Etiology and Pathogenesis of CDG Syndrome

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CDG syndrome is a recently identified hereditary disease with unique neurological and general somatic manifestations, and its etiology and pathogenesis are have been unknown up till recently. We tried to analyze molecular abnormalities in somatic cells from patients with this disease. Among several lysosomal enzymes, beta-hexosaminidase and alpha-fucosidase showed high catalytic activities in serum. The electrofocusing pattern of the latter revealed an increase of protein bands moving more toward the anode, indicating an increase of sialic acid-containing glyco-protein molecules. Serum transferrin and antithrombin contained abnormal molecules of small size detected by immunoblotting. The mature alpha-subunit of beta-hexosaminidase was increased in cultured fibroblasts, but normal extracellularly. In these cells, phosphomannomutase activity was extremely low in two patients. This abnormality probably induces a decrease of intra-cellular mannose 1-phosphate and GDP-mannose, resulting in insufficient glycosylation of glycoprotein molecules.