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Molecular epidemiology, genotype–phenotype correlation and BH 4 responsiveness in Spanish patients with phenylketonuria
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نویسنده
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Aldámiz-Echevarría Luis ,Llarena Marta ,Bueno María A ,Dalmau Jaime ,Vitoria Isidro ,Fernández-Marmiesse Ana ,Andrade Fernando ,Blasco Javier ,Alcalde Carlos ,Gil David ,García María C ,González-Lamuño Domingo ,Ruiz Mónica ,Ruiz María A ,Peña-Quintana Luis ,González David ,Sánchez-Valverde Felix ,Desviat Lourdes R ,Pérez Belen ,Couce María L
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منبع
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journal of human genetics - 2016 - دوره : 61 - شماره : 8 - صفحه:731 -744
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چکیده
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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.
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آدرس
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Cruces University Hospital, Unit of Metabolism, Spain, Cruces University Hospital, Unit of Metabolism, Spain, Virgen del Rocío University Hospital, Dietetics and Nutrition Unit, Spain, La Fe University Hospital, Nutrition and Metabolopathologies Unit, Spain, La Fe University Hospital, Nutrition and Metabolopathologies Unit, Spain, Health Research Institute of Santiago de Compostela (IDIS), Department of Pediatrics, Unit of Diagnosis and Treatment of Congenital Metabolic Diseases, Spain, Cruces University Hospital, Unit of Metabolism, Spain, Carlos Haya University Hospital, Hepatology and Child Nutrition Unit, Spain, Río Hortega University Hospital, Paediatrics Unit, Spain, Virgen de la Arrixaca University Hospital, Gastroenterology Unit, Spain, Miguel Servet University Hospital, Metabolic Pathologies Unit, Spain, Marqués de Valdecilla University Hospital, Nephrology and Metabolism Unit, Spain, Nuestra Señora de la Candelaria University Hospital, Paediatrics Unit, Spain, Son Espases University Hospital, Metabolic Pathologies and Neuropaediatrics Unit, Spain, Mother and Child Hospital Complex, Hepatology and Nutrition Unit, Spain, Maternal and Child Hospital, Metabolic Pathologies Unit, Spain, Virgen del Camino Hospital, Gastroenterology and Paediatric Nutrition Unit, Spain, Centro de Biología Molecular Severo Ochoa CSIC-UAM, Spain, Centro de Biología Molecular Severo Ochoa CSIC-UAM, Spain, Health Research Institute of Santiago de Compostela (IDIS), Department of Pediatrics, Unit of Diagnosis and Treatment of Congenital Metabolic Diseases, Spain
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Authors
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