title: Phenylalanine hydroxylase deficiency in south Italy: Genotype-phenotype correlations, identification of a novel mutant PAH allele and prediction of BH4 responsiveness.
abstract: We investigated the mutation spectrum of the phenylalanine hydroxylase gene (PAH) in a cohort of patients from 33 Italian PKU families. Mutational screening of the known coding region, including conventional intron splice sites, was performed by direct sequencing of the patients' genomic DNA. Thirty-three different disease causing mutations were identified in our patient group, including 19 missense, 6 splicing, 3 nonsense, 5 deletions, with a detection rate of 100%. The most prevalent mutation was the IVS10-11G>A, accounting for 12.1% of PKU alleles studied. Other frequent mutations were: p.R261Q (9.1%), p.P281L (7.6%), and p.R408W (6.1%). We also identified one novel missense mutation, p.H290Q. A spectrum of 31 different genotypes was observed and a genotype based predictions of BH4-responsiveness were assessed. Among all genotypes, 13 were predicted to be BH4-responsive represented by thirteen PKU families. In addition, genotype-phenotype correlations were performed. This study reveals the importance of a full genotyping of PKU patients and the prediction of BH4-responsiveness, not only because of the definitive diagnosis and prediction of the optimal diet, but also to point out those patients that could benefit from new therapeutic approach. They may potentially benefit from BH4 therapy which, combined with a less strict diet, or eventually in special cases as monotherapy, may contribute to reduce nutritional deficiencies and minimize neurological and psychological dysfunctions.
authors.affiliation: Genetica Medica, Dipartimento di Medicina Clinica e Sperimentale, Università degli Studi di Foggia, Italy. Electronic address: roberta.trunzo@unifg.it.
authors.forename: Roberta
authors.initials: R
authors.lastname: Trunzo
authors.affiliation: Genetica Medica, Dipartimento di Medicina Clinica e Sperimentale, Università degli Studi di Foggia, Italy.
authors.forename: Rosa
authors.initials: R
authors.lastname: Santacroce
authors.affiliation: Genetica Medica, Dipartimento di Medicina Clinica e Sperimentale, Università degli Studi di Foggia, Italy.
authors.forename: Giovanna
authors.initials: G
authors.lastname: D'Andrea
authors.affiliation: Genetica Medica, Dipartimento di Medicina Clinica e Sperimentale, Università degli Studi di Foggia, Italy.
authors.forename: Vittoria
authors.initials: V
authors.lastname: Longo
authors.affiliation: Genetica Medica, Dipartimento di Medicina Clinica e Sperimentale, Università degli Studi di Foggia, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: De Girolamo
authors.affiliation: Genetica Medica, Dipartimento di Medicina Clinica e Sperimentale, Università degli Studi di Foggia, Italy.
authors.forename: Claudia
authors.initials: C
authors.lastname: Dimatteo
authors.affiliation: Genetica Medica, Dipartimento di Medicina Clinica e Sperimentale, Università degli Studi di Foggia, Italy.
authors.forename: Angelica
authors.initials: A
authors.lastname: Leccese
authors.affiliation: Genetica Medica, Dipartimento di Medicina Clinica e Sperimentale, Università degli Studi di Foggia, Italy.
authors.forename: Valeria
authors.initials: V
authors.lastname: Bafunno
authors.affiliation: Ospedale Pediatrico "Giovanni XXIII", Bari, Italy.
authors.forename: Vincenza
authors.initials: V
authors.lastname: Lillo
authors.affiliation: Ospedale Pediatrico "Giovanni XXIII", Bari, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Papadia
authors.affiliation: Genetica Medica, Dipartimento di Medicina Clinica e Sperimentale, Università degli Studi di Foggia, Italy.
authors.forename: Maurizio
authors.initials: M
authors.lastname: Margaglione
mesh_terms: D000293:Adolescent; D000328:Adult; D000483:Alleles; D001708:Biopterins / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D002648:Child; D002675:Child, Preschool; D004247:DNA / Q000235:genetics; D004032:Diet; D056726:Genetic Association Studies; D005838:Genotype; D006801:Humans; D007223:Infant; D007558:Italy; D009154:Mutation; D010641:Phenotype; D010649:Phenylalanine / Q000097:blood; D010661:Phenylketonurias / Q000178:diet therapy / Q000188:drug therapy* / Q000235:genetics*; D011379:Prognosis; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D001708:Biopterins; D010649:Phenylalanine; D004247:DNA; C003402:sapropterin
keywords: BH(4) responsiveness prediction; Genotype–phenotype correlation; Hyperphenylalaninemia