{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,9]],"date-time":"2026-10-09T23:19:33Z","timestamp":1791587973901,"version":"4.3.4"},"reference-count":43,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2026,5,13]],"date-time":"2026-05-13T00:00:00Z","timestamp":1778630400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Society for Phenylketonuria"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Nutrients"],"abstract":"<jats:p>Background: Sapropterin allows dietary liberalisation in responsive individuals with phenylketonuria (PKU), increasing natural protein intake and reducing dependence on protein substitutes (PSs). As PSs provide essential micronutrients, dietary liberalisation may increase the risk of nutritional insufficiency. Evidence describing detailed micronutrient intake in sapropterin-treated children remains limited. Methods: This secondary analysis evaluated dietary protein and micronutrient intake after 24 months of sapropterin treatment in 21 responsive children from a prospective longitudinal study. Caregiver-completed three-day food records were analysed for protein, calcium, iron, zinc, vitamin D, and vitamin B12, with micronutrient intakes compared with UK dietary reference values (DRVs). Results: Mean total protein intake was 75 \u00b1 14 g\/day, comprising 30 \u00b1 16 g\/day natural protein and 45 \u00b1 21 g\/day protein equivalent from PSs; natural protein tolerance ranged from 8 to 66 g\/day. PSs contributed most micronutrients: calcium 80%, iron 84%, zinc 87%, vitamin D 96%, and vitamin B12 78%. Median micronutrient intakes exceeded DRVs for most children; however, four had intakes below DRVs, almost exclusively when PSs were reduced or omitted. One child consuming &gt;40 g\/day natural protein without PSs had low iron (51%), zinc (90%), and vitamin D (4%) intakes. A non-adherent adolescent had low intakes of calcium (46%), iron (64%), zinc (41%), and vitamin D (60%). Another child receiving 60 g\/day protein equivalent from PSs had marginally low vitamin D intake (85%) due to lower fortification. Children maintaining regular PS use met micronutrient requirements. Conclusions: After two years of sapropterin treatment, dietary liberalisation increased natural protein intake but did not consistently ensure adequate micronutrient intake. Micronutrient shortfalls were associated with reduced PS use, emphasising the need for careful dietitian-guided adjustment as diets become more flexible.<\/jats:p>","DOI":"10.3390\/nu18101549","type":"journal-article","created":{"date-parts":[[2026,5,13]],"date-time":"2026-05-13T16:26:37Z","timestamp":1778689597000},"page":"1549","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Protein and Micronutrient Intake After Two Years of Sapropterin Treatment in PKU"],"prefix":"10.3390","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2941-9505","authenticated-orcid":false,"given":"Ozlem","family":"Yilmaz Nas","sequence":"first","affiliation":[{"name":"Dietetic Department, Birmingham Women\u2019s and Children\u2019s Hospital, Birmingham B4 6NH, UK"},{"name":"Department of Nutrition and Dietetics, Ankara Yildirim Beyazit University, Ankara 06760, Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Catherine","family":"Ashmore","sequence":"additional","affiliation":[{"name":"Dietetic Department, Birmingham Women\u2019s and Children\u2019s Hospital, Birmingham B4 6NH, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria Ines","family":"Gama","sequence":"additional","affiliation":[{"name":"Dietetic Department, Birmingham Women\u2019s and Children\u2019s Hospital, Birmingham B4 6NH, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2579-8699","authenticated-orcid":false,"given":"Anne","family":"Daly","sequence":"additional","affiliation":[{"name":"Dietetic Department, Birmingham Women\u2019s and Children\u2019s Hospital, Birmingham B4 6NH, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7654-3621","authenticated-orcid":false,"given":"Sharon","family":"Evans","sequence":"additional","affiliation":[{"name":"Dietetic Department, Birmingham Women\u2019s and Children\u2019s Hospital, Birmingham B4 6NH, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alex","family":"Pinto","sequence":"additional","affiliation":[{"name":"Dietetic Department, Birmingham Women\u2019s and Children\u2019s Hospital, Birmingham B4 6NH, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4697-8042","authenticated-orcid":false,"given":"Yahya","family":"Ozdogan","sequence":"additional","affiliation":[{"name":"Department