{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T11:49:16Z","timestamp":1790596156187,"version":"4.1.0"},"reference-count":38,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2019,10,21]],"date-time":"2019-10-21T00:00:00Z","timestamp":1571616000000},"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>The standard treatment for phenylketonuria (PKU) is a lifelong low-phenylalanine (Phe) diet, supplemented with Phe-free protein substitutes; however, adult patients often show poor adherence to therapy. Alternative treatment options include the use of large neutral amino acids (LNAA). The aim of this study was to determine the Phe, tyrosine (Tyr), and Phe\/Tyr ratio in a cohort of sub-optimally controlled adult patients with classical PKU treated with a new LNAA formulation. Twelve patients received a Phe-restricted diet plus a slow-release LNAA product taken three times per day, at a dose of 1 g\/kg body weight (mean 0.8 \u00b1 0.24 g\/kg\/day), over a 12-month period. The product is in a microgranulated formulation, which incorporates all amino acids and uses sodium alginate as a hydrophilic carrier to prolong its release. This LNAA formulation provides up to 80% of the total protein requirement, with the rest of the protein supplied by natural food. Patients had fortnightly measurements of Phe and Tyr levels over a 12-month period after the introduction of LNAA. All patients completed the 12-month treatment period. Overall, adherence to the new LNAA tablets was very good compared with a previous amino acid mixture, for which taste was a major complaint by patients. Phe levels remained unchanged (p = 0.0522), and Tyr levels increased (p = 0.0195). Consequently, the Phe\/Tyr ratio decreased significantly (p &lt; 0.05) in the majority of patients treated. In conclusion, LNAA treatment increases Tyr levels in sub-optimally controlled adult PKU patients, while offering the potential to improve their adherence to treatment.<\/jats:p>","DOI":"10.3390\/nu11102541","type":"journal-article","created":{"date-parts":[[2019,10,21]],"date-time":"2019-10-21T11:37:55Z","timestamp":1571657875000},"page":"2541","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":21,"title":["Large Neutral Amino Acid Therapy Increases Tyrosine Levels in Adult Patients with Phenylketonuria: A Long-Term Study"],"prefix":"10.3390","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2224-4706","authenticated-orcid":false,"given":"Alessandro P.","family":"Burlina","sequence":"first","affiliation":[{"name":"Neurology Unit, San Bassiano Hospital, 36061 Bassano del Grappa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chiara","family":"Cazzorla","sequence":"additional","affiliation":[{"name":"Division of Inherited Metabolic Diseases, Department of Woman\u2019s and Child\u2019s Health, University Hospital, 35128 Padova, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pamela","family":"Massa","sequence":"additional","affiliation":[{"name":"Division of Inherited Metabolic Diseases, Department of Woman\u2019s and Child\u2019s Health, University Hospital, 35128 Padova, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3157-2979","authenticated-orcid":false,"given":"Giulia","family":"Polo","sequence":"additional","affiliation":[{"name":"Division of Inherited Metabolic Diseases, Department of Woman\u2019s and Child\u2019s Health, University Hospital, 35128 Padova, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christian","family":"Loro","sequence":"additional","affiliation":[{"name":"Division of Inherited Metabolic Diseases, Department of Woman\u2019s and Child\u2019s Health, University Hospital, 35128 Padova, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniela","family":"Gueraldi","sequence":"additional","affiliation":[{"name":"Division of Inherited Metabolic Diseases, Department of Woman\u2019s and Child\u2019s Health, University Hospital, 35128 Padova, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7724-137X","authenticated-orcid":false,"given":"Alberto B.","family":"Burlina","sequence":"additional","affiliation":[{"name":"Division of Inherited Metabolic Diseases, Department of Woman\u2019s and Child\u2019s Health, University Hospital, 35128 Padova, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2019,10,21]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1417","DOI":"10.1016\/S0140-6736(10)60961-0","article-title":"Phenylketonuria","volume":"376","author":"Blau","year":"2010","journal-title":"Lancet"},{"key":"ref_2","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_3","doi-asserted-by":"crossref","first-page":"87","DOI":"10.1016\/j.ymgme.2014.02.013","article-title":"Phenylketonuria Scientific Review Conference: State of the science and future research needs","volume":"112","author":"Camp","year":"2014","journal-title":"Mol. Genet. Metab."},{"key":"ref_4","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_5","doi-asserted-by":"crossref","first-page":"S136","DOI":"10.1007\/PL00014375","article-title":"Diet and compliance in phenylketonuria","volume":"159","author":"MacDonald","year":"2000","journal-title":"Eur. J. Pediatr."