O-glycosylation defects with structural changes of the central nervous system – new members of the CDG family

The aim of our studies is to further characterize the clinical and biochemical phenotype of patients with Congenital muscular dystrophies (CMD) due to abnormal O-glycosylation, which are new members of the CDG family (congenital disorders of glycosylation). CMDs are a heterogeneous group of autosomal recessive inherited defects. The dystrophin-glycoprotein complex (DGC) plays an essential role in linking the basement membrane with the cytoskeleton in muscle and brain. CMDs associated with defects in the DGC show a dissociation of this structural linkage. The key molecule within the DGC is the heavily glycosylated dystroglycan. In several CMD syndromes primary deficiencies in glycosyltransferases involved in O-glycosylation have recently been identified. Abnormal glycosylation of dystroglycan has been described for Walker-Warburg syndrome (WWS), Fukuyama muscular dystrophy, Muscle-Eye-Brain (MEB) disease and Fukutin-related protein deficiency (MCD 1C). Immunhistochemical, electron microscopical and Western-blotting results of diagnostic muscle biopsies show secondary reduction of laminin2 and alpha-dystro-glycan. Screening approaches for O-glycosylation defects are needed and a first diagnostic tool by determination of the Apo CIII isoforms (core 1 O-glycoprotein) has been established.

As several CMD patients show structural malformations of the brain, the results underline the crucial role of correct glycosylation of basement membrane components and their receptors for the maintenance of the extracellular matrix.

Keywords: congenital muscular dystrophies, dystroglycan, glycosylation defects