Phenylalanine hydroxylase deficiency: molecular epidemiology and predictable BH4-responsiveness in South Portugal PKU patients
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Phenylalanine hydroxylase deficiency: molecular epidemiology and predictable BH4-responsiveness in South Portugal PKU patients. / Rivera, Isabel; Mendes, Dina; Afonso, Ângela; Barroso, Madalena; Ramos, Ruben; Janeiro, Patrícia; Oliveira, Anabela; Gaspar, Ana; Tavares de Almeida, Isabel.
in: MOL GENET METAB, Jahrgang 104 Suppl, 2011, S. S86-92.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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TY - JOUR
T1 - Phenylalanine hydroxylase deficiency: molecular epidemiology and predictable BH4-responsiveness in South Portugal PKU patients
AU - Rivera, Isabel
AU - Mendes, Dina
AU - Afonso, Ângela
AU - Barroso, Madalena
AU - Ramos, Ruben
AU - Janeiro, Patrícia
AU - Oliveira, Anabela
AU - Gaspar, Ana
AU - Tavares de Almeida, Isabel
N1 - Copyright © 2011 Elsevier Inc. All rights reserved.
PY - 2011
Y1 - 2011
N2 - Hyperphenylalaninemia (HPA, OMIM #261600), which includes phenylketonuria (PKU), is caused by mutations in the gene encoding phenylalanine hydroxylase (PAH), being already described more than 600 different mutations. Genotype-phenotype correlation is a useful tool to predict the metabolic phenotype, to establish the better tailored diet and, more recently, to assess the potential responsiveness to BH(4) therapy, a current theme on PKU field. The aim of this study was the molecular analysis of the PAH gene, evaluation of genotype-phenotype relationships and prediction of BH(4)-responsiveness in the HPA population living in South Portugal. We performed the molecular characterization of 83 HPA patients using genomic DNA extracted from peripheral blood samples or Guthrie cards. PAH mutations were scanned by PCR amplification of exons and related intronic boundaries, followed by direct sequence analysis. Intragenic polymorphisms were determined by PCR-RFLP analysis. The results allowed the full characterization of 67 patients. The mutational spectrum encompasses 34 distinct mutations, being the most frequent IVS10nt-11G>A (14.6%), V388M (10.8%), R261Q (8.2%) and R270K (7.6%), which account for 46% of all mutant alleles. Moreover, 12 different haplotypes were identified and most mutations were associated with a single one. Notably, more than half of the 34 mutations belong to the group of more than 70 mutations already identified in BH(4)-responsive patients, according to BIOPKU database. Fifty one different genotypic combinations were found, most of them in single patients and involving a BH(4)-responsive mutation. In conclusion, a significant number (30-35%) of South Portugal PKU patients may potentially benefit from BH(4) 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.
AB - Hyperphenylalaninemia (HPA, OMIM #261600), which includes phenylketonuria (PKU), is caused by mutations in the gene encoding phenylalanine hydroxylase (PAH), being already described more than 600 different mutations. Genotype-phenotype correlation is a useful tool to predict the metabolic phenotype, to establish the better tailored diet and, more recently, to assess the potential responsiveness to BH(4) therapy, a current theme on PKU field. The aim of this study was the molecular analysis of the PAH gene, evaluation of genotype-phenotype relationships and prediction of BH(4)-responsiveness in the HPA population living in South Portugal. We performed the molecular characterization of 83 HPA patients using genomic DNA extracted from peripheral blood samples or Guthrie cards. PAH mutations were scanned by PCR amplification of exons and related intronic boundaries, followed by direct sequence analysis. Intragenic polymorphisms were determined by PCR-RFLP analysis. The results allowed the full characterization of 67 patients. The mutational spectrum encompasses 34 distinct mutations, being the most frequent IVS10nt-11G>A (14.6%), V388M (10.8%), R261Q (8.2%) and R270K (7.6%), which account for 46% of all mutant alleles. Moreover, 12 different haplotypes were identified and most mutations were associated with a single one. Notably, more than half of the 34 mutations belong to the group of more than 70 mutations already identified in BH(4)-responsive patients, according to BIOPKU database. Fifty one different genotypic combinations were found, most of them in single patients and involving a BH(4)-responsive mutation. In conclusion, a significant number (30-35%) of South Portugal PKU patients may potentially benefit from BH(4) 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.
KW - Biopterin
KW - Child, Preschool
KW - DNA Mutational Analysis
KW - Genetic Association Studies
KW - Haplotypes
KW - Humans
KW - Molecular Epidemiology
KW - Phenotype
KW - Phenylalanine Hydroxylase
KW - Phenylketonurias
KW - Portugal
KW - Journal Article
U2 - 10.1016/j.ymgme.2011.07.026
DO - 10.1016/j.ymgme.2011.07.026
M3 - SCORING: Journal article
C2 - 21871829
VL - 104 Suppl
SP - S86-92
JO - MOL GENET METAB
JF - MOL GENET METAB
SN - 1096-7192
ER -