of Nutrition and Dietetics, Ankara Yildirim Beyazit University, Ankara 06760, Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2896-3509","authenticated-orcid":false,"given":"Anita","family":"MacDonald","sequence":"additional","affiliation":[{"name":"Dietetic Department, Birmingham Women\u2019s and Children\u2019s Hospital, Birmingham B4 6NH, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,5,13]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"109125","DOI":"10.1016\/j.ymgme.2025.109125","article-title":"European guidelines on diagnosis and treatment of phenylketonuria: First revision","volume":"145","author":"MacDonald","year":"2025","journal-title":"Mol. Genet. Metab."},{"key":"ref_2","first-page":"8","article-title":"Phenylketonuria (PKU): A problem solved?","volume":"6","author":"Brown","year":"2016","journal-title":"Mol. Genet. Metab. Rep."},{"key":"ref_3","first-page":"39","article-title":"Living with phenylketonuria in adulthood: The PKU ATTITUDE study","volume":"16","author":"Cazzorla","year":"2018","journal-title":"Mol. Genet. Metab. Rep."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"411","DOI":"10.1080\/03007995.2020.1847717","article-title":"The management of phenylketonuria in adult patients in Italy: A survey of six specialist metabolic centers","volume":"37","author":"Burlina","year":"2021","journal-title":"Curr. Med. Res. Opin."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1515\/IJAMH.2004.16.1.41","article-title":"Blood phenylalanine control in adolescents with phenylketonuria","volume":"16","author":"Walter","year":"2004","journal-title":"Int. J. Adolesc. Med. Health"},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Yagudina, R., Kulikov, A., Serpik, V., Protsenko, M., and Kopeyka, K. (2024). Factors affecting adherence to a low phenylalanine diet in patients with phenylketonuria: A systematic review. Nutrients, 16.","DOI":"10.3390\/nu16183119"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"107684","DOI":"10.1016\/j.ymgme.2023.107684","article-title":"Metabolic control and clinical outcome in adolescents with phenylketonuria","volume":"140","author":"Nardecchia","year":"2023","journal-title":"Mol. Genet. Metab."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"190","DOI":"10.1016\/j.ymgme.2017.01.001","article-title":"Adherence to clinic recommendations among patients with phenylketonuria in the United States","volume":"120","author":"Jurecki","year":"2017","journal-title":"Mol. Genet. Metab."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"591","DOI":"10.1038\/gim.2013.10","article-title":"Newborn screening 50 years later: Access issues faced by adults with PKU","volume":"15","author":"Berry","year":"2013","journal-title":"Genet. Med."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"84","DOI":"10.1016\/j.ymgme.2015.04.003","article-title":"Neurocognitive and neuroimaging outcome of early treated young adult PKU patients: A longitudinal study","volume":"115","author":"Nardecchia","year":"2015","journal-title":"Mol. Genet. Metab."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1353","DOI":"10.1002\/jimd.12413","article-title":"Long-term cognitive and psychosocial outcomes in adults with phenylketonuria","volume":"44","author":"Aitkenhead","year":"2021","journal-title":"J. Inherit. Metab. Dis."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1016\/0168-5597(91)90036-W","article-title":"The development of auditory and visual evoked potentials in early treated phenylketonuric children","volume":"80","author":"Cardona","year":"1991","journal-title":"Electroencephalogr. Clin. Neurophysiol.\/Evoked Potentials Sect."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"125","DOI":"10.1016\/j.ymgme.2013.03.020","article-title":"White matter integrity and executive abilities in individuals with phenylketonuria","volume":"109","author":"Hershey","year":"2013","journal-title":"Mol. Genet. Metab."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"445","DOI":"10.1016\/j.ymgme.2014.01.012","article-title":"Variability in phenylalanine control predicts IQ and executive abilities in children with phenylketonuria","volume":"111","author":"Hood","year":"2014","journal-title":"Mol. Genet. Metab."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1466","DOI":"10.1345\/aph.1M050","article-title":"Sapropterin: A new therapeutic agent for phenylketonuria","volume":"43","author":"Hegge","year":"2009","journal-title":"Ann. Pharmacother."