{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,5]],"date-time":"2026-08-05T03:39:10Z","timestamp":1785901150918,"version":"3.56.0"},"reference-count":51,"publisher":"Elsevier BV","issue":"4","license":[{"start":{"date-parts":[[2009,4,1]],"date-time":"2009-04-01T00:00:00Z","timestamp":1238544000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/www.elsevier.com\/tdm\/userlicense\/1.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecular Genetics and Metabolism"],"published-print":{"date-parts":[[2009,4]]},"DOI":"10.1016\/j.ymgme.2009.01.002","type":"journal-article","created":{"date-parts":[[2009,2,9]],"date-time":"2009-02-09T09:13:07Z","timestamp":1234170787000},"page":"158-163","source":"Crossref","is-referenced-by-count":103,"title":["Optimizing the use of sapropterin (BH4) in the management of phenylketonuria"],"prefix":"10.1016","volume":"96","author":[{"given":"Nenad","family":"Blau","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amaya","family":"B\u00e9langer-Quintana","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M\u00fcbeccel","family":"Demirkol","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fran\u00e7ois","family":"Feillet","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marcello","family":"Giovannini","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anita","family":"MacDonald","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Friedrich K.","family":"Trefz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francjan J.","family":"van Spronsen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"78","reference":[{"key":"10.1016\/j.ymgme.2009.01.002_bib1","doi-asserted-by":"crossref","first-page":"286","DOI":"10.1159\/000469218","article-title":"Enzymology of the phenylalanine-hydroxylating system","volume":"38","author":"Kaufman","year":"1987","journal-title":"Enzyme"},{"key":"10.1016\/j.ymgme.2009.01.002_bib2","doi-asserted-by":"crossref","first-page":"831","DOI":"10.1002\/humu.20526","article-title":"The PAH gene, phenylketonuria, and a paradigm shift","volume":"28","author":"Scriver","year":"2007","journal-title":"Hum. Mutat."},{"issue":"Suppl.","key":"10.1016\/j.ymgme.2009.01.002_bib3","doi-asserted-by":"crossref","first-page":"1561S","DOI":"10.1093\/jn\/137.6.1561S","article-title":"Management of phenylketonuria and hyperphenylalaninemia","volume":"137","author":"de Baulny","year":"2007","journal-title":"J. Nutr."},{"key":"10.1016\/j.ymgme.2009.01.002_bib4","series-title":"PKU and BH4: Advances in Phenylketonuria and Tetrahydrobiopterin Research","first-page":"443","article-title":"A PAH gene knowledge base: content, informatics, utilization","author":"Scriver","year":"2006"},{"key":"10.1016\/j.ymgme.2009.01.002_bib5","doi-asserted-by":"crossref","first-page":"345","DOI":"10.1002\/humu.10192","article-title":"Phenylketonuria mutations in Europe","volume":"21","author":"Zschocke","year":"2003","journal-title":"Hum. Mutat."},{"key":"10.1016\/j.ymgme.2009.01.002_bib6","series-title":"The Metabolic and Molecular Bases of Inherited Disease","first-page":"1667","article-title":"Hyperphenylalaninemia: phenylalanine hydroxylase deficiency","author":"Scriver","year":"2001"},{"key":"10.1016\/j.ymgme.2009.01.002_bib7","first-page":"31","article-title":"Phenylketonuria: an inborn error of phenylalanine metabolism","volume":"29","author":"Williams","year":"2008","journal-title":"Clin. Biochem. Rev."},{"key":"10.1016\/j.ymgme.2009.01.002_bib8","series-title":"PKU and BH4: Advances in Phenylketonuria and Tetrahydrobiopterin","first-page":"161","article-title":"Laboratory diagnosis of phenylketonuria","author":"Dhondt","year":"2006"},{"issue":"Suppl. 