RESUMEN
Major advances in the identification of genes implicated in idiopathic epilepsy have been made. Generalized epilepsy with febrile seizures plus (GEFS+), benign familial neonatal convulsions and nocturnal frontal lobe epilepsy, three autosomal dominant idiopathic epilepsies, result from mutations affecting voltage-gated sodium and potassium channels, and nicotinic acetylcholine receptors, respectively. Disruption of GABAergic neurotransmission mediated by gamma-aminobutyric acid (GABA) has been implicated in epilepsy for many decades. We now report a K289M mutation in the GABA(A) receptor gamma2-subunit gene (GABRG2) that segregates in a family with a phenotype closely related to GEFS+ (ref. 8), an autosomal dominant disorder associating febrile seizures and generalized epilepsy previously linked to mutations in sodium channel genes. The K289M mutation affects a highly conserved residue located in the extracellular loop between transmembrane segments M2 and M3. Analysis of the mutated and wild-type alleles in Xenopus laevis oocytes confirmed the predicted effect of the mutation, a decrease in the amplitude of GABA-activated currents. We thus provide the first genetic evidence that a GABA(A) receptor is directly involved in human idiopathic epilepsy.
Asunto(s)
Epilepsia/genética , Mutación , Receptores de GABA-A/genética , Secuencia de Aminoácidos , Segregación Cromosómica , Secuencia Conservada , Conductividad Eléctrica , Epilepsia Benigna Neonatal/genética , Epilepsia del Lóbulo Frontal/genética , Epilepsia Generalizada/genética , Femenino , Humanos , Masculino , Modelos Moleculares , Datos de Secuencia Molecular , Linaje , Subunidades de Proteína , Convulsiones Febriles/genética , Homología de Secuencia de AminoácidoRESUMEN
11 patients with rheumatoid arthritis were treated with intravenous immunoglobulin (IVGG). In 6 patients clinical results were impressive, although lasting responses could be achieved in 3 patients only. This treatment was immunomodulating, since the immunoregulatory T-cell ratio (CD4/CD8) decreased following therapy by reducing CD4-positive cells in-vivo. By use of anti-mu-antibodies as a B-cell specific mitogen, IVGG-treatment was seen to suppress early processes of B cell activation. In parallel to these cellular effects, IVGG led to a reduction in the levels of polyethyleneglycol-precipitated circulating immune complexes as measured by lasernephelometry.