Presentación tardía de una deficiencia de carbamilfosfato sintetasa 1 en un niño de 6 años / Late-onset presentation of carbamoyl phosphate synthetase 1 deficiency in a 6-year-old boy

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[Pyruvate dehydrogenase deficit associated to the C515T mutation in exon 6 of the E1alpha gene]. / Deficit de piruvato deshidrogenasa asociado a la mutacion C515T en el exon 6 del gen E1alpha.

INTRODUCTION: Pyruvate dehydrogenase (PDH) deficiency constitutes the most frequent metabolic origin of congenital lactic acidosis and is also responsible for a less usual form, found exclusively in females, which leads to a dysmorphic syndrome accompanied by severe cerebral malformations. The most common defect affects fraction E1alpha (gene Xp22.1-22.2). AIM: To report the case of a young female with PDH deficiency, dysmorphic syndrome, cerebral deformations and an unidentified mutation in the corresponding gene. CASE REPORT: An 8-month-old female with microcephaly, a narrow forehead, nasal hypoplasia, anteverted nostrils, thin lips, axial hypotonia, epileptic seizures and an umbilical hernia. Magnetic resonance imaging of the brain revealed intense supra- and infratentorial cortico-subcortical atrophy, ventricular dilatation and agenesis of the corpus callosum. Lactic and pyruvic acid concentrations were high both in blood and in cerebrospinal fluid (CSF), and the level of alanine was high in CSF. Muscular histology results were normal. PDH complex activity in fibroblasts and in muscle tissue, as well as that of the mitochondrial respiratory chain complexes in muscle homogenate, were found to be normal. A molecular genetic study of the gene for PDHE1alpha, both in formed elements in the blood and in fibroblasts, showed a C > T change in nucleotide 515 (C515T) of exon 6, which causes a P172L change in the protein. A study of 108 controls ruled out the possibility of a polymorphism. The parents did not have the mutation. CONCLUSIONS: The C515T mutation of exon 6 of the gene for PDH E1alpha is described. Normal activity of the PDH complex in fibroblasts and in muscle tissue does not exclude this condition.

Deficit de piruvato deshidrogenasa asociado a la mutación C515T en el exon 6 del gen E1 / Pyruvate dehydrogenase deficit associated to the C515T mutation in exon 6 of the E1 gene

Introducción. La deficiencia de piruvato deshidrogenasa(PDH) constituye la base metabólica más frecuente de las acidosislácticas congénitas y también es responsable de una forma menoshabitual, exclusiva del sexo femenino, que cursa con un síndromedismórfico asociado a graves malformaciones cerebrales. El defectomás común afecta a la fracción E1α (gen Xp22.1-22.2). Objetivo.Presentar el caso de una niña con deficiencia de PDH, síndromedismórfico, malformaciones cerebrales y una mutación no descritaen el gen correspondiente. Caso clínico. Niña de 8 meses deedad con microcefalia, frente estrecha, hipoplasia nasal, narinasantevertidas, labios finos, hipotonía axial, crisis epilépticas y herniaumbilical. La resonancia magnética cerebral evidenció unaatrofia corticosubcortical intensa supra e infratentorial, dilataciónventricular y agenesia del cuerpo calloso. Las concentraciones deácido láctico y pirúvico estaban elevadas en la sangre y el líquidocefalorraquídeo (LCR), y la de alanina estaba elevada en el LCR.La histología muscular fue normal. La actividad del complejo de laPDH en los fibroblastos y en el músculo, así como la de los complejosde la cadena respiratoria mitocondrial en homogenado muscular,fueron normales. El estudio genético molecular del gen parala PDH E1α, tanto en elementos formes de la sangre como en fibroblastos,demostró un cambio C > T en el nucleótido 515 (C515T)del exón 6, que causa un cambio P172L en la proteína. El estudio de108 controles descartó que se tratase de un polimorfismo. Los padresno presentaban la mutación. Conclusiones. Se describe la mutaciónC515T en el exón 6 del gen para la PDH E1α. La actividadnormal del complejo de la PDH en los fibroblastos y en el músculono excluye esta entidad

