alpha-mannosidosis in the guinea pig: A new animal model for lysosomal storage disorders

alpha-Mannosidosis is a lysosomal storage disorder resulting from deficient activity of lysosomal alpha-mannosidase. It has been described previously in humans, cattle, and cats, and is characterized in all of these species p rincipally by neuronal storage leading to progressive mental deterioration. Two guinea pigs with stunted growth, progressive mental dullness, behavior al abnormalities, and abnormal posture and gait, showed a deficiency of aci dic alpha-mannosidase activity in leukocytes, plasma, fibroblasts, and whol e liver extracts. Fractionation of liver demonstrated a deficiency of lysos omal (acidic) alpha-mannosidase activity. Thin layer chromatography of urin e and tissue extracts confirmed the diagnosis by demonstrating a pattern of excreted and stored oligosaccharides almost identical to that of urine fro m a human alpha-mannosidosis patient. Widespread neuronal vacuolation was o bserved throughout the CNS, including the cerebral cortex, hippocampus, tha lamus, cerebellum, midbrain, pens, medulla, and the dorsal and ventral hems of the spinal cord. Lysosomal vacuolation also occurred in many other visc eral tissues and was particularly severe in pancreas, thyroid, epididymis, and peripheral ganglion. Axonal spheroids were observed in some brain regio ns, but gliosis and demyelination were not observed. Ultrastructurally, mos t vacuoles in both the CNS and visceral tissues were lucent or contained fi ne fibrillar or flocculent material. Rare large neurons in the cerebral cor tex contained fine membranous structures. Skeletal abnormalities were very mild. alpha-Mannosidosis in the guinea pig closely resembles the human dise ase and will provide a convenient model for investigation of new therapeuti c strategies for neuronal storage diseases, such as enzyme replacement and gene replacement therapies.