku-historical_perspective.pdf">here</a> (pdf) for a historical perspective.</p></div></div><div id="pku.Genetically_Related_Allelic_Disorder"><h2 id="_pku_Genetically_Related_Allelic_Disorder_">Genetically Related (Allelic) Disorders</h2><p>No phenotypes other than those discussed in this <i>GeneReview</i> are known to be associated with pathogenic variants of <i>PAH</i>.</p></div><div id="pku.Differential_Diagnosis"><h2 id="_pku_Differential_Diagnosis_">Differential Diagnosis</h2><p><b>Tetrahydrobiopterin (BH<sub>4</sub>) deficiency.</b> Hyperphenylalaninemia may also result from the impaired synthesis or recycling of tetrahydrobiopterin (BH<sub>4</sub>), the cofactor in the phenylalanine, tyrosine, and tryptophan hydroxylation reactions. All of the HPAs caused by BH<sub>4</sub> deficiency are inherited in an autosomal recessive manner. They account for approximately 2% of individuals with elevated Phe levels in most populations. However, for individuals with elevated Phe from populations in which PAH is less common (e.g., Japan), the risk to the affected individual of having a disorder of pterin metabolism is much higher. BH<sub>4</sub> is also involved in catecholamine, serotonin, and nitric oxide biosynthesis (see <a href="http://www.biopku.org/home/pah.asp" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">biopku.org</a>).</p><ul><li class="half_rhythm"><div>Defects in BH<sub>4</sub> synthesis result from guanosine triphosphate cyclohydrolase (GTPCH) deficiency (OMIM <a href="https://omim.org/entry/233910" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">233910</a>) caused by biallelic pathogenic variants in <i>GCH1</i> or from 6-pyruvoyl tetrahydrobiopterin synthase (PTPS) deficiency (OMIM <a href="https://omim.org/entry/261640" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">261640</a>) caused by biallelic pathogenic variants in <i>PTS</i>.</div></li><li class="half_rhythm"><div>Impaired recycling of BH<sub>4</sub> is caused by dihydropteridine reductase (DHPR) deficiency (OMIM <a href="https://omim.org/entry/261630" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">261630</a>) caused by biallelic pathogenic variants in <i>QDPR</i> or by pterin-4 acarbinolamine dehydratase (PCBD) deficiency (OMIM <a href="https://omim.org/entry/264070" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">264070</a>) caused by biallelic pathogenic variants in <i>PCBD1</i>.</div></li></ul><p><a class="bibr" href="#pku.REF.vockley.2014" rid="pku.REF.vockley.2014">Vockley et al [2014]</a> emphasize that all neonates with persistent hyperphenylalaninemia must be screened for the BH<sub>4</sub> deficiencies. The following tests are best performed in specialized centers. Prenatal diagnosis is possible for all forms of BH<sub>4</sub> deficiencies. The following screening tests are essential:</p><ul><li class="half_rhythm"><div>Pterins are measured in urine or blood.</div></li><li class="half_rhythm"><div>Erythrocyte dihydropterine reductase should be measured on whole blood spotted on filter paper. A quantitative assay for urinary neopterin and biopterin can confirm results obtained from the filter paper samples. Reference values are available for different age groups.</div></li><li class="half_rhythm"><div>Abnormal pterin levels and ratios should prompt enzyme testing for possible deficiencies of: GTP cyclohydrolase, 6-pyruvoyl-tetrahydropterin synthase, dihydropteridine reductase, or pterin carbinolamine-4α-dehydratase.</div></li></ul><p>The typical (severe) forms of GTPCH, PTPS, and DHPR deficiency have the following variable, but common, findings: intellectual disability, convulsions, disturbance of tone and posture, drowsiness, irritability, abnormal movements, recurrent hyperthermia without infections, hypersalivation, and swallowing difficulties. Microcephaly is common in PTPS and DHPR deficiencies. Plasma phenylalanine concentrations can vary from slightly above normal (>120 µmol/L) to as high as 2,500 µmol/L. Mild forms of BH<sub>4</sub> deficiency have no clinical signs.</p><p>PCD deficiency, sometimes referred to as "primapterinuria," is associated with benign transient hyperphenylalaninemia and patients are at risk for MODY-type diabetes at puberty.</p><p>In principle, BH<sub>4</sub> deficiencies are treatable. Treatment requires the normalization of BH<sub>4</sub> availability and of blood Phe concentration and restoration of the BH<sub>4</sub>-dependent hydroxylation of tyrosine and tryptophan. This is achieved by BH<sub>4</sub> supplementation along with dietary modification, neurotransmitter precursor replacement therapy, and supplements of folinic acid in DHPR deficiency. The treatment should be initiated early and probably continued for life [<a class="bibr" href="#pku.REF.blau.2001" rid="pku.REF.blau.2001">Blau et al 2001</a>, <a class="bibr" href="#pku.REF.ponzone.2006" rid="pku.REF.ponzone.2006">Ponzone et al 2006</a>].</p><p>More information on the BH<sub>4</sub> deficiencies can be found at <a href="http://www.biopku.org/home/pah.asp" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">www.biopku.org</a>.</p></div><div id="pku.Management"><h2 id="_pku_Management_">Management</h2><div id="pku.Evaluations_Following_Initial_Diagno"><h3>Evaluations Following Initial Diagnosis</h3><p>To establish the extent of disease and needs in an individual diagnosed with phenylalanine hydroxylase (PAH) deficiency, the following evaluations are recommended:</p><ul><li class="half_rhythm"><div>Medical biochemical genetics consultation, if not already done, and evaluation by a metabolic dietician able to begin a low-Phe, age-appropriate diet</div></li><li class="half_rhythm"><div>Blood phenylalanine concentration and estimation of phenylalanine tolerance [<a class="bibr" href="#pku.REF.kayaalp.1997.1309" rid="pku.REF.kayaalp.1997.1309">Kayaalp et al 1997</a>, <a class="bibr" href="#pku.REF.guldberg.1998.71" rid="pku.REF.guldberg.1998.71">Guldberg et al 1998</a>]. Because the PAH genotype may not always predict phenotype (see <a href="#pku.GenotypePhenotype_Correlations">Genotype-Phenotype Correlations</a>), the individual's diet should be tailored to the estimated phenylalanine tolerance irrespective of genotype.</div></li><li class="half_rhythm"><div>For individuals diagnosed outside the newborn period, formal developmental, behavioral, neuropsychological, and mental health evaluation</div></li></ul></div><div id="pku.Treatment_of_Manifestations"><h3>Treatment of Manifestations</h3><p>Treatment for affected individuals of all ages can be difficult and is enhanced with the teaching and support of an experienced health care team consisting of physicians, nutritionists, genetic counselors, social workers, nurses, and psychologists. See <a href="https://www.acmg.net/docs/Phenylalanine_Hydrosylase_Deficiency_Practice_Guideline_AOP_Jan_2013.pdf" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">ACMG Management Guidelines for PKU</a>.</p><div id="pku.Treatment_of_Classic_PKU"><h4>Treatment of Classic PKU</h4><p><b>Restriction of dietary phenylalanine.</b> The generally accepted goal of treatment for individuals with PAH deficiency is normalization of the concentrations of Phe (phenylalanine) and Tyr (tyrosine) in the blood and thus prevention of the cognitive deficits that are attributable to this disorder [<a class="bibr" href="#pku.REF.burgard.1999.46" rid="pku.REF.burgard.1999.46">Burgard et al 1999</a>].</p><p>Genetic Metabolic Dieticians International (GMDI) has <a href="https://southeastgenetics.org/ngp/guidelines.php/90/PKU%20Nutrition%20Guidelines/Version%201.12" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">PKU Nutrition Management Guidelines</a> that are continually updated.</p><p>Any provider managing the diet of an individual with PAH deficiency should use these resources and work closely with a dietician knowledgeable in the care and management of a person with this diagnosis.</p><p><a class="bibr" href="#pku.REF.singh.2014.121" rid="pku.REF.singh.2014.121">Singh et al [2014]</a> provide the following dietary recommendations:</p><ul><li class="half_rhythm"><div>Maintain blood Phe between 120 and 360 μmol/L throughout the life span.</div></li><li class="half_rhythm"><div>Monitor blood Phe most frequently during times of increased anabolism: infancy, childhood, and pregnancy. The NIH recommends measurement of blood phenylalanine levels on a weekly basis for the first year of life, on a biweekly basis until age 13 years, and on a monthly basis thereafter [<a class="bibr" href="#pku.REF.camp.2014.87" rid="pku.REF.camp.2014.87">Camp et al 2014</a>]. Care must be taken to avoid long periods of low blood Phe concentration, which is also harmful to brain development and function.</div></li><li class="half_rhythm"><div>Monitor blood Phe consistently, preferably two to three hours after eating.</div></li><li class="half_rhythm"><div>Evaluate individual nutritional needs, ability to adhere to recommendations, and access to treatment options when choosing appropriate interventions (medical food, modified low-protein food, large neutral amino acids [LNAAs], and sapropterin) to achieve blood PHE in the target range.