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.

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.