1/11. 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.- - - - - - - - - - ranking = 1keywords = storage (Clic here for more details about this article) |
2/11. Application of delayed extraction matrix-assisted laser desorption ionization time-of-flight mass spectrometry for analysis of sphingolipids in cultured skin fibroblasts from sphingolipidosis patients.sphingolipidoses are caused by defects of enzymes involved in the hydrolysis of sphingolipids. Using delayed extraction matrix-assisted laser desorption ionization time-of-flight mass spectrometry (DE MALDI-TOF-MS), we analyzed sphingolipids in cultured skin fibroblasts from patients with sphingolipidoses, including: (a) Farber disease (FD, acid ceramidase deficiency); (b) gaucher disease (GD); (c) Niemann-Pick disease type C (NPDC); and (d) GM1-gangliosidosis (GM1G). Crude lipids were extracted from about 50 mg wet weight of cultured skin fibroblasts. After mild alkaline treatment, a sphingolipid fraction was prepared from the crude lipids and analyzed by DE MALDI-TOF-MS. The results were as follows: (a) in fibroblasts from the FD patient, the ceramide/sphingomyelin and ceramide/monohexosylceramide ratios were both significantly high; (b) in the GD patient, the glucosylceramide/sphingomyelin ratio was increased; on the other hand; (c) in the NPDC patient, the monohexosylceramide/sphingomyelin ratio was within normal range; and (d) in the GM1G patient, no specific data were obtained. sphingolipids in cultured fibroblasts can be evaluated by DE MALDI-TOF-MS, whereas GM1-ganglioside or its asialo derivatives are not detectable. With this DE MALDI-TOF-MS method, ceramide or monohexosylceramide accumulating in cultured fibroblasts from cases of sphingolipidoses, such as FD and GD, respectively, can be easily detected.- - - - - - - - - - ranking = 0.022301179097336keywords = enzyme (Clic here for more details about this article) |
3/11. Mild ichthyosis in a 4-year-old boy with multiple sulphatase deficiency.We report a 4-year-old boy with multiple sulphatase deficiency (MSD). His early health was good. By the end of his first year there were concerns about developmental delay but by 26 months he showed clear evidence of regression in that he was barely able to sit unsupported and had lost all fine motor and communication skills. At that time he also had widespread mild ichthyosis that cleared completely with the use of emollients. The neurological deterioration suggested a diagnosis of metachromatic leucodystrophy, and a reduction in the leucocyte arylsulphatase A activity was detected. The ichthyosis suggested steroid sulphatase deficiency, and a reduction in the leucocyte steroid sulphatase activity was detected. The enzyme deficiency was much less marked for steroid sulphatase than for arylsulphatase A in this boy. This diversity in enzyme activities is typical of MSD and correlates with the mild ichthyosis in this child. This case shows that even mild ichthyosis should prompt measurement of steroid sulphatase activity in a child of either sex with unexplained neurological deterioration.- - - - - - - - - - ranking = 0.044602358194673keywords = enzyme (Clic here for more details about this article) |
4/11. An unusual case of phospholipidosis.We present the results of a structural, histochemical and lipid-chromatographic study of tissues obtained at postmortem from an unusual case of phospholipidosis. A previous biopsy of the appendix and liver (Elleder et al., 1975a) had revealed a predominance of phosphoglyceride storage, principally of lysobisphosphatidic acid (LBPA) postmortem material showed that this lipid was stored exclusively in central neurons. In the spleen and the lymph node, however, sphingomyelin (SP) was shown, histochemically and chromatographically, to be the main lipid stored. Total sphingomyelinase (SPase) activity in the appendix was reduced to about 50% of normal. Neuroaxonal dystrophy (nad) and a conspicuous discrepancy between the degree of distension of some neurons and their lipid content deserve special mention. The case is contrasted with classical sphingomyelinosis; the complexity of the Niemann-Pick group of diseases is discussed as an indication of the difficulties of classification of any atypical case.- - - - - - - - - - ranking = 0.2keywords = storage (Clic here for more details about this article) |
