beta-Mannosidosis, an inherited defect of glycoprotein catabolism previously identified in goats and humans, has been recently diagnosed in Salers cattle. This disorder is associated with deficiency of lysosomal beta-mannosidase and accumulation of oligosaccharides. Analysis of bovine beta-mannosidosis neuropathology was initiated to determine whether independently arising gene defects in cattle and goats result in expression of similar lesions. Brain, spinal cord, and selected peripheral nerves from seven affected newborn Salers calves and three normal newborn calves were available for gross, light microscopic, and electron microscopic analysis. Gross examination revealed hydrocephalus of variable severity and myelin deficiency in the cerebral hemispheres, cerebellum, and brainstem. Microscopic examination revealed cytoplasmic vacuolation, myelin deficiency, and axonal spheroids of similar type and distribution to that reported in affected goats. Cytoplasmic vacuolation resulting from lysosomal storage showed consistent variation among cell types. Myelin deficits were more severe in the cerebral hemispheres and cerebellum than in the spinal cord. Axonal spheroids occurred in the cerebrum, brainstem, cerebellum, and trigeminal nerve endings. The presence of similar lesions in bovine and caprine beta-mannosidosis supports a direct relationship with the gene defect.
[Show abstract][Hide abstract] ABSTRACT: Lysosomal beta-mannosidase was purified 160,000-fold in 24% yield from bovine kidney by a four-step purification procedure, which included concanavalin A-Sepharose, immunoaffinity, TSK-butyl and h.p.l.c. cation-exchange chromatography. When analysed by SDS/PAGE and detected by Coomassie Blue or silver staining, the purified enzyme preparation consists of two prominent peptides (100 and 110 kDa) and a third minor peptide (84 kDa). These three peptides are immunologically related and are consistently associated with beta-mannosidase activity in all chromatographic steps. Removal of N-linked carbohydrate from the 84, 100 and 110 kDa peptides decreases their molecular sizes to 75, 86 and 91 kDa respectively. Bovine kidneys lacking beta-mannosidase, activity, acquired from calves affected with beta-mannosidosis, do not contain detectable quantities of the three beta-mannosidase peptides, as judged by monoclonal- and polyclonal-antibody reactivity.
[Show abstract][Hide abstract] ABSTRACT: An aberrant beta-mannosidosis phenotype in a 5-month-old triplet goat kid was characterized by a late postnatal onset of mild neurological symptoms. Necropsy examination revealed relatively normal myelination; however, the distribution of cytoplasmic vacuolation in the kidney and brain was similar to that observed in neonatal beta-mannosidosis. Variable engraftment of donor stem cells, resulting from transplacental transfusion of stem cells from a normal sibling during the immunotolerant period, may have modified the expected severe beta-mannosidosis phenotype. This investigation was designed to determine the effects of a possible chimeric state on organ-specific metabolic perturbations. Residual beta-mannosidase enzyme activity was found in plasma, kidney, liver and spleen but not in brain. Other lysosomal enzyme activities were comparable to normal values. Immunoreactive beta-mannosidase was estimated to be less than 10% of normal levels. Kidney, brain grey matter and brain white matter contained 33%, 12% and 4%, respectively, of the oligosaccharides expected in the organs of beta-mannosidosis animals. There were no detectable oligosaccharides or cytoplasmic vacuolation in the liver or spleen. Studies of this possible chimera provided preliminary evidence for the efficacy of prenatal treatment of early-onset neurodegenerative disorders.
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