An asymptomatic heterozygous female with fabry disease: implications for enzyme replacement therapy.

We report an asymptomatic female with Fabry disease immunohistochemically diagnosed by renal biopsy. She was initially diagnosed as having nephrotic syndrome, and renal biopsy was performed for pathological diagnosis. The renal specimen revealed non-specific findings (minor glomerular abnormalities) for nephrotic syndrome. Numerous laminated bodies in glomerular epithelial cells in electron microscopic findings and accumulations of ceramidetrihexoside immunohistochemically were observed and she was diagnosed with Fabry disease. However, no other laboratory data or clinical findings supported the diagnosis of Fabry disease. Since the efficacy of recombinant human alpha-galactosidase replacement therapy in this disease has been reported, whether enzyme replacement therapy for subclinical Fabry female patients is indicated or not is an important issue.

Pseudo-clinical Fabry's disease without alpha galactosidase deficiency.

The authors describe two cases of clinical Fabry's disease. The first patient presents a deficiency of alpha galactosidase and a urinary excretion of ceramide trihexosides and dihexosides ; the second patient had a normal alpha galactosidase and normal excretion of urinary lipids. In this latter case the Km and the activity of the enzyme measured at different pH were similar to those of normal enzyme. The other lysosomal enzymes, beta galactosidase, beta glucosidase, hexosaminidases A and B, alpha fucosidase, arylsulfatases, phosphatase acids were also measured in patient 2 and all have normal activities. There is no urinary excretion of glycolipids or mucopolysaccharides. Yet this patient has an accumulation of material in his fibroblasts and renal cells. The authors also present a genetic study.

Properties of the residual alpha-galactosidase activity in the tissues of a Fabry hemizygote.

The properties of the residual alpha-galactosidase activity in kidney, liver, spleen, fibroblasts and urine of a Fabry hemizygote have been studied using p-nitrophenyl-alpha-galactoside and 4-methylumbelliferyl-alpha-galactoside as substrates. In addition, alpha-galactosidase activity in urine has been determined with ceramidetrihexoside as substrate. The residual alpha-galactosidase activity of Fabry, measured with artificial substrate, is stimulated (6-35%) by myo-inositol and only slightly inhibited by melibiose (7-17%) in all the materials used. In contrast, the alpha-galactosidase of normal tissues and urine is inhibited (36-48%) by myo-inositol and inhibited to a much greater extent (40-50%) by melibiose. The KM for artificial substrate of the residual activity of Fabry is higher than that of the alpha-galactosidase in normal kidney, liver, spleen, fibroblasts and urine. The residual activity of Fabry is generally more stable to heating than the activity in the normal materials, although exceptions were noted. When these properties are compared with those of the alpha-galactosidase isoenzymes in normal tissues and body fluids, the residual activity of Fabry material seems to be very similar to the minor component of normal tissue (alpha-galactosidase B). Moreover, the pH optimum curve of this minor component and of the Fabry alpha-galactosidase in urine are similar, whereas the major isoenzyme (alpha-galactosidase A) shows a curve much more like that of normal urine. The findings with ceramidetrihexoside as substrate indicate a possible discrepancy. Alpha-Galactosidase A hydrolyses ceramidetrihexoside, Fabry urine preparation does not. However, alpha-galactosidase B of normal urine shows a slight but definite ceramidetrihexosidase activity. No contamination of the B preparation with alpha-galactosidase A could be detected. The minimum hypothesis, supported by most of the experimental evidence, is that the residual activity of Fabry and normal alpha-galactosidase B are identical.