RESUMEN
Metachromatic leukodystrophy (MLD) is a lysosomal disorder caused by arylsulfatase A (ARSA) deficiency. It is classified into three forms according to the age of onset of symptoms (late infantile, juvenile, and adult). We carried out a cross-sectional and retrospective study, which aimed to determine the epidemiological, clinical, and biochemical profile of MLD patients from a national reference center for Inborn Errors of Metabolism in Brazil. Twenty-nine patients (male, 17) agreed to participate in the study (late infantile form: 22; juvenile form: 4; adult form: 1; asymptomatic: 2). Mean ages at onset of symptoms and at biochemical diagnosis were, respectively, 19 and 39 months for late infantile form and 84.7 and 161.2 months for juvenile form. The most frequently reported first clinical symptom/sign of the disease was gait disturbance and other motor abnormalities (72.7%) for late infantile form and behavioral and cognitive alterations (50%) for juvenile form. Leukocyte ARSA activity level did not present significant correlation with the age of onset of symptoms (r = -0.09, p = 0.67). Occipital white matter and basal nuclei abnormalities were not found in patients with the late infantile MLD. Our results suggest that there is a considerable delay between the age of onset of signs and symptoms and the diagnosis of MLD in Brazil. Correlation between ARSA activity and MLD clinical form was not found. Further studies on the epidemiology and natural history of this disease with larger samples are needed, especially now when specific treatments should be available in the near future.
Asunto(s)
Cerebrósido Sulfatasa/deficiencia , Leucocitos/enzimología , Leucodistrofia Metacromática/diagnóstico , Adolescente , Edad de Inicio , Biomarcadores/sangre , Biomarcadores/orina , Brasil/epidemiología , Cerebrósido Sulfatasa/sangre , Niño , Preescolar , Estudios Transversales , Técnicas de Diagnóstico Oftalmológico , Progresión de la Enfermedad , Electroencefalografía , Oftalmopatías/diagnóstico , Oftalmopatías/enzimología , Oftalmopatías/epidemiología , Femenino , Trastornos Neurológicos de la Marcha/diagnóstico , Trastornos Neurológicos de la Marcha/enzimología , Trastornos Neurológicos de la Marcha/epidemiología , Humanos , Lactante , Leucodistrofia Metacromática/tratamiento farmacológico , Leucodistrofia Metacromática/enzimología , Leucodistrofia Metacromática/epidemiología , Leucoencefalopatías/diagnóstico , Leucoencefalopatías/enzimología , Leucoencefalopatías/epidemiología , Imagen por Resonancia Magnética , Masculino , Trastornos Mentales/diagnóstico , Trastornos Mentales/enzimología , Trastornos Mentales/epidemiología , Valor Predictivo de las Pruebas , Pronóstico , Estudios Retrospectivos , Sulfoglicoesfingolípidos/orina , Factores de Tiempo , Adulto JovenRESUMEN
The authors describe a 50-year-old man who was evaluated for a rigid spine syndrome with onset at age 15, and subsequent walking difficulties. Cardiac and pulmonary functions were normal. Deltoid biopsy revealed the presence of small vacuoles and increased glycogen with Periodic Acid Schiff staining in a limited number of fibers. Acid alpha-glucosidase staining was decreased in leucocytes, and genetic analysis identified the presence of two mutations in that gene. This observation suggests that Pompe disease should be considered in the differential diagnosis of rigid spine syndrome, even in patients without respiratory involvement or with a muscle biopsy showing only mild histopathological changes.
