GM2-ganglioside metabolism in situ in mucolipidosis IV fibroblasts

Mucolipidosis IV (ML IV) is an inherited lysosomal disorder for which the primary biochemical defect has not been identified. In order to detect any defect in glycosphingolipid metabolism, we have examined the metabolism of sphingosine-labeled (H-3)G(M2) in situ in fibroblasts from patients diagnosed with ML IV. Fibroblasts were exposed for 10 days in medium containing (H-3)G(M2) (15 uM; Sp. Act. 35000 cpm/nmole), washed, harvested and analyzed for radioactivity in extracted lipids. Control cells metabolized about half of the internalized ganglioside, mostly to ceramide. In ML IV fibroblasts, 70-80% of the cellular radioactivity was present as G(M2) indicating reduced degradation. This is not as severe as in G(M2) gangliosidosis as a small amount of G(M2) was metabolized in ML IV cells to ceramide. Since there is no defect in the lysosomal enzyme profile in these cells, it is possible that an abnormality in the translocation of membrane constituents to the lysosomes may explain the slower ganglioside metabolism.