title: Long-term follow-up of patients with phenylketonuria treated with tetrahydrobiopterin: a seven years experience.
abstract: BACKGROUND
  Phenylketonuria (PKU) is an autosomal recessive disorder caused by the deficiency of phenylalanine hydroxylase that catalyzes the conversion of phenylalanine to tyrosine, using tetrahydrobiopterin (BH4) as coenzyme. Besides dietary phenylalanine restriction, new therapeutic options are emerging, such as the treatment with BH4 in subgroups of PKU patients responding to a loading test with BH4.
  
  
  METHODS
  A no-profit open-label interventional trial with long-term oral BH4 therapy, sponsored by the Italian Medicines Agency (AIFA), was performed in a group of 17 PKU patients resulted as BH4 responders among 46 subjects analyzed for BH4-responsiveness (prot. FARM5MATC7). We report on efficacy and safety data of BH4 therapy and analyze factors predicting BH4-responsiveness and long-term response to BH4. A BH4-withdrawal test was used as a proof of the efficacy of long-term therapy with BH4.
  
  
  RESULTS
  Forty-four percent of the patients responded to the 48 h-long loading test with BH4. All the phenotypic classes were represented. Genotype was the best predictor of responsiveness, along with lower phenylalanine levels at diagnosis, higher tolerance and lower phenylalanine/tyrosine ratio before the test. In BH4 responder patients, long-term BH4 therapy resulted safe and effective in increasing tolerance while maintaining a good metabolic control. The BH4 withdrawal test, performed in a subset of patients, showed that improved tolerance was directly dependent on BH4 assumption. Tolerance to phenylalanine was re-evaluated in 43.5% of patients and was longitudinally analyzed in 5 patients.
  
  
  CONCLUSIONS
  Long-term treatment with BH4 is safe and effective in increasing tolerance to phenylalanine. There is real need to assess the actual tolerance to phenylalanine in PKU patients to ameliorate quality of life, improve nutritional status, avoiding unnecessarily restricted diets, and interpret the effects of new therapies for PKU.
authors.affiliation: Department of Translational Medicine-Section of Pediatrics, Federico II University, Via S. Pansini 5, 80131, Naples, Italy. iris.scala@libero.it.
authors.forename: Iris
authors.initials: I
authors.lastname: Scala
authors.affiliation: Department of Pediatrics, Magna Graecia University, Catanzaro, Italy. dconcolino@unicz.it.
authors.forename: Daniela
authors.initials: D
authors.lastname: Concolino
authors.affiliation: Department of Translational Medicine-Section of Pediatrics, Federico II University, Via S. Pansini 5, 80131, Naples, Italy. roberto.dellacasa@unina.it.
authors.forename: Roberto
authors.initials: R
authors.lastname: Della Casa
authors.affiliation: Department of Clinical Medicine and Surgery, Physiology Nutrition Unit, Federico II University, Naples, Italy. nastasi.annamaria@gmail.com.
authors.forename: Anna
authors.initials: A
authors.lastname: Nastasi
authors.affiliation: Department of Translational Medicine-Section of Pediatrics, Federico II University, Via S. Pansini 5, 80131, Naples, Italy. ungarocarla@libero.it.
authors.forename: Carla
authors.initials: C
authors.lastname: Ungaro
authors.affiliation: Department of Translational Medicine-Section of Pediatrics, Federico II University, Via S. Pansini 5, 80131, Naples, Italy. lultimodeimohicani@libero.it.
authors.forename: Serena
authors.initials: S
authors.lastname: Paladino
authors.affiliation: Department of Clinical Medicine and Surgery, Federico II University, Naples, Italy. brunella.capaldo@unina.it.
authors.forename: Brunella
authors.initials: B
authors.lastname: Capaldo
authors.affiliation: Department of Molecular Medicine and Medical Biotechnology, Federico II University, Naples, Italy. margherita.ruoppolo@unina.it.|CEINGE-Biotecnologie Avanzate s.c.ar.l., Naples, Italy. margherita.ruoppolo@unina.it.
authors.forename: Margherita
authors.initials: M
authors.lastname: Ruoppolo
authors.affiliation: CEINGE-Biotecnologie Avanzate s.c.ar.l., Naples, Italy. aurora.daniele@unina2.it.|Dipartimento di Scienze e Tecnologie Ambientali Biologiche Farmaceutiche, Seconda Università degli Studi di Napoli, Caserta, Italy. aurora.daniele@unina2.it.
authors.forename: Aurora
authors.initials: A
authors.lastname: Daniele
authors.affiliation: Department of Pediatrics, Magna Graecia University, Catanzaro, Italy. giusebona@libero.it.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Bonapace
authors.affiliation: Department of Translational Medicine-Section of Pediatrics, Federico II University, Via S. Pansini 5, 80131, Naples, Italy. pietro.strisciuglio@unina.it.
authors.forename: Pietro
authors.initials: P
authors.lastname: Strisciuglio
authors.affiliation: Department of Translational Medicine-Section of Pediatrics, Federico II University, Via S. Pansini 5, 80131, Naples, Italy. parenti@unina.it.
authors.forename: Giancarlo
authors.initials: G
authors.lastname: Parenti
authors.affiliation: Department of Translational Medicine-Section of Pediatrics, Federico II University, Via S. Pansini 5, 80131, Naples, Italy. andria@unina.it.
authors.forename: Generoso
authors.initials: G
authors.lastname: Andria
mesh_terms: D000293:Adolescent; D001708:Biopterins / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000627:therapeutic use; D002648:Child; D002675:Child, Preschool; D004334:Drug Administration Schedule; D005260:Female; D005838:Genotype; D006801:Humans; D008297:Male; D010649:Phenylalanine / Q000097:blood; D010661:Phenylketonurias / Q000188:drug therapy*; D055815:Young Adult
chemical_list: D001708:Biopterins; D010649:Phenylalanine; C003402:sapropterin