Prosaposin Deficiency - a Rarely Diagnosed, Rapidly Progressing, Neonatal Neurovisceral Lipid Storage Disease. Report of a Further Patient

Abstract

An infant presented with multifocal myoclonus and cyanotic hypoxemia immediately after birth, and severe feeding problems, a protein-losing enteropathy, massive ascites and grand-mal epilepsy marked his rapid downhill course, with death at 17 weeks. At 2 weeks, brain MRI revealed grey matter heterotopias in the parieto-occipital regions suggestive of a cortical morphogenetic disorder. In cultured skin fibroblasts, lipid storage and reduced activities of ceramidase, galactosylceramide beta-galactosidase and glucosylceramide beta-glucosidase were evident. Autopsy disclosed generalised lysosomal lipid storage with macrophages and adrenal cortex prominently affected. The pattern of stored lipids in cultured fibroblasts and in dewaxed spleen tissue blocks was compatible with a diagnosis of prosaposin (pSap) deficiency (pSap-d). Neuropathologically, there was a pronounced generalised neurolysosomal storage combined with a severe depletion of cortical neurons and extreme paucity of myelin and oligodendroglia. This pathology, in particular the massive neuronal loss, differed from that in other neurolipidoses and could be explained by the reduced hydrolysis of multiple sphingolipids and the loss of pSap's neurotrophic function. The absence of immunostainable saposins on tissue sections and the presence of a homozygous c.1 A > T mutation in the prosaposin gene confirmed the diagnosis. PSap-d may be an underdiagnosed condition in infants with severe neurological and dystrophic signs starting immediately after birth.

An association screen of myelin-related genes implicates the chromosome 22q11 PIK4CA gene in schizophrenia

“…52 PSAP also has additional functions unrelated to sphingolipid catabolism, including neurotrophic functions. 53 PSAP has been implicated in metachromatic leukodystrophy, a disorder with psychiatric symptoms that may mimic schizophrenia.…”

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.…”

Prosaposin, a regulator of estrogen receptor alpha, promotes breast cancer growth

“…PSAP-deficiency in human and mice is lethal. (18,19) Prosaposin knock-out mice also present with a series of developmental abnormalities in the nervous system and male reproductive organs. (18,20) Recent investigations show that PSAP could prevent cell death or apoptosis and promote cell survival.…”

“…(18,19) Prosaposin knock-out mice also present with a series of developmental abnormalities in the nervous system and male reproductive organs. (18,20) Recent investigations show that PSAP could prevent cell death or apoptosis and promote cell survival. (21,22) Koochekpour et al (23) focus on the function of PSAP in prostate cancer and find PSAP is overexpressed in prostate cancer, and also upregulates androgen receptor (AR) and prostate specific antigen (PSA) expression and activity in prostate cancer cells.…”