5/11. Difficulty in recognizing multiple sulfatase deficiency in an infant.We describe the difficulty in recognizing multiple sulfatase deficiency (MSD; Online Mendelian Inheritance in Man [OMIM] database No. 272200) in an infant. MSD is a rare autosomal recessive disorder that affects the posttranslational activation of various sulfatase enzymes. It is both biochemically and clinically variable. Currently, there are 12 known sulfatases in humans, and the clinical presentation of MSD is a unique composite of those individual enzyme defects. Here we report a black girl who presented with bilateral broad thumbs and great toes, both with angulation deformities at birth. rubinstein-taybi syndrome (OMIM No. 180849) was considered initially. The detection of inclusion bodies in her white blood cells at 37 months of age led to the appropriate diagnostic workups for lysosomal storage diseases. Elevation of urine mucopolysaccharides provided additional clues, and the fibroblast enzyme assays finally established the diagnosis. Broad thumbs and great toes are rare features of MSD, and to the best of our knowledge such a bilateral congenital anomaly with angulation deformities has never been reported before to be associated with MSD.- - - - - - - - - - ranking = 3.6587794300865keywords = lysosomal storage, storage disease, storage, enzyme (Clic here for more details about this article) |
6/11. Sphingolipid activator protein deficiency in a 16-week-old atypical gaucher disease patient and his fetal sibling: biochemical signs of combined sphingolipidoses.We describe a patient who presented shortly after birth with hyperkinetic behaviour, myoclonia, respiratory insufficiency and hepatosplenomegaly. Gaucher-like storage cells were found in bone marrow. A liver biopsy showed massive lysosomal storage morphologically different to that in known lipid storage disorders. Biochemically, the patient had partial deficiencies of beta-galactocerebrosidase, beta-glucocerebrosidase and ceramidase in skin fibroblast extracts, but the sphingomyelinase activity was normal. Glucosyl ceramide and ceramide were elevated in liver tissue. Loading of cultured fibroblasts with radioactive sphingolipid precursors indicated a profound defect in ceramide catabolism. Immunological studies in fibroblasts showed a total absence of cross-reacting material to sphingolipid activator protein 2 (SAP-2). The patient died at 16 weeks of age. The fetus from his mother's next pregnancy was similarly affected. The possibility that the disorder results from a primary defect at the level of SAP-2 is discussed. We have named this unique disorder SAP deficiency.- - - - - - - - - - ranking = 3.6032064499427keywords = lysosomal storage, storage (Clic here for more details about this article) |
7/11. Sphingomyelin lipidosis variant with cirrhosis in the pediatric age group.Two children with a variant of sphingomyelin lipidosis had otherwise unexplained cirrhosis that was histologically inactive and appeared to run an indolent course. The primary clinical problems involved the central nervous system, with vertical supranuclear ophthalmoplegia being the most distinctive feature. Biochemical analysis of cultured skin fibroblasts obtained from one of the children revealed that sphingomyelinase activity was 42% of control values. The typical inconspicuous hepatic storage and cirrhosis, coupled with the important morphologic finding of sea-blue histiocytes in the marrow, suggested that in cases of unexplained infantile or childhood cirrhosis the marrow should be closely examined for such histiocytes. Likewise, in cases of sea-blue histiocytes without evident etiology, with or without cirrhosis, this disease should be considered.- - - - - - - - - - ranking = 0.2keywords = storage (Clic here for more details about this article) |
8/11. Farber's disease: a fine structural study.A 1-week-old baby boy presented with hepatosplenomegaly, coarse facial features, and cloudy corneas. A metabolic storage disease was considered and he underwent cutaneous and liver biopsy. By light microscopy the skin was normal. kupffer cells were enlarged and had foamy cytoplasm. Ultrastructural examination of skin and liver demonstrated features compatible with Farber's disease: curvilinear and "banana" bodies, zebra-like structures, and concentric lamellar bodies. A deficiency of lysosomal acid ceramidase was subsequently demonstrated in cultured fibroblasts and in liver tissue corroborating the ultrastructural findings.- - - - - - - - - - ranking = 0.58866944285175keywords = storage disease, storage (Clic here for more details about this article) |