</div></li><li class="half_rhythm"><div>Include breast milk [<a class="bibr" href="#pku.REF.vockley.2014" rid="pku.REF.vockley.2014">Vockley et al 2014</a>] and/or infant formula as sources of Phe in the diet of an infant with PAH deficiency.</div></li><li class="half_rhythm"><div>Recommend that medical food be consumed throughout the day for optimal metabolic control.</div></li><li class="half_rhythm"><div>Track Phe intake by any of several methods, including counting milligrams or exchanges of PHE or grams of protein.</div></li><li class="half_rhythm"><div>Maintain blood Tyr in the normal range.</div></li><li class="half_rhythm"><div>Maintain other nutrients and micronutrients at RDA levels, including calcium, vitamin D, iron, and B vitamins. Due to the protein-restricted dietary components, micronutrients found in animal products must be carefully monitored and supplemented, as needed.</div></li><li class="half_rhythm"><div>Provide counseling and education specific to the needs of the individual with PAH deficiency (and/or his/her caregivers) to help maintain appropriate blood Phe throughout the life span.</div></li></ul><p><b>Sapropterin (Kuvan<sup>®</sup>).</b> BH<sub>4</sub> responsiveness, as determined by a 30% decrease in Phe plasma levels on plasma amino acid analysis, is determined based on response to a pharmacologic dose of BH<sub>4</sub> (10-20 mg/kg per day):</p><ul><li class="half_rhythm"><div>All affected individuals except those with two <i>trans</i> pathogenic null variants should ideally undergo a trial with sapropterin supplementation. The trial needs to be conducted when Phe levels have been stable and dietary intake can remain unchanged, so that any change in Phe level is the result of the medication; for some affected individuals it is a challenge to conduct a trial of therapy. The most common dose given is 20 mg/kg per day. Lower trial doses may lead to false negative responsiveness results [<a class="bibr" href="#pku.REF.vockley.2014" rid="pku.REF.vockley.2014">Vockley et al 2014</a>].</div></li><li class="half_rhythm"><div>Affected individuals who are responsive should continue this medication with compensatory dietary Phe liberalization, as needed, to maintain a safe Phe level between 120 and 360 μmol/L.</div></li><li class="half_rhythm"><div>The majority of individuals with mild or moderate PKU may be responsive to sapropterin while up to 10% of individuals with classic PKU show a response [<a class="bibr" href="#pku.REF.bernegger.2002.304" rid="pku.REF.bernegger.2002.304">Bernegger & Blau 2002</a>, <a class="bibr" href="#pku.REF.p_rezdue_as.2004.1083" rid="pku.REF.p_rezdue_as.2004.1083">Pérez-Dueñas et al 2004</a>, <a class="bibr" href="#pku.REF.zurfl_h.2006.725" rid="pku.REF.zurfl_h.2006.725">Zurflüh et al 2006</a>]. Reviewed in <a class="bibr" href="#pku.REF.ho.2014.49" rid="pku.REF.ho.2014.49">Ho & Christodoulou [2014]</a>.</div></li></ul><p>Click <a href="/books/NBK1504/bin/pku-mech_action.pdf">here</a> (pdf) for more information on the proposed mechanism of action of sapropterin.</p><p><b>Large neutral amino acids (LNAA) transporters.</b> LNAA may decrease the plasma Phe concentration in affected adolescents and adults; however, it should not be used in women of childbearing age (see <a href="#pku.Pregnancy_Management">Pregnancy Management</a>).</p><p>Click <a href="/books/NBK1504/bin/pku-mech_action.pdf">here</a> (pdf) for more information on the proposed mechanism of action of LNAA.</p></div><div id="pku.Treatment_for_NonClassic_Hyperphenyl"><h4>Treatment for Non-Classic Hyperphenylalaninemia</h4><p>While debate continues, many experts believe that dietary treatment is unnecessary for many of the individuals in this class.</p><ul><li class="half_rhythm"><div>Individuals with <b>Phe levels >600 μmol/L (10 mg/dL)</b> are treated by most centers, in recognition of the finding of head MRI changes and neuropsychological findings in at least some affected individuals.</div></li><li class="half_rhythm"><div>Treatment in individuals with <b>Phe levels consistently <600 μmol/L but >360 μmol/L</b> remains controversial [<a class="bibr" href="#pku.REF.weglage.2001.532" rid="pku.REF.weglage.2001.532">Weglage et al 2001</a>, <a class="bibr" href="#pku.REF.hanley.2011.23" rid="pku.REF.hanley.2011.23">Hanley 2011</a>, <a class="bibr" href="#pku.REF.van_spronsen.2011.651" rid="pku.REF.van_spronsen.2011.651">van Spronsen 2011</a>].</div><ul><li class="half_rhythm"><div>Thirty-one individuals with PAH deficiency who were never treated and whose plasma Phe concentrations did not exceed 600 µmol/L had normal cognitive neuropsychological development.</div></li><li class="half_rhythm"><div>The American College of Medical Genetics and Genomics guidelines on the diagnosis and management of PAH (PKU) state: "…treatment of infants with sustained blood Phe levels >360 µmol/L is recommended following appropriate review of the controversy with patients."</div></li></ul></li><li class="half_rhythm"><div>If the <b>Phe levels remain between 120 and 360 µmol/L</b>, treatment is not recommended; however, children should be followed for plasma Phe levels closely during the first two years of life, then on an annual or biennial basis [<a class="bibr" href="#pku.REF.vockley.2014" rid="pku.REF.vockley.2014">Vockley et al 2014</a>].</div></li><li class="half_rhythm"><div>Care should be taken so that women of childbearing age in this group receive proper counseling about the teratogenic effects of elevated maternal plasma Phe concentration (i.e., "maternal HPA/PKU") on the developing fetus [<a class="bibr" href="#pku.REF.weglage.2001.532" rid="pku.REF.weglage.2001.532">Weglage et al 2001</a>] (see <a href="#pku.Pregnancy_Management">Pregnancy Management</a>).</div></li></ul></div><div id="pku.Other_1"><h4>Other</h4><p><b>Neuropsychiatric testing</b> may be considered to identify learning differences. Referral to appropriate developmental services is indicated to optimize developmental outcome.</p><p><b>Bone health assessment.</b> Current literature regarding the utility of DXA (dual-energy x-ray absorptiometry) scans is controversial; however, bone health should be considered in the overall health of an affected individual [<a class="bibr" href="#pku.REF.coakley.2016.363" rid="pku.REF.coakley.2016.363">Coakley et al 2016</a>].</p></div></div><div id="pku.Prevention_of_Primary_Manifestations"><h3>Prevention of Primary Manifestations</h3><p>See <a href="#pku.Treatment_of_Manifestations">Treatment of Manifestations</a>.</p></div><div id="pku.Surveillance"><h3>Surveillance</h3><p><b>Plasma Phe and Tyr concentrations</b> in individuals with classic PKU must be monitored regularly [<a class="bibr" href="#pku.REF.national_institutes_of_health_consensus_development_panel.2001.972" rid="pku.REF.national_institutes_of_health_consensus_development_panel.2001.972">National Institutes of Health Consensus Development Panel 2001</a>] (see <a href="#pku.Treatment_of_Manifestations">Treatment of Manifestations</a>).</p><ul><li class="half_rhythm"><div>In infants, frequent in-clinic visits are recommended until Phe levels are stabilized, followed by weekly blood level monitoring of Phe and tyrosine levels until age one with closer monitoring during periods of rapid growth or diet transitions. In addition, plasma amino acid levels should be regularly monitored to foster optimal growth during the first year of life.</div></li><li class="half_rhythm"><div>Between ages one and 12 years, biweekly to monthly sampling may be adequate.</div></li><li class="half_rhythm"><div>In adolescents and adults who are stable and well controlled, blood level monitoring can be monthly.</div></li></ul><p><b>Nutritional assessment</b> should include growth evaluation and assessment of micronutrient intake and needs.</p><ul><li class="half_rhythm"><div>Some clinics perform monitoring of plasma amino acids, transthyretin, complete blood count, ferritin, and 25-OH vitamin D every six months in infants and annually thereafter even if growth is appropriate and analysis of the diet shows adequate intake.</div></li><li class="half_rhythm"><div>If there is evidence for suboptimal dietary intake or overreliance on nutritionally incomplete medical foods, evaluation of plasma amino acids (full panel), transthyretin, albumin, complete blood count, ferritin, 25-OH vitamin D, electrolytes, renal function, liver function, albumin, vitamin B<sub>12</sub>, red blood cell essential fatty acids, trace minerals (zinc, copper, selenium), vitamin A, and folic acid should be considered [<a class="bibr" href="#pku.REF.singh.2014.121" rid="pku.REF.singh.2014.121">Singh et al 2014</a>, <a class="bibr" href="#pku.REF.vockley.2014" rid="pku.REF.vockley.2014">Vockley et al 2014</a>].</div></li></ul><p><b>Assessment of developmental milestones</b> and overall developmental progress should take place at every visit.</p><p><b>Screening for mental illness</b> should be considered at every visit and performed at regular intervals by primary care providers.</p></div><div id="pku.AgentsCircumstances_to_Avoid"><h3>Agents/Circumstances to Avoid</h3><p>Aspartame, an artificial sweetener in widespread use, contains phenylalanine. Persons with PKU should either avoid products containing aspartame or calculate intake of Phe and adapt diet components accordingly.