Introduction. Pyruvate dehydrogenase (PDH) deficiency constitutes the most frequent metabolic origin of congenitallactic acidosis and is also responsible for a less usual form, found exclusively in females, which leads to a dysmorphicsyndrome accompanied by severe cerebral malformations. The most common defect affects fraction E1α (gene Xp22.1-22.2).Aim. To report the case of a young female with PDH deficiency, dysmorphic syndrome, cerebral deformations and anunidentified mutation in the corresponding gene. Case report. An 8-month-old female with microcephaly, a narrow forehead,nasal hypoplasia, anteverted nostrils, thin lips, axial hypotonia, epileptic seizures and an umbilical hernia. Magneticresonance imaging of the brain revealed intense supra- and infratentorial cortico-subcortical atrophy, ventricular dilatationand agenesis of the corpus callosum. Lactic and pyruvic acid concentrations were high both in blood and in cerebrospinalfluid (CSF), and the level of alanine was high in CSF. Muscular histology results were normal. PDH complex activity infibroblasts and in muscle tissue, as well as that of the mitochondrial respiratory chain complexes in muscle homogenate, werefound to be normal. A molecular genetic study of the gene for PDH E1α, both in formed elements in the blood and infibroblasts, showed a C > T change in nucleotide 515 (C515T) of exon 6, which causes a P172L change in the protein. A studyof 108 controls ruled out the possibility of a polymorphism. The parents did not have the mutation. Conclusions. The C515Tmutation of exon 6 of the gene for PDH E1α is described. Normal activity of the PDH complex in fibroblasts and in muscletissue does not exclude this condition

[Galactosemia: the genotype and phenotype of seven patients]. / Galactosemia: genotipo y fenotipo de siete pacientes.

INTRODUCTION: Despite early dietary therapy, many patients with galactosemia show a neurodegenerative disease specially evident in speech impairment and movement disorders. Magnetic resonance imaging of the brain, show cerebral white matter changes with hypomielinization bilateral and symetrical periventricular hypersignal in T2. PATIENTS AND METHODS: We presented clinical and neuroradiological data of seven children (3 to 12 years of age) with classical galactosemia. All had a typical presentation in neonatal period. Two children had normal development (10 and 12 years-old), four presented developmental delay (10, 7, 4 and 3 years-old), and one showed a dystonic cerebral palsy (kernicterus). RESULTS: The brain MRI showed the typical involvement of white matter, in five children, and basal ganglia abnormalities in the kernicterus patient. Three patients are homozygous for Q188R mutation and two are compound heterozygous. CONCLUSION: We found a positive correlation among developmental delay, white matter involvement and Q188R mutation.

Galactosemia: genotipo y fenotipo de siete pacientes / Galactosemia: the genotype and phenotype of seven patients

Introducción. A pesar de los tratamientos precoces basados en la nutrición, muchos pacientes con galactosemia presentan una enfermedad neurodegenerativa que se manifiesta fundamentalmente a través de alteraciones del lenguaje y discinesias. En las imágenes obtenidas mediante la resonancia magnética (RM) cerebral se pueden visualizar dos tipos distintos de alteraciones: una primera, que se manifiesta con hiperseñal difusa y poco intensa de la sustancia blanca de los centros semiovales, y una segunda, con focos de hiperseñal más intensos rodeando las puntas ventriculares de predominio posterior. Pacientes y métodos. Presentamos los datos clínicos y de imagen de siete niños de edades comprendidas entre los 3 y los 12 años con galactosemia clásica. El inicio había ocurrido típicamente durante la lactancia. Dos niños se desarrollaron de forma normal (10 y 12 años), cuatro presentaban un retraso del desarrollo (10, 7, 4 y 3 años) y uno presentaba una parálisis cerebral distónica (kernícterus). Resultados. La RM cerebral reveló la afectación típica de la sustancia blanca en cinco de los niños: uno con alteración difusa y cuatro con ambos tipos de alteraciones. El paciente con kernícterus mostró lesiones en los ganglios basales. Tres pacientes son homocigóticos para la mutación Q188R, y dos son heterocigóticos compuestos. Conclusión. Se ha hallado una correlación positiva entre el retraso en el desarrollo, la afectación de la sustancia blanca y la mutación clásica Q188R (AU)

