Pathophysiology of lysosomal storage disorders

In most lysosomal storage disorders, an inherited deficiency of a specific lysosomal enzyme results in the accumulation of unde-graded substrates within the lysosome. In others, accumulation of storage product results from the deficiency or malfunction of activator proteins, transport proteins or enzymes responsible for the processing of other lysosomal macromolecules. The involvement of over 40 different genes has been characterized, with many exhibiting a large number of different mutations. The resulting diseases are grouped according to the major stored substance, for example mucopolysaccharidoses (MPS), sphin-golipidoses and glycoproteinoses. Storage product within the lysosomes causes disruption of cellular organization and disturbance of normal function. Different lysosomal storage diseases have characteristic organ distribution patterns of the abnormal metabolites and therefore recognizable pathological manifestations. For example, in MPS III (Sanfilippo disease) there is accumulation of heparan sulphate, an essential component of the neuronal membrane. This results in mental retardation. In contrast, in MPS IV (Morquio disease) accumulation of keratan

Figure 19.1 Routes of lysosomal enzyme cycling. Extracellular enzyme binds to the plasma membrane via mannose 6-phosphate receptors and is internalized by a clathrin-coated vesicle into an early endosome. As the early endosome acidifies to become a late endosome, the enzyme dissociates from the mannose 6-phosphate receptor, which recycles to the plasma membrane. The late endosome fuses with a primary lysosome derived from the Golgi apparatus to form a secondary lysosome, which may remain in the cell as a residual body or fuse with the plasma membrane in the process of exocytosis of digested products.

Sanfilippo Disease Etiology

sulphate results in severe skeletal deformities. However, even within a discrete storage disorder there are often wide-ranging clinical manifestations. Individual mutations of the relevant enzymes give rise to variable levels of residual enzyme activity. This may result in different sites of storage and rates of accumulation producing clear genotype-phenotype correlations. More often, however, the genotype-phenotype relationship is unclear, with even siblings known to have the same mutation exhibiting disparate disease manifestations. This suggests that genetic or environmental factors other than residual enzyme level impacts upon the disease phenotype. Although knowledge of the genetics and biochemistry of the disorders has recently improved substantially, little is known of the pathological processes that actually result in end-organ damage. The enormous variability in symptom severity cannot be explained simply by differences in the overall burden of storage product but suggests a complex host reaction to abnormal cells. This may result in cytokine secretion, cellular proliferation, enhancement of other enzyme levels, and effects on metabolites and energy expenditure. In Gaucher's disease (GD), where storage cells are macrophages that play an essential role in host physiology and pathogenesis of inflammatory and immunological responses, a wide variety of enzymes, cytokines and coagulation factors are perturbed (Table 19.1). Interleukin 1 (IL-1), IL-6, IL-10 and tumour necrosis factor (TNF) have been implicated in GD pathogenesis. Elevated serum levels of IL-6, which is produced by macrophages, endothelial cells, fibroblasts and T cells, have been found to correlate with an index of severity in GD patients, and may be instrumental in the pathogenesis of B-cell dysregulation and bone disease. IL-10, which in general inhibits the synthesis of other inflammatory cytokines, is also elevated and may represent an abnormal state of immune activation.

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