Caprine Beta-mannosidosis, an autosomal recessive defect of glycoprotein catabolism, is characterized by a unique pattern of myelin deficiency and provides the opportunity to investigate a potentially new pathogenetic mechanism of dysmyelinogenesis in a genetic disorder in which the biochemical defect has been identified. This lethal disorder is associated with deficiency of Beta-mannosidase activity and accumulation of oligosaccharides. Major lesions, in addition to the myelin paucity, include wide-spread cytoplasmic vacuolation in the nervous system and viscera, and axonal spheroids in the brain. The neonatal and prenatal myelin deficiency, which is not a common feature of other glycoprotein catabolic disorders, shows marked variation in severity among central nervous system regions; oligodendrocyte dysfunction is the hypothesized basis of these deficits. A major limitation to date in investigation of oligodendrocyte defects has been the lack of availability of an in vitro system. The proposed research is designed (1) to establish cultures of isolated oligodendrocytes from normal goats to test possible toxic effects of accumulated oligosaccharides and (2) to attempt to establish cultures of isolated oligodendrocytes from affected goats so that intrinsic metabolic, structural and/or functional defects can be characterized. If Beta-mannosidosis oligodendrocytes can be successfully maintained in vitro, then several approaches will be used to define abnormalities in affected oligodendrocytes and to investigate regional differences; these approaches include light and electron microscopy, assessment of the ability of cells to myelinate dorsal root ganglia neurites in vitro, and analysis of lipid metabolism. Results of all studies may better define the pathogenesis in Beta-mannosidoisis. Of special significance for future research is the potential of using isolated affected oligodendrocytes as an in vitro system to explore possible therapeutic approaches in this genetic dysmelinating disorder.