1","key":"10.1016\/j.ymgme.2009.01.002_bib9","first-page":"3","article-title":"Expanded newborn screening in Istanbul","volume":"30","author":"Demirkol","year":"2007","journal-title":"J. Inherit. Metab. Dis."},{"key":"10.1016\/j.ymgme.2009.01.002_bib10","doi-asserted-by":"crossref","first-page":"101","DOI":"10.1016\/j.ymgme.2004.03.006","article-title":"The metabolic and molecular bases of tetrahydrobiopterin-responsive phenylalanine hydroxylase deficiency","volume":"82","author":"Blau","year":"2004","journal-title":"Mol. Genet. Metab."},{"key":"10.1016\/j.ymgme.2009.01.002_bib11","first-page":"805","article-title":"Sapropterin dihydrochloride (Kuvan\/Phenoptin), an orally active synthetic form of BH4 for the treatment of phenylketonuria","volume":"10","author":"Burnett","year":"2007","journal-title":"IDrugs"},{"key":"10.1016\/j.ymgme.2009.01.002_bib12","unstructured":"National Institutes of Health. Phenylketonuria (PKU): Screening and Management. NIH Consensus Statement 2000. Available at http:\/\/www.consensus.nih.gov\/2000\/2000Phenylketonuria113Program.pdf (accessed December 2008)."},{"key":"10.1016\/j.ymgme.2009.01.002_bib13","doi-asserted-by":"crossref","first-page":"474","DOI":"10.1080\/87565640802101482","article-title":"Twenty-five years of research on neurocognitive outcomes in early-treated phenylketonuria: intelligence and executive function","volume":"33","author":"DeRoche","year":"2008","journal-title":"Dev. Neuropsychol."},{"key":"10.1016\/j.ymgme.2009.01.002_bib14","doi-asserted-by":"crossref","first-page":"548","DOI":"10.1023\/A:1005669610722","article-title":"Behaviour and school achievement in patients with early and continuously treated phenylketonuria","volume":"23","author":"Stemerdink","year":"2000","journal-title":"J. Inherit. Metab. Dis."},{"key":"10.1016\/j.ymgme.2009.01.002_bib15","doi-asserted-by":"crossref","first-page":"1","DOI":"10.2307\/1166208","article-title":"Prefrontal cortex cognitive deficits in children treated early and continuously for PKU","volume":"62","author":"Diamond","year":"1997","journal-title":"Monogr. Soc. Res. Child Dev."},{"key":"10.1016\/j.ymgme.2009.01.002_bib16","doi-asserted-by":"crossref","first-page":"63","DOI":"10.1159\/000012719","article-title":"Diet in phenylketonuria: how long? Policies under discussion","volume":"42","author":"Endres","year":"1998","journal-title":"Ann. Nutr. Metab."},{"key":"10.1016\/j.ymgme.2009.01.002_bib17","doi-asserted-by":"crossref","first-page":"165","DOI":"10.1515\/IJAMH.2003.15.2.165","article-title":"Phenylalanine-restricted diet should be life long. A case report on long-term follow-up of an adolescent with untreated phenylketonuria","volume":"15","author":"Merrick","year":"2003","journal-title":"Int. J. Adolesc. Med. Health"},{"key":"10.1016\/j.ymgme.2009.01.002_bib18","doi-asserted-by":"crossref","first-page":"345","DOI":"10.1542\/peds.99.3.345","article-title":"Psychiatric disorders in adult patients with early-treated phenylketonuria","volume":"99","author":"Pietz","year":"1997","journal-title":"Pediatrics"},{"key":"10.1016\/j.ymgme.2009.01.002_bib19","doi-asserted-by":"crossref","first-page":"137","DOI":"10.1023\/B:BOLI.0000028725.37345.62","article-title":"Prevalence of stimulant use for attentional dysfunction in children with phenylketonuria","volume":"27","author":"Arnold","year":"2004","journal-title":"J. Inherit. Metab. Dis."},{"key":"10.1016\/j.ymgme.2009.01.002_bib20","doi-asserted-by":"crossref","first-page":"267","DOI":"10.1016\/j.pediatrneurol.2005.05.003","article-title":"School performance in early and continuously treated phenylketonuria","volume":"33","author":"Gassi\u00f3","year":"2005","journal-title":"Pediatr. Neurol."