[{"data":1,"prerenderedAt":-1},["ShallowReactive",2],{"detail-sidebar-cat-0-en-105":3,"doc-seo-466694-105":59,"doc-detail-466694-en":131},{"code":4,"msg":5,"data":6},0,"success",[7,13,18,23,28,33,38,43,48,51,55],{"id":8,"doc_module":4,"doc_module_name":9,"category_name":10,"show_sort_weight":11,"slug":12},1,"Document","Story & Novel",90,"story-novel",{"id":14,"doc_module":4,"doc_module_name":9,"category_name":15,"show_sort_weight":16,"slug":17},2,"Literature",80,"literature",{"id":19,"doc_module":4,"doc_module_name":9,"category_name":20,"show_sort_weight":21,"slug":22},4,"Exam",70,"exam",{"id":24,"doc_module":4,"doc_module_name":9,"category_name":25,"show_sort_weight":26,"slug":27},5,"Comic",60,"comic",{"id":29,"doc_module":4,"doc_module_name":9,"category_name":30,"show_sort_weight":31,"slug":32},6,"Technology",50,"technology",{"id":34,"doc_module":4,"doc_module_name":9,"category_name":35,"show_sort_weight":36,"slug":37},7,"Healthcare",40,"healthcare",{"id":39,"doc_module":4,"doc_module_name":9,"category_name":40,"show_sort_weight":41,"slug":42},8,"Research & Report",30,"research-report",{"id":44,"doc_module":4,"doc_module_name":9,"category_name":45,"show_sort_weight":46,"slug":47},9,"Religion & Spirituality",20,"religion-spirituality",{"id":46,"doc_module":4,"doc_module_name":9,"category_name":49,"show_sort_weight":46,"slug":50},"World Cup","world-cup",{"id":52,"doc_module":4,"doc_module_name":9,"category_name":53,"show_sort_weight":52,"slug":54},10,"Lifestyle","lifestyle",{"id":56,"doc_module":4,"doc_module_name":9,"category_name":57,"show_sort_weight":24,"slug":58},19,"General","general",{"code":4,"msg":60,"data":61},"ok",{"site_id":62,"language":63,"slug":64,"title":65,"keywords":66,"description":67,"schema_data":68,"social_meta":124,"head_meta":126,"extra_data":128,"updated_unix":130},105,"en","cognitive-functioning-in-phenylketonuria-a-lifespan-perspective","Cognitive Functioning in Phenylketonuria - A Lifespan Perspective","","Phenylketonuria (PKU) is a hereditary metabolic disorder marked by impaired phenylalanine metabolism, causing neurotoxic phenylalanine accumulation and measurable cognitive impairment. Research has largely emphasized cognition from middle childhood to early adulthood, while very young and older PKU patients remain understudied. This review argues for targeted research in these age ranges due to early cognitive development’s long-term impact and the potential role of PKU and metabolic control in later cognitive decline.",{"@graph":69,"@context":123},[70,84,106],{"@type":71,"itemListElement":72},"BreadcrumbList",[73,77,79,82],{"item":74,"name":75,"@type":76,"position":8},"https://docshare.wps.com","Home","ListItem",{"item":78,"name":9,"@type":76,"position":14},"https://docshare.wps.com/document/",{"item":80,"name":35,"@type":76,"position":81},"https://docshare.wps.com/document/healthcare/",3,{"item":83,"name":65,"@type":76,"position":19},"https://docshare.wps.com/document/cognitive-functioning-in-phenylketonuria-a-lifespan-perspective/466694/",{"url":83,"name":65,"@type":85,"image":86,"author":91,"headline":65,"publisher":94,"fileFormat":97,"inLanguage":63,"description":67,"dateModified":98,"datePublished":99,"encodingFormat":97,"isAccessibleForFree":100,"interactionStatistic":101},"DigitalDocument",{"url":87,"@type":88,"width":89,"height":90},"https://docshare.wps.com/thumbnails/cognitive-functioning-in-phenylketonuria-a-lifespan-perspective/466694.png","ImageObject",300,407,{"name":92,"@type":93},"Mimi","Person",{"url":74,"name":95,"@type":96},"DocShare","Organization","application/pdf","2026-11-04","2026-09-30",true,{"@type":102,"interactionType":103,"userInteractionCount":105},"InteractionCounter",{"@type":104},"ViewAction",12,{"@type":107,"mainEntity":108},"FAQPage",[109,115,119],{"name":110,"@type":111,"acceptedAnswer":112},"What is the core cause of cognitive impairment in phenylketonuria (PKU)?","Question",{"text":113,"@type":114},"PKU results from inability to metabolize phenylalanine, leading to neurotoxic phenylalanine accumulation in the body and brain. This accumulation is linked to cognitive impairment and behavioral problems.","Answer",{"name":116,"@type":111,"acceptedAnswer":117},"Why does the review emphasize very young and older PKU patients?",{"text":118,"@type":114},"Most research has focused on middle childhood, adolescence, and early adulthood, creating a gap for very young and aging patients. The review highlights the importance of early cognitive development and the concern that cognitive decline may be accelerated in older PKU patients.",{"name":120,"@type":111,"acceptedAnswer":121},"Which cognitive domains show prominent deficits in PKU?",{"text":122,"@type":114},"Studies report deficits across multiple domains, with the most prominent findings in executive functioning and sustained attention. Executive functioning includes working memory, cognitive flexibility, and inhibitory control.","https://schema.org",{"og:url":83,"og:type":125,"og:title":65,"og:site_name":95,"og:description":67},"article",{"robots":127,"canonical":83},"index,follow",{"doc_id":129,"site_id":62},466694,1791033931,{"code":4,"msg":5,"data":132},{"doc_id":129,"user_id":133,"nickname":92,"user_avatar":134,"doc_module":4,"category_id":34,"category_name":35,"doc_title":65,"doc_description":67,"doc_content":135,"file_id":136,"file_url":137,"file_type":138,"file_size":139,"view_count":105,"is_deleted":4,"is_public":8,"is_downloadable":8,"audit_status":8,"page_count":140,"language":141,"language_code":63,"site_id":62,"html_lang":63,"table_of_contents":142,"faqs":143,"seo_title":144,"seo_description":67,"update_tm":145,"read_time":146,"preview_page_count":4},2336477974920,"https://ap-avatar.wpscdn.com/davatar_155a257f0dc6eb9ab79c44ca47cae57d","Review  \nCognitive Functioning in Phenylketonuria: A Lifespan Perspective  \nStephan Huijbregts 1, * and Cristina Romani 2  \nAcademic Editor: Jae Hee Kang  \nReceived: 18 November 2025  \nRevised: 19 December 2025  \nAccepted: 28 December 2025  \nPublished: 1 January 2026  \nCopyright: © 2026 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license.  \n1 Education and Child Studies, Leiden Institute for Brain and Cognition, Leiden University, 2333 AK Leiden, The Netherlands  \n2 School of Psychology, College of Health and Life Sciences, Aston University, Birmingham B4 7ET, UK; [c.romani@aston.ac.uk](c.romani@aston.ac.uk)  \n* Correspondence: [shuijbregts@fsw.leidenuniv.nl](shuijbregts@fsw.leidenuniv.nl)  \nAbstract  \nPhenylketonuria (PKU) is a hereditary metabolic disorder characterized by the inability to metabolize phenylalanine, leading to neurotoxic accumulation of phenylalanine and significant cognitive impairment. While extensive research has focused on the cognitive outcomes in middle childhood, adolescence, and early adulthood, there is a notable paucity of studies addressing the cognitive functioning of very young and older PKU patients. This review underscores the necessity for further research in these populations, particularly because of the importance of early cognitive development for later cognitive and behavioral functioning and because of the potential implications of PKU and metabolic control forage-related cognitive decline.  \nKeywords: phenylketonuria; cognition; executive functioning; early childhood; aging; biomarkers; neurodevelopmental disorders; neurodegenerative diseases  \n1. Introduction  \nPhenylketonuria (PKU; OMIM \\#261600) is a genetic disorder resulting from a deficiency in phenylalanine hydroxylase, leading to elevated levels of phenylalanine in the blood. Early diagnosis and dietary management are crucial in preventing intellectual disability and other behavioral deficits. Whereas those risks are significantly reduced after early and continuous dietary treatment, many studies have shown persisting deficits in specific cognitive and behavioral domains [1–9] . Associations between the level of impairment and Phenylalanine (Phe) levels have also been demonstrated regularly. Accumulation of Phe in the blood and (subsequently) the brain may lead to cognitive impairment and behavioral problems in different ways, with most evidence present for pathways leading to neurotransmitter deficiencies and myelin damage [10–14] . Not many PKU patients over the age of 50, who have been treated early (from birth onwards) and continuously, can at present be found because the introduction of Newborn Screening (NBS), detecting PKU, only took place from the 1970s in most countries. Therefore, there is a fear, supported by preliminary evidence, that cognitive impairments will be exacerbated in older patients: the cognitive decline associated with general aging might be accelerated in PKU patients [15,16] . This fear is mainly based on the overlap in aspects of pathophysiology involved in PKU and dementia-related conditions such as Alzheimer’s Disease (AD) and Parkinson’s Disease (PD) . Looking at the other end of the age spectrum, it is well-known that building blocks of cognitive functions already develop during infancy and early childhood (roughly between ages 0 and 7 years), and that early development largely shapes further cognitive development [17–20] . Therefore, this is another life stage that needs much more attention in PKU  \nresearch. Another important reason for zooming in on early cognitive development, especially in PKU, is the ongoing discussion on (strictness of) dietary and subsequent metabolic control in different stages of life [21–23] . There are some studies in children with PKU showing a direct impact of changing Phe levels (through dietary interventions) on cognitive and behaviora","cbCaieCqbEuomaWK","https://ap.wps.com/l/cbCaieCqbEuomaWK","pdf",380494,23,"English","# Introduction\n## Cognitive risks and lifelong cognitive development\n## Dietary/metabolic control and cognitive outcomes\n# Cognitive Functioning in PKU\n## Assessment approaches across age groups\n## Executive functioning and sustained attention deficits","[{\"question\":\"What is the core cause of cognitive impairment in phenylketonuria (PKU)?\",\"answer\":\"PKU results from inability to metabolize phenylalanine, leading to neurotoxic phenylalanine accumulation in the body and brain. This accumulation is linked to cognitive impairment and behavioral problems.\"},{\"question\":\"Why does the review emphasize very young and older PKU patients?\",\"answer\":\"Most research has focused on middle childhood, adolescence, and early adulthood, creating a gap for very young and aging patients. The review highlights the importance of early cognitive development and the concern that cognitive decline may be accelerated in older PKU patients.\"},{\"question\":\"Which cognitive domains show prominent deficits in PKU?\",\"answer\":\"Studies report deficits across multiple domains, with the most prominent findings in executive functioning and sustained attention. Executive functioning includes working memory, cognitive flexibility, and inhibitory control.\"}]","Cognitive Functioning in Phenylketonuria - A Lifespan Perspective | PDF",1790771693,58]