</p></div><div id="pku.Evaluation_of_Relatives_at_Risk"><h3>Evaluation of Relatives at Risk</h3><p>It is appropriate to evaluate sibs of a proband in order to identify as early as possible those who would benefit from initiation of treatment. Note: Because phenotypic variability may be significant, previously undiagnosed and even apparently asymptomatic sibs of an affected individual may also be affected [<a class="bibr" href="#pku.REF.vockley.2014" rid="pku.REF.vockley.2014">Vockley et al 2014</a>].</p><p>Evaluations can include:</p><ul><li class="half_rhythm"><div>Measurement of blood concentration of phenylalanine and newborn screening in newborn sibs of an individual with PKU if prenatal testing was not done;</div></li><li class="half_rhythm"><div>Molecular genetic testing if the pathogenic variants in the family are known;</div></li><li class="half_rhythm"><div>Blood concentration of phenylalanine and tyrosine to clarify the disease status of older at-risk sibs if the pathogenic variants in the family are not known.</div></li></ul><p>See <a href="#pku.Related_Genetic_Counseling_Issues">Genetic Counseling</a> for issues related to testing of at-risk relatives for genetic counseling purposes.</p></div><div id="pku.Pregnancy_Management"><h3>Pregnancy Management</h3><div id="pku.Women_with_PAH_Deficiency"><h4>Women with PAH Deficiency</h4><p>Women with PAH deficiency who have received appropriate treatment throughout childhood and adolescence have normal physical and essentially normal intellectual and behavioral development. However, if the woman has elevated plasma Phe concentrations during pregnancy, the fetus is at high risk for malformations and intellectual disability, since phenylalanine is a potent teratogen (see <a href="#pku.Clinical_Characteristics">Clinical Characteristics</a>) [<a class="bibr" href="#pku.REF.rouse.2004.235" rid="pku.REF.rouse.2004.235">Rouse & Azen 2004</a>, <a class="bibr" href="#pku.REF.prick.2012.374" rid="pku.REF.prick.2012.374">Prick et al 2012</a>].</p><p>The <a href="https://www.acog.org/clinical/clinical-guidance/committee-opinion/articles/2020/04/management-of-women-with-phenylalanine-hydroxylase-deficiency-phenylketonuria" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">American College of Obstetrics and Gynecology Committee Opinion on the Management of Women with Phenylketonuria</a>, the American College of Medical Genetics and Genomics guidelines on the diagnosis and management of PAH deficiency [<a class="bibr" href="#pku.REF.vockley.2014" rid="pku.REF.vockley.2014">Vockley et al 2014</a>], and <a class="bibr" href="#pku.REF.singh.2014.121" rid="pku.REF.singh.2014.121">Singh et al [2014]</a> suggest the following management of an affected woman prior to and during pregnancy.</p><p>
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<b>Preconception</b>
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</p><ul><li class="half_rhythm"><div>Genetic counseling regarding the teratogenic effects of elevated maternal Phe concentration on the developing fetus and recurrence risks for PAH deficiency in the fetus</div></li><li class="half_rhythm"><div>Achievement and maintenance of the maternal Phe concentration at less than 360 µmol/L for three months prior to conception</div></li><li class="half_rhythm"><div>Assessment of early osteopenia risk</div></li><li class="half_rhythm"><div>Discontinuation of LNAA treatment</div></li></ul><p>
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<b>During pregnancy</b>
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</p><ul><li class="half_rhythm"><div>Co-monitor in conjunction with practitioners from an experienced metabolic center.</div></li><li class="half_rhythm"><div>Maternal Phe concentration of 120-360 µmol/L during pregnancy is recommended. In unplanned pregnancies, rapid reinitiation of a Phe-restricted diet should be advised based on current knowledge of the fetal risks.</div></li><li class="half_rhythm"><div>Despite limited data, sapropterin supplementation may be appropriate in addition to dietary therapy.</div></li><li class="half_rhythm"><div>Monitor dietary intake of pregnant women with PAH deficiency to ensure nutrient adequacy with proper proportion of protein, fat, and carbohydrates.</div></li><li class="half_rhythm"><div>Evaluate for fetal anomalies by high-resolution ultrasound and fetal echocardiogram.</div></li></ul><p>
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<b>Post partum</b>
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</p><ul><li class="half_rhythm"><div>Provide coordinated care in the postpartum period</div></li><li class="half_rhythm"><div>Breastfeeding may be pursued if the infant does not have PAH deficiency.</div></li></ul></div></div><div id="pku.Therapies_Under_Investigation"><h3>Therapies Under Investigation</h3><p>Although the treatment of PKU with phenylalanine-restricted diets has been hugely successful, the poor palatability of the diet results in poor compliance in adolescence and adulthood. A number of attempts to find other treatment modalities for PKU are ongoing.</p><p><b>Enzyme substitution.</b> Under investigation is the administration of the enzyme phenylalanine ammonia lyase (PAL), a plant-derived enzyme that converts phenylalanine to trans-cinnamic acid and ammonia. The version currently under investigation is the PEGylation (conjugation with polyethylene glycol) of PAL, since it has been found to decrease the immune response to PAL [<a class="bibr" href="#pku.REF.g_mez.2005.986" rid="pku.REF.g_mez.2005.986">Gámez et al 2005</a>, <a class="bibr" href="#pku.REF.sarkissian.2005.s22" rid="pku.REF.sarkissian.2005.s22">Sarkissian & Gámez 2005</a>]. Clinical trials with this protected form of injectable enzyme are currently under way. The results of the Phase I trial showed effectiveness by reducing blood Phe by 54% in the participants receiving the highest dose. The Phe level nadir was at six days and response lasted 21 days. Adverse reactions included rash, antibody accumulation to both PAL and the PEGylation component, and injection site reaction [<a class="bibr" href="#pku.REF.longo.2014.37" rid="pku.REF.longo.2014.37">Longo et al 2014</a>].</p><p><b>Cell-directed therapies.</b> Liver repopulation with PAH-expressing cells is being investigated. Hepatocyte transplantation has been successful in animal models and in humans for other liver-based inborn errors of metabolism, such as glycogen storage disorders and urea cycle defects. Research continues to identify the best ways to allow for transferred hepatocytes to have cell growth advantage over native hepatocytes (reviewed in <a class="bibr" href="#pku.REF.strisciuglio.2014.1007" rid="pku.REF.strisciuglio.2014.1007">Strisciuglio & Concolino [2014]</a>).</p><p><b>Gene therapies.</b> Liver-directed gene therapy does not result in a permanent correction of PAH activity in animal models. Delivery to muscle was successful in increasing conversion of Phe to Tyr in mice (reviewed in <a class="bibr" href="#pku.REF.strisciuglio.2014.1007" rid="pku.REF.strisciuglio.2014.1007">Strisciuglio & Concolino [2014]</a>).</p><p>Search <a href="https://clinicaltrials.gov/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">ClinicalTrials.gov</a> in the US and <a href="https://www.clinicaltrialsregister.eu/ctr-search/search" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">EU Clinical Trials Register</a> in Europe for access to information on clinical studies for a wide range of diseases and conditions.</p></div></div><div id="pku.Genetic_Counseling"><h2 id="_pku_Genetic_Counseling_">Genetic Counseling</h2><p>
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<i>Genetic counseling is the process of providing individuals and families with
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information on the nature, mode(s) of inheritance, and implications of genetic disorders to help them
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make informed medical and personal decisions. The following section deals with genetic
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risk assessment and the use of family history and genetic testing to clarify genetic
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status for family members; it is not meant to address all personal, cultural, or
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ethical issues that may arise or to substitute for consultation with a genetics
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professional</i>. —ED.</p><div id="pku.Mode_of_Inheritance"><h3>Mode of Inheritance</h3><p>Phenylalanine hydroxylase (PAH) deficiency is inherited in an autosomal recessive manner.</p></div><div id="pku.Risk_to_Family_Members"><h3>Risk to Family Members</h3><p>
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<b>Parents of a proband</b>
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</p><ul><li class="half_rhythm"><div>The parents of an affected child are obligate heterozygotes (i.e., carriers of one <i>PAH</i> pathogenic variant).</div></li><li class="half_rhythm"><div>Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.</div></li></ul><p>
