Congenital Disorders of Glycosylation

Abstract

Congenital defects of glycosylation (CDG) are genetic diseases due to deficient glycosylation of glycoconjugates (glycoproteins, glycolipids, and glycosylphosphatidylinositol anchors). Since the first clinical description of patients with CDG, this disease family has shown an exponential expansion. We know actually nearly 50 CDG that can be divided in four groups: (1) defects in protein N-glycosylation (n: 16), (2) defects in protein O-glycosylation (n: 11), (3) defects in glycolipid and glycosylphosphatidylinositol anchor glycosylation, and (4) defects in multiple glycosylation pathways and in other glycosylation pathways. In 2008–2009 a novel, transparent CDG nomenclature was introduced that covers all (known and still to be discovered) CDG. It consists of the official gene symbol (unitalicized) followed by “-CDG.” The majority of CDG patients show neurological disease associated with variable involvement of nearly all other organs. Only a few CDG are pauci-organ/mono-organ diseases (e.g., TUSC3-CDG (brain), EXT1/EXT2-CDG (cartilage), GNE-CDG (skeletal muscles), SEC23B-CDG (erythrocytes)). All known CDG present autosomal recessive inheritance except for MAGT1-CDG (X-linked) and EXT1/EXT2-CDG (autosomal dominant). Some CDG can be diagnosed clinically such as EXT1/EXT2-CDG. Two screening techniques are available: serum transferrin isofocusing (or other techniques such as capillary zone electrophoresis) for the diagnosis of protein N-glycosylation disorders associated with sialic acid deficiency and serum apolipoprotein C-III isofocusing for the diagnosis of core 1 mucin type O-glycans. Treatment possibilities are still frustratingly limited. An efficient therapy is available for only one CDG, namely, oral mannose for MPI-CDG. Since about 1 % of the human genome is involved in glycosylation, it appears that most CDG have still to be discovered. Elucidation of the basic defects of these CDG will increasingly require next-generation sequencing techniques such as whole genome sequencing.