title: 6R-tetrahydrobiopterin treated PKU patients below 4 years of age: Physical outcomes, nutrition and genotype.
abstract: OBJECTIVE
  Phenylalanine-restricted diets have proven effective in treating phenylketonuria. However, such diets have occasionally been reported to hinder normal development. Our study aimed to assess whether treating 0-4-year-old phenylketonuric patients with 6R-tetrahydrobiopterin might prevent growth retardation later in life.
  
  
  METHODS
  We conducted a longitudinal retrospective study which examined anthropometric characteristics of phenylketonuric patients on 6R-tetrahydrobiopterin therapy (22 subjects), and compared them with a group of phenylketonuric patients on protein-restricted diets (44 subjects). Nutritional issues were also considered. We further explored possible relationships between mutations in the PAH gene, BH4 responsiveness and growth outcome.
  
  
  RESULTS
  No significant growth improvements were observed in either the group on 6R-tetrahydrobiopterin treatment (height Z-score: initial= -0.57 ± 1.54; final=-0.52 ± 1.29; BMI Z-score: initial=0.17 ± 1.05; final=0.18 ± 1.00) or the diet-only group (height Z-score: initial=-0.92 ± 0.96; final= -0.78 ± 1.08; BMI Z-score: initial=0.17 ± 0.97; final=-0.07 ± 1.03) over the 1-year observation period. Furthermore, we found no significant differences (p>0.05) between the two groups at any of the time points considered (0, 6 and 12 months). Patients on 6R-tetrahydrobiopterin increased their phenylalanine intake (from 49.1 [25.6-60.3] to 56.5 [39.8-68.3] mgkg(-1)day(-1)) and natural protein intake (from 1.0 [0.8-1.7] to 1.5 [1.0-1.8] g kg(-1)day(-1)), and some patients managed to adopt normal diets. Higher phenylalanine and natural protein intakes were positively correlated with better physical outcomes in the diet-only group (p<0.05). No correlation was found between patient genotype and physical outcomes, results being similar regardless of the nutritional approach used. We did not detect any side effects due to 6R-tetrahydrobiopterin administration.
  
