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.
The mainstay of treating patients with phenylketonuria (PKU) is based on a Phe-restricted diet, restrictive in natural protein combined with Phe-free L-amino acid supplements and low protein foods. ...This PKU diet seems to reduce atherogenesis and confer protection against cardiovascular diseases but the results from the few published studies have been inconclusive. The aim of our study was to evaluate the relationship between the lipid profile and several treatment-related risk factors in patients with hyperphenylalaninaemia (HPA) in order to optimize their monitoring.
We conducted a cross-sectional multicentre study. A total of 141 patients with HPA were classified according to age, phenotype, type of treatment and dietary adherence. Annual median blood phenylalanine (Phe) levels, Phe tolerance, anthropometric measurements, blood pressure (BP) and biochemical parameters (triglycerides, total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), low density lipoprotein-cholesterol (LDL-C), apolipoprotein A (ApoA), apolipoprotein B (ApoB), vitamin B12, total homocysteine (tHcy), Methionine (Met), high sensitivity C-Reactive Protein (hsCRP) were collected for each patient.
Plasma TC levels were lower in patients with PKU than in the mild-HPA group (150 ± 31 vs. 164 ± 22 mg/dL), and there was a weak inverse correlation between plasma TC and Phe levels. HDL-C, LDL-C, ApoA and ApoB levels were lower in the PKU group than in mild-HPA. Patients with PKU had higher systolic BP than the mild-HPA group and there was found a quadratic correlation between median Phe levels and systolic BP (p = 6.42e(-5)) and a linear correlation between median Phe levels and diastolic BP (p = 5.65e(-4)). In overweight or obese PKU patients (24.11 %), biochemical parameters such as TC, triglycerides, LDL-C, tHcy, hsCRP and BP were higher. By contrast, HDL-C was lower in these patients.
Our data show a direct correlation between lipid profile parameters and good adherence to the diet in PKU patients. However, lipid profile in overweight or obese patients displayed an atherogenic profile, in addition to higher hsCRP concentrations and BP. Our study contributes to a better understanding of the relationship between phenotype and treatment in patients with HPA, which could be useful in improving follow-up strategies and clinical outcome.
Research Ethics Committee of Santiago-Lugo 2015/393. Registered 22 September 2015, retrospectively registered.
OBJETIVOS
Comparar la efectividad de tres estrategias de de-implementación dirigidas al proceso de toma de decisiones clínicas para reducir la prescripción potencialmente inapropiada (PIP) de ...estatinas en prevención primaria de la enfermedad cardiovascular (ECV) en pacientes de bajo riesgo.
MATERIAL Y MÉTODOS
Ensayo experimental con grupo de control emparejado adicional con la participación de 118 médicos/médicas de familia (MF) de Osakidetza con una tasa basal de incidencia anual de PIP de estatinas > 0. Todos los MF están expuestos a una estrategia «no reflexiva» de ayuda a la toma de decisiones clínicas basada en avisos y recordatorios incorporadas en la historia clínica. A un grupo de dichos profesionales (n = 59) se le asignó aleatoriamente a recibir además una estrategia de información basada en los principios de difusión del conocimiento, mientras que un segundo grupo (n = 59) recibió adicionalmente una estrategia reflexiva basada en informes de auditoría/feedback. La medida principal de resultado es la tasa de nuevas PIP de estatinas a los 6 meses de la puesta en marcha de las estrategias, en mujeres de 45-74 años u hombres de 40-74 años sin ECV, con colesterol elevado y un riesgo cardiovascular
RESULTADOS
Tras 6 meses de implantación de las estrategias, con respecto a la tasa de entrada en estudio, se observó una reducción relativa del riesgo (RRR) de recibir una PIP de estatinas de un 31% en el grupo de profesionales expuestos a la estrategia de ayudas y diseminación, mientras que en el grupo de auditoría/feedback se logró una reducción de un 45%.
CONCLUSIONES
Las estrategias de de-implementación dirigidas a la toma de decisiones clínicas muestran ser factibles y efectivas para reducir la PIP de estatinas en prevención primaria de la ECV en Atención Primaria.
CEI
El presente estudio cuenta con la aprobación del Comité Ético de Investigación con Medicamentos de Euskadi, con código interno EOM2022018 y recogido en acta 06/2022.
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 BH sub(4) 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. BH sub(4) responsiveness was evaluated using a 6R-BH sub(4) loading test. We assessed genotype-phenotype associations and genotype-BH sub(4) 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-BH sub(4) loading test: 102 were responders (87, carried either one or two BH sub(4)-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 BH sub(4) responsiveness, which is relevant for patient management, treatment and follow-up.
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