Research Article: Prosaposin Deficiency and Saposin B Deficiency (Activator-Deficient Metachromatic Leukodystrophy): Report on Two Patients Detected by Analysis of Urinary Sphingolipids and Carrying Novel PSAP Gene Mutations

Date Published: April 06, 2009

Publisher: Wiley Subscription Services, Inc., A Wiley Company

Author(s): Ladislav Kuchař, Jana Ledvinová, Martin Hřebíček, Helena Myšková, Lenka Dvořáková, Linda Berná, Petr Chrastina, Befekadu Asfaw, Milan Elleder, Margret Petermöller, Heidi Mayrhofer, Martin Staudt, Ingeborg Krägeloh-Mann, Barbara C Paton, Klaus Harzer.


Prosaposin deficiency (pSap-d) and saposin B deficiency (SapB-d) are both lipid storage disorders caused by mutations in the PSAP gene that codes for the 65–70 kDa prosaposin protein, which is the precursor for four sphingolipid activator proteins, saposins A–D. We report on two new patients with PSAP gene defects; one, with pSap-d, who had a severe neurovisceral dystrophy and died as a neonate, and the other with SapB-d, who presented with a metachromatic leukodystrophy-like disorder but had normal arylsulfatase activity. Screening for urinary sphingolipids was crucial to the diagnosis of both patients, with electrospray ionization tandem mass spectrometry also providing quantification. The pSap-d patient is the first case with this condition where urinary sphingolipids have been investigated. Multiple sphingolipids were elevated, with globotriaosylceramide showing the greatest increase. Both patients had novel mutations in the PSAP gene. The pSap-d patient was homozygous for a splice-acceptor site mutation two bases upstream of exon 10. This mutation led to a premature stop codon and yielded low levels of transcript. The SapB-d patient was a compound heterozygote with a splice-acceptor site variant exclusively affecting the SapB domain on one allele, and a 2 bp deletion leading to a null, that is, pSap-d mutation, on the other allele. Phenotypically, pSap-d is a relatively uniform disease of the neonate, whereas SapB-d is heterogeneous with a spectrum similar to that in metachromatic leukodystrophy. The possible existence of genotypes and phenotypes intermediate between those of pSap-d and the single saposin deficiencies is speculated. © 2009 Wiley-Liss, Inc.

Partial Text

Prosaposin (pSap) is a non-enzymic 65–70 kDa glycoprotein encoded by the PSAP gene [Sandhoff et al., 2001]. Amongst its roles, pSap is the precursor for four saposins (Saps) A–D, which are formed by proteolysis. The Saps, also known as sphingolipid activator proteins, are indispensable cofactors for the intralysosomal degradation of a number of sphingolipids and seem to interact directly with the specific lipid hydrolases and/or facilitate presentation of the lipid substrates to these enzymes [Sandhoff et al., 2001; Spiegel et al., 2005]. Defects in the PSAP gene can cause a deficiency of either the entire pSap protein (prosaposin deficiency, pSap-d) or an individual Sap: SapA-d, SapB-d, SapC-d, or SapD-d, with, to date, SapD-d only being reported in an animal model [Matsuda et al., 2004]. In humans, pSap-d is a unique neonatal condition with an acute generalized neurovisceral dystrophy associated with the storage of multiple sphingolipids, whereas each isolated Sap deficiency is generally similar to a particular sphingolipid hydrolase-deficiency, namely, SapA-d to Krabbe leukodystrophy [Spiegel et al., 2005], SapB-d to metachromatic leukodystrophy (MLD), and SapC-d to Gaucher disease [Sandhoff et al., 2001]. The pathologies and biochemical phenotypes observed in pSap-d and the single Sap-deficient diseases have provided indirect insight into the specific roles and normal functions, including certain neurotrophic effects, of p-Sap and/or the individual Saps.

Disorders caused by defects in the PSAP gene [Sandhoff et al., 2001] form a poorly known sub-group of lysosomal lipid storage diseases that are clinically and metabolically highly variable. Reports on the few known cases of pSap-d [Harzer et al., 1989; Bradová et al., 1993; Hůlková et al., 2001; Millat et al., 2003; Elleder et al., 2005] have indicated that this disorder should be considered in the differential diagnosis of neonates with unexplained neurologic signs, in particular, if these are combined with visceral involvement. The central nervous system changes in pSap-d may be caused not only by early lipid storage, but also by primary deficits in the organization of cerebral architecture, since pSap and/or some of its products are known to have essential neurotrophic functions. The present pSap-d patient was clinically and biochemically very similar to the earlier reported pSap-d patients [Harzer et al., 1989; Bradová et al., 1993; Hůlková et al., 2001; Millat et al., 2003; Elleder et al., 2005].




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