Asunto(s)
Enfermedad del Almacenamiento de Glucógeno Tipo II/enzimología , Enfermedad del Almacenamiento de Glucógeno Tipo II/genética , Enfermedades Musculares/enzimología , Enfermedades Musculares/genética , Enfermedades de la Columna Vertebral/enzimología , Factores de Edad , Edad de Inicio , Biopsia , Análisis Mutacional de ADN , Trastornos Neurológicos de la Marcha/enzimología , Trastornos Neurológicos de la Marcha/genética , Trastornos Neurológicos de la Marcha/fisiopatología , Glucógeno/análisis , Glucógeno/metabolismo , Enfermedad del Almacenamiento de Glucógeno Tipo II/complicaciones , Humanos , Leucocitos/enzimología , Masculino , Persona de Mediana Edad , Limitación de la Movilidad , Músculo Esquelético/enzimología , Músculo Esquelético/patología , Músculo Esquelético/fisiopatología , Enfermedades Musculares/complicaciones , Mutación/genética , Reacción del Ácido Peryódico de Schiff , Enfermedades de la Columna Vertebral/genética , Enfermedades de la Columna Vertebral/fisiopatología , Columna Vertebral/patología , Columna Vertebral/fisiopatología , alfa-Glucosidasas/deficiencia , alfa-Glucosidasas/genéticaRESUMEN
Formation of a glial scar is one of the major obstacles to axonal growth after injury to the adult CNS. In this study, we have addressed this issue by focusing on reactive astrocytes in a mouse model of spinal cord injury (SCI). First, we attempted to identify profile changes in the expression of astrocytic gliosis 10 days after injury by using gliosis-specific microdissection, genome-wide microarray, and MetaCore(trade mark) pathway analysis. This systematic data processing revealed many intriguing activated pathways. However, considering that proliferation/mitosis is one of the most prominent features of reactive astrocytes, we focused on the functional role of the Ras-MEK-ERK signaling cascades in reactive astrocytes. SCI-induced proliferation of reactive astrocytes in the lesion is in accordance with the increase in the expression and phosphorylation of MEK-ERK. Second, to reduce reactive gliosis after SCI, liposomes containing the interferon-beta (IFN-beta) gene were administered locally 30 min after injury. At 14 days after this treatment, GFAP-positive intensity and MEK-ERK phosphorylation at the lesion were reduced. In the animals receiving the IFN-beta gene, significant recovery of neurobehavior and parameters of electrophysiology following SCI was revealed by assessments of rotarod performance and improvements in the Basso Mouse Scale for locomotion and cortical motor-evoked potentials. SCI resulted in the degeneration of biotinylated dextran amine-labeled descending corticospinal tract axons, but the IFN-beta gene delivery induced regrowth of a large number of corticospinal tract axons. These results suggest that liposome-mediated IFN-beta gene delivery inhibits glial scar formation after SCI and promotes functional recovery.
Asunto(s)
Astrocitos/efectos de los fármacos , Gliosis/tratamiento farmacológico , Interferón Tipo I/genética , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Traumatismos de la Médula Espinal/fisiopatología , Traumatismos de la Médula Espinal/terapia , Médula Espinal/fisiopatología , Animales , Biomarcadores/análisis , Biomarcadores/metabolismo , Modelos Animales de Enfermedad , Quinasas MAP Reguladas por Señal Extracelular/efectos de los fármacos , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Femenino , Trastornos Neurológicos de la Marcha/enzimología , Trastornos Neurológicos de la Marcha/fisiopatología , Trastornos Neurológicos de la Marcha/terapia , Técnicas de Transferencia de Gen , Terapia Genética/métodos , Proteína Ácida Fibrilar de la Glía/análisis , Proteína Ácida Fibrilar de la Glía/metabolismo , Gliosis/enzimología , Gliosis/fisiopatología , Liposomas/uso terapéutico , Quinasas Quinasa Quinasa PAM/efectos de los fármacos , Quinasas Quinasa Quinasa PAM/metabolismo , Sistema de Señalización de MAP Quinasas/fisiología , Ratones , Ratones Endogámicos C57BL , Fosforilación , Recuperación de la Función/efectos de los fármacos , Recuperación de la Función/fisiología , Médula Espinal/enzimología , Traumatismos de la Médula Espinal/enzimologíaRESUMEN
Calcium-dependent mechanisms, particularly those mediated by Ca(2+)/calmodulin (CaM)-dependent protein kinase II (CaMKII), have been implicated in neurotoxicant-induced neuropathy. However, it is unknown whether similar mechanisms exist in 2,5-hexanedione (HD)-induced neuropathy. For that, we investigated the changes of CaM, CaMKII, protein kinase C (PKC) and polymerization ratios (PRs) of NF-L, NF-M and NF-H in cerebral cortex (CC, including total cortex and some gray), spinal cord (SC) and sciatic nerve (SN) of rats treated with HD at a dosage of 1.75 or 3.50 mmol/kg for 8 weeks (five times per week). The results showed that CaM contents in CC, SC and SN were significantly increased, which indicated elevation of Ca(2+) concentrations in nerve tissues. CaMKII contents and activities were also increased in CC and were positively correlated with gait abnormality, but it could not be found in SC and SN. The increases of PKC contents and activities were also observed in SN and were positively correlated with gait abnormality. Except for that of NF-M in CC, the PRs of NF-L, NF-M and NF-H were also elevated in nerve tissues, which was consistent with the activation of protein kinases. The results suggested that CaMKII might be partly (in CC but not in SC and SN) involved in HD-induced neuropathy. CaMKII and PKC might mediate the HD neurotoxicity by altering the NF phosphorylation status and PRs.
