{"id":210,"date":"2023-01-11T05:07:15","date_gmt":"2023-01-11T05:07:15","guid":{"rendered":"https:\/\/pkudsehcp-dev-001.azurewebsites.net\/en-us\/phenylketonuria\/?page_id=210"},"modified":"2024-07-22T14:02:12","modified_gmt":"2024-07-22T14:02:12","slug":"genetics-and-pathophysiology","status":"publish","type":"page","link":"https:\/\/hcp.biomarin.com\/en-us\/pku\/overview\/genetics-and-pathophysiology\/","title":{"rendered":"Genetics and Pathophysiology"},"content":{"rendered":"<div id=\"acf-block-63f5bff5e4f75\" class=\"hero hero-no-overlay\">\n            <div class=\"hero-background-image hero-background-image-desktop\" style=\"background-image: url(https:\/\/hcp.biomarin.com\/en-us\/pku\/wp-content\/uploads\/sites\/2\/2023\/06\/new-pku-internal-hero-2.jpg?v=0.85);\"><\/div>\n\t    <div class=\"hero-background-image hero-background-image-mobile\" style=\"background-image: url(https:\/\/hcp.biomarin.com\/en-us\/pku\/wp-content\/uploads\/sites\/2\/2023\/03\/hero-815x800.jpg);\"><\/div>\n    \t<div class=\"overlay\"><\/div>\n\t<div class=\"wrapper\">\n\t\t<div class=\"inner-wrapper\">\n\t\t\t<div class=\"hero-content\">\n\t\t\t    \t\t\t        <ul class=\"breadcrumb\">\n\t\t\t            \t\t\t                                                                        <li><a href=\"https:\/\/hcp.biomarin.com\/en-us\/pku\/overview\/\">What is PKU?<\/a><\/li>\n                            \t\t\t                                                                        <li>Genetics and Pathophysiology<\/li>\n                            \t\t\t            \t\t\t        <\/ul>\n\t\t\t    \t\t\t\t\t\t\t\t\t\t\t\t    <h1>PKU: a rare, autosomal recessive disorder<sup>1,2<\/sup>\n<\/h1>\n\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t<\/div>\n\t\t<\/div>\n\t<\/div>\n<\/div>\n\n\n<div id=\"acf-block-63f5bff5e6d1b\" class=\"block split-content bg-band bg-band-alternative block-zero-top block-zero-bottom\" data-muted-autoplay=\"false\">\n\t<div class=\"wrapper\">\n\t\t<div class=\"inner-wrapper\">\n\t\t                                                                <div class=\"content-block\">\n                                                                                                <h2>Genetics of PKU<\/h2>\n<ul>\n<li>Most cases (~98%) of phenylketonuria (PKU) are caused by variants in the gene encoding the phenylalanine hydroxylase (PAH) enzyme resulting in low enzymatic activity<sup>3,4<\/sup><\/li>\n<li>PAH is expressed mainly in the liver<sup>3<\/sup><\/li>\n<li>PAH defects can range from mild folding defects in the protein to absence or deficiency of PAH expression<sup>2<\/sup><\/li>\n<li>PAH deficiency presents a spectrum of severity. Most severe are individuals with complete enzyme deficiency, or classical PKU (blood phenylalanine (Phe) levels &gt;1200 \u03bcmol\/L)<sup>2<\/sup><\/li>\n<li>As PAH catalyzes the hydroxylation of Phe to tyrosine (Tyr), PAH deficiency impairs the conversion of Phe to Tyr. This causes the amino acid Phe to build up in the blood and brain leading to a range of intellectual disabilities, as well as neurological, neuropsychiatric, and psychosocial consequences<sup>3<\/sup><\/li>\n<li>PKU is inherited as an autosomal recessive condition. Those who have only 1 PAH mutation (eg, parents of a child with phenylketonuria) are carriers and have none of the biochemical or clinical characteristics of PKU<sup>3<\/sup><\/li>\n<\/ul>\n                                                                                    <\/div>\n                    \n                                            <div class=\"content-block\">\n                                                                                                <h3 style=\"text-align: center\"><strong>Phe metabolism<sup>3<\/sup><\/strong><\/h3>\n                                                                                                                                                                                                                                                                                                                    \n                                                                                                                \n                                                                                                                \n                                    \n                                    <figure>\n                                        <div class=\"image image-responsive image-rounded\">\n                                                                                            <div class=\"image-desktop\">\n                                                    <img decoding=\"async\" class=\"\" src=\"https:\/\/hcp.biomarin.com\/en-us\/pku\/wp-content\/uploads\/sites\/2\/2024\/02\/1.2_PHE-Metabolism-DESKTOP-1900x1764.png\" alt=\"Information Graphic\" \/>                                                <\/div>\n                                                <div class=\"image-mobile\">\n                                                    <img decoding=\"async\" class=\"\" src=\"https:\/\/hcp.biomarin.com\/en-us\/pku\/wp-content\/uploads\/sites\/2\/2024\/02\/1.2_PHE-Metabolism-MOBILE.png?v=0.85\" alt=\"Information graphic\" \/>                                                <\/div>\n                                                                                    <\/div>\n                                                                            <\/figure>\n                                                                                    <\/div>\n                                                \t\t<\/div>\n\t<\/div>\n<\/div>\n\n<div id=\"acf-block-63f5bff5e6d62\" class=\"block wrapped-content bg-band bg-band-white block-zero-top block-zero-bottom\">\n    <div class=\"wrapper\">\n        <div class=\"inner-wrapper\">\n                \n<div id=\"acf-block-63f5bff5e6d7a\" class=\"block-wysiwyg\">\n            <h2>High and\/or variable Phe levels can have neurotoxic effects on the brain<sup>5<\/sup><\/h2>\n<p>&nbsp;<\/p>\n<h3 style=\"text-align: center\"><strong>Blood-brain barrier physiology<sup>5,6<\/sup><\/strong><\/h3>\n    <\/div>\n\n<figure id=\"acf-block-63f5bff5e6d91\">\n    <div class=\"image image-responsive image-rounded\">\n                    <div class=\"image-desktop\">\n\t\t\t    <img decoding=\"async\" class=\"\" src=\"https:\/\/hcp.biomarin.com\/en-us\/pku\/wp-content\/uploads\/sites\/2\/2024\/07\/PKU_DSE_Website_infographix_V7_1.2_Blood-Brain-Physiology_Dsktp-1900x883.jpg\" alt=\"\" \/>\t\t\t<\/div>\n\t\t\t<div class=\"image-mobile\">\n\t\t\t    <img decoding=\"async\" class=\"\" src=\"https:\/\/hcp.biomarin.com\/en-us\/pku\/wp-content\/uploads\/sites\/2\/2024\/07\/PKU_DSE_Website_infographix_V7_1.2_Blood-Brain-Physiology_Mbl-scaled.jpg?v=0.85\" alt=\"\" \/>\t\t\t<\/div>\n            <\/div>\n            <figcaption><p><small>Adapted from van Spronsen et al. <em>Nat Rev Dis Primers.<\/em> 2021<\/small><\/p>\n<\/figcaption>\n    <\/figure>\n        <\/div>\n    <\/div>\n<\/div>\n\n<div id=\"acf-block-63f5bff5e6da3\" class=\"block wrapped-content bg-band bg-band-alternative block-zero-top block-zero-bottom\">\n    <div class=\"wrapper\">\n        <div class=\"inner-wrapper\">\n                \n<div id=\"acf-block-63f5bff5e6db3\" class=\"block-wysiwyg\">\n            <h2>Elevated Phe in the brain affects normal white matter morphology and impairs neurotransmitter synthesis<sup>7<\/sup><\/h2>\n    <\/div>\n\n<figure id=\"acf-block-63f5bff5e6dc6\">\n    <div class=\"image image-rounded\">\n                    <img decoding=\"async\" class=\"\" src=\"https:\/\/hcp.biomarin.com\/en-us\/pku\/wp-content\/uploads\/sites\/2\/2024\/07\/brain-infographic_6.svg\" alt=\"\" \/>            <\/div>\n    <\/figure>\n        <\/div>\n    <\/div>\n<\/div>\n\n<div id=\"acf-block-63f5bff5e6dd7\" class=\"block wrapped-content block-tight-top block-zero-bottom\">\n    <div class=\"wrapper\">\n        <div class=\"inner-wrapper\">\n                \n<div id=\"acf-block-63f5bff5e6de8\" class=\"block-wysiwyg\">\n            <h2>Learn more about PKU<\/h2>\n    <\/div>\n        <\/div>\n    <\/div>\n<\/div>\n\n<div id=\"acf-block-65f08945ed441\" class=\"block call-to-action call-to-action-no-overlay\">\n    <div class=\"wrapper\">\n\t\t<div class=\"inner-wrapper\">\n\t\t\t<div class=\"box\" style=\"background-image: url(https:\/\/hcp.biomarin.com\/en-us\/pku\/wp-content\/uploads\/sites\/2\/2024\/03\/Screenshot-2024-03-12-at-16.59.18.png?v=0.85);\">\n\t\t\t\t<div class=\"overlay\"><\/div>\n\t\t\t\t<div class=\"cta-content\">\n\t\t\t\t                            <div class=\"cta-image\">\n                            <img decoding=\"async\" class=\"\" src=\"https:\/\/hcp.biomarin.com\/en-us\/pku\/wp-content\/uploads\/sites\/2\/2024\/02\/2.1_depression-Icon-card-ow.svg\" alt=\"\" \/>                        <\/div>\n                    \t\t\t\t\t<div class=\"cta-content-main\">\n                        <div class=\"content-block\">\n\t\t\t\t\t        \t\t\t\t\t        \t\t\t\t\t\t        <h2 class=\"h3\">The burden of PKU impacts daily life.