Congenital disorders of glycosylation (CDGs) are due to defects in the synthesis of the
glycan moiety of
glycoproteins or other
glycoconjugates. This review is devoted mainly to the clinical aspects of protein glycosylation defects. There are two main types of protein glycosylation: N-glycosylation and O-glycosylation. N-glycosylation generally consists of an assembly pathway (in cytosol and endoplasmic reticulum) and a processing pathway (in endoplasmic reticulum and Golgi). O-glycosylation lacks a processing pathway but is otherwise more complex. Sixteen disease-causing defects are known in protein glycosylation: 12 in N-glycosylation and four in O-glycosylation. The N-glycosylation defects comprise eight assembly defects (CDG-I) designated CDG-Ia to CDG-Ih, and four processing defects (
CDG-II) designated
CDG-IIa to
CDG-IId. By far the most frequent is CDG-Ia (phosphomannomutase-2 deficiency). It affects the nervous system and many other organs. Its clinical expression varies from extremely severe to very mild (and thus probably underdiagnosed). The most interesting disease in this group is CDG-Ib (
phosphomannose isomerase deficiency) because it is so far the only efficiently treatable CDG (
mannose treatment). It has a hepatic-intestinal presentation. The O-glycosylation defects comprise two O-xylosylglycan defects (a
progeroid variant of Ehlers-Danlos syndrome and the
multiple exostoses syndrome) and two O-mannosylglycan defects (
Walker-Warburg syndrome and
muscle-eye-brain disease). All known CDGs have a recessive inheritance except for
multiple exostoses syndrome, which is dominantly inherited. There is a rapidly growing group of putative CDGs with a large spectrum of clinical presentations (CDG-x). Serum
transferrin iso-electrofocusing remains the cornerstone of the screening for N-glycosylation defects associated with
sialic acid deficiency. Abnormal patterns can be grouped in to type 1 and type 2. However, a normal pattern does not exclude these defects. Screening for the other CDGs is much more difficult, particularly when the defect is organ- or system-restricted. The latter group promises to become an important new chapter in CDG. It is concluded that CDGs will eventually cover the whole clinical spectrum of paediatric and adult disease manifestations.