SPATIOTEMPORAL PROGRESSION OF DEMYELINATION IN TWITCHER MOUSE - WITH CLINICOPATHOLOGICAL CORRELATION

The twitcher (twi/twi) is an authentic murine model of human globoid c ell leukodystrophy (GLD), caused by a deficiency of galactosylceramida se. Similar to human GLD, the twitcher shows progressive deterioration of neurological function and its neuropathology is characterized by a collection of periodic acid-Schift stain (PAS)-positive macrophages i n the areas of demyelination. However, there are some differences in t he clinico-pathological aspects between human and murine GLD. We inves tigated the spacio-temporal progression of neuropathology in the twitc her from postnatal day (PND) 10 to 45. No clinical symptoms or neuropa thological changes were apparent in twi/twi until PND 15. Generally, i nfiltration of macrophages, concomitant with myelin degeneration, was recognized in the cerebellar white matter and the brain stem after PND 20, then in cerebral white matter after PND 25, and in cerebral and c erebellar gray matter after PND 30. The demyelination was very severe in the radix of the 8th and the 5th cranial nerves. The neurological s ymptoms such as tremor, spasticity and cranial nerve dysfunction were well correlated with the progression of pathological changes. Demyelin ation progressed in an orderly fashion such that myelin degeneration b egan 10 to 20 days after the commencement of myelination in any of the given nerve fiber tracts. This suggests that there are no significant differences in the metabolism of galactocerebroside in the myelin and myelin-forming cells in individual nerve fiber tracts throughout the murine brain. Over-expression of glial fibrillary acidic protein was a lready present before the initiation of obvious demyelination. In addi tion to the areas of, demyelination, focal clustering of PAS-positive cells were seen in close association with neurons in the basal ganglia and hippocampus in this murine GLD twitcher, whereas in human GLD, PA S-positive cells tended to be limited within the white matter. Underst anding of these orderly patterns of neuropathological features is of e ssential importance for evaluating the results of the forthcoming gene therapy.