Lysosomes are heterogeneous subcellular organelles containing specific hydrolyses that allow selective processing or degradation of proteins, nucleic acids, carbohydrates, and lipids. There are more than 40 different lysosomal storage diseases (LSDs), classified according to the nature of the stored material (Table 432e-1). Several of the most prevalent disorders are reviewed here: Tay-Sachs disease, Fabry disease, Gaucher disease, Niemann-Pick disease, lysosomal acid lipase deficiencies, the mucopolysaccharidoses, and Pompe disease. LSDs should be considered in the differential diagnosis of patients with neurologic, renal, or muscular degeneration and/or unexplained hepatomegaly, splenomegaly, cardiomyopathy, or skeletal dysplasias and deformations. Physical findings are disease specific, and enzyme assays or genetic testing can be used to make a definitive diagnosis. Although the nosology of LSDs segregates the variants into distinct phenotypes, these are heuristic; in the clinic, each disease exhibits—to some degree—a continuous spectrum of manifestations, from severe to attenuated variants.
Lysosomal biogenesis involves ongoing synthesis of lysosomal hydrolases, membrane constitutive proteins, and new membranes. Lysosomes originate from the fusion of trans-Golgi network vesicles with late endosomes. Progressive vesicular acidification accompanies the maturation of these vesicles; this gradient facilitates the pH-dependent dissociation of receptors and ligands and also activates lysosomal hydrolases. Lysosomes are components of the lysosome/autophagy/mitophagy system, which can be disrupted in the LSDs.
Abnormalities at any biosynthetic step can impair enzyme activation and lead to a lysosomal storage disorder. After leader sequence clipping, remodeling of complex oligosaccharides (including the lysosomal targeting ligand mannose-6-phosphate as well as high-mannose oligosaccharide chains of many soluble lysosomal hydrolases) occurs during transit through the Golgi. Lysosomal integral or associated membrane proteins are sorted to the membrane or interior of the lysosome by several different peptide signals. Phosphorylation, sulfation, additional proteolytic processing, and macromolecular assembly of heteromers occur concurrently. Such posttranslational modifications are critical to enzyme function, and defects can result in multiple enzyme/protein deficiencies.
The final common pathway for LSDs is the accumulation of specific macromolecules within tissues and cells that normally have a high flux of these substrates. The majority of lysosomal enzyme deficiencies result from point mutations or genetic rearrangements at a locus that encodes a single lysosomal hydrolase. However, some mutations cause deficiencies of several different lysosomal hydrolases by alteration of the enzymes/proteins involved in targeting, active site modifications, or macromolecular association or trafficking. All LSDs are inherited as autosomal recessive disorders except for Hunter (mucopolysaccharidosis type II), Danon, and Fabry diseases, which are X-linked. Substrate accumulation leads to lysosomal distortion, which has significant pathologic consequences. In addition, abnormal amounts of metabolites may also have pharmacologic effects important to disease pathophysiology and propagation.
For many LSDs, the accumulated substrates are endogenously synthesized within particular tissue sites of pathology. Other diseases have greater exogenous substrate supplies. For example, they are delivered by low-density lipoprotein receptor–mediated uptake in Fabry and cholesteryl ester storage diseases (CESDs) or by phagocytosis in Gaucher disease ...