The molecular basis of lysosomal storage diseases and their treatment

Abstract

The lysosomal system is the main intracellular mechanism for the catabolism of naturally occurring endogenous and exogenous macromolecules and the subsequent recycling of their constituent monomeric components. It also plays an important part in processing essential metabolites. A genetic defect in a protein responsible for maintaining the lysosomal system results in the accumulation within lysosomes of partially degraded molecules, the initial step in the process leading to a lysosomal storage disease. The defective protein can be a luminal lysosomal enzyme or protein cofactor, a lysosomal membrane protein or a protein involved in the post-translational modification or transport of lysosomal proteins. Over 40 lysosomal storage diseases are known and they have a collective incidence of ≈ 1 in 7000–8000 live births. Most of the genes for the lysosomal proteins have been cloned, permitting mutation analysis in individual cases. This information can be used for genotype/phenotype correlation, genetic counselling and the selection of patients for novel forms of therapy, such as substrate deprivation or dispersal, enzyme replacement, bone-marrow transplantation and gene transfer.