<sup>1<\/sup>\n<\/h2>\n\t\t\t\t\t\t    \t\t\t\t\t\t    \t\t\t\t\t    <\/div>\n\t\t\t\t\t                                <div class=\"content-block\">\n                                <p><a class=\"button button-arrow\" href=\"https:\/\/hcp.biomarin.com\/en-us\/pku\/patient-stories\/\" target=\"_self\">Learn how<\/a><\/p>\n                            <\/div>\n\t\t\t\t\t                        <\/div>\n\t\t\t\t<\/div>\n\t\t\t<\/div>\n\t\t<\/div>\n\t<\/div>\n<\/div>\n\n<div id=\"acf-block-63f5bff5e6dd7\" class=\"block wrapped-content block-tight-top block-tight-bottom\">\n    <div class=\"wrapper\">\n        <div class=\"inner-wrapper\">\n                \n<div id=\"acf-block-63f5bff5e6de8\" class=\"block-wysiwyg\">\n            <p><small><strong>References: 1.<\/strong> Ashe K, Kelso W, Farrand S, et al. Psychiatric and cognitive aspects of phenylketonuria: the limitations of diet and promise of new treatments. Front Psychiatry. 2019;10:561. doi:10.3389\/fpsyt.2019.00561. <strong>2.<\/strong> Vockley J, Andersson HC, Antshel KM, et al. American College of Medical Genetics and Genomics Therapeutic Committee. Phenylalanine hydroxylase deficiency: diagnosis and management guidelines. <em>Genet Med<\/em>. 2014;16(2):188-200. <strong>3.<\/strong> Blau N, van Spronsen FJ, Levy HL. Phenylketonuria. <em>Lancet<\/em>. 2010;376(9750):1417-1427. <strong>4.<\/strong> Rocha JC, MacDonald A. Treatment options and dietary supplements for patients with phenylketonuria.<em> Expert Opin Orphan Drugs<\/em>. 2018;6(11):667-681. <strong>5.<\/strong> van Wegberg AMJ, MacDonald A, Ahring K, et al. The complete European guidelines of phenylketonuria: diagnosis and treatment. <em>Orphanet J Rare Dis<\/em>. 2017;12(1):162. doi:10.1186\/s13023-017-0685-2. <strong>6.<\/strong>\u00a0van Spronsen FJ, Blau N, Harding C, et al. Phenylketonuria. <em>Nat Rev Dis Primers<\/em>. 2021;7(1):36. doi:10.1038\/s41572-021-00267-0. <strong>7<\/strong><strong>.<\/strong> Anderson PJ, Leuzzi V. White matter pathology in phenylketonuria. Mol Genet Metab. 2010;99(suppl 1):S3-S9. <strong>8. <\/strong>Christ SE, Price MH, Bodner KE, Saville C, Moffitt AJ, Peck D. Morphometric analysis of gray matter integrity in individuals with early-treated phenylketonuria. <em>Mol Genet Metab<\/em>. 2016;118(1):3-8. <strong>9.<\/strong> White DA, Antenor-Dorsey JV, Grange DK, et al. White matter integrity and executive abilities following treatment with tetrahydrobiopterin (BH4) in individuals with phenylketonuria. <em>Mol Genet Metab<\/em>. 2013;110(3):213\u2013217. <strong>10.<\/strong> Schuck PF, Malgarin F, Cararo JH, Cardoso F, Streck EL, Ferreira GC. Phenylketonuria pathophysiology: on the role of metabolic alterations. Aging Dis. 2016;6(5):390-399. <strong>11.<\/strong> Adler-Abramovich L, Vaks L, Carny O, et al. Phenylalanine assembly into toxic fibrils suggest amyloid etiology in phenylketonuria. <em>Nat Chem Biol<\/em>. 2012;8(8):701-706.<\/small><\/p>\n    <\/div>\n        <\/div>\n    <\/div>\n<\/div>","protected":false},"excerpt":{"rendered":"","protected":false},"author":3,"featured_media":0,"parent":205,"menu_order":0,"comment_status":"closed","ping_status":"closed","template":"","meta":{"_acf_changed":false,"inline_featured_image":false,"footnotes":""},"acf":[],"yoast_head":"<!-- This site is optimized with the Yoast SEO plugin v23.1 - https:\/\/yoast.com\/wordpress\/plugins\/seo\/ -->\n<title>Genetics and pathophysiology of phenylketonuria (PKU)<\/title>\n<meta name=\"description\" content=\"Phenylketonuria (PKU): an autosomal recessive inborn error of phenylalanine (Phe) metabolism caused by variants in gene encoding.\" \/>\n<meta name=\"robots\" content=\"index, follow, max-snippet:-1, max-image-preview:large, max-video-preview:-1\" \/>\n<link rel=\"canonical\" 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