Glycosaminoglycans and oligosaccharides disorders: Glycosaminoglycans synthesis defects, mucopolysaccharidoses, oligosaccharidoses and sialic acid disorders

Glycosaminoglycans, (GAGs, mucopolysaccharides) are essential constituents of connective tissue, including cartilage and vessel walls. They are composed of long sugar chains, containing highly sulfated, alternating uronic acid and hexosamine residues, assembled into repeating units. The polysaccharide chains are bound to specific core proteins within complex macromolecules called proteoglycans (PG). GAGs are grouped in two families: sulfated GAGs, mainly represented by chondroitin sulfate (CS), dermatan sulfate (DS), keratan sulfate (KS), heparan sulfate (HS) and heparin (Fig. 41.1) and nonsulfated GAGs including mainly hyaluronan (HA). PG biosynthesis involves several enzymes and transporters in four main steps: core protein synthesis, GAG synthesis (including the linker tetrasaccharide and subsequent chain elongation), GAG sulfation and PG secretion. Core protein synthesis occurs in the rough endoplasmic reticulum where some early modifications, such as N-glycosylation, take place. The core protein then moves to the Golgi apparatus for GAG biosynthesis (see also Chaps. 43, and 44). Degradation of GAGs takes place inside the lysosomes and requires several acid hydrolases. Deficiencies of specific degradative enzymes are the cause of a variety of eponymous disorders, collectively termed mucopolysaccharidoses (MPSs).