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1016\/j.ymgme.2012.02.008","article-title":"Application of the WHOQOL-100 for the assessment of quality of life of adult patients with inherited metabolic diseases","volume":"106","author":"Cazzorla","year":"2012","journal-title":"Mol. Genet. Metab."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"155","DOI":"10.1016\/j.ymgme.2012.12.006","article-title":"Psychiatric symptoms in adults with phenylketonuria","volume":"108","author":"Bilder","year":"2013","journal-title":"Mol. Genet. Metab."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"665","DOI":"10.1007\/s10545-010-9073-y","article-title":"The reality of dietary compliance in the management of phenylketonuria","volume":"33","author":"MacDonald","year":"2010","journal-title":"J. Inherit. Metab. Dis."},{"key":"ref_9","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_10","first-page":"57","article-title":"Living with Phenylketonuria: Lessons from the PKU community","volume":"17","author":"Ford","year":"2018","journal-title":"Mol. Genet. Metab. Rep."},{"key":"ref_11","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_12","doi-asserted-by":"crossref","first-page":"1851","DOI":"10.1038\/s41436-018-0403-z","article-title":"Evidence-and consensus-based recommendations for the use of pegvaliase in adults with phenylketonuria","volume":"21","author":"Longo","year":"2019","journal-title":"Genet. Med."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"2122","DOI":"10.1056\/NEJMoa021654","article-title":"Tetrahydrobiopterin as an alternative treatment for mild phenylketonuria","volume":"347","author":"Muntau","year":"2002","journal-title":"N. Engl. J. Med."},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Pena, M.J., Pinto, A., Daly, A., MacDonald, A., Azevedo, L., Rocha, J.C., and Borges, N. (2018). The use of glycomacropeptide in patients with phenylketonuria: A systematic review and meta-analysis. Nutrients, 10.","DOI":"10.3390\/nu10111794"},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Van Vliet, D., Bruinenberg, V.M., Mazzola, P.N., van Faassen, M.H., de Blaauw, P., Kema, I.P., Heiner-Fokkema, M.R., van Anholt, R.D., van der Zee, E.A., and van Spronsen, F.J. (2015). Large neutral amino acid supplementation exerts its effect through three synergistic mechanisms: Proof of principle in phenylketonuria mice. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0143833"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"671","DOI":"10.1007\/s10545-010-9216-1","article-title":"Large neutral amino acids in the treatment of PKU: From theory to practice","volume":"33","author":"Hoeksma","year":"2010","journal-title":"J. Inherit. Metab. Dis."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"23629","DOI":"10.1074\/jbc.273.37.23629","article-title":"Expression cloning and characterization of a transporter for large neutral amino acids activated by the heavy chain of 4F2 antigen (CD98)","volume":"273","author":"Kanai","year":"1998","journal-title":"J. Biol. Chem."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"233","DOI":"10.1146\/annurev.bi.22.070153.001313","article-title":"Metabolism of amino acids and proteins","volume":"22","author":"Christensen","year":"1953","journal-title":"Annu. Rev. Biochem."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1169","DOI":"10.1172\/JCI5017","article-title":"Large neutral amino acids block phenylalanine transport into brain tissue in patients with phenylketonuria","volume":"103","author":"Pietz","year":"1999","journal-title":"J. Clin. Investig."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"153","DOI":"10.1007\/s10545-007-0556-4","article-title":"Double blind placebo control trial of large neutral amino acids in treatment of PKU: Effect on blood phenylalanine","volume":"30","author":"Matalon","year":"2007","journal-title":"J. Inherit. Metab. Dis."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"732","DOI":"10.1007\/s10545-006-0395-8","article-title":"Large neutral amino acids in the treatment of phenylketonuria (PKU)","volume":"29","author":"Matalon","year":"2006","journal-title":"J. Inherit. Metab. Dis."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1038\/ejcn.2016.166","article-title":"Long-term treatment of phenylketonuria with a new medical food containing large neutral amino acids","volume":"71","author":"Concolino","year":"2017","journal-title":"Eur. J. Clin. Nutr."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"110","DOI":"10.1016\/S1096-7192(03)00078-7","article-title":"Large neutral amino acid therapy and phenylketonuria: A promising approach to treatment","volume":"79","author":"Koch","year":"2003","journal-title":"Mol. Genet. Metab."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"999","DOI":"10.1016\/j.jpeds.2012.10.015","article-title":"Large neutral amino acid supplementation increases melatonin synthesis in phenylketonuria: A new biomarker","volume":"162","author":"Yano","year":"2013","journal-title":"J. Pediatr."