{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T08:18:46Z","timestamp":1790065126052,"version":"4.0.1"},"reference-count":16,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2019,10,25]],"date-time":"2019-10-25T00:00:00Z","timestamp":1571961600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Nutrients"],"abstract":"<jats:p>Phenylketonuria (PKU) management is aimed at preventing neurocognitive and psychosocial dysfunction by keeping plasma phenylalanine concentrations within the recommended target range. It can be questioned, however, whether universal plasma phenylalanine target levels would result in optimal neurocognitive outcomes for all patients, as similar plasma phenylalanine concentrations do not seem to have the same consequences to the brain for each PKU individual. To better understand the inter-individual differences in brain vulnerability to high plasma phenylalanine concentrations, we aimed to identify untreated and\/or late-diagnosed PKU patients with near-normal outcome, despite high plasma phenylalanine concentrations, who are still alive. In total, we identified 16 such cases. While intellectual functioning in these patients was relatively unaffected, they often did present other neurological, psychological, and behavioral problems. Thereby, these \u201cunusual\u201d PKU patients show that the classical symptomatology of untreated or late-treated PKU may have to be rewritten. Moreover, these cases show that a lack of intellectual dysfunction despite high plasma phenylalanine concentrations does not necessarily imply that these high phenylalanine concentrations have not been toxic to the brain. Also, these cases may suggest that different mechanisms are involved in PKU pathophysiology, of which the relative importance seems to differ between patients and possibly also with increasing age. Further research should aim to better distinguish PKU patients with respect to their cerebral effects to high plasma phenylalanine concentrations.<\/jats:p>","DOI":"10.3390\/nu11112572","type":"journal-article","created":{"date-parts":[[2019,10,25]],"date-time":"2019-10-25T04:41:27Z","timestamp":1571978487000},"page":"2572","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":32,"title":["Untreated PKU Patients without Intellectual Disability: What Do They Teach Us?"],"prefix":"10.3390","volume":"11","author":[{"given":"Danique","family":"van Vliet","sequence":"first","affiliation":[{"name":"University of Groningen, University Medical Center Groningen, Beatrix Children\u2019s Hospital, 9700 RB Groningen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9402-4833","authenticated-orcid":false,"given":"Annemiek M.J.","family":"van Wegberg","sequence":"additional","affiliation":[{"name":"University of Groningen, University Medical Center Groningen, Beatrix Children\u2019s Hospital, 9700 RB Groningen, The Netherlands"},{"name":"Department of Gastroenterology, Radboud University Medical Center, 6500 HB Nijmegen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kirsten","family":"Ahring","sequence":"additional","affiliation":[{"name":"Department of PKU, Kennedy Center, Copenhagen University Hospital, DK-2600 Glostrup, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1542-7050","authenticated-orcid":false,"given":"Miroslaw","family":"Bik-Multanowski","sequence":"additional","affiliation":[{"name":"University Children\u2019s Hospital, Jagiellonian University, 30-663 Krakow, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kari","family":"Casas","sequence":"additional","affiliation":[{"name":"Medical Genetics, Sanford Health, Fargo, ND 58102, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bozena","family":"Didycz","sequence":"additional","affiliation":[{"name":"University Children\u2019s Hospital, Jagiellonian University, 30-663 Krakow, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maja","family":"Djordjevic","sequence":"additional","affiliation":[{"name":"Mother and Child Health Care Institute of Serbia Dr Vukan Cupic, School of Medicine, University of Belgrade, 11070 Belgrade, Serbia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jozef L.","family":"Hertecant","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Tawam Hospital, 15258 Al-Ain, UAE"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vincenzo","family":"Leuzzi","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Child Neurology and Psychiatry, Sapienza University of Rome, 00185 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Per","family":"Mathisen","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Oslo University Hospital, 0318 Oslo, Norway"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesca","family":"Nardecchia","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Child Neurology and Psychiatry, Sapienza University of Rome, 00185 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kimberly K.","family":"Powell","sequence":"additional","affiliation":[{"name":"Department of Genetics and Metabolism, Chapel Hill hospital, University of North Carolina, Chapel Hill, NC 27599-7487, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Frank","family":"Rutsch","sequence":"additional","affiliation":[{"name":"Department of General Pediatrics, Muenster University Children\u2019s Hospital, 48149 Muenster, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maja","family":"Stojiljkovic","sequence":"additional","affiliation":[{"name":"Institute of Molecular Genetics and Genetic Engineering, University of Belgrade, 11000 Belgrade, Serbia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fritz K.","family":"Trefz","sequence":"additional","affiliation":[{"name":"Dietmar-Hopp Metabolic Center, University Children\u2019s Hospital, 69120 Heidelberg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Natalia","family":"Usurelu","sequence":"additional","affiliation":[{"name":"Institute of Mother and Child, Centre of Reproductive Health and Medical Genetics, MD-2060 Chisinau, Moldova"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Callum","family":"Wilson","sequence":"additional","affiliation":[{"name":"Newborn Metabolic Screening Unit, LabPlus, Auckland City Hospital, Auckland 1142, New Zealand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Clara D.","family":"van Karnebeek","sequence":"additional","affiliation":[{"name":"Departments of Pediatrics and Clinical Genetics, Emma Children\u2019s Hospital, Academic Medical Centre, 1105 AZ Amsterdam, The Netherlands"},{"name":"Department of Pediatrics, Centre for Molecular Medicine, and Department of Pediatrics, Radboud University Medical Centre, 6525 XZ Nijmegen, The Netherlands"},{"name":"Therapeutics, University of British Columbia, Vancouver, BC V5Z 4H4, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"William B.","family":"Hanley","sequence":"additional","affiliation":[{"name":"Clinical and Biochemical Genetics, Department of Pediatrics, The Hospital for Sick Children and the University of Toronto, Toronto, ON M5G 1X8, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francjan J.","family":"van Spronsen","sequence":"additional","affiliation":[{"name":"University of Groningen, University Medical Center Groningen, Beatrix Children\u2019s Hospital, 9700 RB Groningen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2019,10,25]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"743","DOI":"10.1016\/S2213-8587(16)30320-5","article-title":"Key European Guidelines for the Diagnosis and Management of Patients with Phenylketonuria","volume":"5","author":"Ahring","year":"2017","journal-title":"Lancet Diabetes Endocrinol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"162","DOI":"10.1186\/s13023-017-0685-2","article-title":"The Complete European Guidelines on Phenylketonuria: Diagnosis and Treatment","volume":"12","author":"MacDonald","year":"2017","journal-title":"Orphanet J. 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