RESUMEN
Glutaric acidemia type I (GA1) is caused by severe deficiency of glutaryl-CoA dehydrogenase activity, resulting in an accumulation of glutaric acid and glutarylcarnitine (C5DC) in the organism. Patients affected by GA1 are asymptomatic in the neonate period but usually manifest chronically progressive neurodegeneration apart from severe encephalopathic crises associated with acute striatum necrosis. Neurological manifestations like dyskinesia, dystonia, hypotonia, muscle stiffness, and spasticity are present. Treatment is based on protein/lysine restriction and l-carnitine supplementation. In this work, we evaluated markers of neurodegeneration and inflammation, namely BDNF (brain-derived neurotrophic factor), NCAM (neuronal adhesion molecule), PDGF-AA (platelet-derived growth factor), and cathepsin-d in plasma of six treated GA1 patients. We first found marked increases of plasma C5DC concentrations in GA1 patients, as well as increased levels of the markers BDNF and cathepsin-d as compared to those of age-matched healthy children. Furthermore, C5DC concentrations were highly correlated with the levels of cathepsin-d. These results may demonstrate that brain tissue degeneration is present in GA1 patients and that there is a relationship between increased metabolites concentrations with this process. To the best of our knowledge, this is so far the first study showing altered peripheral parameters of neurodegeneration and inflammation in GA1 patients.
Asunto(s)
Errores Innatos del Metabolismo de los Aminoácidos/sangre , Encefalopatías Metabólicas/sangre , Factor Neurotrófico Derivado del Encéfalo/sangre , Catepsina D/sangre , Glutaril-CoA Deshidrogenasa/deficiencia , Degeneración Nerviosa/diagnóstico , Errores Innatos del Metabolismo de los Aminoácidos/complicaciones , Biomarcadores/sangre , Encefalopatías Metabólicas/complicaciones , Niño , Preescolar , Femenino , Glutaril-CoA Deshidrogenasa/sangre , Humanos , Lactante , Recién Nacido , Masculino , Degeneración Nerviosa/sangre , Degeneración Nerviosa/etiología , Moléculas de Adhesión de Célula Nerviosa/sangre , Factor de Crecimiento Derivado de Plaquetas/metabolismoRESUMEN
The neural cell adhesion molecule (NCAM) is involved in the intercellular junctions of neurons and glial cells. We investigated its relevance as a biomarker in gliomas which main characteristic is their high invasiveness. We studied by Western blot the pattern of serum NCAM bands in patients with gliomas (n = 34), with brain metastasis of different primary cancers (n = 27) and with benign brain tumors (n = 22)] compared with healthy controls (n = 69). For densitometric analysis NCAM bands > or = 130 kDa (HMW) and <130 kDa (LMW) were clustered. We observed that glioma patients presented higher NCAM HMW and lower NCAM LMW levels than control subjects (P < 0.01). A similar pattern was found in patients with brain metastasis or brain benign tumors, suggesting that the pattern of serum NCAM bands would be useful to detect brain tumor pathology. On the other hand, serum NCAM expression was not associated with the main clinicopathological features of gliomas, including overall survival. Interestingly, we found that 9/12 patients with glioma showed a significant decrease in NCAM HMW/LMW ratio between 1-3 months after successful tumor removal. Thus, serum NCAM could be a useful marker for monitoring treatment.NCAM expression was also analyzed at tissular level in 59 glioma sections from paraffined tumors. We observed that NCAM immunostaining was inversely correlated with the histological grade of malignancy, remaining this association in a multivariate analysis. Besides, loss of NCAM staining was significantly associated with bad prognosis in an univariate analysis.
Asunto(s)
Biomarcadores de Tumor/metabolismo , Neoplasias Encefálicas/metabolismo , Regulación Neoplásica de la Expresión Génica/fisiología , Glioma/metabolismo , Moléculas de Adhesión de Célula Nerviosa/metabolismo , Adulto , Anciano , Biomarcadores de Tumor/sangre , Encéfalo/metabolismo , Neoplasias Encefálicas/mortalidad , Neoplasias Encefálicas/secundario , Estudios de Casos y Controles , Femenino , Perfilación de la Expresión Génica , Glioma/mortalidad , Glioma/patología , Humanos , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patología , Masculino , Melanoma/metabolismo , Melanoma/secundario , Persona de Mediana Edad , Moléculas de Adhesión de Célula Nerviosa/sangre , Isoformas de Proteínas , Neoplasias Cutáneas/metabolismo , Neoplasias Cutáneas/patología , Estadísticas no Paramétricas , Análisis de Supervivencia , Neoplasias del Cuello Uterino/metabolismo , Neoplasias del Cuello Uterino/patologíaRESUMEN
Memory impairment is a process associated with alterations in neuronal plasticity, synapses formation, and stabilization. As the neural cell adhesion molecule (NCAM) plays a key role in synaptic bond stabilization, we analyzed the usefulness of soluble NCAM isoforms in the diagnosis of patients with dementia of the Alzheimer type (DAT). NCAM was measured in the sera of 70 control subjects and 43 DAT patients (with different severity of cognitive impairment, GDS), employing Western blot and densitometric quantification. LMW-NCAM bands (100-130 kDa) decreased significantly with age independently of sex. DAT patients presented values of LMW-NCAM and HMW-NCAM significantly higher than healthy controls of similar age (higher than 130 kDa). Only LMW-NCAM was associated with GDS. Our results suggest that NCAM could be involved in the pathogenesis of DAT disorder and that serum NCAM levels could be useful as differential diagnostic markers of the disease.