  
  CONCLUSIONS
  Our study indicates that treating 0-4-year-old phenylketonuric patients with 6R-tetrahydrobiopterin is safe. However, poor developmental outcomes were observed, despite increasing the intake of natural proteins. Genotype could be a valid predictor of tetrahydrobiopterin-responsiveness, since patients who carried the same genotype responded similarly to the 6R-tetrahydrobiopterin loading test. On the other hand, harbouring 6R-tetrahydrobiopterin responsive genotypes did not predispose patients to better physical outcomes.
authors.affiliation: Division of Metabolism, BioCruces Health Research Institute, CIBER de Enfermedades Raras (CIBERER), Plaza de Cruces 12, 48903, Barakaldo, Spain. Electronic address: luisjose.aldamiz-echevarazuara@osakidetza.eus.
authors.forename: Luis
authors.initials: L
authors.lastname: Aldámiz-Echevarría
authors.affiliation: Metabolic Disorders, Dietetics and Nutrition Unit, Virgen del Rocío University Hospital, Manuel Siurot Avenue s/n, 41013, Sevilla, Spain. Electronic address: mbuenod@yahoo.es.
authors.forename: María A
authors.initials: MA
authors.lastname: Bueno
authors.affiliation: Unit of Diagnosis and Treatment of Congenital Metabolic Diseases, Neonatology Service, Department of Pediatrics. Hospital Clinico Universitario de Santiago de Compostela, CIBER de Enfermedades Raras (CIBERER), IDIS, Spain. Electronic address: maria.luz.couce.pico@sergas.es.
authors.forename: María L
authors.initials: ML
authors.lastname: Couce
authors.affiliation: Division of Metabolism, BioCruces Health Research Institute, CIBER de Enfermedades Raras (CIBERER), Plaza de Cruces 12, 48903, Barakaldo, Spain. Electronic address: laboratorio.metabolismo.cruces@osakidetza.eus.
authors.forename: Sergio
authors.initials: S
authors.lastname: Lage
authors.affiliation: Nutrition and Metabolopathologies Unit, La Fe University Hospital, Bulevar Sur s/n, 46026, Valencia, Spain. Electronic address: dalmau_jai@gva.es.
authors.forename: Jaime
authors.initials: J
authors.lastname: Dalmau
authors.affiliation: Nutrition and Metabolopathologies Unit, La Fe University Hospital, Bulevar Sur s/n, 46026, Valencia, Spain. Electronic address: Vitoria_isi@gva.es.
authors.forename: Isidro
authors.initials: I
authors.lastname: Vitoria
authors.affiliation: Division of Metabolism, BioCruces Health Research Institute, CIBER de Enfermedades Raras (CIBERER), Plaza de Cruces 12, 48903, Barakaldo, Spain. Electronic address: marta.llarenafernandez@osakidetza.eus.
authors.forename: Marta
authors.initials: M
authors.lastname: Llarena
authors.affiliation: Division of Metabolism, BioCruces Health Research Institute, CIBER de Enfermedades Raras (CIBERER), Plaza de Cruces 12, 48903, Barakaldo, Spain. Electronic address: fernando.andradelodeiro@osakidetza.eus.
authors.forename: Fernando
authors.initials: F
authors.lastname: Andrade
authors.affiliation: Gastroenterology, Hepatology and Child Nutrition Unit, Carlos Haya University Hospital, Avda. Arroyo de los Ángeles s/n, 29011, Málaga, Spain. Electronic address: javierblascoalonso@yahoo.es.
authors.forename: Javier
authors.initials: J
authors.lastname: Blasco
authors.affiliation: Paediatrics Unit, Río Hortega University Hospital, Calle Dulzaina 2, 47012, Valladolid, Spain. Electronic address: calcalma@saludcastillayleon.es.
authors.forename: Carlos
authors.initials: C
authors.lastname: Alcalde
authors.affiliation: Gastroenterology Unit, Virgen de la Arrixaca University Hospital, Ctra. Madrid-Cartagena s/n, El Palmar, 30120, Murcia, Spain. Electronic address: d.gil.ortega@gmail.com.
authors.forename: David
authors.initials: D
authors.lastname: Gil
authors.affiliation: Metabolic Pathologies Unit, Miguel Servet University Hospital, Paseo de Isabel La Católica 1-3, 50009, Zaragoza, Spain. Electronic address: igarciaji@salud.aragon.es.
authors.forename: María C
authors.initials: MC
authors.lastname: García
authors.affiliation: Nephrology and Metabolism Unit, Marqués de Valdecilla University Hospital, Avda. Valdecilla 25, 39008, Santander, Spain. Electronic address: Domingo.gonzalez-lamuno@unican.es.
authors.forename: Domingo
authors.initials: D
authors.lastname: González-Lamuño
authors.affiliation: Paediatrics Unit, Nuestra Señora de la Candelaria University Hospital, Carretera del Rosario 145, 38010, Santa Cruz de Tenerife, Spain. Electronic address: monicarpons@yahoo.es.
authors.forename: Mónica
authors.initials: M
authors.lastname: Ruiz
authors.affiliation: Metabolic Pathologies and Neuropaediatrics Unit, Son Espases University Hospital, Carretera de Valldemossa 79, 07120, Palma de Mallorca, Spain. Electronic address: ma.ruiz@ssib.es.
authors.forename: María A
authors.initials: MA
authors.lastname: Ruiz
authors.affiliation: Paediatric Gastroenterology, Hepatology and Nutrition Unit, Mother and Child Hospital Complex, Avda. Marítima del Sur s/n, 35016, Las Palmas de Gran Canaria, Spain. Electronic address: lpena@dcc.ulpgc.es.
authors.forename: Luis
authors.initials: L
authors.lastname: Peña-Quintana
authors.affiliation: Metabolic Pathologies Unit, Maternal and Child Hospital, Calle de la Violeta 1, 06010, Badajoz, Spain. Electronic address: davidglezt@gmail.com.
authors.forename: David
authors.initials: D
authors.lastname: González
authors.affiliation: Gastroenterology and Paediatric Nutrition Unit, Virgen del Camino Hospital, C/ De Irunlarrea 4, 31008, Pamplona, Spain. Electronic address: felix.sanchez.valverde@cfnavarra.es.
authors.forename: Felix
authors.initials: F
authors.lastname: Sánchez-Valverde
mesh_terms: D001708:Biopterins / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000627:therapeutic use; D001827:Body Height; D001835:Body Weight; D002675:Child, Preschool; D018753:Diet, Protein-Restricted; D005260:Female; D005838:Genotype; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008137:Longitudinal Studies; D008297:Male; D009154:Mutation; D009752:Nutritional Status; D010649:Phenylalanine / Q000008:administration & dosage / Q000097:blood; D010661:Phenylketonurias / Q000178:diet therapy / Q000188:drug therapy* / Q000235:genetics / Q000503:physiopathology; D012189:Retrospective Studies; D013030:Spain
chemical_list: D001708:Biopterins; D010649:Phenylalanine; C003402:sapropterin
keywords: Growth; Phenylketonuria; Physical outcomes; Tetrahydrobiopterin