Eficacia de la 4-aminopiridina en el tratamiento de pacientes diagnosticados de ataxia con downbeat nystagmus de causa idiopática

L'atàxia amb downbeat nystamgus (ADBN) es una síndrome clínica que cursa amb atàxia vestíbulo-cerebel•losa i downbeat nystagmus. Es va valorar la seguretat i eficàcia del bloquejador de canal de potassi 4-aminopiridina (4-AP) pel tractament d'aquesta entitat. Es varen incloure nou pacients, es va realitzar una avaluació basal i visites mensuals fins als 90 dies. El fàrmac va ser ben tolerat. El 33% dels pacients van presentar milloria objectiva a l'escala de l'equilibri de Berg i el 66% milloria subjectiva i major autonomia. El nombre total de caigudes va disminuir desde 13 fins a 1. La 4-AP millora l'equilibri en pacients amb ADBN.

Encefalopatía de Wernicke: descripción de 26 casos

La encefalopatía de Wernicke es una enfermedad por déficit de tiamina. Su causa más frecuente es el enolismo. La clínica típica es la tríada de trastornos de la motilidad ocular, ataxia y confusión mental. Objetivo: Descripción de los casos de encefalopatía de Wernicke diagnosticados en el Hospital General de Valencia entre los años 2000 y 2009. Resultados: De los 26 casos recogidos, el 88.46% presentaban como causa el enolismo. La tríada clásica se presentaba en menos del 50%, siendo el síntoma más frecuente la ataxia (80.76%). Las regiones más afectadas en RM eran el área periventricular y el tálamo.

Progressive Purkinje Cell Degeneration in tambaleante Mutant Mice Is a Consequence of a Missense Mutation in HERC1 E3 Ubiquitin Ligase

The HERC gene family encodes proteins with two characteristic domains: HECT and RCC1-like. Proteins with HECT domain shave been described to function as ubiquitin ligases, and those that contain RCC1-like domains have been reported to function as GTPases regulators. These two activities are essential in a number of important cellular processes such as cell cycle, cell signaling, and membrane trafficking. Mutations affecting these domains have been found associated with retinitis pigmentosa, amyotrophic lateral sclerosis, and cancer. In humans, six HERC genes have been reported which encode two subgroups of HERC proteins: large (HERC1-2) and small (HERC3-6). The giant HERC1 protein was the first to be identified. It has been involved in membrane trafficking and cell proliferation/growth through its interactions with clathrin, M2-pyruvate kinase, and TSC2 proteins. Mutations affecting other members of the HERC family have been found to be associated with sterility and growth retardation. Here, we report the characterization of a recessive mutation named tambaleante, which causes progressive Purkinje cell degeneration leading to severe ataxia with reduced growth and lifespan in homozygous mice aged over two months. We mapped this mutation in mouse chromosome 9 and then performed positional cloning. We found a GuA transition at position 1448, causing a Gly to Glu substitution (Gly483Glu) in the highly conserved N- terminal RCC1-like domain of the HERC1 protein. Successful transgenic rescue, with either a mouse BAC containing the normal copy of Herc1 or with the human HERC1 cDNA, validated our findings. Histological and biochemical studies revealed extensive autophagy associated with an increase of the mutant protein level and a decrease of mTOR activity. Our observations concerning this first mutation in the Herc1 gene contribute to the functional annotation of the encoded E3 ubiquitin ligase and underline the crucial and unexpected role of this protein in Purkinje cell physiology.