Chapter 45: Lysosomal Disorders

INTRODUCTION

The lysosomes, named after a Greek term that means “digestive bodies,” were discovered in 1955 by De Duve.¹ They are spherical organelles, contained by a single-layer membrane, that are present in all nucleated cells and are important for degradation of macromolecules and homeostasis of the cell. Lysosomes also play an important role in the processes of phagocytosis and antigen presentation, which are necessary for regulation of inflammation and control of autoimmunity. The lysosome–endosomal system is intimately involved in regulation of autophagy, apoptosis, and cell death. An integral part of the intracellular recycling process, lysosomes contain hydrolytic enzymes that digest cell components and degrade complex cellular substrates such as glycoproteins, mucopolysaccharides (glycosaminoglycans), oligosaccharides, and lipids into simpler components during normal cellular turnover. A block in the degradation of these substrates leads to abnormal accumulation of complex macromolecules within lysosomes (Figure 45-1).

The concept of lysosomal disorders (LDs) was developed in 1963, following the discovery that Pompe disease was caused by a deficiency in α-glucosidase.² LDs are inherited conditions that are caused by defects in enzymes, enzyme activator proteins, membrane proteins, transporters, or enzyme targeting to the lysosome with resulting abnormal storage of complex macromolecules. When a lysosomal pathway is blocked, there is progressive accumulation of a variety of partially degraded intermediate metabolic products such as triglycerides, sterols, sphingolipids, sulfatides, sphingomyelin, gangliosides, and lipofuscins.³ The increasing storage of substrates within lysosomes results in impaired function of the affected organs.

The pathological features of the various LDs depend on the nature of the stored substrate and the organs where storage occurs. Substrate accumulation occurs primarily in the organs where they are synthesized (eg, liver, spleen, bone, and nervous system). This explains in part the varied organ involvement and symptomatology of these disorders.

Defective targeting of lysosomal enzymes to lysosomes (eg, I-cell disease), abnormal lysosomal membrane proteins (eg, Danon disease), and defective egress of substrate (eg, infantile sialic acid storage disease/Salla disease) also may cause abnormal storage. As the lysosomes enlarge, cellular and organ function are increasingly impaired. The exact causes of such impairment, however, are still the subject of investigation.

Because a wide range of clinical features are encountered in LDs, disease pathogenesis presumably involves the activation of various deleterious biochemical pathways or cellular processes. The release of acid hydrolases into the cytoplasm undoubtedly causes cellular damage, but such an occurrence has not been clearly established. In theory, defective transport of substrates into and out of lysosomes secondary to abnormal storage may play a role in disease pathogenesis, especially in disorders that involve membrane lipids (eg, sphingolipidoses). Dysregulation of apoptosis may cause disease manifestations in some LDs. Indeed, increased ...