Introduction. Despite early dietary therapy, many patients with galactosemia show a neurodegenerative disease specially evident in speech impairment and movement disorders. Magnetic resonance imaging of the brain, show cerebral white matter changes with hypomielinization bilateral and symetrical periventricular hypersignal in T2. Patients and methods. We presented clinical and neuroradiological data of seven children (3 to 12 years of age) with classical galactosemia. All had a typical presentation in neonatal period. Two children had normal development (10 and 12 years-old), four presented developmental delay (10, 7, 4 and 3 years-old), and one showed a dystonic cerebral palsy (kernicterus). Results. The brain MRI showed the typical involvement of white matter, in five children, and basal ganglia abnormalities in the kernicterus patient. Three patients are homozygous for Q188R mutation and two are compound heterozygous. Conclusion. We found a positive correlation among developmental delay, white matter involvement and Q188R mutation (AU)

[Severe fulminant form of neonatal citrullinemia. Report of a case]. / Forma grave fulminante de citrulinemia neonatal. Comunicación de un caso.

INTRODUCTION: Citrullinemia is an autosomal recessive disease, which is caused by a deficiency of the argininosuccinate synthetase. The neonatal forms are serious and many times are associated with a high level of mortality. CASE REPORT: A newborn that came in again on her third day of life due to a apneic episodes which required mechanical ventilation. Previously, she rejected feeding, had poor suction, lethargy and remarkable hypoactivity. During the following hours, she showed serious neurologycal deterioration with multifocal convulsions and coma, passing away 20 hours after admission due to endocraneal hypertension. The metabolic evaluation confirmed very significant hyperammonemia, with important increase of citrullin and glutamin, and arginine in the low limits of normality. She was treated with sodium benzoate and arginine and she also needed exanguinotransfusion. It was not possible to put her on hemodyalisis. The findings of the autopsy confirmed massive cerebral edema and characteristic hystological changes in the liver. The determination of the enzymatical activity in liver tissue showed a partial deficiency, with a residual activity of 25% of the average control. CONCLUSIONS: This is a case of fulminant neonatal citrullinemia that we considered of interest in order to draw the attention of the clinical on this type of diseases. The prognosis depends on early diagnosis, witch is based on clinical suspicion and analytical determination of ammonia in every newborn with unexplained vomiting, lethargy or other symptoms of encephalopathy.

Forma grave fulminante de citrulinemia neonatal. Comunicación de un caso / Severe fulminant form of neonatal citrullinemia. Report of a case

Introducción. La citrulinemia es una afección autosómica recesiva, debida a una deficiencia de la argininsuccinato sintetasa (ASS); las formas neonatales son graves y se asocian a un alto índice de mortalidad. Caso clínico. Recién nacida que reingresa al tercer día de vida por episodios apneicos, que requirieron intubación y ventilación mecánica. Previamente, presentó rechazo de las tomas, mala succión, letargia e hipoactividad marcada. En las horas siguientes presentó grave deterioro neurológico, con convulsiones multifocales y coma; falleció a las 20 horas de su ingreso por un cuadro de hipertensión endocraneal. La evaluación metabólica confirmó una hiperamonemia muy significativa, con importante aumento de citrulina y glutamina, adsí como arginina en los límites bajos de la normalidad. Se trató con benzoato sódico y arginina, y se le realizó una exanguinotransfusión de doble volumen; no fue posible practicarle hemodiálisis. Los hallazgos de la autopsia confirmaron un edema cerebral masivo y cambios histológicos característicos en el hígado. La medida de la actividad enzimática en el tejido hepático reveló una deficiencia parcial, con una actividad residual del 25 por ciento de la media control. Conclusión. Se trata de una observación de citrulinemia neonatal de curso fulminante que consideramos de interés, con la finalidad de alertar al clínico sobre este tipo de patología, ya que el pronóstico se va a relacionar con el diagnóstico precoz, basado en la sospecha clínica y determinación del amonio en todo recién nacido con vómitos inexplicables, letargia u otros signos de encefalopatía (AU)