},{"key":"10.1016\/j.ymgme.2009.01.002_bib21","doi-asserted-by":"crossref","first-page":"91","DOI":"10.1007\/s11065-007-9021-2","article-title":"Meta-analysis of neuropsychological symptoms of adolescents and adults with PKU","volume":"17","author":"Moyle","year":"2007","journal-title":"Neuropsychol. Rev."},{"issue":"Suppl. 2","key":"10.1016\/j.ymgme.2009.01.002_bib22","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":"10.1016\/j.ymgme.2009.01.002_bib23","doi-asserted-by":"crossref","first-page":"145","DOI":"10.1007\/s10545-007-0552-8","article-title":"Phenylketonuria: dietary and therapeutic challenges","volume":"30","author":"Giovannini","year":"2007","journal-title":"J. Inherit. Metab. Dis."},{"key":"10.1016\/j.ymgme.2009.01.002_bib24","doi-asserted-by":"crossref","first-page":"319","DOI":"10.1023\/A:1025186217369","article-title":"Administration of protein substitute and quality of control in phenylketonuria: a randomized study","volume":"26","author":"MacDonald","year":"2003","journal-title":"J. Inherit. Metab. Dis."},{"key":"10.1016\/j.ymgme.2009.01.002_bib25","first-page":"33","article-title":"The time has come: a new scene for PKU treatment","volume":"5","author":"Santos","year":"2006","journal-title":"Genet. Mol. Res."},{"issue":"Suppl.","key":"10.1016\/j.ymgme.2009.01.002_bib26","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1111\/j.1651-2227.1994.tb13457.x","article-title":"Feeding problems in young PKU children","volume":"407","author":"MacDonald","year":"1994","journal-title":"Acta Paediatr."},{"issue":"Suppl 2","key":"10.1016\/j.ymgme.2009.01.002_bib27","first-page":"S21","article-title":"Phenylketonuria diet in adolescents\u2014energy and nutrient intake\u2014is it adequate?","volume":"65","author":"Link","year":"1989","journal-title":"Postgrad. Med. J."},{"key":"10.1016\/j.ymgme.2009.01.002_bib28","doi-asserted-by":"crossref","first-page":"127","DOI":"10.1023\/B:BOLI.0000028784.11080.9b","article-title":"A new, low-volume protein substitute for teenagers and adults with phenylketonuria","volume":"27","author":"MacDonald","year":"2004","journal-title":"J. Inherit. Metab. Dis."},{"key":"10.1016\/j.ymgme.2009.01.002_bib29","doi-asserted-by":"crossref","first-page":"526","DOI":"10.1007\/s10545-006-0234-y","article-title":"\u2018Ready to drink\u2019 protein substitute is easier is for people with phenylketonuria","volume":"29","author":"MacDonald","year":"2006","journal-title":"J. Inherit. Metab. Dis."},{"key":"10.1016\/j.ymgme.2009.01.002_bib30","doi-asserted-by":"crossref","first-page":"304","DOI":"10.1016\/S1096-7192(02)00171-3","article-title":"High frequency of tetrahydrobiopterin-responsiveness among hyperphenylalaninemias: a study of 1919 patients observed from 1988 to 2002","volume":"77","author":"Bernegger","year":"2002","journal-title":"Mol. Genet. Metab."},{"key":"10.1016\/j.ymgme.2009.01.002_bib31","doi-asserted-by":"crossref","first-page":"627","DOI":"10.1016\/j.jpeds.2007.02.017","article-title":"Assessment of tetrahydrobiopterin (BH4) responsiveness in phenylketonuria","volume":"150","author":"Fiege","year":"2007","journal-title":"J. Pediatr."},{"issue":"Suppl.1","key":"10.1016\/j.ymgme.2009.01.002_bib32","doi-asserted-by":"crossref","first-page":"S75","DOI":"10.1016\/j.ymgme.2005.06.026","article-title":"Long-term treatment of patients with mild and classical phenylketonuria by tetrahydrobiopterin","volume":"86","author":"Trefz","year":"2005","journal-title":"Mol. Genet. Metab."