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Molecular epidemiology, genotype-phenotype correlation and BH4 responsiveness in Spanish patients with phenylketonuria

Data de publicació:

Autors de IIS La Fe

Autors aliens a IIS La Fe

  • Aldamiz-Echevarria, L
  • Llarena, M
  • Bueno, MA
  • Fernandez-Marmiesse, A
  • Andrade, F
  • Blasco, J
  • Alcalde, C
  • Gil, D
  • Garcia, MC
  • Gonzalez-Lamuno, D
  • Ruiz, M
  • Ruiz, MA
  • Pena-Quintana, L
  • Gonzalez, D
  • Sanchez-Valverde, F
  • Desviat, LR
  • Perez, B
  • Couce, ML

Grups d'Investigació

Abstract

Phenylketonuria (PKU), the most common inborn error of amino acid metabolism, is caused by mutations in the phenylalanine-4-hydroxylase (PAH) gene. This study aimed to assess the genotype-phenotype correlation in the PKU Spanish population and the usefulness in establishing genotype-based predictions of BH4 responsiveness in our population. It involved the molecular characterization of 411 Spanish PKU patients: mild hyperphenylalaninemia non-treated (mild HPA-NT) (34%), mild HPA (8.8%), mild-moderate (20.7%) and classic (36.5%) PKU. BH4 responsiveness was evaluated using a 6R-BH4 loading test. We assessed genotype-phenotype associations and genotype-BH4 responsiveness in our population according to literature and classification of the mutations. The mutational spectrum analysis showed 116 distinct mutations, most missense (70.7%) and located in the catalytic domain (62.9%). The most prevalent mutations were c.1066-11G>A (9.7%), p.Val388Met (6.6%) and p.Arg261Gln (6.3%). Three novel mutations (c.61-13del9, p.Ile283Val and p.Gly148Val) were reported. Although good genotype-phenotype correlation was observed, there was no exact correlation for some genotypes. Among the patients monitored for the 6R-BH4 loading test: 102 were responders (87, carried either one or two BH4-responsive alleles) and 194 non-responders (50, had two non-responsive mutations). More discrepancies were observed in non-responders. Our data reveal a great genetic heterogeneity in our population. Genotype is quite a good predictor of phenotype and BH4 responsiveness, which is relevant for patient management, treatment and follow-up.

Dades de la publicació

ISSN/ISSNe:
1434-5161, 1435-232X

JOURNAL OF HUMAN GENETICS  NATURE PUBLISHING GROUP

Tipus:
Article
Pàgines:
731-744
PubMed:
27121329
Factor d'Impacte:
1,280 SCImago ℠
Quartil:
Q2 SCImago ℠

Cites Rebudes en Web of Science: 23

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