A novel mutation in the coding region of the prosaposin gene leads to a complete deficiency of prosaposin and saposins, and is associated with a complex sphingolipidosis dominated by lactosylceramide accumulation

Abstract

A fatal infantile storage disorder with hepatosplenomegaly and severe neurological disease is described. Sphingolipids, including monohexosylceramides (mainly glucosylceramide), dihexosylceramides (mainly lactosylceramide), globotriaosyl ceramide, sulphatides, ceramides and globotetraosyl ceramide, were stored in the tissues. In general, cholesterol and sphingomyelin levels were unaltered. The storage process was generalized and affected a number of cell types, with histiocytes, which infiltrated a number of visceral organs and the brain, especially involved. The ultrastructure of the storage lysosomes was membranous with oligolamellar, mainly vesicular, profiles. Infrequently, there were Gaucher-like lysosomes in histiocytes. The neuropathology was severe and featured neuronal storage and loss with a massive depopulation of cortical neurons and pronounced fibrillary astrocytosis. There was a paucity of myelin and stainable axons in the white matter with signs of active demyelination. Immunohistochemical investigations indicated that saposins A, B, C and D were all deficient. The patient was homozygous for a 1 bp deletion (c.803delG) within the SAP-B domain of the prosaposin gene which leads to a frameshift and premature stop codon. In the heterozygous parents, mutant cDNA was detected by amplification refractory mutation analysis in the nuclear, but not the cytoplasmic, fraction of fibroblast RNA, indicating that the mutant mRNA was rapidly degraded. The storage process in the proband resembled that of a published case from an unrelated family. Saposins were also deficient in this case, leading to its reclassification as prosaposin deficiency, and her mother was found to be a carrier for the same c.803delG mutation. Both of the investigated families came from the same district of eastern Slovakia.

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.…”

Multi-system disorders of glycosphingolipid and ganglioside metabolism

“…Such secondary accumulations of GSLs and gangliosides are common features associated with neuropathology in several LSDs, e.g., Niemann-Pick diseases with GM2 and other GSL accumulation (218)(219)(220). Pronounced increases in gangliosides, GlcCer, and LacCer occur in prosaposin defi ciency ( 178,190 ) and increases in GM2 and GM3 are evident in the cathepsin D-defi cient mouse ( 221 ), as they are in the CNS of several mucopolysaccharidoses, MLD, Tay-Sachs disease, and Gaucher disease ( 222 ). Importantly, in neurons with secondary gangliosides accumulation, the pathological changes were essentially identical to those in the gangliosidosis ( 223 ).…”

Spiral Ganglion Degeneration and Hearing Loss as a Consequence of Satellite Cell Death in Saposin B-Deficient Mice

“…In mice, targeted disruption of ASA results in diminished in vivo enzyme activity, a resulting accumulation of sulfatide in white matter, and a neurological phenotype without demyelination, including deafness, that manifests by 24 months of age [postnatal month 24 (P24mo); Hess et al, 1996].…”