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<b>Sibs of a proband</b>
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</p><ul><li class="half_rhythm"><div class="half_rhythm">At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.</div><div class="half_rhythm">Significant intrafamilial variability has been observed in PAH deficiency; thus, the phenotype observed in the proband may not be consistent with or predicative of the phenotype in affected sibs [<a class="bibr" href="#pku.REF.disilvestre.1991.1014" rid="pku.REF.disilvestre.1991.1014">DiSilvestre et al 1991</a>, <a class="bibr" href="#pku.REF.scriver.1999.267" rid="pku.REF.scriver.1999.267">Scriver & Waters 1999</a>, <a class="bibr" href="#pku.REF.weglage.2002.431" rid="pku.REF.weglage.2002.431">Weglage et al 2002</a>, <a class="bibr" href="#pku.REF.camp.2014.87" rid="pku.REF.camp.2014.87">Camp et al 2014</a>].</div></li><li class="half_rhythm"><div class="half_rhythm">Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.</div></li></ul><p>
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<b>Offspring of a proband</b>
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</p><ul><li class="half_rhythm"><div>Children born of one parent with PAH deficiency and one parent with two normal <i>PAH</i> alleles are obligate heterozygotes.</div></li><li class="half_rhythm"><div>If one parent is affected and the other parent is a carrier, offspring have a 50% chance of being heterozygous and a 50% chance of being affected.</div></li><li class="half_rhythm"><div>If the mother is the affected parent, maternal HPA/PKU is a critical issue (see Clinical Description, <a href="#pku.Children_Born_to_Women_with_PAH_Defi">Children Born to Women with PAH Deficiency</a>).</div></li></ul><p><b>Other family members.</b> Each sib of the proband's unaffected parents is at a 50% risk of being a carrier of a <i>PAH</i> pathogenic variant.</p></div><div id="pku.Carrier_Detection"><h3>Carrier Detection</h3><p><b>Molecular genetic testing</b> for at-risk relatives requires prior identification of the <i>PAH</i> pathogenic variants in the family. ACMG guidelines recommend the use of molecular genetic testing to identify carriers in a family with a known <i>PAH</i> pathogenic variant [<a class="bibr" href="#pku.REF.vockley.2014" rid="pku.REF.vockley.2014">Vockley et al 2014</a>]. If molecular genetic testing is not possible, biochemical analysis can be used.</p><p><b>Biochemical testing</b> relies on plasma Phe concentration and the Phe/Tyr ratio, with or without phenylanine loading [<a class="bibr" href="#pku.REF.freehauf.1984.1180" rid="pku.REF.freehauf.1984.1180">Freehauf et al 1984</a>, <a class="bibr" href="#pku.REF.blitzer.1986.347" rid="pku.REF.blitzer.1986.347">Blitzer et al 1986</a>]. Hormones associated with pregnancy have been shown to alter the Phe/Tyr ratio; thus, biochemical analysis cannot be used to determine carrier status during pregnancy, shortly after pregnancy, or with oral contraceptive use.</p><p>Partners of an individual affected with or known to be a carrier of PAH deficiency may be interested in carrier testing. Analysis of <i>PAH</i> can be offered, with appropriate counseling about limits of sensitivity. Guidelines for biochemical carrier testing have not been established; and the predictive value of biochemical testing has been studied on a limited basis only.</p></div><div id="pku.Related_Genetic_Counseling_Issues"><h3>Related Genetic Counseling Issues</h3><p>See Management, <a href="#pku.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>
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<b>Family planning</b>
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</p><ul><li class="half_rhythm"><div>Young women affected with PAH deficiency should receive counseling regarding the teratogenic effects of elevated maternal plasma Phe concentration (i.e., "maternal HPA/PKU") when they reach childbearing age [<a class="bibr" href="#pku.REF.weglage.2001.532" rid="pku.REF.weglage.2001.532">Weglage et al 2001</a>] (see <a href="#pku.Pregnancy_Management">Pregnancy Management</a>).</div></li><li class="half_rhythm"><div>The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.</div></li><li class="half_rhythm"><div>It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.</div></li></ul><p><b>DNA banking.</b> Because it is likely that testing methodology and our understanding of genes, pathogenic mechanisms, and diseases will improve in the future, consideration should be given to banking DNA from probands in whom a molecular diagnosis has not been confirmed (i.e., the causative pathogenic mechanism is unknown).</p></div><div id="pku.Prenatal_Testing_and_Preimplantation"><h3>Prenatal Testing and Preimplantation Genetic Testing</h3><p>Once the <i>PAH</i> pathogenic variants have been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing for PAH deficiency are possible.</p><p>Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. Prenatal diagnosis has been found by some families to be of value when decisions that will affect care of their child need to be made prenatally. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.</p></div></div><div id="pku.Resources"><h2 id="_pku_Resources_">Resources</h2><p>
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<i>GeneReviews staff has selected the following disease-specific and/or umbrella
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support organizations and/or registries for the benefit of individuals with this disorder
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and their families. GeneReviews is not responsible for the information provided by other
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organizations. For information on selection criteria, click <a href="/books/n/gene/app4/?report=reader">here</a>.</i></p>
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<ul><li class="half_rhythm"><div>
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<b>British Inherited Metabolic Disease Group (BIMDG)</b>
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</div><div>TEMPLE (Tools Enabling Metabolic Parents LEarning)</div><div>United Kingdom</div><div>
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<a href="https://bimdg.org.uk/store/temple//B20030_TEMPLE_PKU_A5_DIGITAL_-_Final_841093_23062020.pdf" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">PKU</a>
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</div></li><li class="half_rhythm"><div>
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<b>Canadian PKU and Allied Disorders Inc. </b>
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</div><div>Canada</div><div><b>Phone:</b> 877-226-7581</div><div><b>Email:</b> info@canpku.org</div><div>
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<a href="http://www.canpku.org" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">www.canpku.org</a>
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</div></li><li class="half_rhythm"><div>
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<b>March of Dimes</b>
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</div><div>
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<a href="https://www.marchofdimes.org/find-support/topics/birth/pku-phenylketonuria-your-baby" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">PKU (Phenylketonuria) in your baby</a>
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</div></li><li class="half_rhythm"><div>
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<b>Medical Home Portal</b>
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</div><div>
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<a href="https://www.medicalhomeportal.org/diagnoses-and-conditions/pku-and-pterin-defects" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">PKU and Pterin Defects</a>
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</div></li><li class="half_rhythm"><div>
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<b>MedlinePlus</b>
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</div><div>
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<a href="https://medlineplus.gov/genetics/condition/phenylketonuria/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">Phenylketonuria</a>
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</div></li><li class="half_rhythm"><div>
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<b>National PKU Alliance</b>
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</div><div>
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<a href="http://npkua.org/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">National PKU Alliance</a>
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</div></li><li class="half_rhythm"><div>
|
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<b>National PKU News</b>
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</div><div>
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<a href="https://pkunews.org/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">www.pkunews.org</a>
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</div></li><li class="half_rhythm"><div>
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<b>National Society for PKU (NSPKU)</b>
