Defects in degradation of blood group A and B glycosphingolipids in Schindler and Fabry diseases

Skin fibroblast cultures from patients with inherited lysosomal enzymopathies, alpha-N-acetylgalactosaminidase (alpha-NAGA) and alpha-galactosidase A deficiencies (Schindler and Fabry disease, respectively), and from normal controls were used to study in situ degradation of blood group A and B glycosphingolipids. Glycosphingolipids A-6-2 (GalNAc (alpha1-->3)[Fucalpha-->2]Gal(beta1-->4)GlcNAc(beta1-->3)Gal(beta1-->4)Glc (beta1-->1')Cer, IV2-alpha-fucosyl-IV3-alpha-N-acetylgalactosaminyhieolactotetraosylceramide), B-6-2 (Gal(alpha1-->3)[Fucalpha1-->2] Gal (beta1-->4)GlcNAc(beta1-->3)Gal(beta1-->4)Glc(beta1-->1')Cer, IV2- alpha-fucosyl-IV3-alpha-galactosylneolactotetraosylceramide), and globoside (GalNAc(beta1-->3)Gal(alpha1-->4)Gal(beta1-->4)Glc(beta1-->1) Cer, globotetraosylceramide) were tritium labeled in their ceramide moiety and used as natural substrates. The degradation rate of glycolipid A-6-2 was very low in fibroblasts of all the alpha-NAGA-deficient patients (less than 7% of controls), despite very heterogeneous clinical pictures, ruling out different residual enzyme activities as an explanation for the clinical heterogeneity. Strongly elevated urinary ex cretion of blood group A glycolipids was detected in one patient with blood group A, secretor status (five times higher than upper limit of controls), in support of the notion that blood group A-active glycolipids may contribute as storage compounds in blood group A patients. When glycolipid B-6-2 was fed to alpha-galactosidase A-deficient cells, the degradation rate was surprisingly high (50% of controls), while that of globotriaosylceramide was reduced to less than 15% of control average, presumably reflecting differences in the lysosomal enzymology of polar glycolipids versus less-polar ones.Relatively high-degree degradation of substrates with alpha-D-Galactosyl moieties hints at a possible contribution of other enzymes. Defects in degradation of blood group A and B glycosphingolipids in Schindler and Fabry diseases.