title: Genotype-phenotype associations in French patients with phenylketonuria and importance of genotype for full assessment of tetrahydrobiopterin responsiveness.
abstract: BACKGROUND
  Mutations in Phenylalanine Hydroxylase (PAH) gene cause phenylketonuria. Sapropterin (BH4), the enzyme cofactor, is an important therapeutical strategy in phenylketonuria. However, PAH is a highly polymorphic gene and it is difficult to identify BH4-responsive genotypes. We seek here to improve prediction of BH4-responsiveness through comparison of genotypes, BH4-loading test, predictions of responsiveness according to the literature and types and locations of mutations.
  
  
  METHODS
  A total of 364 French patients among which, 9 % had mild hyperphenylalaninemia, 17.7 % mild phenylketonuria and 73.1 % classical phenylketonuria, benefited from a 24-hour BH4-loading test and had the PAH gene sequenced and analyzed by Multiplex Ligation Probe Amplification.
  
  
  RESULTS
  Overall, 31.6 % of patients were BH4-responsive. The number of different mutations found was 127, including 26 new mutations. The mutations c.434A > T, c.500A > T, c.529G > C, c.1045 T > G and c.1196 T > C were newly classified as being BH4-responsive. We identified 261 genotypes, among which 46 were newly recognized as being BH4-responsive. Even though patients carry 2 responsive alleles, BH4-responsiveness cannot be predicted with certainty unless they present mild hyperphenylalaninemia. BH4-responsiveness cannot be predicted in patients carrying one responsive mutation only. In general, the milder the phenotype is, the stronger the BH4-response is. Almost exclusively missense mutations, particularly in exons 12, 11 and 8, are associated with BH4-responsiveness and any other type of mutation predicts a negative response.
  