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"700","DOI":"10.1016\/j.jpeds.2008.11.040","article-title":"Efficacy of sapropterin dihydrochloride in increasing phenylalanine tolerance in children with phenylketonuria: A phase III, randomized, double-blind, placebo-controlled study","volume":"154","author":"Trefz","year":"2009","journal-title":"J. Pediatr."},{"key":"ref_17","first-page":"101264","article-title":"Risk of inadequate protein and micronutrient intakes in patients with PKU with an increased phe-tolerance: Impact of a micronutrient-dense protein substitute","volume":"45","author":"Rohde","year":"2025","journal-title":"Mol. Genet. Metab. Rep."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"101683","DOI":"10.1016\/j.gim.2026.101683","article-title":"Effect of long-term sepiapterin treatment on dietary phenylalanine tolerance in patients with phenylketonuria: Interim results from the Phase 3 APHENITY Extension Study","volume":"28","author":"Peters","year":"2026","journal-title":"Genet. Med."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"933","DOI":"10.1080\/14656566.2025.2498477","article-title":"Sepiapterin for the treatment of phenylketonuria","volume":"26","author":"Williams","year":"2025","journal-title":"Expert Opin. Pharmacother."},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Yilmaz Nas, O., Ashmore, C., Gama, M.I., Daly, A., Evans, S., Pinto, A., Ozdogan, Y., and MacDonald, A. (2026). Two-Year Outcomes of Sapropterin Treatment in Children with Phenylketonuria: A Longitudinal Observational Study of Metabolic, Dietary, and Psychosocial Effects. Nutrients, 18.","DOI":"10.3390\/nu18030446"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"192","DOI":"10.1186\/s13023-018-0923-2","article-title":"One-year follow-up of B vitamin and Iron status in patients with phenylketonuria provided tetrahydrobiopterin (BH4)","volume":"13","author":"Brantley","year":"2018","journal-title":"Orphanet J. Rare Dis."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"345","DOI":"10.1016\/j.ymgme.2021.06.002","article-title":"Nutrition status of adults with phenylketonuria treated with pegvaliase","volume":"133","author":"Viau","year":"2021","journal-title":"Mol. Genet. Metab."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"109705","DOI":"10.1016\/j.ymgme.2025.109705","article-title":"Dietetic guidance for nutritional management of people with phenylketonuria receiving sepiapterin","volume":"147","author":"MacDonald","year":"2025","journal-title":"Mol. Genet. Metab."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"119","DOI":"10.1038\/ejcn.2013.218","article-title":"PKU patients on a relaxed diet may be at risk for micronutrient deficiencies","volume":"68","author":"Rohde","year":"2014","journal-title":"Eur. J. Clin. Nutr."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"149","DOI":"10.1007\/8904_2013_273","article-title":"Dietary habits and metabolic control in adolescents and young adults with phenylketonuria: Self-imposed protein restriction may be harmful","volume":"Volume 13","author":"Das","year":"2013","journal-title":"JIMD Reports-Case and Research Reports"},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Ilgaz, F., Marsaux, C., Pinto, A., Singh, R., Rohde, C., Karabulut, E., G\u00f6kmen-\u00d6zel, H., Kuhn, M., and MacDonald, A. (2021). Protein substitute requirements of patients with phenylketonuria on BH4 treatment: A systematic review and meta-analysis. Nutrients, 13.","DOI":"10.3390\/nu13031040"},{"key":"ref_27","first-page":"62","article-title":"The challenge of long-term tetrahydrobiopterin (BH4) therapy in phenylketonuria: Effects on metabolic control, nutritional habits and nutrient supply","volume":"4","author":"Thiele","year":"2015","journal-title":"Mol. Genet. Metab. Rep."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"294","DOI":"10.1016\/j.ymgme.2012.09.021","article-title":"Long-term treatment with tetrahydrobiopterin in phenylketonuria: Treatment strategies and prediction of long-term responders","volume":"107","author":"Hennermann","year":"2012","journal-title":"Mol. Genet. Metab."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"129","DOI":"10.1159\/000479746","article-title":"Effects of inadequate amino acid mixture intake on nutrient supply of adult patients with phenylketonuria","volume":"71","author":"Hochuli","year":"2017","journal-title":"Ann. Nutr. Metab."