RESUMEN
Young children are at increased risk for valproic acid (VPA) hepatotoxicity. Urinary organic acid profiles, as a surrogate of mitochondrial function, were obtained in children 1.9 to 17.3 years of age (n = 52) who were undergoing treatment with VPA for seizure disorders. Age-matched patients receiving treatment with carbamazepine (CBZ; n = 50) and healthy children not undergoing treatment (n = 22) served as controls. Age-related changes in organic acid profiles were observed in all three groups. Although the untreated and CBZ control groups were indistinguishable from each other with respect to the principal-component analysis (PCA) score plots of the subjects, a distinct boundary was apparent between the VPA and each of the control groups. Interindividual variability was observed in the VPA-induced alterations in endogenous pathways corresponding to branched-chain amino acid metabolism and oxidative stress. The data suggest that more detailed metabolomic analysis may provide novel insights into biological mechanisms and predictive biomarkers for children at highest risk for serious toxicity.
Asunto(s)
Ácidos Carboxílicos/orina , Metaboloma/efectos de los fármacos , Metaboloma/fisiología , Ácido Valproico/metabolismo , Ácido Valproico/farmacología , Adolescente , Factores de Edad , Niño , Preescolar , Femenino , Humanos , Lactante , Ácido Láctico/orina , Masculino , Análisis de Componente Principal , Estudios Retrospectivos , Resultado del TratamientoRESUMEN
BACKGROUND: Ethylmalonic encephalopathy (EE) is a rare autosomal recessive metabolic disorder characterised by progressive encephalopathy, recurrent petechiae, acrocyanosis and chronic diarrhoea, with a fatal outcome in early in life. METHODS: 14 patients with EE were investigated for mutations in the ETHE1 gene. RESULTS: Of the 14 patients, 5 were found to carry novel mutations. CONCLUSIONS: This work expands our knowledge of the causative mutations of EE.
Asunto(s)
Encefalopatías Metabólicas Innatas/genética , Proteínas Mitocondriales/genética , Mutación Missense , Proteínas de Transporte Nucleocitoplasmático/genética , Adolescente , Secuencia de Aminoácidos , Secuencia de Bases , Encefalopatías Metabólicas Innatas/metabolismo , Carnitina/análogos & derivados , Carnitina/metabolismo , Niño , Preescolar , Estudios de Cohortes , ADN/química , ADN/genética , Femenino , Humanos , Lactante , Masculino , Modelos Moleculares , Datos de Secuencia Molecular , Reacción en Cadena de la Polimerasa , Polimorfismo de Nucleótido Simple , Alineación de SecuenciaRESUMEN
Approximately 5% of patients with neurofibromatosis type 1 (NF1) have deletions of the entire NF1 gene. The phenotype usually includes early onset, large number of neurofibromas, presence of congenital anomalies, cognitive deficiency, and variable dysmorphic features and growth abnormalities. Connective tissue abnormalities are not generally recognised as a part of NF1 microdeletion syndrome, but mitral valve prolapse, joint laxity, and/or soft skin on the palms have been reported in a few patients. We describe clinical findings in six newly diagnosed patients with NF1 microdeletions, five of whom presented with connective tissue abnormalities. A literature review of the clinical findings associated with NF1 microdeletion was also performed. Our report confirms that connective tissue dysplasia is common in patients with NF1 microdeletions. Given the potential for associated cardiac manifestation, screening by echocardiogram may be warranted. Despite the large number (>150) of patients with known NF1 microdeletions, the clinical phenotype remains incompletely defined. Additional reports of patients with NF1 microdeletions, including comprehensive clinical and molecular information, are needed to elucidate possible genotype-phenotype correlation.