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</div><div>United Kingdom</div><div><b>Phone:</b> 030 3040 1090</div><div><b>Email:</b> info@nspku.org</div><div>
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<a href="http://www.nspku.org/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">www.nspku.org</a>
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</div></li><li class="half_rhythm"><div>
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<b>Metabolic Support UK</b>
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</div><div>United Kingdom</div><div><b>Phone:</b> 0845 241 2173</div><div>
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<a href="https://metabolicsupportuk.org/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">metabolicsupportuk.org</a>
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</div></li><li class="half_rhythm"><div>
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<b>National Organization for Rare Disorders (NORD)</b>
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</div><div><b>Phone:</b> 800-999-6673</div><div>
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<a href="https://rarediseases.org/for-patients-and-families/help-access-medications/patient-assistance-programs-2/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">RareCare® Patient Assistance Programs</a>
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</div></li><li class="half_rhythm"><div>
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<b>Newborn Screening in Your State</b>
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</div><div>Health Resources & Services Administration</div><div>
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<a href="https://newbornscreening.hrsa.gov/your-state" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">newbornscreening.hrsa.gov/your-state</a>
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</div></li></ul>
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</div><div id="pku.Molecular_Genetics"><h2 id="_pku_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 class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figpkumolgenTA"><a href="/books/NBK1504/table/pku.molgen.TA/?report=objectonly" target="object" title="Table A." class="img_link icnblk_img" rid-ob="figobpkumolgenTA"><img class="small-thumb" src="/corehtml/pmc/css/bookshelf/2.26/img/table-icon.gif" alt="Table Icon" /></a><div class="icnblk_cntnt"><h4 id="pku.molgen.TA"><a href="/books/NBK1504/table/pku.molgen.TA/?report=objectonly" target="object" rid-ob="figobpkumolgenTA">Table A.</a></h4><p class="float-caption no_bottom_margin">Phenylalanine Hydroxylase Deficiency: Genes and Databases </p></div></div><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figpkumolgenTB"><a href="/books/NBK1504/table/pku.molgen.TB/?report=objectonly" target="object" title="Table B." class="img_link icnblk_img" rid-ob="figobpkumolgenTB"><img class="small-thumb" src="/corehtml/pmc/css/bookshelf/2.26/img/table-icon.gif" alt="Table Icon" /></a><div class="icnblk_cntnt"><h4 id="pku.molgen.TB"><a href="/books/NBK1504/table/pku.molgen.TB/?report=objectonly" target="object" rid-ob="figobpkumolgenTB">Table B.</a></h4><p class="float-caption no_bottom_margin">OMIM Entries for Phenylalanine Hydroxylase Deficiency (View All in OMIM) </p></div></div><p><b>Gene structure.</b>
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<i>PAH</i> contains 13 exons and spans 90 kb; the genomic sequence is known to code for a 2.6-kb mature messenger RNA. For a detailed summary of gene and protein information, see <a href="/books/NBK1504/?report=reader#pku.molgen.TA">Table A</a>, <b>Gene</b>.</p><p><b>Pathogenic variants.</b> More than 900 different pathogenic variants in <i>PAH</i> have been identified to date; see <a href="/books/NBK1504/?report=reader#pku.molgen.TA">Table A</a>, <b>Locus-Specific Databases</b> and <b>HGMD</b>. The majority of pathogenic variants in <i>PAH</i> are missense, nonsense, frameshift, and splice variants. Large deletions account for fewer than 1% of disease alleles in most populations, but accounted for 3% of disease alleles in the Czech population [<a class="bibr" href="#pku.REF.kozak.2006.300" rid="pku.REF.kozak.2006.300">Kozak et al 2006</a>].</p><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figpkuTpahvariantsdiscussedinthisgen"><a href="/books/NBK1504/table/pku.T.pah_variants_discussed_in_this_gen/?report=objectonly" target="object" title="Table 4. " class="img_link icnblk_img" rid-ob="figobpkuTpahvariantsdiscussedinthisgen"><img class="small-thumb" src="/corehtml/pmc/css/bookshelf/2.26/img/table-icon.gif" alt="Table Icon" /></a><div class="icnblk_cntnt"><h4 id="pku.T.pah_variants_discussed_in_this_gen"><a href="/books/NBK1504/table/pku.T.pah_variants_discussed_in_this_gen/?report=objectonly" target="object" rid-ob="figobpkuTpahvariantsdiscussedinthisgen">Table 4. </a></h4><p class="float-caption no_bottom_margin"><i>PAH</i> Variants Discussed in This <i>GeneReview</i> </p></div></div><p><b>Normal gene product.</b> The normal product of <i>PAH</i> is the protein phenylalanine hydroxylase (PAH), containing 452 amino acids (<a href="https://www.ncbi.nlm.nih.gov/protein/NP_000268.1" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">NP_000268.1</a>). PAH enzymes can exist as tetramers and dimers in equilibrium [<a class="bibr" href="#pku.REF.hufton.1998.295" rid="pku.REF.hufton.1998.295">Hufton et al 1998</a>]. The PAH enzyme hydroxylates phenylalanine to tyrosine, this reaction being the rate-limiting step in the major pathway by which phenylalanine is catabolized to CO<sub>2</sub> and water [<a class="bibr" href="#pku.REF.scriver.2001" rid="pku.REF.scriver.2001">Scriver & Kaufman 2001</a>].</p><p><b>Abnormal gene product.</b> The pathogenic variants that confer the most severe phenotypes are known or predicted to completely abolish PAH activity. These "null" variants are of various types. Missense pathogenic variants usually permit the enzyme to retain some degree of residual activity; however, it is difficult to assess severity in vivo because the in vivo activity is not the simple equivalent of the in vitro enzymatic phenotype [<a class="bibr" href="#pku.REF.waters.1998.4" rid="pku.REF.waters.1998.4">Waters et al 1998</a>, <a class="bibr" href="#pku.REF.gjetting.2001.132" rid="pku.REF.gjetting.2001.132">Gjetting et al 2001</a>].</p></div><div id="pku.References"><h2 id="_pku_References_">References</h2><div id="pku.Published_Guidelines__Consensus_Stat"><h3>Published Guidelines / Consensus Statements</h3><ul class="simple-list"><li class="half_rhythm"><p><div class="bk_ref" id="pku.REF1">Canadian Task Force on the Preventive Health Care. Screening for phenylketonuria. The Canadian Guide to Clinical Preventive Health Care. Available <a href="https://canadiantaskforce.ca/wp-content/uploads/2016/09/1994-red-brick-en.pdf" ref="pagearea=cite-ref&targetsite=external&targetcat=link&targettype=uri">online</a>. 1994. Accessed 3-25-22.</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="pku.REF2">Committee on Genetics. Management of women with phenylalanine hydroxylase deficiency (phenylketonuria). American College of Obstetricians and Gynecologists Committee Opinion April 2020. Number 802. Available <a href="https://www.acog.org/clinical/clinical-guidance/committee-opinion/articles/2020/04/management-of-women-with-phenylalanine-hydroxylase-deficiency-phenylketonuria" ref="pagearea=cite-ref&targetsite=external&targetcat=link&targettype=uri">online</a>. 2020. Accessed 3-25-22.</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="pku.REF.singh.2014.121">Singh RH, Rohr F, Frazier D, Cunningham A, Mofidi S, Ogata B, Splett PL, Moseley K, Huntington K, Acosta PB, Vockley J, Van Calcar SC. Recommendations for the nutrition management of phenylalanine hydroxylase deficiency. <span><span class="ref-journal">Genet Med. </span>2014;<span class="ref-vol">16</span>:121–31.</span> [<a href="/pmc/articles/PMC3918542/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC3918542</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/24385075" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 24385075</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="pku.REF.vockley.2014">Vockley J, Andersson HC, Antshel KM, Braverman NE, Burton BK, Frazier DM, Mitchell J, Smith WE, Thompson BH, Berry SA; American College of Medical Genetics and Genomics Therapeutics Committee. Phenylalanine hydroxylase deficiency: diagnosis and management guideline. 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Pharmacokinetics of orally administered tetrahydrobiopterin in patients with phenylalanine hydroxylase deficiency. <span><span class="ref-journal">J Inherit Metab Dis. </span>2006;<span class="ref-vol">29</span>:725–31.