Developmental analysis of CNS pathology in the lysosomal storage disease α-mannosidosis

The lysosomal storage disease α-mannosidosis is due to absence or defective function of lysosomal α-mannosidase, resulting in primary storage of undegraded mannose-rich oligosaccharides. Disease has been described in humans, cattle, cats, mice, and guinea pigs and is characterized in all species by progressive neurologic deterioration and premature death. We analyzed the neurodegenerative processes relative to clinical disease in α-mannosidosis guinea pigs as a human disease model, from birth to end-stage disease. Before the onset of obvious neurologic abnormalities at 2 months, we observed widespread neuronal lysosomal vacuolation including secondary accumulation of GM3 ganglioside, widespread axonal spheroids, and reduced myelination of white matter. Histopathologic changes subsequently showed rapid progression in severity in a pattern common to a number of different lysosomal storage disorders, with additional abnormalities including accumulation of GM2 ganglioside and cholesterol, astrogliosis, neuron loss particularly in the cerebellum, and activation and infiltration of the CNS with microglia/macrophages. End-stage clinical disease was seen at 10 to 14 months of age. Our findings show that complex neuropathologic changes in α-mannosidosis guinea pigs are already present at birth, before clinical changes are evident, and similar events are likely to occur in patients with this disorder.