Sphingolipid activator protein deficiency in a 16-week-old atypical Gaucher disease patient and his fetal sibling: Biochemical signs of combined sphingolipidoses

Abstract

We describe a patient who presented shortly after birth with hyperkinetic behaviour, myoclonia, respiratory insufficiency and hepatosplenomegaly. Gaucher-like storage cells were found in bone marrow. A liver biopsy showed massive lysosomal storage morphologically different to that in known lipid storage disorders. Biochemically, the patient had partial deficiencies of beta-galactocerebrosidase, beta-glucocerebrosidase and ceramidase in skin fibroblast extracts, but the sphingomyelinase activity was normal. Glucosyl ceramide and ceramide were elevated in liver tissue. Loading of cultured fibroblasts with radioactive sphingolipid precursors indicated a profound defect in ceramide catabolism. Immunological studies in fibroblasts showed a total absence of cross-reacting material to sphingolipid activator protein 2 (SAP-2). The patient died at 16 weeks of age. The fetus from his mother's next pregnancy was similarly affected. The possibility that the disorder results from a primary defect at the level of SAP-2 is discussed. We have named this unique disorder SAP deficiency.

Glucosylceramide transfer from lysosomes—the missing link in molecular pathology of glucosylceramidase deficiency: A hypothesis based on existing data

“…This partially resembles the situation in prosaposin deficiency and in Niemann-Pick type C. However, in the former, caused by multiple sphingolipid hydrolase deficiency, due to the absence of all sphingolipid activator proteins (Saps), the high level of GlcCer storage in the visceral region might be explained by the presence of numerous storage macrophages (Elleder et al 2005b), which may even be transformed into Gaucher-type cells (Harzer et al 1989;Hulkova et al 2001). Studies on the distribution of GlcCer in storage-affected cell types in this disorder may bring a final resolution, as it is highly probable that GlcCer is restricted to macrophages.…”

Identification of prosaposin as a neurotrophic factor.

“…A similar survey in rat brain demonstrated widespread prosaposin immunoreactivity in neurons (9). Total prosaposin deficiency in humans due to a point mutation in the start codon of the prosaposin gene (24) resulted in severe neurological deterioration evident at birth with prominent cortical hypomyelination and cerebral atrophy (25). Northern analysis during embryonic development (day 12) demonstrated high concentrations ofprosaposin mRNA in mouse brain and dorsal root ganglia indicative of a developmental role (8).…”

Identification of the binding and activating sites of the sphingolipid activator protein, saposin C, with glucocerebrosidase

“…It has been suggested by others that a deficiency of saposin C can cause disease with the Gaucher-like phenotype: three patients with normal in vitro glucocerebrosidase activity but with an absence of saposin C have recently been reported (Christomanou et al, 1986(Christomanou et al, , 1989Harzer et al, 1989). All three cases presented neurologic disorders and were fatal.…”