Preventing sensory loss in a mouse model of lysosomal storage disease

The lysosomal storage diseases (LSDs) include more than 40 genetic disorders in the function of specific hydrolytic enzymes that catabolize glycosaminoglycans (GAGs), glycoproteins, and lipids (Gieselman, 1995; Sands et al., 1997b; Daly and Sands, 1998; Meikle et al., 1999). Typically, the degradation of these cellular components involves the sequential action of many hydrolases, each of which remove specific terminal residues. Thus, when a specific lysosomal enzyme is defective, macromolecules containing its substrate residue will accumulate, and any cells normally degrading these will show abnormal lysosomal storage. If the affected macromolecules are normally located extracellularly, then the cells showing lysosomal storage may be of a different type than those involved in synthesis, and have a phagocytic function. Individually, LSDs are rare. As a group, however, they occur with an incidence estimated at 1 in 6700 live births (Meikle et al., 1999). Because any single enzyme defect can impair the breakdown of several types of macromolecules that are likely to be widely distributed across organs and tissues, LSDs are syndromes. At least 12 LSDs are associated with hearing loss (the mucopolysaccharidoses, Tay-Sachs, GM gangliosidosis, Neimann-Pick, Fabry, galactosialidosis, and aspartylglucosamineuria) (Schuknecht, 1993; Gorlin, 1995).