Twitcher mice with only a single active galactosylceramide synthase gene exhibit clearly detectable but therapeutically minor phenotypic improvements

Cross-breeding of mouse mutants, each defective in either synthesis (CGT kn ockout) or degradation (twitcher) of galactosylceramide, generates hybrids with a genotype of gale (-/-), cgt (+/-), in addition to doubly deficient m ice. They are Ideally suited to test the potential usefulness of limiting s ynthesis of the substrate as a treatment of genetic disorders due to degrad ative enzyme defects. The rate of accretion of galactosylceramide in the br ain of CGT knockout carrier mice (cgt (+/-)) is approximately two-thirds of the normal, suggesting a gene-level compensation for the reduced gene dosa ge. Phenotype of twitcher mice with a single dose of normal cgt gene was in deed milder with statistical significance, albeit only slightly. Compared a mong 10 paired littermates, the difference in the life span was 7 +/- 3.9 d ays (S.D.) and the difference in the maximum attained body weight was 1.9 /- 1.2 g (S.D,), Neuropathologists were able to distinguish blindly gale (- /-), cgt (+/-) mice from galc (-/-), cgt (+/+) mice. The brain psychosine l evel in gale (-/-), cgt (+/-) mice was also approximately two-thirds of the gale (-/-), cgt (+/+) mice. These observations indicate that reduction of galactosylceramide synthesis to two-thirds of the normal revel results in m inor but clearly detectable phenotypic improvements. Because of the detrime ntal consequences of drastic reduction in galactosylceramide synthesis that may be required for pragmatically meaningful improvements, this approach b y itself is unlikely to be useful as the sole treatment but may be helpful as a supplement to other therapies. (C) 2000 Wiley-Liss, Inc.