Felipedia

Feline mannosidosis

Mannosidosis is a lysosomal storage disease resulting from a deficiency of the enzyme alpha-D-mannosidase in various organs, including brain, kidney and liver. Lysosomal alpha-D-mannosidase is involved in the catabolism of N-linked glycoproteins through the sequential degradation of high-mannose, hybrid, and complex oligosaccharides. In feline alpha-mannosidosis, the accumulated oligosaccharides primarily represent intact oligomannosyl moieties of N-linked glycans rather than the products of residual alpha-mannosidase activity. As a consequence of this enzyme deficiency, there is intralysosomal accumulation of glycoprotein-derived, mannose-rich oligosaccharides. This rare disease has been reported in a 7 month old Domestic Shorthair (DSH) cat, in Domestic Longhaired (DLH) cats aged between 7 and 15 months, and in Persian kittens. There is considerable heterogeneity among these reports regarding clinical onset, clinical course, and pathology. All cats have signs of apparent cerebellar dysfunction, including ataxia-dysmetria and intention tremors. However, stillbirths and neonatal deaths may occur in Persian litters and many affected animals may not survive the first 6 months of life. Some affected cats show gingival hyperplasia, bizarre behaviour, such as running in circles, jumping without provocation, and standing in the water bowl, and progressive dementia and apathy. Other findings include corneal changes, open suture lines in calvaria, thymic aplasia, hepatomegaly, and polycystic kidneys. In the DSH cat, thoracic limb deformation due to lateral dysplasia of the carpus was noted at 4 months of age. Other findings included radiographic abnormalities of the spine and long bones, cataracts and tapetal changes, hepatomegaly, lymphadenopathy, and thickened peripheral nerves. In DLH cats, additional clinical signs such as lurching, falling, opisthotonos, paraplegia, megaoesophagus and systolic heart murmur have been reported; however, none had evidence of hepatomegaly, skeletal deformities or ocular abnormalities.


Microscopic detail of mannoside granules in neurones	Ultrastructure of alpha-mannosidose

Microscopic lesions are characterized by extensive vacuolation of neurons and glial cells of the nervous system (more in astrocytes than oligodendrocytes), as well as in spinal and enteric ganglia. Numerous vacuolated macrophages may be seen in peripheral nerves and in perivascular spaces of the CNS, and in a variety of parenchymal organs. Poor myelination of the cerebral white matter (especially in the corona radiata) and axonal spheroid formation (torpedoes, neuroaxonal dystrophy) in cerebral and cerebellar white matter, thalamic radiations, and cerebellar roof nuclei have been observed in Persian kittens, while abnormally thin myelin was noted in DSH cats. Neither these changes nor the extensive vacuolation of hepatocytes and pancreatic acinar cells seen in Persian and DSH cats, were observed in the DLH cats, although abundant axonal spheroids were found ultrastructurally in DLH cats. Immunocytochemical studies showed that the spheroids reacted positively with glutamic acid decarboxylase, the synthetic enzyme for the inhibitory neurotransmitter, gamma- aminobutyric acid. Extensive Purkinje cell loss was seen only in the DLH cats. In all cats, ultrastructural findings indicate that most neurons contain empty membrane-bound vacuoles or only small amounts of finely granular material. Some neuronal cytosomes have linear membranous profiles and vesicular or lamellar, membranous cytoplasmic bodies. Lipofuscin-like inclusions may be seen in larger neurons. Vacuoles are present in CNS vascular endothelial cells and pericytes. Neuritogenesis, as determined by Golgi staining, is not as prominent in cortical neurons of mannosidosis cats as it is in other storage disorders, such as gangliosidosis, sphingomyelinosis, and mucopolysaccharidosis; however, meganeurites, secondary neurite formation, and various types of dendritic changes have been observed. Very similar changes have been reported in swainsonine-induced feline a-mannosidosis.

Diagnosis is based on demonstrating a deficiency of acidic a-mannosidase in brain, liver or kidney, or detecting mannose-rich oligosaccharides in urine. A three-fold increase in the level of alpha-D-mannoside has been reported in liver and brain of affected cats. Lectin histochemistry on formalin-fixed, paraffin-embedded tissue sections is also a simple, reliable method for diagnosing alpha-mannosidosis. Cytoplasmic vacuolation is seen in blood lymphocytes and monocytes in Giemsa-stained blood smears. It is possible to distinguish between heterozygous and affected kittens by using enzyme assay and oligosaccharide determination in placenta: a-mannosidase activity is < 10% of control in affected kittens, and < 50% in heterozygous kittens. Prognosis is poor. Treatment strategies are being investigated in colonies of affected cats. The cDNA encoding lysosomal alpha-mannosidase has been cloned in the Persian cat, and not surprisingly, in accordance with the variable clinical and pathological features, genetic studies have shown there is molecular heterogeneity for feline alpha-mannosidosis. Researchers at the University of Pennsylvania, School of Veterinary Medicine, have also reported that retrovirus vector transfer of a new human alpha-mannosidase cDNA resulted in high-level expression of alpha-mannosidase enzymatic activity in deficient human and feline fibroblasts. In a recent study by this group using Persian crossbred cats with a four base pair deletion in the gene encoding alpha-mannosidase, there was evidence of defective myelination in both CNS and PNS. Magnetic resonance imaging of the brains of affected cats revealed diffuse white matter signal abnormalities throughout the brain. Quantitative magnetization transfer imaging showed a 8 - 16% decrease in the magnetization transfer ratio in the white matter of affected cats compared to normal cats indicating myelin abnormalities. Histology confirmed myelin loss throughout the cerebrum and cerebellum. Affected cats showed slow motor nerve conduction velocity and increased F-wave latency. Single nerve fibre teasing revealed significant demyelination-remyelination in peripheral nerves. Ultrastructural findings in peripheral nerves included presence of numerous membrane-bound vacuoles within Schwann cell cytoplasm, endoneurial and perineurial macrophages, endothelial cells, and pericytes. The cytosomes were either empty or contained a fine fibrillar material. Many myelinated fibres were thinly myelinated and there was scattered presence of onion-bulbs and naked axons. A significant increase in the G-ratio (axon diameter divided by fibre diameter) was identified in affected cats suggesting a decrease in total fibre diameter associated with myelin loss and/or hypomyelination.