[Clinical findings and mutational spectrum in Venezuelan patients with delayed diagnosis of phenylketonuria]. / Hallazgos clínicos y espectro mutacional en pacientes venezolanos con diagnóstico tardío de fenilcetonuria.

INTRODUCTION: Massive neonatal screening for phenylketonuria (PKU) began in developed countries in 1963, and eventually disappeared as a cause of mental retardation. Yet, this is not the case in most developing countries. AIM: To describe the phenotype and the genotype of PKU patients with a delayed diagnosis in order to draw attention to the importance of neonatal studies and molecular diagnosis. PATIENTS AND METHODS: Clinical data were collected from five unrelated patients by means of a medical assessment. The molecular study was conducted using the DGGE, sequencing and/or restriction analysis techniques to search for mutations in the PAH gene. RESULTS. Owing to the delayed diagnosis all the patients presented severe clinical manifestations, such as psychomotor retardation, atypical behaviours and language disorders. Four of them presented epilepsy and there were two cases of microcephaly. The phenotype was as expected, given the genotype. Seven different mutations were detected in the 10 alleles that were studied. The IVS10nt +5 g>t mutation was the most frequent, followed by the Venezuelan mutation S349L. Furthermore, two patients presented mutated proteins with residual activity, and good results were obtained using BH4 therapy. CONCLUSIONS: In our country, as in most developing countries, PKU neonatal studies are performed but the programme does not cover the whole neonatal population. In this work, we want to stress the importance of neonatal studies in the welfare of children, as well as the use of molecular diagnosis to improve the therapeutic orientation and genetic counselling of the families involved.

Hallazgos clínicos y espectro mutacional en pacientes venezolanos con diagnóstico tardío de fenilcetonuria / Clincial findings and mutational spectrum in Venezuelan patients with delayed diagnosis of phenylketonuria

Introducción. En 1963 comenzó el cribado neonatal masivo de fenilcetonuria (PKU) en países desarrollados, queacabó desapareciendo como causa de retraso mental. Sin embargo, éste no es el caso en la mayoría de los países en vías de desarrollo. Objetivo. Describir el fenotipo y el genotipo de pacientes con diagnóstico tardío de PKU, con el fin de resaltar la importancia del estudio neonatal y el diagnóstico molecular. Pacientes y métodos. Se recogieron datos clínicos de cinco pacientes no relacionados mediante evaluación médica. El estudio molecular se realizó empleando las técnicas de DGGE, secuenciación y/o análisis de restricción para la búsqueda de mutaciones en el gen PAH. Resultados. Todos los pacientes presentaronmanifestaciones clínicas graves debidas al diagnóstico tardío, como retraso psicomotor, conductas atípicas y trastornos del lenguaje. Cuatro de ellos presentaron epilepsia y dos, microcefalia. El fenotipo fue el esperado de acuerdo con el genotipo. Se detectaron siete mutaciones diferentes en los 10 alelos estudiados. La mutación IVS10nt+5g>t fue la más frecuente,seguida de la mutación venezolana S349L. Por otra parte, dos pacientes presentan proteínas mutadas con actividadresidual, y pudieron verse beneficiados de la terapia con BH4. Conclusiones. En Venezuela, al igual que en gran parte de los países en vías de desarrollo, se realiza el estudio neonatal de PKU pero el programa no cubre toda la población neonatal. En este trabajo se quiere destacar la importancia del estudio neonatal en el bienestar de los niños, y el uso del diagnóstico molecular para mejorar la orientación terapéutica y la asesoría genética de la familia

Introduction. Massive neonatal screening for phenylketonuria (PKU) began in developed countries in 1963, and eventually disappeared as a cause of mental retardation. Yet, this is not the case in most developing countries. Aim. To describe the phenotype and the genotype of PKU patients with a delayed diagnosis in order to draw attention to the importance of neonatal studies and molecular diagnosis. Patients and methods. Clinical data were collected from five unrelated patients by means of a medical assessment. The molecular study was conducted using the DGGE, sequencing and/or restriction analysis techniques to search for mutations in the PAH gene. Results. Owing to the delayed diagnosis all thepatients presented severe clinical manifestations, such as psychomotor retardation, atypical behaviours and language disorders. Four of them presented epilepsy and there were two cases of microcephaly. The phenotype was as expected, given the genotype. Seven different mutations were detected in the 10 alleles that were studied. The IVS10nt+5g>t mutation was themost frequent, followed by the Venezuelan mutation S349L. Furthermore, two patients presented mutated proteins with residual activity, and good results were obtained using BH4 therapy. Conclusions. In our country, as in most developingcountries, PKU neonatal studies are performed but the programme does not cover the whole neonatal population. In this work, we want to stress the importance of neonatal studies in the welfare of children, as well as the use of molecular diagnosis to improve the therapeutic orientation and genetic counselling of the families involved