Molecular epidemiology, genotype-phenotype correlation and BH4 responsiveness in Spanish patients with phenylketonuria.
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.
Unit of Metabolism, Cruces University Hospital, BioCruces Health Research Institute, GCV-CIBER de Enfermedades Raras (CIBERER), Plaza de Cruces s/n, Barakaldo, Spain.
Luis
L
Aldámiz-Echevarría
Unit of Metabolism, Cruces University Hospital, BioCruces Health Research Institute, GCV-CIBER de Enfermedades Raras (CIBERER), Plaza de Cruces s/n, Barakaldo, Spain.
Marta
M
Llarena
Metabolic Disorders, Dietetics and Nutrition Unit, Virgen del Rocío University Hospital, Manuel Siurot Avenue s/n, Sevilla, Spain.
María A
MA
Bueno
Nutrition and Metabolopathologies Unit, La Fe University Hospital, Bulevar Sur s/n, Valencia, Spain.
Jaime
J
Dalmau
Nutrition and Metabolopathologies Unit, La Fe University Hospital, Bulevar Sur s/n, Valencia, Spain.
Isidro
I
Vitoria
Unit of Diagnosis and Treatment of Congenital Metabolic Diseases, Department of Pediatrics, Hospital Clínico Universitario de Santiago de Compostela, CIBERER, Health Research Institute of Santiago de Compostela (IDIS), A Choupana, s/n, Santiago de Compostela, A Coruña, Spain.
Ana
A
Fernández-Marmiesse
Unit of Metabolism, Cruces University Hospital, BioCruces Health Research Institute, GCV-CIBER de Enfermedades Raras (CIBERER), Plaza de Cruces s/n, Barakaldo, Spain.
Fernando
F
Andrade
Gastroenterology, Hepatology and Child Nutrition Unit, Carlos Haya University Hospital, Avda. Arroyo de los Ángeles s/n, Málaga, Spain.
Javier
J
Blasco
Paediatrics Unit, Río Hortega University Hospital, Valladolid, Spain.
Carlos
C
Alcalde
Gastroenterology Unit, Virgen de la Arrixaca University Hospital, Ctra. Madrid-Cartagena s/n, El Palmar, Murcia, Spain.
David
D
Gil
Metabolic Pathologies Unit, Miguel Servet University Hospital, Zaragoza, Spain.
María C
MC
García
Nephrology and Metabolism Unit, Marqués de Valdecilla University Hospital, Santander, Spain.
Domingo
D
González-Lamuño
Paediatrics Unit, Nuestra Señora de la Candelaria University Hospital, Santa Cruz de Tenerife, Spain.
Mónica
M
Ruiz
Metabolic Pathologies and Neuropaediatrics Unit, Son Espases University Hospital, Palma de Mallorca, Spain.
María A
MA
Ruiz
Paediatric Gastroenterology, Hepatology and Nutrition Unit, Mother and Child Hospital Complex, Avda. Marítima del Sur s/n, Las Palmas de Gran Canaria, Spain.
Luis
L
Peña-Quintana
Metabolic Pathologies Unit, Maternal and Child Hospital, Badajoz, Spain.
David
D
González
Gastroenterology and Paediatric Nutrition Unit, Virgen del Camino Hospital, Pamplona, Spain.
Felix
F
Sánchez-Valverde
Centro de Diagnóstico de Enfermedades Moleculares, Centro de Biología Molecular Severo Ochoa CSIC-UAM, CIBERER, IdiPaz, Madrid, Spain.
Lourdes R
LR
Desviat
Centro de Diagnóstico de Enfermedades Moleculares, Centro de Biología Molecular Severo Ochoa CSIC-UAM, CIBERER, IdiPaz, Madrid, Spain.
Belen
B
Pérez
Unit of Diagnosis and Treatment of Congenital Metabolic Diseases, Department of Pediatrics, Hospital Clínico Universitario de Santiago de Compostela, CIBERER, Health Research Institute of Santiago de Compostela (IDIS), A Choupana, s/n, Santiago de Compostela, A Coruña, Spain.
María L
ML
Couce
D000483:Alleles; D056947:Enzyme Replacement Therapy; D005787:Gene Frequency; D056726:Genetic Association Studies; D018740:Genetic Heterogeneity; D005838:Genotype; D006801:Humans; D017720:Molecular Epidemiology; D009154:Mutation; D010641:Phenotype; D010651:Phenylalanine Hydroxylase / Q000235:genetics* / Q000378:metabolism; D010661:Phenylketonurias / Q000175:diagnosis / Q000453:epidemiology* / Q000235:genetics* / Q000628:therapy; D013030:Spain / Q000453:epidemiology
D010651:Phenylalanine Hydroxylase