Glycosphingolipid studies of visceral tissues and brain from type 1 Gaucher disease variants

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Abstract
Glucosylceramide and glucosylsphingosine isolated from spleen, liver and brain were quantitated and characterized in 2 unrelated patients with Gaucher disease, neither of whom had clinical or neuropathologic evidence of neuronal involvement. Visceral glucosylceramide accumulation did not differ in the 2 patients. Hepatic glucosylsphingosine content was 2-fold greater in a young severely affected 3-yr-old American Black patient compared to that in a 56-yr-old Ashkenazi Jewish patient. Significant differences in glycosphingolipid content and composition were observed in the brains of these 2 cases. Cerebral and cerebellar cortical glucosylceramide accumulated to a greater extent (3-fold) in the severely affected 3-yr-old patient compared to that in the older case. The compositions of the acyl and sphingosyl base residues of glucosylceramide in the cerebral and cerebellar cortices from the Ashkenazi Jewish patient were similar to those in normal individuals. In comparison, the gray matter glucosylceramide in the severely affected patient had increased percentages of stearic acid (18:0) and eicosasphingenine (d20:1), suggesting that the accumulated substrate was derived from the brain ganglioside pool. Glucosylsphingosine was found in large amounts only in cerebral and cerebellar cortices from the severely affected patient. The glycolipid content and composition in this patient was similar to that found in the Norrbottnian (Type 3) form of Gaucher disease. The differences in glucosylceramide acyl and sphingosyl base composition in gray matter from the severely affected patient and that in the Ashkenazi Jewish patient suggested that the accumulated substrates were metabolized differently by the residual enzymes in each case. Since both glucosylceramide and glucosylsphingosine are substrates of the normal enzyme, the data suggested that the allelic mutations of acid .beta.-glucosidase can differentially alter the catabolism of these substrates and result in the different phenotypes of Gaucher disease.