},{"issue":"Suppl. 1","key":"10.1016\/j.ymgme.2009.01.002_bib33","doi-asserted-by":"crossref","first-page":"S86","DOI":"10.1016\/j.ymgme.2005.05.013","article-title":"Long-term treatment with tetrahydrobiopterin increases phenylalanine tolerance in children with severe phenotype of phenylketonuria","volume":"86","author":"Hennermann","year":"2005","journal-title":"Mol. Genet. Metab."},{"key":"10.1016\/j.ymgme.2009.01.002_bib34","doi-asserted-by":"crossref","first-page":"700","DOI":"10.1007\/s10545-007-0605-z","article-title":"The response of patients with phenylketonuria and elevated serum phenylalanine to treatment with oral sapropterin dihydrochloride (6R-tetrahydrobiopterin): a phase II, multicentre, open-label, screening study","volume":"30","author":"Burton","year":"2007","journal-title":"J. Inherit. Metab. Dis."},{"key":"10.1016\/j.ymgme.2009.01.002_bib35","unstructured":"Food and Drug Administration. Medical review (Sapropterin; 6R-tetrahydro-biopterin). Available at www.fda.gov\/cder\/foi\/nda\/2007\/022181s000_MedR_P1.pdf (accessed August 2008)."},{"key":"10.1016\/j.ymgme.2009.01.002_bib36","doi-asserted-by":"crossref","first-page":"504","DOI":"10.1016\/S0140-6736(07)61234-3","article-title":"Efficacy of sapropterin dihydrochloride (tetrahydrobiopterin, 6R-BH4) for reduction of phenylalanine concentration in patients with phenylketonuria: a phase III randomised placebo-controlled study","volume":"370","author":"Levy","year":"2007","journal-title":"Lancet"},{"key":"10.1016\/j.ymgme.2009.01.002_bib37","unstructured":"Kuvan\u00ae US Prescribing Information. Available at www.kuvan.com (accessed August 2008)."},{"key":"10.1016\/j.ymgme.2009.01.002_bib38","doi-asserted-by":"crossref","unstructured":"F.K. Trefz, B.K. Burton, N. Longo, M. Martinez-Pardo Casanova, D.J. Gruskin, A. Dorenbaum, E.D. Kakkis, E.A. Crombez, D.K. Grange, P. Harmatz, M.H. Lipson, A. Milanowski, L.M. Randolph, J. Vockley, C.B. Whitley, J.A. Wolff, J. Bebchuk, H. Christ-Schmidt, J.B Hennermann; for the Sapropterin Study Group, Efficacy of sapropterin dihydrochloride in increasing phenylalanine tolerance in children with phenylketonuria: a phase III, randomized, double-blind, placebo-controlled study, J. Pediatr., in press.","DOI":"10.1016\/j.jpeds.2008.11.040"},{"key":"10.1016\/j.ymgme.2009.01.002_bib39","doi-asserted-by":"crossref","first-page":"2851","DOI":"10.1002\/ajmg.a.32562","article-title":"Safety and efficacy of 22 weeks of treatment with sapropterin dihydrochloride in patients with phenylketonuria","volume":"146A","author":"Lee","year":"2008","journal-title":"Am. J. Med. Genet. A."},{"key":"10.1016\/j.ymgme.2009.01.002_bib40","doi-asserted-by":"crossref","first-page":"2","DOI":"10.1007\/s10545-007-9979-1","article-title":"Defining tetrahydrobiopterin (BH4)-responsiveness in PKU","volume":"31","author":"Blau","year":"2008","journal-title":"J. Inherit. Metab. Dis."},{"key":"10.1016\/j.ymgme.2009.01.002_bib41","doi-asserted-by":"crossref","first-page":"287","DOI":"10.1016\/j.ymgme.2007.09.017","article-title":"Recommendations for evaluation of responsiveness to tetrahydrobiopterin (BH(4)) in phenylketonuria and its use in treatment","volume":"92","author":"Levy","year":"2007","journal-title":"Mol. Genet. Metab."},{"key":"10.1016\/j.ymgme.2009.01.002_bib42","doi-asserted-by":"crossref","first-page":"67","DOI":"10.1007\/s10545-007-0572-4","article-title":"Classifying tetrahydrobiopterin responsiveness in the hyperphenylalaninaemias","volume":"31","author":"Langenbeck","year":"2008","journal-title":"J. Inherit. Metab. Dis."