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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.

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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

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INTRODUCTION: Glutaric aciduria type I is an autosomal recessive inborn error of metabolism that is due to a deficiency of the enzyme glutaryl-CoA dehydrogenase, which gives rise to an accumulation of glutaric and 3-hydroxyglutaric acids in biological fluids. Clinical features present as a sudden-onset severe neurological disorder, characterised by extrapyramidal signs (dystonia-dyskinesia), hypotonia, irritability, macrocephaly and degeneration of the basal ganglia; it may also manifest with unspecific symptoms, such as hypotonia and psychomotor retardation. AIMS: To describe the clinical, biochemical, neuroimaging and molecular aspects in six Venezuelan patients and to highlight the importance of an early diagnosis of glutaric aciduria type I so as to be able to establish early treatment and thus prevent the neurological damage produced by this disease. CASE REPORTS: Two patients were referred because of macrocephaly, hypotonia and psychomotor retardation, and four more following an encephalopathic crisis. In all of them, neuroimaging studies showed delays in myelination, bilateral frontotemporal hypoplasia and symmetric widening of the Sylvian fissures with poor opercularisation. Urinary organic acid analyses showed raised levels of glutaric and 3-hydroxyglutaric acids, and a molecular analysis confirmed the diagnosis. CONCLUSIONS: Organic acid analysis should be indicated in all patients who present macrocephaly, hypotonia, psychomotor retardation or an encephalopathic crisis of unknown causation. This study allowed us to determine the behaviour of the disease in Venezuela, since no epidemiological data exist in the country.

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Introducción. La aciduria glutárica tipo I es un error congénito del metabolismo, con herencia autosómica recesiva, debido a la deficiencia de la enzima glutaril-CoA deshidrogenasa, que da lugar a la acumulación de ácido glutárico y 3-hidroxiglutárico en fluidos biológicos. El cuadro clínico se presenta como un trastorno neurológico grave, de inicio súbito, caracterizado por signos extrapiramidales (distonía-discinesia), hipotonía, irritabilidad, macrocefalia y degeneración de los ganglios basales; o puede manifestarse con síntomas inespecíficos, como hipotonía y retraso psicomotor. Objetivos. Describir los aspectos clínicos, bioquímicos, de neuroimagen y moleculares en seis pacientes venezolanos y resaltar la importancia del diagnóstico precoz de la aciduria glutárica tipo I para instaurar tratamiento temprano y evitar el daño neurológico que esta enfermedad produce. Casos clínicos. Se remitieron dos pacientes por macrocefalia, hipotonía y retraso psicomotor, y cuatro posteriores a una crisis encefalopática. Los estudios de neuroimagen mostraron en todos ellos retraso en la mielinización, hipoplasia frontotemporal bilateral y ensanchamiento simétrico de las cisuras de Silvio con pobre opercularización. El análisis de ácidos orgánicos en orina mostró niveles incrementados de los ácidos glutárico y 3-hidroxiglutárico, y el análisis molecular permitió la confirmación del diagnóstico. Conclusiones. En todo paciente que se presenta con macrocefalia, hipotonía, retraso psicomotor o una crisis encefalopática sin causa determinada debe indicarse el análisis de ácidos orgánicos. Este estudio permitió conocer el comportamiento de la enfermedad en Venezuela, ya que no existen datos epidemiológicos en el país

Introduction. Glutaric aciduria type I is an autosomal recessive inborn error of metabolism that is due to a deficiency of the enzyme glutaryl-CoA dehydrogenase, which gives rise to an accumulation of glutaric and 3-hydroxyglutaric acids in biological fluids. Clinical features present as a sudden-onset severe neurological disorder, characterised by extrapyramidal signs (dystonia-dyskinesia), hypotonia, irritability, macrocephaly and degeneration of the basal ganglia; it may also manifest with unspecific symptoms, such as hypotonia and psychomotor retardation. Aims. To describe the clinical, biochemical, neuroimaging and molecular aspects in six Venezuelan patients and to highlight the importance of an early diagnosis of glutaric aciduria type I so as to be able to establish early treatment and thus prevent the neurological damage produced by this disease. Case reports. Two patients were referred because of macrocephaly, hypotonia and psychomotor retardation, and four more following an encephalopathic crisis. In all of them, neuroimaging studies showed delays in myelination, bilateral frontotemporal hypoplasia and symmetric widening of the Sylvian fissures with poor opercularisation. Urinary organic acid analyses showed raised levels of glutaric and 3-hydroxyglutaric acids, and a molecular analysis confirmed the diagnosis. Conclusions. Organic acid analysis should be indicated in all patients who present macrocephaly, hypotonia, psychomotor retardation or an encephalopathic crisis of unknown causation. This study allowed us to determine the behaviour of the disease in Venezuela, since no epidemiological data exist in the country

