Caprine beta-mannosidosis is an autosomal recessive defect of glycoprotein catabolism characterized by a unique pattern of myelin deficiency. This animal model provides the opportunity to investigate a potentially new pathogenic mechanism of dysmyelinogenesis in a genetic disorder in which the biochemical defect has been identified. This disorder, associated with deficiency of beta-mannoisdase and accumulation of oligosaccharides, is evident at birth. Severe neurological deficits include a marked intention tremor. In addition to the myelin paucity, other major lesions include widespread cytoplasmic vaculation in the nervous system and viscera, and axonal spheroids in the brain. The neonatal myelin deficiency, which is not a common feature of other glycoprotein catabolic disorders, shows marked variation in severity among central nervous system regions; primary or secondary oligodendrocyte dysfunction is the hypothesized basis of these deficits. The proposed research is designed to investigate the pathogenesis of the myelin lesions and the basis of the regional variation through morphological, morphometric, cell culture and biochemical studies. In order to determine where the block in myelination occurs, the sequence of events during development will be studied using light microscopic, electron microscopic, immunocytochemical and morphometric techniques. To assess possible changes in early differentiation of oligodendrocytes and astrocytes, their proliferation will be examined using tritiated thymidine. Possible intrinsic defects in oligodendrocyte function will be investigated by determining whether glial cells from beta-mannosidosis goats show the same abnormalities in culture as are expressed in vivo. A possible role of accumulated oligosaccharides in producing glial cell dysfunction will be investigated in vitro and in vivo. Myelin composition will be analyzed in selected areas to explore the basis of the regional variation. Thus important information related to the pathogenesis of myelin deficiency in beta-mannosidosis will be obtained by investigating the stages of myelination at which cellular pathological changes occur, the nature of the developmental abnormalities, possible intrinsic defects in oligodendrocytes, potential toxic effects of accumulated oligosaccharides, and biochemical correlates of the regional variation.
