| Abstract: | "Twitcher' is a recently recognized mouse mutant which, on the basis of morphological and enzymatic criteria, represents a murine model for globoid-cell leukodystrophy in man. In the twitcher mouse, myelin sheaths develop normally in peripheral nerves until about the fifteenth day when the rate of myelination declines, demyelination begins and Krabbe-type inclusions are seen in macrophages and Schwann cells. With age, demyelination becomes extensive, affecting fibres of all sizes. The axons are relatively spared, although they are smaller than normal. Twitcher peripheral nerves transplanted into normal hosts show, after 2 months, all the characteristics associated with globoid-cell leukodystrophy. After longer periods of time, however, pathological changes within the grafts appear considerably improved with only occasional evidence of myelin loss, little endoneurial oedema and few globoid cells. Migration of host Schwann cells into the graft can be excluded as a possible explanation. In the experiments reported here, we have attempted to determine whether the morphological improvement of grafted twitcher nerves is accompanied by an increase in activity of the enzyme galactosylceramidase. Our results show that galactosylceramidase activity in twitcher sciatic nerves grafted into normal hosts is variable after 1-2 months but indistinguishable from those in the host nerves and much higher than those in intact twitcher nerves after 4.5-9 months. In addition to migration of host Schwann cells, other tissues originating from the host can be excluded as cause of the high enzyme activity. This is the first evidence of long-term in vivo enzyme replacement, accompanied by improved pathology, in a genetic sphingolipidosis. |