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/17091341" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 17091341</span></a>]</div></p></li></ul></div></div><div id="pku.Chapter_Notes"><h2 id="_pku_Chapter_Notes_">Chapter Notes</h2><div id="pku.Author_History"><h3>Author History</h3><p>Carol L Greene, MD, FAAP, FACMG (2016-present) <br />John J Mitchell, MD; McGill University, Montreal (2005-2016) <br />Debra S Regier, MD, PhD, FAAP, FACMG (2016-present)<br />Shannon Ryan, MSc; Montreal Children's Hospital (2000-2005)<br />Charles R Scriver, MD; Montreal Children's Hospital (2000-2013)</p></div><div id="pku.Revision_History"><h3>Revision History</h3><ul><li class="half_rhythm"><div>5 January 2017 (dsr) Revision: corrections suggested by expert reader</div></li><li class="half_rhythm"><div>20 October 2016 (ma) Comprehensive update posted live</div></li><li class="half_rhythm"><div>31 January 2013 (me) Comprehensive update posted live</div></li><li class="half_rhythm"><div>4 May 2010 (me) Comprehensive update posted live</div></li><li class="half_rhythm"><div>29 March 2007 (me) Comprehensive update posted live</div></li><li class="half_rhythm"><div>19 July 2005 (jm) Revision: duplication/deletion testing clinically available</div></li><li class="half_rhythm"><div>8 July 2004 (me) Comprehensive update posted live</div></li><li class="half_rhythm"><div>13 August 2002 (me) Comprehensive update posted live</div></li><li class="half_rhythm"><div>10 January 2000 (me) Review posted live</div></li><li class="half_rhythm"><div>16 July 1999 (dsr) Original submission</div></li></ul></div></div><div id="bk_toc_contnr"></div></div></div><div class="fm-sec"><h2 id="_NBK1504_pubdet_">Publication Details</h2><h3>Author Information and Affiliations</h3><div class="contrib half_rhythm"><span itemprop="author">Debra S Regier</span>, MD, PhD, FAAP, FACMG<div class="affiliation small">Children's National Medical Center
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Washington, DC<div><span class="email-label">Email: </span><a href="mailto:dev@null" data-email="gro.lanoitansnerdlihc@reigerd" class="oemail">gro.lanoitansnerdlihc@reigerd</a></div></div></div><div class="contrib half_rhythm"><span itemprop="author">Carol L Greene</span>, MD, FAAP, FACMG<div class="affiliation small">University of Maryland School of Medicine
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Baltimore, Maryland<div><span class="email-label">Email: </span><a href="mailto:dev@null" data-email="ude.dnalyramu.sdep@eneergc" class="oemail">ude.dnalyramu.sdep@eneergc</a></div></div></div><h3>Publication History</h3><p class="small">Initial Posting: <span itemprop="datePublished">January 10, 2000</span>; Last Revision: <span itemprop="dateModified">January 5, 2017</span>.</p><h3>Copyright</h3><div><div class="half_rhythm"><a href="/books/about/copyright/">Copyright</a> © 1993-2025, University of Washington, Seattle. GeneReviews is
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contact: <a href="mailto:dev@null" data-email="ude.wu@tssamda" class="oemail">ude.wu@tssamda</a>.</p></div></div><h3>Publisher</h3><p><a href="http://www.washington.edu" ref="pagearea=page-banner&targetsite=external&targetcat=link&targettype=publisher">University of Washington, Seattle</a>, Seattle (WA)</p><h3>NLM Citation</h3><p>Regier DS, Greene CL. Phenylalanine Hydroxylase Deficiency. 2000 Jan 10 [Updated 2017 Jan 5]. 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></p></div><div class="small-screen-prev"><a href="/books/n/gene/gr_22q13_3/?report=reader"><svg xmlns="http://www.w3.org/2000/svg" viewBox="0 0 100 100" preserveAspectRatio="none"><path d="M75,30 c-80,60 -80,0 0,60 c-30,-60 -30,0 0,-60"></path><text x="20" y="28" textLength="60" style="font-size:25px">Prev</text></svg></a></div><div class="small-screen-next"><a href="/books/n/gene/prs/?report=reader"><svg xmlns="http://www.w3.org/2000/svg" viewBox="0 0 100 100" preserveAspectRatio="none"><path d="M25,30c80,60 80,0 0,60 c30,-60 30,0 0,-60"></path><text x="20" y="28" textLength="60" style="font-size:25px">Next</text></svg></a></div></article><article data-type="table-wrap" id="figobpkuTmoleculargenetictestingusedin"><div id="pku.T.molecular_genetic_testing_used_in" class="table"><h3><span class="label">Table 1. </span></h3><div class="caption"><p>Molecular Genetic Testing Used in Phenylalanine Hydroxylase Deficiency</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK1504/table/pku.T.molecular_genetic_testing_used_in/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__pku.T.molecular_genetic_testing_used_in_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_pku.T.molecular_genetic_testing_used_in_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Gene <sup>1</sup></th><th id="hd_h_pku.T.molecular_genetic_testing_used_in_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Method</th><th id="hd_h_pku.T.molecular_genetic_testing_used_in_1_1_1_3" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Proportion of Probands with Pathogenic Variants <sup>2</sup> Detectable by Method</th></tr></thead><tbody><tr><td headers="hd_h_pku.T.molecular_genetic_testing_used_in_1_1_1_1" rowspan="2" scope="row" colspan="1" style="text-align:left;vertical-align:middle;">
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<i>PAH</i>
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</td><td headers="hd_h_pku.T.molecular_genetic_testing_used_in_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Sequence analysis <sup>3</sup></td><td headers="hd_h_pku.T.molecular_genetic_testing_used_in_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">97%-99%</td></tr><tr><td headers="hd_h_pku.T.molecular_genetic_testing_used_in_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">Gene-targeted deletion/duplication analysis <sup>4</sup></td><td headers="hd_h_pku.T.molecular_genetic_testing_used_in_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><1%-3% <sup>5</sup></td></tr></tbody></table></div><div class="tblwrap-foot"><div><dl class="temp-labeled-list small"><dl class="bkr_refwrap"><dt>1. </dt><dd><div id="pku.TF.1.1"><p class="no_margin">See <a href="/books/NBK1504/?report=reader#pku.molgen.TA">Table A. Genes and Databases</a> for chromosome locus and protein.</p></div></dd></dl><dl class="bkr_refwrap"><dt>2. </dt><dd><div id="pku.TF.1.2"><p class="no_margin">See <a href="#pku.Molecular_Genetics">Molecular Genetics</a> for information on allelic variants detected in this gene.</p></div></dd></dl><dl class="bkr_refwrap"><dt>3. </dt><dd><div id="pku.TF.1.3"><p class="no_margin">Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click <a href="/books/n/gene/app2/?report=reader">here</a>.</p></div></dd></dl><dl class="bkr_refwrap"><dt>4. </dt><dd><div id="pku.TF.1.4"><p class="no_margin">Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.</p></div></dd></dl><dl class="bkr_refwrap"><dt>5. </dt><dd><div id="pku.TF.1.5"><p class="no_margin">This technique has been used to detect abnormal dosage in 20% of uncharacterized PKU alleles [<a class="bibr" href="#pku.REF.gable.2003.379" rid="pku.REF.gable.2003.379">Gable et al 2003</a>] and therefore duplications and deletions may account for up to 3% of pathogenic variants in the Czech population [<a class="bibr" href="#pku.REF.kozak.2006.300" rid="pku.REF.kozak.2006.300">Kozak et al 2006</a>].</p></div></dd></dl></dl></div></div></div></article><article data-type="table-wrap" id="figobpkuTcommonpathogenicchangesinpaha"><div id="pku.T.common_pathogenic_changes_in_pah_a" class="table"><h3><span class="label">Table 2. </span></h3><div class="caption"><p>Common Pathogenic Changes in <i>PAH</i> and Their Responsiveness to Sapropterin</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK1504/table/pku.T.common_pathogenic_changes_in_pah_a/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__pku.T.common_pathogenic_changes_in_pah_a_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_pku.T.common_pathogenic_changes_in_pah_a_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">cDNA</th><th id="hd_h_pku.T.common_pathogenic_changes_in_pah_a_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Protein</th><th id="hd_h_pku.T.common_pathogenic_changes_in_pah_a_1_1_1_3" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Cases in PAHdb</th><th id="hd_h_pku.T.common_pathogenic_changes_in_pah_a_1_1_1_4" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Responsive to Sapropterin</th></tr></thead><tbody><tr><td headers="hd_h_pku.T.common_pathogenic_changes_in_pah_a_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">c.1222C>T</td><td headers="hd_h_pku.T.common_pathogenic_changes_in_pah_a_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">p.Arg408Trp</td><td headers="hd_h_pku.T.common_pathogenic_changes_in_pah_a_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">6.7%</td><td headers="hd_h_pku.T.common_pathogenic_changes_in_pah_a_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><10%</td></tr><tr><td headers="hd_h_pku.T.common_pathogenic_changes_in_pah_a_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">c.1066-11G>A<br />(IVS10-11G>A)</td><td headers="hd_h_pku.T.common_pathogenic_changes_in_pah_a_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td><td headers="hd_h_pku.T.common_pathogenic_changes_in_pah_a_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">5.3%</td><td headers="hd_h_pku.T.common_pathogenic_changes_in_pah_a_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><10%</td></tr><tr><td headers="hd_h_pku.T.common_pathogenic_changes_in_pah_a_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">c.194T>C</td><td