RT Journal Article
T1 Molecular epidemiology, genotype-phenotype correlation and BH4 responsiveness in Spanish patients with phenylketonuria.
A1 Aldamiz-Echevarria, Luis
A1 Llarena, Marta
A1 Bueno, Maria A
A1 Dalmau, Jaime
A1 Vitoria, Isidro
A1 Fernandez-Marmiesse, Ana
A1 Andrade, Fernando
A1 Blasco, Javier
A1 Alcalde, Carlos
A1 Gil, David
A1 García, María C
A1 Gonzalez-Lamuño, Domingo
A1 Ruiz, Monica
A1 Ruiz, Maria A
A1 Peña-Quintana, Luis
A1 Gonzalez, David
A1 Sanchez-Valverde, Felix
A1 Desviat, Lourdes R
A1 Perez, Belen
A1 Couce, Maria L
K1 Alleles
K1 Enzyme Replacement Therapy
K1 Gene Frequency
K1 Genetic Association Studies
K1 Genetic Heterogeneity
AB 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.
PB Nature Publishing Group
YR 2016
FD 2016-04-28
LK http://hdl.handle.net/10668/10033
UL http://hdl.handle.net/10668/10033
LA en
NO Aldámiz-Echevarría L, Llarena M, Bueno MA, Dalmau J, Vitoria I, Fernández-Marmiesse A, et al. Molecular epidemiology, genotype-phenotype correlation and BH4 responsiveness in Spanish patients with phenylketonuria. J Hum Genet. 2016 Aug;61(8):731-44
DS RISalud
RD Aug 7, 2025