Asunto(s)
Proteína Quinasa Tipo 2 Dependiente de Calcio Calmodulina/metabolismo , Calmodulina/metabolismo , Hexanonas/toxicidad , Sistema Nervioso/efectos de los fármacos , Síndromes de Neurotoxicidad/etiología , Proteína Quinasa C/metabolismo , Animales , Peso Corporal/efectos de los fármacos , Membrana Celular/metabolismo , Corteza Cerebral/efectos de los fármacos , Corteza Cerebral/enzimología , Citosol/enzimología , Marcha/efectos de los fármacos , Trastornos Neurológicos de la Marcha/inducido químicamente , Trastornos Neurológicos de la Marcha/enzimología , Cojera Animal/inducido químicamente , Cojera Animal/enzimología , Masculino , Sistema Nervioso/enzimología , Sistema Nervioso/fisiopatología , Proteínas de Neurofilamentos/metabolismo , Síndromes de Neurotoxicidad/enzimología , Síndromes de Neurotoxicidad/fisiopatología , Fosforilación , Ratas , Ratas Wistar , Nervio Ciático/efectos de los fármacos , Nervio Ciático/enzimología , Médula Espinal/efectos de los fármacos , Médula Espinal/enzimología , Factores de Tiempo , Regulación hacia ArribaRESUMEN
Granulocyte colony-stimulating factor (G-CSF) is a potent hematopoietic factor. Recently, this factor has been shown to exhibit neuroprotective effects on many CNS injuries. Spinal cord ischemic injury that frequently results in paraplegia is a major cause of morbidity after thoracic aorta operations. In the present study, we examined the neuroprotective role of G-CSF on spinal cord ischemia-induced neurological dysfunctions and changes in the mitogen-activated protein kinase (MAPK) and Akt signaling pathways in the spinal cord. Spinal cord ischemia was induced in male Wistar rats by occluding the descending aorta with a 2F Fogarty catheter for 12 min 30 s. Immediately after ischemia surgery, the rats were administered G-CSF (10 mug) or saline by intrathecal (i.t.) injection. The rats were divided into four groups: control, ischemia plus saline, ischemia plus G-CSF and G-CSF alone. The neurological dysfunctions were assessed by calculating the motor deficit index after ischemia surgery. The expressions of MAPK and Akt were studied using Western blotting and double immunohistochemistry. First, we observed that ischemia plus i.t. G-CSF can significantly reduce the motor function defects and downregulate phospho-p38 and phospho-c-Jun N-terminal kinase protein expressions-this can be compared with the ischemia plus saline group. In addition, G-CSF inhibited the ischemia-induced activation of p38 in the astrocytes. Furthermore, we concluded that i.t. G-CSF produced a significant increase in phospho-Akt and phospho-ERK in the motor neurons and exhibited beneficial effects on the spinal cord ischemia-induced neurological defects.
Asunto(s)
Factor Estimulante de Colonias de Granulocitos/uso terapéutico , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Fármacos Neuroprotectores/uso terapéutico , Proteínas Proto-Oncogénicas c-akt/efectos de los fármacos , Isquemia de la Médula Espinal/tratamiento farmacológico , Médula Espinal/efectos de los fármacos , Animales , Modelos Animales de Enfermedad , Quinasas MAP Reguladas por Señal Extracelular/efectos de los fármacos , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Trastornos Neurológicos de la Marcha/tratamiento farmacológico , Trastornos Neurológicos de la Marcha/enzimología , Trastornos Neurológicos de la Marcha/fisiopatología , Inmunohistoquímica , Inyecciones Espinales , Proteínas Quinasas JNK Activadas por Mitógenos/efectos de los fármacos , Proteínas Quinasas JNK Activadas por Mitógenos/metabolismo , Sistema de Señalización de MAP Quinasas/fisiología , Masculino , Paresia/tratamiento farmacológico , Paresia/enzimología , Paresia/fisiopatología , Fosforilación/efectos de los fármacos , Proteínas Proto-Oncogénicas c-akt/metabolismo , Ratas , Ratas Wistar , Recuperación de la Función/efectos de los fármacos , Recuperación de la Función/fisiología , Médula Espinal/enzimología , Médula Espinal/fisiopatología , Isquemia de la Médula Espinal/enzimología , Isquemia de la Médula Espinal/fisiopatología , Resultado del Tratamiento , Proteínas Quinasas p38 Activadas por Mitógenos/efectos de los fármacos , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismoRESUMEN
Primary trauma to the spinal cord triggers a cascade of cellular and molecular events that promote continued tissue damage and expansion of the lesion for extended periods following the initial injury. Oxidative and nitrosative stresses play an important role in progression of spinal cord injury (SCI). In an attempt to explore the biochemical origin of oxidative/nitrosative stress associated with secondary SCI, we studied expression of the superoxide (O2*-)-generating enzyme, NAD(P)H oxidase, antioxidant enzymes [superoxide dismutase (CuZn SOD, Mn SOD), catalase, glutathione peroxidase (GPX)], nitric oxide synthases (NOS) and a byproduct of NO-O2*- interaction (nitrotyrosine) in the spinal cord tissues of rats 16 h and 14 days after surgical resections of a 5-mm segment of the cord below T8 or sham-operation. Immunodetectable NAD(P)H oxidase subunits (gp91phox and P67phox), Mn SOD, inducible NOS (iNOS), endothelial NOS (eNOS), and nitrotyrosine were elevated in the transected cords on day 1 and day 14. Neuronal NOS (nNOS) was unchanged on day 1 and significantly depressed on day 14. GPX was unchanged on day 1 and significantly elevated on day 14. Catalase was unchanged in the cord tissue surrounding the transection site at both points. Thus, concurrent upregulations of NAD(P)H oxidase, eNOS and iNOS (but not nNOS), work in concert to maintain oxidative and nitrosative stress in the injured cord tissue.
Asunto(s)
Catalasa/metabolismo , Glutatión Peroxidasa/metabolismo , NADPH Oxidasas/metabolismo , Óxido Nítrico Sintasa/metabolismo , Traumatismos de la Médula Espinal/enzimología , Superóxido Dismutasa/metabolismo , Enfermedad Aguda , Animales , Femenino , Depuradores de Radicales Libres/metabolismo , Trastornos Neurológicos de la Marcha/enzimología , Trastornos Neurológicos de la Marcha/etiología , Trastornos Neurológicos de la Marcha/fisiopatología , Miembro Posterior/fisiopatología , Neuronas/enzimología , Neuronas/patología , Nitratos/metabolismo , Óxido Nítrico/metabolismo , Nitrosación , Estrés Oxidativo/fisiología , Ratas , Ratas Sprague-Dawley , Especies Reactivas de Oxígeno/metabolismo , Recuperación de la Función/fisiología , Médula Espinal/enzimología , Médula Espinal/patología , Médula Espinal/fisiopatología , Traumatismos de la Médula Espinal/patología , Traumatismos de la Médula Espinal/fisiopatologíaRESUMEN
N-Acetylglucosaminyltransferase III (GlcNAc-TIII), the product of the Mgat3 gene, transfers the bisecting GlcNAc to the core mannose of complex N-glycans. The addition of this residue is regulated during development and has functional consequences for receptor signaling, cell adhesion, and tumor progression. Mice homozygous for a null mutation at the Mgat3 locus (Mgat3(Delta)) or for a targeted mutation in the Mgat3 gene (previously called Mgat3(neo), but herein renamed Mgat3(T37) because the allele generates inactive GlcNAc-TIII of approximately 37 kDa) were found to exhibit retarded progression of liver tumors. Matrix-assisted laser desorption/ionization time-of-flight mass spectrometry of neutral N-glycans from kidneys revealed no significant differences, and both mutants showed the expected lack of N-glycan species with an additional GlcNAc. However, the two mutants differed in several biological traits. Mgat3(T37/T37) homozygotes in a mixed or 129(SvJ) background were retarded in growth rate and exhibited an altered leg clasp reflex, an altered gait, and defective nursing behavior. Pups abandoned by Mgat3(T37/T37) mothers were rescued by wild-type foster mothers. None of these Mgat3(T37/T37) traits were exhibited by Mgat3(Delta/Delta) mice or by heterozygous mice carrying the Mgat3(T37) mutation. Similarly, no dominant-negative effect was observed in Chinese hamster ovary cells expressing truncated GlcNAc-TIII in the presence of wild-type GlcNAc-TIII. However, compound heterozygotes carrying both the Mgat3(T37) and Mgat3(Delta) mutations exhibited a marked leg clasp reflex, indicating that in the absence of wild-type GlcNAc-TIII, truncated GlcNAc-TIII causes this phenotype. The Mgat3 gene was expressed in brain at embryonic day 10.5 and thereafter and in neurons of adult cerebellum. The mutant Mgat3 gene was also highly expressed in Mgat3(T37/T37) brain. This may be the basis of the unexpected neurological phenotype induced by truncated, inactive GlcNAc-TIII in the mouse.