headers="hd_h_pku.T.common_pathogenic_changes_in_pah_a_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">p.Ile65Thr</td><td headers="hd_h_pku.T.common_pathogenic_changes_in_pah_a_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">4.1%</td><td headers="hd_h_pku.T.common_pathogenic_changes_in_pah_a_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">89%</td></tr><tr><td headers="hd_h_pku.T.common_pathogenic_changes_in_pah_a_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">c.782G>A</td><td headers="hd_h_pku.T.common_pathogenic_changes_in_pah_a_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">p.Arg261Gln</td><td headers="hd_h_pku.T.common_pathogenic_changes_in_pah_a_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">3.6%</td><td headers="hd_h_pku.T.common_pathogenic_changes_in_pah_a_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">78%</td></tr><tr><td headers="hd_h_pku.T.common_pathogenic_changes_in_pah_a_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">c.842C>T</td><td headers="hd_h_pku.T.common_pathogenic_changes_in_pah_a_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">p.Pro281Leu</td><td headers="hd_h_pku.T.common_pathogenic_changes_in_pah_a_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">2.9%</td><td headers="hd_h_pku.T.common_pathogenic_changes_in_pah_a_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">None [<a class="bibr" href="#pku.REF.leuders.2014.101" rid="pku.REF.leuders.2014.101">Leuders et al 2014</a>, <a href="http://www.biopku.org/home/pah.asp" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">biopku<wbr style="display:inline-block"></wbr>​.org</a>]</td></tr><tr><td headers="hd_h_pku.T.common_pathogenic_changes_in_pah_a_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">c.1315+1G>A<br />(IVS12+1G>A)</td><td headers="hd_h_pku.T.common_pathogenic_changes_in_pah_a_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td><td headers="hd_h_pku.T.common_pathogenic_changes_in_pah_a_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">2.8%</td><td headers="hd_h_pku.T.common_pathogenic_changes_in_pah_a_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">12.5% [<a href="http://www.biopku.org/home/pah.asp" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">biopku<wbr style="display:inline-block"></wbr>​.org</a>]<br />None [<a class="bibr" href="#pku.REF.leuders.2014.101" rid="pku.REF.leuders.2014.101">Leuders et al 2014</a>]</td></tr><tr><td headers="hd_h_pku.T.common_pathogenic_changes_in_pah_a_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">c.473G>A</td><td headers="hd_h_pku.T.common_pathogenic_changes_in_pah_a_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">p.Arg158Gln</td><td headers="hd_h_pku.T.common_pathogenic_changes_in_pah_a_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">2.7%</td><td headers="hd_h_pku.T.common_pathogenic_changes_in_pah_a_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><10%</td></tr></tbody></table></div><div class="tblwrap-foot"><div><dl class="temp-labeled-list small"><dl class="bkr_refwrap"><dt></dt><dd><div><p class="no_margin">Data obtained from: PAHdb accessed 5/8/2016 (<a href="http://www.biopku.org/home/pah.asp" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">biopku<wbr style="display:inline-block"></wbr>​.org</a>); and <a class="bibr" href="#pku.REF.leuders.2014.101" rid="pku.REF.leuders.2014.101">Leuders et al [2014]</a>. All changes with >2.5% frequency in the PAHdb database were included. In database searches, homozygosity was assumed for calculations; however, this is a rare finding in consanguineous individuals. It is recommended that all affected individuals be tested for personal responsiveness. Genetic changes shown affect >2.5% of the database population. See <a href="http://www.biopku.org/home/pah.asp" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">biopku<wbr style="display:inline-block"></wbr>​.org</a> for the most up-to-date information and additional references.</p></div></dd></dl></dl></div></div></div></article><article data-type="table-wrap" id="figobpkuTprevalenceofpahdeficiencybypo"><div id="pku.T.prevalence_of_pah_deficiency_by_po" class="table"><h3><span class="label">Table 3. </span></h3><div class="caption"><p>Prevalence of PAH Deficiency by Population</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK1504/table/pku.T.prevalence_of_pah_deficiency_by_po/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__pku.T.prevalence_of_pah_deficiency_by_po_lrgtbl__"><table><thead><tr><th id="hd_h_pku.T.prevalence_of_pah_deficiency_by_po_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Population</th><th id="hd_h_pku.T.prevalence_of_pah_deficiency_by_po_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">PAH Deficiency in Live Births</th><th id="hd_h_pku.T.prevalence_of_pah_deficiency_by_po_1_1_1_3" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Carrier Rate</th><th id="hd_h_pku.T.prevalence_of_pah_deficiency_by_po_1_1_1_4" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Reference</th></tr></thead><tbody><tr><td headers="hd_h_pku.T.prevalence_of_pah_deficiency_by_po_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Turks</td><td headers="hd_h_pku.T.prevalence_of_pah_deficiency_by_po_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">1:2,600</td><td headers="hd_h_pku.T.prevalence_of_pah_deficiency_by_po_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">1/26</td><td headers="hd_h_pku.T.prevalence_of_pah_deficiency_by_po_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<a class="bibr" href="#pku.REF.ozalp.2001.97" rid="pku.REF.ozalp.2001.97">Ozalp et al [2001]</a>
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</td></tr><tr><td headers="hd_h_pku.T.prevalence_of_pah_deficiency_by_po_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Irish</td><td headers="hd_h_pku.T.prevalence_of_pah_deficiency_by_po_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">1:4,500</td><td headers="hd_h_pku.T.prevalence_of_pah_deficiency_by_po_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">1/33</td><td headers="hd_h_pku.T.prevalence_of_pah_deficiency_by_po_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<a class="bibr" href="#pku.REF.dilella.1986.743" rid="pku.REF.dilella.1986.743">DiLella et al [1986]</a>
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</td></tr><tr><td headers="hd_h_pku.T.prevalence_of_pah_deficiency_by_po_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Northern European origin, East Asian</td><td headers="hd_h_pku.T.prevalence_of_pah_deficiency_by_po_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">1:10,000</td><td headers="hd_h_pku.T.prevalence_of_pah_deficiency_by_po_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">1/50</td><td headers="hd_h_pku.T.prevalence_of_pah_deficiency_by_po_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<a class="bibr" href="#pku.REF.scriver.2001" rid="pku.REF.scriver.2001">Scriver & Kaufman [2001]</a>
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</td></tr><tr><td headers="hd_h_pku.T.prevalence_of_pah_deficiency_by_po_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Japanese</td><td headers="hd_h_pku.T.prevalence_of_pah_deficiency_by_po_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">1:143,000</td><td headers="hd_h_pku.T.prevalence_of_pah_deficiency_by_po_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">1/200</td><td headers="hd_h_pku.T.prevalence_of_pah_deficiency_by_po_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<a class="bibr" href="#pku.REF.aoki.1988.429" rid="pku.REF.aoki.1988.429">Aoki & Wada [1988]</a>
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</td></tr><tr><td headers="hd_h_pku.T.prevalence_of_pah_deficiency_by_po_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Finnish, Ashkenazi Jewish</td><td headers="hd_h_pku.T.prevalence_of_pah_deficiency_by_po_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">1:200,000</td><td headers="hd_h_pku.T.prevalence_of_pah_deficiency_by_po_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">1/225</td><td headers="hd_h_pku.T.prevalence_of_pah_deficiency_by_po_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<a class="bibr" href="#pku.REF.scriver.2001" rid="pku.REF.scriver.2001">Scriver & Kaufman [2001]</a>
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</td></tr></tbody></table></div></div></article><article data-type="table-wrap" id="figobpkumolgenTA"><div id="pku.molgen.TA" class="table"><h3><span class="label">Table A.</span></h3><div class="caption"><p>Phenylalanine Hydroxylase Deficiency: Genes and Databases</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK1504/table/pku.molgen.TA/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__pku.molgen.TA_lrgtbl__"><table class="no_bottom_margin"><tbody><tr><th id="hd_b_pku.molgen.TA_1_1_1_1" rowspan="1" colspan="1" style="vertical-align:top;">Gene</th><th id="hd_b_pku.molgen.TA_1_1_1_2" rowspan="1" colspan="1" style="vertical-align:top;">Chromosome Locus</th><th id="hd_b_pku.molgen.TA_1_1_1_3" rowspan="1" colspan="1" style="vertical-align:top;">Protein</th><th id="hd_b_pku.molgen.TA_1_1_1_4" rowspan="1" colspan="1" style="vertical-align:top;">Locus-Specific Databases</th><th id="hd_b_pku.molgen.TA_1_1_1_5" rowspan="1" colspan="1" style="vertical-align:top;">HGMD</th><th id="hd_b_pku.molgen.TA_1_1_1_6" rowspan="1" colspan="1" style="vertical-align:top;">ClinVar</th></tr><tr><td headers="hd_b_pku.molgen.TA_1_1_1_1" rowspan="1" colspan="1" style="vertical-align:top;">