  
  CONCLUSIONS
  This study is the first of its kind, in a French population, to identify the phenotype associated with several combinations of PAH mutations. As others, it highlights the necessity of performing simultaneously BH4 loading test and molecular analysis in monitoring phenylketonuria patients.
authors.affiliation: Reference Center for Inherited Metabolic Diseases, University Hospital of Nancy, 9 ave Forêt de Haye, BP 184, 54511, Vandoeuvre-lès-Nancy, France.|INSERM U954, Department of Nutrition-Genetics-Environmental Risk Exposure, University of Lorraine, 9 ave Forêt de Haye, BP 184, 54511, Vandoeuvre-lès-Nancy, France.
authors.forename: Elise
authors.initials: E
authors.lastname: Jeannesson-Thivisol
authors.affiliation: Reference Center for Inherited Metabolic Diseases, University Hospital of Nancy, 9 ave Forêt de Haye, BP 184, 54511, Vandoeuvre-lès-Nancy, France.|INSERM U954, Department of Nutrition-Genetics-Environmental Risk Exposure, University of Lorraine, 9 ave Forêt de Haye, BP 184, 54511, Vandoeuvre-lès-Nancy, France.
authors.forename: François
authors.initials: F
authors.lastname: Feillet
authors.affiliation: Reference Center for Inherited Metabolic Diseases, University Hospital of Nancy, 9 ave Forêt de Haye, BP 184, 54511, Vandoeuvre-lès-Nancy, France.|INSERM U954, Department of Nutrition-Genetics-Environmental Risk Exposure, University of Lorraine, 9 ave Forêt de Haye, BP 184, 54511, Vandoeuvre-lès-Nancy, France.
authors.forename: Céline
authors.initials: C
authors.lastname: Chéry
authors.affiliation: Reference Center for Inherited Metabolic Diseases, University Hospital of Nancy, 9 ave Forêt de Haye, BP 184, 54511, Vandoeuvre-lès-Nancy, France.|INSERM U954, Department of Nutrition-Genetics-Environmental Risk Exposure, University of Lorraine, 9 ave Forêt de Haye, BP 184, 54511, Vandoeuvre-lès-Nancy, France.
authors.forename: Pascal
authors.initials: P
authors.lastname: Perrin
authors.affiliation: Reference Center for Inherited Metabolic Diseases, University Hospital of Nancy, 9 ave Forêt de Haye, BP 184, 54511, Vandoeuvre-lès-Nancy, France.|INSERM U954, Department of Nutrition-Genetics-Environmental Risk Exposure, University of Lorraine, 9 ave Forêt de Haye, BP 184, 54511, Vandoeuvre-lès-Nancy, France.
authors.forename: Shyue-Fang
authors.initials: SF
authors.lastname: Battaglia-Hsu
authors.affiliation: Reference Center for Inherited Metabolic Diseases, University Hospital of Nancy, 9 ave Forêt de Haye, BP 184, 54511, Vandoeuvre-lès-Nancy, France.|INSERM U954, Department of Nutrition-Genetics-Environmental Risk Exposure, University of Lorraine, 9 ave Forêt de Haye, BP 184, 54511, Vandoeuvre-lès-Nancy, France.
authors.forename: Bernard
authors.initials: B
authors.lastname: Herbeth
authors.affiliation: Reference Center for Inherited Metabolic Diseases, Timone Hospital, Marseille, France.
authors.forename: Aline
authors.initials: A
authors.lastname: Cano
authors.affiliation: Department of Biochemistry and Genetics, Angers University Hospital, Angers, France.
authors.forename: Magalie
authors.initials: M
authors.lastname: Barth
authors.affiliation: Reference Center for Inherited Metabolic Diseases, Hospices Civils de Lyon, Bron, France.
authors.forename: Alain
authors.initials: A
authors.lastname: Fouilhoux
authors.affiliation: Reference Center for Inherited Metabolic Diseases, Jeanne de Flandres Hospital, Lille, France.
authors.forename: Karine
authors.initials: K
authors.lastname: Mention
authors.affiliation: Department of Pediatric Medicine, Clocheville Hospital, Tours, France.
authors.forename: François
authors.initials: F
authors.lastname: Labarthe
authors.affiliation: Reference Center for Inherited Metabolic Diseases, Necker-Enfants Malades Hospital, Paris, France.
authors.forename: Jean-Baptiste
authors.initials: JB
authors.lastname: Arnoux
authors.affiliation: Department of Internal Medicine, Tours University Hospital, Tours, France.
authors.forename: François
authors.initials: F
authors.lastname: Maillot
authors.affiliation: Department of Pediatrics, Amiens University-Hospital, Amiens, France.
authors.forename: Catherine
authors.initials: C
authors.lastname: Lenaerts
authors.affiliation: Pediatric Hematology and Oncology, Rouen University-Hospital, Rouen, France.
authors.forename: Cécile
authors.initials: C
authors.lastname: Dumesnil
authors.affiliation: Department of Pediatrics, Lenval Hospital, Nice, France.
authors.forename: Kathy
authors.initials: K
authors.lastname: Wagner
authors.affiliation: Department of Pediatrics, Hotel-Dieu Hospital, Clermont-Ferrand, France.
authors.forename: Daniel
authors.initials: D
authors.lastname: Terral
authors.affiliation: Department of Pediatric Hepatology and Metabolic Diseases, Children Hospital, Toulouse, France.
authors.forename: Pierre
authors.initials: P
authors.lastname: Broué
authors.affiliation: Department of Pediatrics, CHRU Morvan, Brest, France.
authors.forename: Loïc
authors.initials: L
authors.lastname: de Parscau
authors.affiliation: Department of Pediatrics, Saint-Etienne University-Hospital, Saint-Etienne, France.
authors.forename: Claire
authors.initials: C
authors.lastname: Gay
authors.affiliation: Pediatric Department, Nantes University Hospital, Nantes, France.
authors.forename: Alice
authors.initials: A
authors.lastname: Kuster
authors.affiliation: Neonatology Department, Mère-Enfant Hospital, Limoges, France.
authors.forename: Antoine
authors.initials: A
authors.lastname: Bédu
authors.affiliation: Department of Neurology, University Hospital of Grenoble, Grenoble, France.
authors.forename: Gérard
authors.initials: G
authors.lastname: Besson
authors.affiliation: Department of Pediatrics, Pellegrin-Enfants Hospital, Bordeaux, France.
authors.forename: Delphine
authors.initials: D
authors.lastname: Lamireau
authors.affiliation: Department of Clinical Genetics, Rennes University Hospital, Rennes, France.
authors.forename: Sylvie
authors.initials: S
authors.lastname: Odent
authors.affiliation: Department of Medical Genetics, Dijon University-Hospital, Dijon, France.
authors.forename: Alice
authors.initials: A
authors.lastname: Masurel
authors.affiliation: Reference Center for Inherited Metabolic Diseases, University Hospital of Nancy, 9 ave Forêt de Haye, BP 184, 54511, Vandoeuvre-lès-Nancy, France.|INSERM U954, Department of Nutrition-Genetics-Environmental Risk Exposure, University of Lorraine, 9 ave Forêt de Haye, BP 184, 54511, Vandoeuvre-lès-Nancy, France.
authors.forename: Jean-Louis
authors.initials: JL
authors.lastname: Guéant
authors.affiliation: Reference Center for Inherited Metabolic Diseases, University Hospital of Nancy, 9 ave Forêt de Haye, BP 184, 54511, Vandoeuvre-lès-Nancy, France. bernard.namour@univ-lorraine.fr.|INSERM U954, Department of Nutrition-Genetics-Environmental Risk Exposure, University of Lorraine, 9 ave Forêt de Haye, BP 184, 54511, Vandoeuvre-lès-Nancy, France. bernard.namour@univ-lorraine.fr.
authors.forename: Fares
authors.initials: F
authors.lastname: Namour
mesh_terms: D001708:Biopterins / Q000031:analogs & derivatives* / Q000627:therapeutic use; D015331:Cohort Studies; D005260:Female; D005602:France / Q000453:epidemiology; D056726:Genetic Association Studies / Q000379:methods*; D005838:Genotype; D006801:Humans; D008297:Male; D010641:Phenotype; D010661:Phenylketonurias / Q000188:drug therapy* / Q000453:epidemiology / Q000235:genetics*; D016896:Treatment Outcome
chemical_list: D001708:Biopterins; C003402:sapropterin