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Congenital disorders of glycosylation (CDG) comprise a continuously growing group of monogenetic inherited diseases in glycoprotein biosynthesis1,2,3,4,5,6 (Figure 44-1) which affect the generation of structurally highly diverse oligosaccharides that are covalently attached to proteins mostly by N-glycosidic linkage to amino groups of asparagine residues, or by O-glycosidic linkage to hydroxyl groups of serine or threonine residues. The oligosaccharide moieties determine crucial biological processes like protein quality control, directed protein transport, enzymatic activity, and protein stability. Deficiencies in this complex metabolic pathway lead to multi-organ diseases with neurologic symptoms often dominating (see At-A-Glance). Based on the glycosylation pattern of serum transferrin in the isoelectric focusing and thereby corresponding to their subcellular localization, CDG have traditionally been subdivided in “CDG-I” and “CDG-II.” CDG-I comprise deficiencies that either diminish the biosynthesis of dolichol-linked oligosaccharides or reduce their transfer onto newly synthesized proteins by the oligosaccharyltransferase complex in the endoplasmic reticulum. CDG-II affect the subsequent trimming and elongation of glycans bound to proteins in the endoplasmic reticulum and Golgi apparatus (Figure 44-1). The identification of a considerable number of new CDG types afforded the improvement of nomenclature which now connect the abbreviation of defective proteins with the term CDG (eg, deficiency of the enzyme phosphomannomutase 2 [PMM2]), formerly known as CDG-Ia, changed to PMM2-CDG (see At-A-Glance). CDG of unknown molecular nature remain CDG-Ix or CDG-IIx. Here we focus on N-glycosylation defects including those which are combined with mucin-type O-glycosylation involvement, as deficiencies in O-mannosylation leading to muscular dystrophies with neurological impairment have recently been reviewed elsewhere.7,8
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