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<a href="/gene/5053" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=gene">
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<i>PAH</i>
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</a>
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</td><td headers="hd_b_pku.molgen.TA_1_1_1_2" rowspan="1" colspan="1" style="vertical-align:top;">
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<a href="https://www.ncbi.nlm.nih.gov/genome/gdv/?context=gene&acc=5053" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">12q23<wbr style="display:inline-block"></wbr>​.2</a>
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</td><td headers="hd_b_pku.molgen.TA_1_1_1_3" rowspan="1" colspan="1" style="vertical-align:top;">
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<a href="http://www.uniprot.org/uniprot/P00439" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">Phenylalanine-4-hydroxylase</a>
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</td><td headers="hd_b_pku.molgen.TA_1_1_1_4" rowspan="1" colspan="1" style="vertical-align:top;">
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<a href="http://databases.lovd.nl/shared/genes/PAH" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">PAH database</a>
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<br />
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<a href="http://www.biopku.org/home/pah.asp" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">Phenylalanine Hydroxylase Gene Locus-Specific Database - PAHvdb</a>
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</td><td headers="hd_b_pku.molgen.TA_1_1_1_5" rowspan="1" colspan="1" style="vertical-align:top;">
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<a href="http://www.hgmd.cf.ac.uk/ac/gene.php?gene=PAH" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">PAH</a>
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</td><td headers="hd_b_pku.molgen.TA_1_1_1_6" rowspan="1" colspan="1" style="vertical-align:top;">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar/?term=PAH[gene]" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">PAH</a>
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</td></tr></tbody></table></div><div class="tblwrap-foot"><div><dl class="temp-labeled-list small"><dl class="bkr_refwrap"><dt></dt><dd><div id="pku.TFA.1"><p class="no_margin">Data are compiled from the following standard references: gene from
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<a href="http://www.genenames.org/index.html" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">HGNC</a>;
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chromosome locus from
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<a href="http://www.omim.org/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">OMIM</a>;
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protein from <a href="http://www.uniprot.org/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">UniProt</a>.
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For a description of databases (Locus Specific, HGMD, ClinVar) to which links are provided, click
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<a href="/books/n/gene/app1/?report=reader">here</a>.</p></div></dd></dl></dl></div></div></div></article><article data-type="table-wrap" id="figobpkumolgenTB"><div id="pku.molgen.TB" class="table"><h3><span class="label">Table B.</span></h3><div class="caption"><p>OMIM Entries for Phenylalanine Hydroxylase Deficiency (<a href="/omim/261600,612349" 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/NBK1504/table/pku.molgen.TB/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__pku.molgen.TB_lrgtbl__"><table><tbody><tr><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
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<a href="/omim/261600" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=omim">261600</a></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">PHENYLKETONURIA; PKU</td></tr><tr><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
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<a href="/omim/612349" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=omim">612349</a></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">PHENYLALANINE HYDROXYLASE; PAH</td></tr></tbody></table></div></div></article><article data-type="table-wrap" id="figobpkuTpahvariantsdiscussedinthisgen"><div id="pku.T.pah_variants_discussed_in_this_gen" class="table"><h3><span class="label">Table 4. </span></h3><div class="caption"><p><i>PAH</i> Variants Discussed in This <i>GeneReview</i></p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK1504/table/pku.T.pah_variants_discussed_in_this_gen/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__pku.T.pah_variants_discussed_in_this_gen_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_pku.T.pah_variants_discussed_in_this_gen_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">DNA Nucleotide Change<br />(Alias) <sup>1</sup></th><th id="hd_h_pku.T.pah_variants_discussed_in_this_gen_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_pku.T.pah_variants_discussed_in_this_gen_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_pku.T.pah_variants_discussed_in_this_gen_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">c.194T>C</td><td headers="hd_h_pku.T.pah_variants_discussed_in_this_gen_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">p.Ile65Thr</td><td headers="hd_h_pku.T.pah_variants_discussed_in_this_gen_1_1_1_3" rowspan="7" colspan="1" style="text-align:left;vertical-align:middle;">
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<a href="https://www.ncbi.nlm.nih.gov/nuccore/NM_000277.1" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">NM_000277<wbr style="display:inline-block"></wbr>​.1</a>
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<br />
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<a href="https://www.ncbi.nlm.nih.gov/protein/NP_000268.1" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">NP_000268<wbr style="display:inline-block"></wbr>​.1</a>
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</td></tr><tr><td headers="hd_h_pku.T.pah_variants_discussed_in_this_gen_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">c.473G>A</td><td headers="hd_h_pku.T.pah_variants_discussed_in_this_gen_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">p.Arg158Gln</td></tr><tr><td headers="hd_h_pku.T.pah_variants_discussed_in_this_gen_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">c.782G>A</td><td headers="hd_h_pku.T.pah_variants_discussed_in_this_gen_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">p.Arg261Gln</td></tr><tr><td headers="hd_h_pku.T.pah_variants_discussed_in_this_gen_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">c.842C>T</td><td headers="hd_h_pku.T.pah_variants_discussed_in_this_gen_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">p.Pro281Leu</td></tr><tr><td headers="hd_h_pku.T.pah_variants_discussed_in_this_gen_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">c.1066-11G>A<br />(IVS10-11G>A)</td><td headers="hd_h_pku.T.pah_variants_discussed_in_this_gen_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr><tr><td headers="hd_h_pku.T.pah_variants_discussed_in_this_gen_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">c.1222C>T</td><td headers="hd_h_pku.T.pah_variants_discussed_in_this_gen_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">p.Arg408Trp</td></tr><tr><td headers="hd_h_pku.T.pah_variants_discussed_in_this_gen_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">c.1315+1G>A<br />(IVS12+1G>A)</td><td headers="hd_h_pku.T.pah_variants_discussed_in_this_gen_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr></tbody></table></div><div class="tblwrap-foot"><div><dl class="temp-labeled-list small"><dl class="bkr_refwrap"><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></dl><dl class="bkr_refwrap"><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/?report=reader">Quick Reference</a> for an explanation of nomenclature.</p></div></dd></dl><dl class="bkr_refwrap"><dt></dt><dd><div><p class="no_margin">See <a href="http://www.biopku.org/home/pah.asp" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">biopku<wbr style="display:inline-block"></wbr>​.org</a> for gene lists and databases.</p></div></dd></dl><dl class="bkr_refwrap"><dt>1. </dt><dd><div id="pku.TF.4.1"><p class="no_margin">Variant designation that does not conform to current naming conventions</p></div></dd></dl></dl></div></div></div></article></div><div id="jr-scripts"><script src="/corehtml/pmc/jatsreader/ptpmc_3.22/js/libs.min.js"> </script><script src="/corehtml/pmc/jatsreader/ptpmc_3.22/js/jr.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></div></div>
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