},{"key":"10.1016\/j.ymgme.2009.01.002_bib43","doi-asserted-by":"crossref","unstructured":"F.K. Trefz, D. Scheible, H. Gotz, G. Frauendienst-Egger, Significance of genotype in tetrahydrobiopterin-responsive phenylketonuria, J. Inherit. Metab. Dis. (2008) Oct 30 [Epub ahead of print].","DOI":"10.1007\/s10545-008-0940-8"},{"key":"10.1016\/j.ymgme.2009.01.002_bib44","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":"10.1016\/j.ymgme.2009.01.002_bib45","doi-asserted-by":"crossref","first-page":"167","DOI":"10.1002\/humu.20637","article-title":"Molecular genetics of tetrahydrobiopterin responsive phenylalanine hydroxylase deficiency","volume":"29","author":"Zurfl\u00fch","year":"2008","journal-title":"Hum. Mutat."},{"key":"10.1016\/j.ymgme.2009.01.002_bib46","doi-asserted-by":"crossref","first-page":"157","DOI":"10.1016\/j.ymgme.2004.06.007","article-title":"Tetrahydrobiopterin responsiveness: results of the BH4 loading test in 31 Spanish PKU patients and correlation with their genotype","volume":"83","author":"Desviat","year":"2004","journal-title":"Mol. Gen. Metab."},{"key":"10.1016\/j.ymgme.2009.01.002_bib47","doi-asserted-by":"crossref","first-page":"104","DOI":"10.1006\/mgme.2001.3168","article-title":"Tetrahydrobiopterin responsiveness in phenylketonuria differs between patients with the same genotype","volume":"73","author":"Lindner","year":"2001","journal-title":"Mol. Genet. Metab."},{"key":"10.1016\/j.ymgme.2009.01.002_bib48","doi-asserted-by":"crossref","first-page":"400","DOI":"10.1002\/humu.9117","article-title":"Tetrahydrobiopterin sensitivity in German patients with mild phenylalanine hydroxylase deficiency","volume":"21","author":"Lindner","year":"2003","journal-title":"Hum. Mutat."},{"key":"10.1016\/j.ymgme.2009.01.002_bib49","doi-asserted-by":"crossref","first-page":"817","DOI":"10.2165\/0003088-200847120-00006","article-title":"Pharmacokinetics of sapropterin in patients with phenylketonuria","volume":"47","author":"Feillet","year":"2008","journal-title":"Clin. Pharmacokinet."},{"key":"10.1016\/j.ymgme.2009.01.002_bib50","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1016\/j.ymgme.2005.07.024","article-title":"Spanish BH(4)-responsive phenylalanine hydroxylase-deficient patients: evolution of seven patients on long-term treatment with tetrahydrobiopterin","volume":"86","author":"Belanger-Quintana","year":"2005","journal-title":"Mol. Genet. Metab."},{"key":"10.1016\/j.ymgme.2009.01.002_bib51","unstructured":"Kuvan\u00ae EU Prescribing Information. Available at http:\/\/www.ec.europa.eu\/enterprise\/pharmaceuticals\/register\/2008\/2008120250811\/anx_50811_en.pdf."}],"container-title":["Molecular Genetics and Metabolism"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.elsevier.com\/content\/article\/PII:S1096719209000055?httpAccept=text\/xml","content-type":"text\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/api.elsevier.com\/content\/article\/PII:S1096719209000055?httpAccept=text\/plain","content-type":"text\/plain","content-version":"vor","intended-application":"text-mining"}],"deposited":{"date-parts":[[2019,5,17]],"date-time":"2019-05-17T22:24:33Z","timestamp":1558131873000},"score":1,"resource":{"primary":{"URL":"https:\/\/linkinghub.elsevier.com\/retrieve\/pii\/S1096719209000055"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2009,4]]},"references-count":51,"journal-issue":{"issue":"4","published-print":{"date-parts":[[2009,4]]}},"alternative-id":["S1096719209000055"],"URL":"https:\/\/doi.org\/10.1016\/j.ymgme.2009.01.002","relation":{},"ISSN":["1096-7192"],"issn-type":[{"value":"1096-7192","type":"print"}],"subject":[],"published":{"date-parts":[[2009,4]]}}}