ABSTRACT
INTRODUCTION Lysosomes are subcellular membrane-bound organelles containing primary acid hydrolases and other proteins responsible for the catabolism of naturally occurring and phagocytized intracellular macromolecules. Lysosomes are in direct continuity with both endosomal and autophagosomal streams in cells, thus forming what has been referred to as the greater lysosomal system and comprising the predominant recycling system of cells.545 As a result of lysosomal malfunction, various molecules accumulate within lysosomes and late endosomes, forming abnormal intracellular inclusions or storage bodies.302 The concept of lysosomal storage disease was established in 1963 when H.G. Hers discovered that in type II glycogenosis (Pompe disease), glycogen accumulated within vacuoles secondary to a defect of an α-1,4-glucosidase normally present in lysosomes. Based on this finding, Hers hypothesized that other so-called storage disorders (e.g. Tay-Sachs and Niemann-Pick diseases) could have a similar causation.209 Hers’ concept of inborn lysosomal disorders included two easily detectable characteristics: (i) a single lysosomal hydrolytic enzyme must be genetically deficient; and (ii) the substrate(s) of that enzyme would, as a consequence, accumulate within pathologically altered secondary lysosomes. In the ensuing years, however, the concept of genetic lysosomal disease evolved to include disorders caused by genetic abnormalities of proteins that are not lysosomal enzymes. These include glycoprotein cofactors for lysosomal enzymes and related soluble proteins essential for lysososmal function, non-lysosomal enzymes involved in the post-translational modification or transport of lysosomal enzymes, and transmembrane proteins responsible for egress of metabolites out of lysosomes and other functions. It is anticipated that this list will grow as a more detailed understanding of
genetic lysosomal diseases have been identified. Although most types of individual lysosomal diseases are rare, when taken as a group their prevalence is 1 per 7700 live births, making them one of the major families of genetic disease.330