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1186\/s12263-017-0553-7","article-title":"The impact of micronutrient status on health: Correlation network analysis to understand the role of micronutrients in metabolic-inflammatory processes regulating homeostasis and phenotypic flexibility","volume":"12","author":"Kremer","year":"2017","journal-title":"Genes Nutr."},{"key":"ref_31","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. Rare Dis."},{"key":"ref_32","unstructured":"Nutritics (Nutritics, 2026). Nutritics, Computer Software."},{"key":"ref_33","unstructured":"Scientific Advisory Committee on Nutrition (SACN) (2026, April 21). Vitamin D and Health, Available online: https:\/\/assets.publishing.service.gov.uk\/government\/uploads\/system\/uploads\/attachment_data\/file\/537616\/SACN_Vitamin_D_and_Health_report.pdf."},{"key":"ref_34","unstructured":"Committee on Medical Aspects of Food and Nutrition Policy (COMA) (1991). Dietary Reference Values for Food Energy and Nutrients for the United Kingdom: Report of the Panel on Dietary Reference Values of the Committee on Medical Aspects of Food Policy, HM Stationery Office."},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Tummolo, A., Carella, R., De Giovanni, D., Di Tullio, V., Lorusso, L., and Bartolomeo, N. (2025). A cross-sectional study on protein substitutes for paediatric phenylketonuria diet: Time to pay attention. Nutrients, 17.","DOI":"10.3390\/nu17111767"},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Tummolo, A., Carella, R., De Giovanni, D., Paterno, G., Simonetti, S., Tolomeo, M., Leone, P., and Barile, M. (2023). Micronutrient deficiency in inherited metabolic disorders requiring diet regimen: A brief critical review. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms242317024"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1016\/j.ymgme.2005.07.024","article-title":"Spanish BH4-responsive phenylalanine hydroxylase-deficient patients: Evolution of seven patients on long-term treatment with tetrahydrobiopterin","volume":"86","author":"Castro","year":"2005","journal-title":"Mol. Genet. Metab."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"175","DOI":"10.1017\/S0007114511000298","article-title":"Adjusting diet with sapropterin in phenylketonuria: What factors should be considered?","volume":"106","author":"MacDonald","year":"2011","journal-title":"Br. J. Nutr."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"427","DOI":"10.1111\/jhn.12346","article-title":"Food acceptance and neophobia in children with phenylketonuria: A prospective controlled study","volume":"29","author":"Evans","year":"2016","journal-title":"J. Hum. Nutr. Diet."},{"key":"ref_40","doi-asserted-by":"crossref","unstructured":"Bugi, M.-A., Jug\u0103naru, I., Isac, R., Simina, I.-E., Munteanu, A.-I., Mang, N., Brad, G.-F., Nicoar\u0103, D.-M., C\u00eernatu, D., and M\u0103rginean, O. (2024). Factors impacting the reduction in neophobia prevalence in phenylketonuria patients. Nutrients, 16.","DOI":"10.3390\/nu16060768"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"633","DOI":"10.1038\/ejcn.2011.205","article-title":"Unrestricted consumption of fruits and vegetables in phenylketonuria: No major impact on metabolic control","volume":"66","author":"Rohde","year":"2012","journal-title":"Eur. J. Clin. Nutr."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"506","DOI":"10.3945\/an.112.002154","article-title":"Health benefits of fruits and vegetables","volume":"3","author":"Slavin","year":"2012","journal-title":"Adv. Nutr."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"112062","DOI":"10.1016\/j.mad.2025.112062","article-title":"Towards defining optimal concentrations of micronutrients in adults to optimize health","volume":"225","author":"Mahadzir","year":"2025","journal-title":"Mech. Ageing Dev."}],"container-title":["Nutrients"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6643\/18\/10\/1549\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,5,19]],"date-time":"2026-05-19T12:13:06Z","timestamp":1779192786000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6643\/18\/10\/1549"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,5,13]]},"references-count":43,"journal-issue":{"issue":"10","published-online":{"date-parts":[[2026,5]]}},"alternative-id":["nu18101549"],"URL":"https:\/\/doi.org\/10.3390\/nu18101549","relation":{},"ISSN":["2072-6643"],"issn-type":[{"value":"2072-6643","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,5,13]]}}}