Introduction. Citrullinemia is an autosomal recessive disease, which is caused by a deficiency of the argininosuccinate synthetase. The neonatal forms are serious and many times are associated with a high level of mortality. Case report. A newborn that came in again on her third day of life due to a apneic episodes which required mechanical ventilation. Previously, she rejected feeding, had poor suction, lethargy and remarkable hypoactivity. During the following hours, she showed serious neurologycal deterioration with multifocal convulsions and coma, passing away 20 hours after admission due to endocraneal hypertension. The metabolic evaluation confirmed very significant hyperammonemia, with important increase of citrullin and glutamin, and arginine in the low limits of normality. She was treated with sodium benzoate and arginine and she also needed exanguinotransfusion. It was not possible to put her on hemodyalisis. The findings of the autopsy confirmed massive cerebral edema and characteristic hystological changes in the liver. The determination of the enzymatical activity in liver tissue showed a partial deficiency, with a residual activity of 25% of the average control. Conclusions. This is a case of fulminant neonatal citrullinemia that we considered of interest in order to draw the attention of the clinical on this type of diseases. The prognosis depends on early diagnosis, witch is based on clinical suspicion and analytical determination of ammonia in every newborn with unexplained vomiting, lethargy or other symptoms of encephalopathy (AU)

Síndrome de Reye-like como manifestación inicial de enfermedad mitocondrial / Reye-like syndrome as an initial manifestation of a mitochondrial disease

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[Ornithine transcarbamylase deficiency. Biochemical studies in the diagnosis of 4 cases and the identification of carriers]. / Deficiencia de ornitina carbamil transferasa. Estudios bioquímicos realizados para el diagnóstico de cuatro casos y la identificación de portadores.

The biochemical studies for the diagnosis of four cases of OCT deficiency are described: two male sibs, with total enzymatic deficiency and neonatal death, and two symptomatic heterozygous females. The enzymatic activity was determined in hepatic necropsy or duodenal biopsy from these patients and carriers were identified among their relatives. The usefulness of the enzymatic analysis compared with the protein loading test followed by the determination of ammonia and orotic acid for the female carrier detection is discussed, and the interest of their identification to prevent the risk of hyperammonemic crisis with possible neurologic sequels is stressed.

[Sudden death of a patient with 3-hydroxy-3-methylglutaryl coenzyme A lyase deficiency]. / Muerte súbita en un paciente con deficiencia de 3-hidroxi-3-metilglutaril-coenzima A liasa.

A new case of neonatal 3-hydroxy-3-methylglutaric aciduria is described. 3-hydroxy-3-methylglutaryl CoA lyase activities in leukocytes demonstrated the patient's homozygosity and the heterozygous character of the parents and two other members of the family. Dietetic management with low fat high carbohydrate diet together with protein restriction and carnitine resulted in a good control of the metabolic acidosis, the hypoglycemia, and the physical and neurological development. Nevertheless, sudden death occurred at the age thirteen months without any previous apparent trouble and the necropsia showed neither signs of infection nor hepatic or cardiac derangement.

[Argininosuccinic aciduria. Comparative studies and detection of carriers in 3 affected families]. / Aciduria argininsuccínica. Estudios comparativos y detección de portadores en tres familias afectas.

Three patients with argininosuccinic aciduria are described. One of them is a neonatal form, with typical acute course and severe hyperammonemia who died on the sixth day of life. Postmortem analysis showed a marked plasmatic accumulation of argininosuccinic acid. Later on, red blood cell ASA-lyase levels demonstrated the heterozygosity of her parents and sisters. The two other patients are late onset forms and were diagnosed after detection of ASA and its anhydrides in plasma and urine. Levels of these metabolites did not correlate with levels of residual ASA-lyase in erythrocytes. Treatment with a hypoproteic diet supplemented with arginine has improved their clinical state. Carriers have been detected in both families. Importance of rapid diagnosis and treatment of hyperammonemic patients in order to prevent neurologic damage is emphasised.