Clinical, pathological, and biochemical studies on an infantile case of sulfatide/G_M1 activator protein deficiency

Abstract

A 28-month-old black male died with severe complications of mental and motor deterioration, seizures, and aspiration. Autopsy demonstrated moderate liver enlargement, normal spleen and kidneys, small testes, and a grossly normal brain. Further examination showed irregular macrogyrae with evidence of a storage or sclerotic process. Thin layer chromatography of the lipids in formalin-fixed tissue demonstrated elevated levels of ceramide trihexoside and possibly sulfatides in liver and a decrease in the ratio of galactosylceramide to sulfatide in brain. Examination of the gangliosides in formalin-fixed brain indicated a slight increase in the percentage of GM1 ganglioside and a clear elevation in GM2 and GM3 gangliosides. Cultured skin fibroblasts had a normal activity for a large number of lysosomal enzymes including arylsulfatase A and galactocerebrosidase. When the cells were loaded with [14C]sulfatide only about 12% of the sulfatide was metabolized after 3 days. Extracts of the cells were subjected to SDS-PAGE and immunoblotting with antisphingolipid activator protein-1 (SAP-1) rabbit antiserum, and no cross-reacting material was detected confirming the diagnosis of metachromatic leukodystrophy caused by SAP-1 deficiency. This patient was clinically more severe than the other patients described previously with this deficiency. Further studies are underway to define the nature of the mutation in this patient.

Characterization of a mutation in a family with saposin B deficiency: a glycosylation site defect.

“…Saposin B activates by a mechanism different from saposins A, C, and D; it interacts with lipid substrates solubilizing them for enzymatic hydrolysis. The physiological significance of saposin B is underscored by the discovery of its absence in a variant form of metachromatic leukodystrophy (activator-deficient metachromatic leukodystrophy) (16)(17)(18). In this report, we present evidence for a single base change as the molecular defect in activator-deficient metachromatic leukodystrophy found in two siblings of consanguineous parents and propose that this mutation gives rise to a glycosylation site defect.…”

pH-dependent Conformational Properties of Saposins and Their Interactions with Phospholipid Membranes

“…Sap C appears to be required in vivo by glucosylceramidase for the hydrolysis of glucosylceramide since a genetic defect of Sap C causes a juvenile variant of Gaucher's disease with glucosylceramide accumulation in tissues (11). A defect of Sap B results in a variant form of metachromatic leukodystrophy with sulfatide accumulation in tissues (12,13). The fact that the absence of one or another saposin causes different pathologies indicates that each saposin has distinct biological functions.…”

Saposin B binds and transfers phospholipids

“…Because of their ability to modulate the lysosomal enzymatic degradation of several sphingolipids (SLs), the saposins play an important role in the pathogenesis of sphingolipidoses, a group of lysosomal storage disorders characterized by SL accumulation (1,2). Mutations affecting the coding region of Sap B cause a variant form of metachromatic leukodystrophy with lysosomal storage of cerebroside sulfate (CS) (3,4).…”

“…Because the lack of Sap B leads to the storage of SLs, especially CS (3,4), the interaction of the saposin with SLs has been investigated extensively. It was shown that Sap B is able to solubilize in vitro several SLs such as CS, ganglioside GM1 (GM1), and globotriaosylceramide, whereas direct interaction with SL hydrolases has never been observed (9)(10)(11)(12).…”