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PubMed1967

Sphingolipidoses.

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Eye Diseases↗
PubMed1980

Application of "high-performance" liquid chromatography to the study of sphingolipidoses.

Quantitative high-performance liquid chromatographic analysis of perbenzoylated sphingolipids has been used to study the correlations of body chemistry to clinical phenomena. Plasma sphingolipids were isolated from 32 Gaucher (beta-glucosidase deficiency) and six Fabry (alpha-galactosidase deficiency) patients by solvent partition and chromatographic separation on silicic acid columns. Plasma sphingolipids from a patient undergoing plasma-exchange were separated from interfering lipids with reversed-phase columns. Liquid-chromatographic analysis of sphingolipids provides useful supportive information for diagnoses because affected individuals are shown to possess increased circulating concentrations of the pathognomonic sphingolipid. We also used this technique to monitor sphingolipid concentrations in plasma and urine sediment during plasma exchange of a p atient with Fabry's disease. Regular plasma exchanges produced and maintained decreased concentrations of sphingolipids in plasma, but near pre-exchange concentrations were observed within days after the therapy was terminated.

Chromatography, High Pressure Liquid↗
PubMed2002

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.

Child, Preschool↗
PubMed1988

[Sphingolipid storage diseases of the central nervous system: bases of biochemical and clinical heterogeneity].

Lysosomal storage disorders are progredient and often fatal diseases most of which result from a pronounced enzyme deficiency. In the case of sphingolipidoses, usually enzymes of sphingolipid catabolism are missing, or only a few percent of normal activity are detectable. For many sphingolipidoses, damage of the central nervous system is characteristic, but neurological and other symptoms can vary greatly, especially in adult variants. This variability is mainly caused by different allelic mutations of the structural genes, resulting in different levels of residual enzyme activity.

Central Nervous System Diseases↗
PubMed1993

Inhibition of protein kinase C activity in mucolipidosis type-4: a model for a new pathogenetic mechanism in inborn errors of metabolism.

Inhibition of protein kinase C [PK-C] activity by sphingosine and its derivatives has been suggested to play a role in the pathogenesis of sphingolipidoses. In the present study, PK-C activity and PK-C-mediated phosphorylation of endogenous substrates were studied in skin fibroblasts from patients with mucolipidosis type 4 [ML-4], in which there is accumulation of the phospholipids phosphatidylcholine, lysophosphatidylcholine, phosphatidylethanolamine as well as gangliosides. Cytosolic PK-C activity in 5 ML-4 cell lines was comparable to that in control cells. PK-C activity in the particulate fraction of these cells was 84 +/- 14 pmol 32P/mg protein per min compared with 267 +/- 26 in control cells. Increasing the concentrations of the activating lipids in the reaction mixture did not enhance PK-C activity in ML-4 cells, suggesting a non-competitive inhibition of the kinase. Following partial purification of the enzyme from the particulate fraction PK-C activity increased to 288 +/- 14 and 339 +/- 12 pmol 32P/mg protein per min in ML-4 and control cells, respectively. The phosphorylation pattern of endogenous substrates in the particulate fraction of ML-4 cells differed from that in control cells both in the absence and in the presence of calcium and activating lipids. We suggest that PK-C may be involved in the pathogenesis of sphingolipidoses and that this may represent an example for a new type of pathogenetic mechanisms in inborn errors of metabolism.

Humans↗
PubMed1976

The cerebral lipidoses.

The disorders presented consist of those clinical entities in which a reasonably well defined lipid storage material accumulated within nervous tissue. Many other progressive, degenerative disorders are suspected of being storage disorders, but their chemical pathology remains unclear. Collectively this group could be designated the sphingolipidoses. In each case, the disease is a genetic disturbance and transmitted as an autosomal recessive. Sphingolipid storage in each disorder is associated with deficient activity of a specific degradative enzyme or enzyme system, and these deficient enzymes are all lysosomal hydrolases. Lysosomal hydrolases catalyze the breakdown of complex molecules in digestive vacuoles (phagocytic or autophagic) within the cells. Lysosomes show structural latency (requiring osmotic shock or freeze thawing in vitro); their enzymes show maximal activity at acidic pH ranges, and on electron microscopic examination they appear as small, electron-dense intracellular bodies. These hydrolytic enzymes seem to have some form of biological vulnerability in terms of their genetic expression, and this vulnerability underlies the sphingolipidoses. Diagnosis in each case is primarily a clinical problem. The presentation of these disorders, especially in intermediate or advanced forms, is sufficiently distinctive to permit a reasonably accurate diagnosis on the basis of history, physical examination, and routine laboratory data. Patients seen in early stages may be more difficult to recognize but follow-up evaluations usually clarify the problem. Specific enzyme assays are now available for confirmation of the diagnosis in these disorders. A frequent finding in this connection is an increase in the activities of noninvolved lysosomal hydrolases in the storage disorders. Once a case is clinically diagnosed, the clinician has the responsibility of ensuring that proper genetic counseling is made available to the affected families. Considerable supportive care is needed in each case. These patients can survive for prolonged periods, and great stress is placed on their families by these prolonged, hopeless illnesses. Since the disorders affect infants or young children, their parents are usually young adults in their early reproductive years. It is essential that they receive information concerning the risk of subsequent pregnancies. Specific diagnosis of the fetus in early pregnancy can be made now by amniocentesis and enzyme assays on cultured fibroblasts. If the fetus is a homozygote on the basis of enzyme assays, the option of therapeutic abortion should be discussed with the family. For many parents there will be considerable sensitivity to the ethical implications of this course and, if any doubt arises, ethical or pastoral consultation should be sought. Although there are no specific therapeutic approaches, a considerable degree of supportive care can and should be given. In the gangliosidoses and late in the course of the leukodystrophies, seizures will present management problems...

Adult↗
PubMed1998

Sphingolipids and cell signalling.

The sphingolipid storage disorders constitute a group of inherited metabolic disorders in which the structure of the stored sphingolipid and the corresponding genetic defect have been established. However, the pathological mechanism(s) behind the disorders has not been fully elucidated. Sphingolipids are known to be recognition molecules involved in intercell communication and altered expression might lead to dyscommunication. The impaired degradation and lysosomal accumulation of specific sphingolipids might influence the metabolism of other molecules and/or intracellular transport, which in turn might alter the distribution of these molecules. However, the progress of these diseases indicates that additional factors, besides the stored sphingolipid itself, might be involved. During the last decade, several sphingolipids have emerged as active participants in intracellular signalling processes such as growth control and apoptosis. Particular interest focused on the sphingolipid metabolites, ceramide and sphingosine, as potential mediators in intracellular events and an altered presence of these metabolites in sphingolipidoses cannot be ruled out. Some sphingolipids have been found to influence cytokine release and thereby might induce immunological processes, which are known to exist in at least one of the sphingolipidoses--Gaucher disease. These processes might already have a pathogenic effect during early development, before significant storage has occurred.

Animals↗