Substrate reduction therapy

© 2007 Springer Science+Business Media, LLC. All rights reserved. The glycosphingolipidoses are a family of storage diseases that arise due to incomplete catabolism of glycosphingolipids (GSLs) in the lysosome (Wraith, 2002). The majority are autosomal recessive disorders and result from mutations in the genes that encode the catabolic enzymes of the lysosome (Winchester, 2004). Clinically they are highly variable (Beck, 2001) but typically have a neurodegenerative course and commonly present in infancy or early childhood (Wraith, 2004). Adult-onset variants also occur (Rapola, 1994; Wraith, 2004). The age of onset is influenced by the residual enzyme activity present, that in turn reflects the impact a specific mutation has on the properties of the enzyme (Rapola, 1994; Winchester, 2004). Little or no activity leads to rapid storage and early onset of symptoms whereas higher levels of residual activity lead to a slower rate of storage and a longer presymptomatic period. In this chapter, we focus on a drug-based therapy that is relevant to all lysosomal diseases involving the storage of glucosylceramidederived GSLs, including Gaucher, Fabry, Tay-Sachs, Sandhoff, and GM1 gangliosidosis. In addition, storage diseases involving the secondary storage of GSLs