Saposin C deficiency due to mutations in PSAP results in a Gaucher-like phenotype, despite normal in vitro glucocerebrosidase activity. (PMID:22652185)
Christomanou et al. (1986) reported a patient with an atypical form of Gaucher disease associated with normal beta-glucosidase activity and deficiency of saposin C, an activator protein that enhances beta-glucosidase activity. The patient had neurologic onset at about ... Christomanou et al. (1986) reported a patient with an atypical form of Gaucher disease associated with normal beta-glucosidase activity and deficiency of saposin C, an activator protein that enhances beta-glucosidase activity. The patient had neurologic onset at about 4 years of age and died at age 14 (Tylki-Szymanska et al., 2007). Christomanou et al. (1989) reported a second patient with atypical Gaucher disease associated with saposin C deficiency. The patient was an 8-year-old boy who presented with transient losses of consciousness, myoclonic jerks, and generalized seizures resistant to antiepileptic drugs. He developed progressive horizontal ophthalmoplegia, pyramidal and cerebellar signs, and died at the age of 15.5 years. Neuropathologic studies, reported by Pampols et al. (1999), demonstrated neuronal cell loss and neuronophagia, massive intraneuronal lipid storage, and lack of perivascular Gaucher cells. Electron microscopy showed different types of storage including lipofuscin granules as well as the cytosomes with parallel arrays of bilayers that are assumed to be formed by stored lipids. General brain lipid composition did not show a remarkable increase or loss of any of the major lipid fractions, but the glucosylceramide concentration in the cortex of several anatomic regions showed a striking increase. Tylki-Szymanska et al. (2007) reported 2 sibs with atypical nonneuronopathic Gaucher disease due to saposin C deficiency. The proband presented at age 35 with massive hepatosplenomegaly, osteopenia, cachexia, anemia, and thrombocytopenia. He had been diagnosed with Gaucher disease as a child, but was lost to follow-up and had no treatment. As an adult, imaging studies showed Erlenmeyer flask bone deformities and no brain abnormalities. His younger sister had less severe symptoms. Beta-glucosidase activity was normal in patient leukocytes and fibroblasts. Both patients showed increased serum glucosylceramide and very high levels of chitotriosidase (CHIT1; 600031).
Vaccaro et al. (2010) characterized the biologic properties of cells from 4 Gaucher patients carrying mutations in the saposin C domain of the PSAP gene. Two patients had mutations involving cysteine residues, whereas the other 2 were compound ... Vaccaro et al. (2010) characterized the biologic properties of cells from 4 Gaucher patients carrying mutations in the saposin C domain of the PSAP gene. Two patients had mutations involving cysteine residues, whereas the other 2 were compound heterozygotes for the L349P (176801.0012) and M1L (176801.0005) mutations. In the 4 saposin C-deficient cell lines, prosaposin was normally processed and sorted, with the lack of saposin C being due mainly to saposin C instability in the late endosomal/lysosomal environment. The decrease or absence of saposin C affected the intracellular localization of glucosylceramidase, which is normally found in acidic organelles such as mature lysosomes but localized to less acidic structures in mutant fibroblasts. The lowest levels of saposin C, and enhanced autophagy, were observed in cells that carried a PSAP mutation involving a cysteine residue. The 4 saposin C-deficient fibroblast lines stored glucosylceramide, ceramide, and cholesterol, the last 2 lipids being clearly localized in lysosomes. A correlation was observed between the type of saposin C mutation and the Gaucher phenotype, with the mutations involving cysteine residues leading to a neurologic variant of Gaucher disease.
In the patient with atypical Gaucher disease and saposin C deficiency reported by Christomanou et al. (1986), Schnabel et al. (1991) identified a heterozygous mutation in the PSAP gene (176801.0004). Studies suggested that the patient was compound heterozygous ... In the patient with atypical Gaucher disease and saposin C deficiency reported by Christomanou et al. (1986), Schnabel et al. (1991) identified a heterozygous mutation in the PSAP gene (176801.0004). Studies suggested that the patient was compound heterozygous for this mutation and another pathogenic mutation in the PSAP gene. In the patient reported by Christomanou et al. (1989), Rafi et al. (1993) and Diaz-Font et al. (2005) identified pathogenic mutations in the PSAP gene (176801.0010 and 176801.0011, respectively). In 2 adult sibs with atypical Gaucher disease due to saposin C deficiency Tylki-Szymanska et al. (2007) identified compound heterozygosity for 2 mutations in the PSAP gene (176801.0005 and 176801.0012).