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.

• MeSH
• Child MeSH
• Heterozygote MeSH
• Homozygote MeSH
• Infant MeSH
• Skin pathology   MeSH
• Humans MeSH
• Magnetic Resonance Imaging MeSH
• Leukodystrophy, Metachromatic genetics   metabolism   pathology   MeSH
• RNA Splice Sites genetics   MeSH
• Brain abnormalities   pathology   MeSH
• Mutation * MeSH
• DNA Mutational Analysis MeSH
• Codon, Nonsense MeSH
• Infant, Newborn MeSH
• Child, Preschool MeSH
• Saposins deficiency   genetics   MeSH
• Sequence Deletion MeSH
• Sphingolipids urine   MeSH
• Check Tag
• Child MeSH
• Infant MeSH
• Humans MeSH
• Male MeSH
• Infant, Newborn MeSH
• Child, Preschool MeSH
• Publication type
• Journal Article MeSH
• Case Reports MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• RNA Splice Sites MeSH
• Codon, Nonsense MeSH
• PSAP protein, human MeSH Browser
• Saposins MeSH
• Sphingolipids MeSH

A neuropathologic study of three cases of prosaposin (pSap) deficiency (ages at death 27, 89 and 119 days), carried out in the standard autopsy tissues, revealed a neurolysosomal pathology different from that in the non-neuronal cells. Non-neuronal storage is represented by massive lysosomal accumulation of glycosphingolipids (glucosyl-, galactosyl-, lactosyl-, globotriaosylceramides, sulphatide, and ceramide). The lysosomes in the central and peripheral neurons were distended by pleomorphic non-lipid aggregates lacking specific staining and autofluorescence. Lipid storage was borderline in case 1, and at a low level in the other cases. Neurolysosomal storage was associated with massive ubiquitination, which was absent in the non-neuronal cells and which did not display any immunohistochemical aggresomal properties. Confocal microscopy and cross-correlation function analyses revealed a positive correlation between the ubiquitin signal and the late endosomal/lysosomal markers. We suppose that the neuropathology most probably reflects excessive influx of non-lipid material (either in bulk or as individual molecules) into the neurolysosomes. The cortical neurons appeared to be uniquely vulnerable to pSap deficiency. Whereas in case 1 they populated the cortex, in cases 2 and 3 they had been replaced by dense populations of both phagocytic microglia and astrocytes. We suggest that this massive neuronal loss reflects a cortical neuronal survival crisis precipitated by the lack of pSap. The results of our study may extend the knowledge of the neurotrophic function of pSap, which should be considered essential for the survival and maintenance of human cortical neurons.

• MeSH
• Antigens, Differentiation, Myelomonocytic metabolism   MeSH
• Antigens, CD metabolism   MeSH
• Child MeSH
• Glial Fibrillary Acidic Protein metabolism   MeSH
• Glycosphingolipids metabolism   MeSH
• GPI-Linked Proteins MeSH
• Humans MeSH
• Lysosomal Storage Diseases metabolism   pathology   MeSH
• Lysosomes metabolism   pathology   MeSH
• Cell Adhesion Molecules, Neuronal metabolism   MeSH
• Cerebral Cortex pathology   MeSH
• Neurons pathology   ultrastructure   MeSH
• Infant, Newborn MeSH
• Autopsy MeSH
• Saposins deficiency   physiology   MeSH
• Ubiquitin metabolism   MeSH
• Check Tag
• Child MeSH
• Humans MeSH
• Male MeSH
• Infant, Newborn MeSH
• Publication type
• Journal Article MeSH
• Case Reports MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• Antigens, Differentiation, Myelomonocytic MeSH
• Antigens, CD MeSH
• CD68 antigen, human MeSH Browser
• Glial Fibrillary Acidic Protein MeSH
• Glycosphingolipids MeSH
• GPI-Linked Proteins MeSH
• limbic system-associated membrane protein MeSH Browser
• Cell Adhesion Molecules, Neuronal MeSH
• PSAP protein, human MeSH Browser
• Saposins MeSH
• Ubiquitin MeSH

Immunohistochemical studies of the presence of lactosylceramide (LacCer) in lysosomal storage disorders (LSDs) were done using anti-LacCer monoclonal antibody of the CDw 17 type (clone MG-2). No sign of an association between LacCer and the lysosomal system in normal cells was observed, except for histiocytes active in phagocytosis. A comparative study of a group of LSDs showed a general tendency for LacCer to increase in storage cells in Niemann-Pick disease type C (NPC), and types A and B, GM1 gangliosidosis, acid lipase deficiency, glycogen storage disease type II and mucopolysaccharidoses. LacCer accumulated in storage cells despite normal activity of relevant lysosomal degrading enzymes. The accumulation of LacCer displayed variability within storage cell populations, and was mostly expressed in neurons in NPC. An absence of the increase in LacCer in storage cells above control levels was seen in neuronal ceroid lipofuscinoses (neurons and cardiocytes) and in Fabry disease. Gaucher and Krabbe cells showed significantly lower levels, or even the absence, of LacCer compared with control macrophages. Results of immunohistochemistry were corroborated by semiquantitative lipid thin-layer chromatography (TLC). It is suggested that different associations of LacCer with the lysosomal storage process may reflect differences in glycosphingolipid turnover induced by the storage-compromised lysosomal/endosomal system.

• MeSH
• Biomarkers analysis   MeSH
• Antigens, CD analysis   metabolism   MeSH
• Chromatography, Thin Layer methods   MeSH
• Child MeSH
• Adult MeSH
• Histiocytes chemistry   metabolism   pathology   MeSH
• Immunohistochemistry methods   MeSH
• Liver chemistry   metabolism   pathology   MeSH
• Lactosylceramides analysis   metabolism   MeSH
• Humans MeSH
• Lysosomal Storage Diseases classification   metabolism   pathology   MeSH
• Macrophages chemistry   metabolism   pathology   MeSH
• Cerebral Cortex chemistry   metabolism   pathology   MeSH
• Neurons chemistry   metabolism   pathology   MeSH
• Spleen chemistry   metabolism   pathology   MeSH
• Check Tag
• Child MeSH
• Adult MeSH
• Humans MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Comparative Study MeSH
• Names of Substances
• Biomarkers MeSH
• Antigens, CD MeSH
• CDw17 antigen MeSH Browser
• Lactosylceramides MeSH

We found two patterns of leptomeningeal storage that reflect two basic visceral storage patterns in Fabry disease. (i) A generalized-type leptomeningeal storage pattern, affecting all main leptomeningeal cell types (external arachnoideal epithelium, fibroblasts, vessel wall elements), was a consistent finding in three cases of classical generalized visceral phenotype. (ii) A localized leptomeningeal storage pattern was expressed, to a high degree, solely in the external arachnoidal epithelium; this pattern was found in one case with the variant visceral-restricted-type storage (confined to the cardiocytes). Thus, the external arachnoidal epithelium may be particularly susceptible to Fabry lipid storage, probably caused by a distinctly larger sustained lysosomal lipid load as compared to other cell types.

• MeSH
• Arachnoid metabolism   pathology   MeSH
• Epithelium metabolism   pathology   MeSH
• Fabry Disease pathology   MeSH
• Humans MeSH
• Lipid Metabolism * MeSH
• Aged MeSH
• Check Tag
• Humans MeSH
• Male MeSH
• Aged MeSH
• Publication type
• Journal Article MeSH