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BACKGROUND: Isoflurane and halothane act in the spinal cord to blunt ascending transmission of impulses to the brain resulting from noxious stimulation. Because intrathecal picrotoxin (an antagonist at the gamma-aminobutyric acid-A receptor) partially reverses the immobilizing effect of isoflurane and halothane, we hypothesized that the electroencephalographic response to noxious stimulation would likewise be partially reversed by intrathecal picrotoxin. METHODS: Rats were anesthetized with isoflurane (n = 8) or halothane (n = 8) and a laminectomy performed. Following determination of minimum alveolar concentration (MAC), the electroencephalogram (EEG) was recorded during separate applications of a hindpaw clamp, tail clamp and electrical current to the tail at 0.8 and 1.2 MAC. Picrotoxin was then applied to the exposed spinal cord and the EEG response to noxious stimulation again determined. RESULTS: The EEG was more active during halothane anesthesia than isoflurane (spectral edge frequency for 95% power: 25.6 +/- 2.1 Hz vs. 23.1 +/- 1.6 Hz, P < 0.05). Noxious stimulation usually caused the EEG to shift to higher frequencies (e.g. for 0.8 MAC halothane, median edge frequency for 50% power: from 7.6 +/- 3.1 Hz to 10.7 +/- 2.6 Hz, P < 0.05). Picrotoxin minimally affected this response. CONCLUSIONS: Noxious stimulation evokes an EEG response that is minimally altered by intrathecal picrotoxin. This suggests that isoflurane and halothane do not have GABAergic actions in the spinal cord that indirectly suppress the EEG response.

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INTRODUCTION: Macrocephaly is a pivotal clinical sign, associated with multiple neurological diseases, particularly neurometabolical ones, such as the glutaric aciduria type I (GA I). This aciduria resulting from the genetical deficiency of the enzyme glutaryl-CoA dehydrogenase (GCDH). Is a relatively common cause of acute metabolic brain damage in early childhood. We report on one case of GA I, with early manifestations since fetal period and a novel mutation. CASE REPORT: Our patient was referred due macrocephaly in utero and occipitofrontal head circumference above the 98 percentile for chronologic age during first few months of life, hypotonia and development delay. The metabolic investigations of organic acids in urine and acylcarnitine profile in blood, the brain magnetic resonance and the molecular analyses of the glutaryl-CoA deshidrogenase gene, confirm the diagnosis. The molecular analysis allowed to identify one previously described mutation A293T and a novel mutation IVS5-2 A>G. CONCLUSION: It is important the recognition of in utero macrocephaly as a sign to early diagnosis of glutaric aciduria type I to initiate specific therapy to prevent the encephalopathic crises and minimize brain damage in patients who are already neurologically impaired.

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INTRODUCTION: L-2-hydroxyglutaric aciduria is a rare inborn error of metabolism, autosomal recessive, identified in about 50 patients. The primary defect is still unknown. The clinical phenotype is variable. Affected individuals show slowly progressive neurodegenerative disorder with cerebellar ataxia and mental retardation. Pyramidal, and extrapyramidal signs, seizures and macrocephaly have been reported. All patients previously described show a pattern of subcortical leukoencephalopathy with nearly empty gyral cores and cerebellar atrophy in neuroimaging studies. The diagnosis is established by detection of increased levels of L-2-hydroxyglutaric acid in urine, plasma and cerebrospinal fluid. CASE REPORTS: We here describe two patients 7 and 9 years old, who presented psychomotor retardation, seizures, progressive cognitive deterioration, and pyramidal, extrapyramidal and cerebellar signs. Magnetic resonance scanning of the brain demonstrated a bilateral subcortical leukoencephalopathy pattern and areas of increased T2-weighted signal in the basal ganglia and cerebellar dentate nuclei. The analysis of organic acids in urine by gas chromatography/mass spectrometry showed elevated 2-hydroxyglutaric acid, 100% of it in the form of L enantiomer. CONCLUSION: The diagnostic consideration is based on clinical findings and typical neuroimaging pattern and is established by detection of L-2-hydroxyglutaric acid in body fluids. Subcortical white matter loss is an important clue to diagnosis.

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BACKGROUND AND OBJECTIVES: Changes in uterine tone have been postulated as the cause of fetal bradycardia following subarachnoid administration of fentanyl for labor analgesia. Such a case occurred in a 20-year-old parturient with an intrauterine pressure catheter in place. METHODS: The patient was given intravenous terbutaline, after which contractions ceased for 20-30 minutes and then resumed. RESULTS: The patient underwent successful cesarean delivery. Retrospective analysis of the data revealed a significant increase in uterine tone and contractions following fentanyl administration. CONCLUSIONS: This case supports the view that changes in uterine tone, producing a hyperdynamic contractile state and a resulting decrease in uteroplacental perfusion, may explain the fetal bradycardia following subarachnoid opioid administration. Cases that do not resolve spontaneously may respond to intravenous terbutaline.

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