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C H A P T E R 53

LYSOSOMAL STORAGE DISEASES:

PERSPECTIVES AND PRINCIPLES

Edward H. Schuchman and Melissa P. Wasserstein

The lysosomal storage diseases (LSDs) are a diverse group of inherited through a series of specific targeting mechanisms unique to these
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disorders caused by the defective function of specific lysosomal pro- proteins (see later and box on Lysosomal Protein Biosynthesis and
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teins (Table 53.1). Originally described by de Duve and colleagues, Sorting).
lysosomes are ubiquitous organelles required to metabolize macro- Coincident with the addition of the β-N-acetylglucosamine
molecules. This includes molecules internalized by cells through the moiety is the addition of a phosphate group to this sugar by the
process of endocytosis, as well as those produced during the natural enzyme N-acetylglucosaminyl-1-phosphotransferase. This modi-
turnover of endogenous cell components (autophagocytosis). More fication is essential for targeting of most lysosomal enzymes, and
than 50 hydrolytic enzymes have been found within the lysosome, as mutations in the gene encoding this enzyme lead to a severe LSD
well as several membrane-embedded transport proteins, ion pumps, (I-cell disease) characterized by the abnormal targeting and secretion
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and other specialized components. Unique to the lysosome is a highly of many lysosomal enzymes. The glucosaminyl residues are sub-
acidic pH, and the enzymes and proteins found within this organelle sequently cleaved, exposing terminal mannose-6-phosphate (M6P)
have evolved to optimally function within this unique environment. residues on the oligosaccharides. Importantly, for any given lysosomal
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Hers was the first to describe enlarged and abnormally shaped enzyme the oligosaccharide chains may be highly heterogeneous,
lysosomes in a patient with Pompe disease (α-glucosidase deficiency), containing varying amounts of M6P, sialic acid, and glucosaminyl
thus delineating the first LSD. To date, more than 50 disorders have sugars.
been attributed to defective lysosomal proteins. Most are inherited as In addition to targeting the enzymes to lysosomes, the oligosac-
autosomal recessive traits, although two are X-linked (Fabry disease charide side chains also participate in the tertiary structure and folding
and mucopolysaccharidosis [MPS] type II [Hunter disease]). In of the proteins, and are in many cases necessary for their activity.
general, LSDs are categorized according to the type of macromolecule(s) Proteolytic processing within the lysosome also may be required for
that accumulate (e.g., lipidoses, mucopolysaccharidoses). The patho- activity, as well as assembly into macromolecular “scaffolds” that may
physiology of these diseases is directly related to these accumulating include protective and/or activator proteins. These events are driven,
material(s), although as the diseases progress many secondary abnor- at least in part, by the low pH of the organelle. Finally, although most
malities also occur. There is also considerable cell and organ specificity lysosomal enzymes use the M6P targeting system, it is also important
among the LSDs that is directly related to the location and function to recognize that non-M6P targeting systems have been described
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of the specific macromolecules affected. and may function alone or in combination with M6P. For example,
the lysosomal membrane proteins (LIMPs or LAMPs) are sorted to
PATHOBIOLOGY OF LYSOSOMAL STORAGE DISEASES the lysosomal membrane through tyrosine residues located near the
carboxyl-terminal end of the proteins.
Biology of the Lysosome and Lysosomal Enzymes:
Basic Principles Pathogenesis of Lysosomal Storage Diseases:
General Concepts
Lysosomes are formed through the fusion of enzyme-containing ves-
icles produced in the trans-Golgi network (TGN) with other vesicles The majority of LSDs result from mutations in genes encoding
such as endosomes or autophagosomes. Central to the formation individual lysosomal enzymes, leading to the intralysosomal accumu-
of a mature lysosome is the establishment of an acidic pH. Mature lation of the enzyme’s substrate. A small number of the diseases also
lysosomes have a pH below 5, which is maintained by proton pumps result from mutations in genes encoding defective transport proteins
found within the lysosomal membrane. Acidification of the compart- that reside within the lysosomal membrane, or by the defective func-
ment is required for proper activation of the hydrolytic enzymes tion of other nonhydrolytic enzymes required for lysosomal enzyme
and the release of macromolecules from their membrane receptors, biosynthesis (e.g., I-cell disease). The type of macromolecules that
providing access to the fully active hydrolytic enzymes. Although accumulate distinguishes two main categories of LSDs: i.e., those
lysosomes have been historically considered discrete organelles, it is that accumulate mucopolysaccharides (mucopolysaccharidoses; MPS
now known that the lysosomal system is highly dynamic and consists diseases), and those that accumulate lipids (lipidoses; see Schulze
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of a series of digestive vesicles with varying pH, hydrolytic enzyme et al and Giugliani et al for reviews). Several carbohydrate storage
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activities, and cellular location. 3 diseases have also been described. With only a few exceptions (e.g.,
Lysosomal function requires the coordinated action of acidic Wolman disease), the lipid substrates stored in the LSDs share a
hydrolyases, acidification machinery and membrane proteins. It common structure that includes a ceramide backbone (2-N-acyl-
has recently been discovered that the diverse genes/gene products sphingosine, i.e., the sphingolipids). More than 100 sphingolipids are
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involved in lysosomal function belong to a gene network–the coor- known with diverse function, and their abnormal accumulation in
dinated lysosomal expression and regulation (CLEAR) network–and the LSDs results in a wide range of physiologic, morphologic, and
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are transcriptionally regulated by the lysosomal “master gene” TFEB. clinical manifestations. For example, progressive lysosomal accumula-
Transcription factor EB (TFEB) positively regulates the expression tion of glycosphingolipids in the central nervous system (CNS) leads
of other genes required to form lysosomes, controls the number of to neurodegeneration, abnormal neurite sprouting, and synapse
lysosomes, and promotes degradation of lysosomal substrates. Key deterioration, whereas storage of these lipids in visceral cells can lead
to the formation of the lysosome is the delivery of the hydrolytic to organomegaly, skeletal abnormalities, pulmonary infiltration, and
enzymes to the acidified vesicles in the TGN. This is accomplished many other manifestations.
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