9/11. A study on enzyme activities of some sphingolipidoses.Enzyme activities were determined in fibroblast cell cultures of eight patients suspected of having a type of sphingolipidosis. The patients were 0 to 4 years of age; four were female and four were male. Thirteen age-matched controls were also included in the study. In one of the cases, hexosaminidase a activity was found to be 0% (43-82%), while in two other cases beta-galactosidase activity was found to be 5 nmol/h/mg protein (100-1035 nmol/h/mg protein) and arylsulfatase activity was found to be 12 nmol/h/mg protein (106-990 nmol/h/mg protein), respectively. Two more enzymes, alpha-galactosidase (11-39 nmol/h/mg protein) and cerebroside beta-galactosidase (3.7-6.9 nmol/h/mg protein), were also evaluated but were found to be in the normal ranges in these patients. Therefore, these patients were considered to have tay-sachs disease, GM1 gangliosidosis and metachromatic leukodystrophy, respectively. The remaining five patients were normal in respect to the five enzyme activities determined. For the prenatal diagnosis of metachromatic leukodystrophy, arylsulfatase A activity was determined in one amniotic cell culture. The activity found in this case was lower than normal (34 nmol/h/mg protein versus 387 nmol/h/mg protein found in three control amniotic cell cultures.- - - - - - - - - - ranking = 0.13380707458402keywords = enzyme (Clic here for more details about this article) |
10/11. Prosaposin deficiency: further characterization of the sphingolipid activator protein-deficient sibs. Multiple glycolipid elevations (including lactosylceramidosis), partial enzyme deficiencies and ultrastructure of the skin in this generalized sphingolipid storage disease.Sphingolipid activator protein (SAP) deficiency, previously described in two sibs and shown to be caused by the absence of the common saposin precursor (prosaposin), was further characterized by biochemical lipid and enzyme studies and by ultrastructural analysis. The 20-week-old fetal sib had increased concentrations of neutral glycolipids, including mono-, di-, tri- and tetrahexosylceramide, in liver, kidney and cultured skin fibroblasts compared with the controls. Glucosylceramide and lactosylceramide were particularly elevated. The kidney of the affected fetus showed additional increases in the concentration of sulphatide, galactosylceramide and digalactosylceramide. Free ceramide was stored in the liver and kidney, and GM3 and GM2 gangliosides were elevated in the liver, but not the brain, of the fetus. phospholipids, however, were normal in the affected fetus. In the liver biopsy of the propositus, who later died at 16 weeks of age, only a few lipids could be studied. Glucosylceramide, dihexosylceramide and ceramide were elevated in agreement with our previous study. Enzyme studies were undertaken using detergent-free liposomal substrate preparations and fibroblast extracts. The sibs' beta-glucocerebrosidase and beta-galactocerebrosidase activities were clearly reduced, but their sphingomyelinase activities were normal. The normal activity of the latter enzyme and the almost normal tissue concentration of sphingomyelin in prosaposin deficiency suggest that the prosaposin-derived SAPs are not required for sphingomyelinase activity in vivo. In keeping with the biochemical findings, skin biopsies from the sibs showed massive lysosomal storage with a vesicular and membranous ultrastructure. The function of SAPs in sphingolipid degradation and the role of SAPs for enzyme activity in vitro are discussed. In addition, the similarity in neutral glycolipid accumulations in Niemann-Pick disease type C and in prosaposin deficiency are noted. The phenotype of the prosaposin deficient sibs resembled acute neuronopathic (type 2) gaucher disease more than Farber disease in several aspects, but their genotype was unique.- - - - - - - - - - ranking = 5.7139924750311keywords = lysosomal storage, storage disease, storage, enzyme (Clic here for more details about this article) |
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