Prosaposin deficiency: further characterization of the sphingolipid activator protein-deficient sibs. Multiple glycolipid elevations (including lactosylceramidosis), partial enzyme deficiencies and ultrastructure of the skin in this generalized sphingolipid storage disease.

Sphingolipid activator protein (SAP) defi- ciency, previously described in two sibs and shown to be caused by the absence of the common saposin precursor (prosaposin), was further characterized by biochemical lipid and enzyme studies and by ultrastructural analysis. The 20-week-old fetal sib had increased concentrations of neutral glycolipids, including mono-, di-, tri- and tetra- hexosylceramide, in liver, kidney and cultured skin fi- broblasts compared with the controls. Glucosylceramide and lactosylceramide were particularly elevated. The kid- ney of the affected fetus showed additional increases in the concentration of sulphatide, galactosylceramide and digalactosylceramide. Free ceramide was stored in the liver and kidney, and GM3 and GM2 gangliosides were ele- vated in the liver, but not the brain, of the fetus. Phospho- lipids, however, were normal in the affected fetus. In the liver biopsy of the propositus, who later died at 16 weeks of age, only a few lipids could be studied. Glucosylce- ramide, dihexosylceramide and ceramide were elevated in agreement with our previous study. Enzyme studies were undertaken using detergent-free liposomal substrate preparations and fibroblast extracts. The sibs' (3-gluco- cerebrosidase and (3-galactocerebrosidase activities were clearly reduced, but their sphingomyelinase activities were normal. The normal activity of the latter enzyme and the almost normal tissue concentration of sphingomyelin in prosaposin deficiency suggest that the prosaposin-derived SAPs are not required for sphingomyelinase activity in vivo. In keeping with the biochemical findings, skin biop- sies from the sibs showed massive lysosomal storage with a vesicular and membranous ultrastructure. The function This paper is dedicated to Prof. Jtirgen Pfeiffer on the occasion of his 70th birthday