RESUMEN

We report the first case of an occurrence of multiphasic acute disseminated encephalomyelitis (ADEM) associated with atypical rubella virus infection with no rash and long-term increased titers of serum anti-rubella IgM in a 17-year-old male who had no history of rubella vaccination. He suffered from at least six clinical exacerbations with disseminated hyperintense lesions on FLAIR MR images during the course of 18 months. Repeated methylprednisolone pulse therapy and intravenous immunoglobulin therapy resolved the exacerbations. In patients with multiphasic ADEM of unknown etiology, clinicians should also consider the possibility of preceding infection with rubella virus.

Asunto(s)

Encefalomielitis Aguda Diseminada/etiología , Virus de la Rubéola/patogenicidad , Rubéola (Sarampión Alemán)/complicaciones , Adolescente , Humanos , Masculino

RESUMEN

Adult-onset autosomal dominant leukodystrophy (ADLD) is a slowly progressive neurological disorder characterized by symmetrical widespread myelin loss in the central nervous system, with a phenotype similar to chronic progressive multiple sclerosis. In this study, we identify a genomic duplication that causes ADLD. Affected individuals carry an extra copy of the gene for the nuclear laminar protein lamin B1, resulting in increased gene dosage in brain tissue from individuals with ADLD. Increased expression of lamin B1 in Drosophila melanogaster resulted in a degenerative phenotype. In addition, an abnormal nuclear morphology was apparent when cultured cells overexpressed this protein. This is the first human disease attributable to mutations in the gene encoding lamin B1. Antibodies to lamin B are found in individuals with autoimmune diseases, and it is also an antigen recognized by a monoclonal antibody raised against plaques from brains of individuals with multiple sclerosis. This raises the possibility that lamin B may be a link to the autoimmune attack that occurs in multiple sclerosis.

Asunto(s)

Duplicación de Gen , Genes Dominantes , Enfermedades Desmielinizantes del Sistema Nervioso Central Hereditarias/genética , Lamina Tipo B/genética , Animales , Secuencia de Bases , Encéfalo/patología , Encéfalo/fisiología , Células Cultivadas , Análisis Mutacional de ADN , Drosophila melanogaster/genética , Femenino , Dosificación de Gen , Ligamiento Genético , Enfermedades Desmielinizantes del Sistema Nervioso Central Hereditarias/patología , Humanos , Masculino , Datos de Secuencia Molecular

RESUMEN

The amyloid beta-protein (Abeta) ending at 42 plays a pivotal role in Alzheimer's disease (AD). We have reported previously that intracellular Abeta42 is associated with neuronal apoptosis in vitro and in vivo. Here, we show that intracellular Abeta42 directly activated the p53 promoter, resulting in p53-dependent apoptosis, and that intracellular Abeta40 had a similar but lesser effect. Moreover, oxidative DNA damage induced nuclear localization of Abeta42 with p53 mRNA elevation in guinea-pig primary neurons. Also, p53 expression was elevated in brain of sporadic AD and transgenic mice carrying mutant familial AD genes. Remarkably, accumulation of both Abeta42 and p53 was found in some degenerating-shape neurons in both transgenic mice and human AD cases. Thus, the intracellular Abeta42/p53 pathway may be directly relevant to neuronal loss in AD. Although neurotoxicity of extracellular Abeta is well known and synaptic/mitochondrial dysfunction by intracellular Abeta42 has recently been suggested, intracellular Abeta42 may cause p53-dependent neuronal apoptosis through activation of the p53 promoter; thus demonstrating an alternative pathogenesis in AD.

Asunto(s)

Enfermedad de Alzheimer/metabolismo , Péptidos beta-Amiloides/metabolismo , Genes p53/genética , Espacio Intracelular/química , Espacio Intracelular/metabolismo , Degeneración Nerviosa/metabolismo , Fragmentos de Péptidos/metabolismo , Regiones Promotoras Genéticas/fisiología , Anciano , Anciano de 80 o más Años , Enfermedad de Alzheimer/patología , Péptidos beta-Amiloides/fisiología , Precursor de Proteína beta-Amiloide/genética , Animales , Apoptosis/genética , Apoptosis/fisiología , Encéfalo/citología , Encéfalo/metabolismo , Encéfalo/patología , Química Encefálica/genética , Células Cultivadas , Citosol/química , ADN/metabolismo , Femenino , Feto , Cobayas , Respuesta al Choque Térmico/genética , Humanos , Peróxido de Hidrógeno/farmacología , Espacio Intracelular/patología , Leucina/genética , Masculino , Proteínas de la Membrana/genética , Ratones , Ratones Mutantes , Ratones Transgénicos , Mutación Missense/genética , Degeneración Nerviosa/patología , Neuroblastoma/patología , Neuronas/química , Neuronas/metabolismo , Fragmentos de Péptidos/fisiología , Presenilina-1 , Regiones Promotoras Genéticas/genética , Unión Proteica , ARN Mensajero/genética , ARN Mensajero/metabolismo , Elementos de Respuesta/fisiología , Células Tumorales Cultivadas , Proteína p53 Supresora de Tumor/biosíntesis , Valina/genética

RESUMEN

Using plasma amyloid beta protein (Abeta42) levels as an intermediate, quantitative phenotype for late onset Alzheimer's disease (LOAD), we previously obtained significant linkage at approximately 80 cM on chromosome 10. Linkage to the same region was obtained independently in a study of affected LOAD sib-pairs. Together, these two studies provide strong evidence for a novel LOAD locus on chromosome 10 that acts to increase Abeta42. VR22 is a large (1.7 Mb) gene located at 80 cM that encodes alpha-T catenin, which is a binding partner of beta catenin. This makes VR22 an attractive candidate gene because beta catenin interacts with presenilin 1, which has many mutations that elevate Abeta42 and cause early onset familial AD. We identified two intronic VR22 SNPs (4360 and 4783) in strong linkage disequilibrium (LD) that showed highly significant association (P=0.0001 and 0.0006) with plasma Abeta42 in 10 extended LOAD families. This association clearly contributed to the linkage at approximately 80 cM because the lod scores decreased when linkage analysis was performed conditional upon the VR22 association. This association replicated in another independent set of 12 LOAD families (P=0.04 for 4783 and P=0.08 for 4360). Bounding of the association region using multiple SNPs showed VR22 to be the only confirmed gene within the region of association. These findings indicate that VR22 has variant(s) which influence Abeta42 and contribute to the previously reported linkage for plasma Abeta42 in LOAD families.

Asunto(s)

Enfermedad de Alzheimer/genética , Mapeo Cromosómico , Cromosomas Humanos Par 10 , Proteínas del Citoesqueleto/genética , Sitios de Carácter Cuantitativo , Adulto , Anciano , Péptidos beta-Amiloides/sangre , Péptidos beta-Amiloides/genética , Femenino , Humanos , Desequilibrio de Ligamiento , Masculino , Persona de Mediana Edad , Linaje , Polimorfismo de Nucleótido Simple , alfa Catenina