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"155","DOI":"10.2147\/PHMT.S49329","article-title":"Dietary intervention in the management of phenylketonuria: Current perspectives","volume":"7","author":"Rocha","year":"2016","journal-title":"Pediatric Health Med. Ther."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"127","DOI":"10.1007\/BF00711746","article-title":"Nutritional value of essential amino acids in the treatment of adults with phenylketonuria","volume":"18","author":"Dotremont","year":"1995","journal-title":"J. Inherit. Metab. Dis."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1312","DOI":"10.1111\/j.1651-2227.1994.tb13025.x","article-title":"Unchanged MRI of myelin in adolescents with PKU supplied with non-phe essential amino acids after dietary relaxation","volume":"83","author":"Lou","year":"1994","journal-title":"Acta Paediatr."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"48","DOI":"10.1016\/j.ymgme.2007.02.002","article-title":"The effects of large neutral amino acid supplements in PKU: An MRS and neuropsychological study","volume":"91","author":"Schindeler","year":"2007","journal-title":"Mol. Genet. Metab."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"20","DOI":"10.1016\/j.jnutbio.2017.09.020","article-title":"Large neutral amino acid supplementation as an alternative to the phenylalanine-restricted diet in adults with phenylketonuria: Evidence from adult Pah-enu2 mice","volume":"53","author":"Bruinenberg","year":"2018","journal-title":"J. Nutr. Biochem."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"313","DOI":"10.1023\/A:1005694122277","article-title":"Measurement of neurotransmitter metabolites in the cerebrospinal fluid of phenylketonuric patients under dietary treatment","volume":"23","author":"Burlina","year":"2000","journal-title":"J. Inherit. Metab. Dis."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"398","DOI":"10.1002\/jimd.12049","article-title":"Cerebrospinal fluid biogenic amines depletion and brain atrophy in adult patients with phenylketonuria","volume":"42","author":"Pilotto","year":"2019","journal-title":"J. Inherit. Metab. Dis."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1016\/j.brainres.2010.03.111","article-title":"Relationships between large neutral amino acid levels in plasma, cerebrospinal fluid, brain microdialysate and brain tissue in the rat","volume":"1334","author":"Bongiovanni","year":"2010","journal-title":"Brain Res."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"128","DOI":"10.1016\/0005-2736(75)90347-8","article-title":"Kinetic analysis of blood-brain barrier transport of amino acids","volume":"401","author":"Pardridge","year":"1975","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"171","DOI":"10.3389\/fphys.2018.00171","article-title":"Functional polarity of microvascular brain endothelial cells supported by neurovascular unit computational model of large neutral amino acid homeostasis","volume":"9","author":"Taslimifar","year":"2018","journal-title":"Front. Physiol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"418","DOI":"10.1016\/j.ymgme.2013.09.001","article-title":"Fluctuations in phenylalanine concentrations in phenylketonuria: A review of possible relationships with outcomes","volume":"110","author":"Cleary","year":"2013","journal-title":"Mol. Genet. Metab."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"360","DOI":"10.3389\/fphys.2019.00360","article-title":"Propagation of plasma L-phenylalanine concentration fluctuations to the neurovascular unit in phenylketonuria: An in silico study","volume":"10","author":"Taslimifar","year":"2019","journal-title":"Front. Physiol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"S109","DOI":"10.1007\/PL00014370","article-title":"The neurochemistry of phenylketonuria","volume":"159","author":"Surtees","year":"2000","journal-title":"Eur. J. Pediatr."},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"Green, B., Rahman, Y., Firman, S., Adam, S., Jenkinson, F., Nicol, C., Adams, S., Dawson, C., Robertson, L., and Dunlop, C. (2019). Improved eating behaviour and nutrient intake in noncompliant patients with phenylketonuria after reintroducing a protein substitute: Observations from a multicentre study. Nutrients, 11.","DOI":"10.3390\/nu11092035"}],"container-title":["Nutrients"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6643\/11\/10\/2541\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T13:28:14Z","timestamp":1760189294000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6643\/11\/10\/2541"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,10,21]]},"references-count":38,"journal-issue":{"issue":"10","published-online":{"date-parts":[[2019,10]]}},"alternative-id":["nu11102541"],"URL":"https:\/\/doi.org\/10.3390\/nu11102541","relation":{},"ISSN":["2072-6643"],"issn-type":[{"value":"2072-6643","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,10,21]]}}}