Substrate Reduction Therapy Reduces Ganglioside Content in Postnatal Cerebrum - Brainstem and Cerebellum in a Mouse Model of GM 1 Gangliosidosis

GM1 gangliosidosis is an incurable lysosomal storage disease caused by a deficiency in acid b-galactosidase (b-gal), resulting in accumulation of ganglioside GM1 and its asialo-form (GA1) primarily in the brain. In this study, we investigated the effects of N-butyldeoxygalacto-nojirimycin (NB-DGJ), an imino sugar that inhibits ganglioside biosynthesis, in normal C57BL/6J (B6) and in b-gal knockout (-/-) mice from p-9 to p-15. This is a period of active cerebellar development and CNS myelinogenesis in the mouse and would be comparable to late stage embryonic and early neonatal development in humans. NB-DGJ significantly reduced total ganglioside and GM1 content in cerebrum-brainstem (C-BS) and in cerebellum of normal and b-gal-/-mice. NB-DGJ had no adverse effects on body weight or C-BS/cerebellar weight, water content, or thickness of the external cerebellar granule cell layer. Sphingomyelin was elevated in