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At least 19 recordsLinked to original sources
PubMed1987

Lipid storage disease: Part III. Ultrastructural evaluation of cultured fibroblasts in sphingolipidoses.

For the purpose of evaluating electron microscopy of tissue culture in making the diagnosis of sphingolipidoses, an ultrastructural study was made on the cultured fibroblasts from 23 patients with the disorders. The characteristic cytoplasmic inclusions were observed in the cultured cells of Fabry disease, Tay-Sachs disease, Sandhoff disease, generalized gangliosidosis, Niemann-Pick disease, metachromatic leukodystrophy, and multiple sulfatase deficiency, and differ in fine structure with these diseases. All these cytoplasmic inclusions were surrounded by a single limiting membrane and enzyme cytochemically showed acid phosphatase activity, indicating their lysosomal origin. Ultrastructurally, the cytoplasmic inclusions showed pleomorphic osmiophilic inclusions in Fabry disease, membranous cytoplasmic bodies (MCB) in Tay-Sachs disease and Sandhoff disease, MCB and vacuolar inclusions containing finely reticulogranular materials in generalized gangliosidosis, myelin-like inclusions in Niemann-Pick disease, concentric lamellar inclusions in metachromatic leukodystrophy, and polymorphic cytoplasmic inclusions in multiple sulfatase deficiency. In the heterozygous carriers of Fabry disease, pleomorphic osmiophilic inclusions were also detected. However, any specific inclusions were not detectable in the cultured fibroblasts of Gaucher disease and Krabbe disease. Availability of electron microscopy in the cultured fibroblasts of sphingolipidoses is discussed.

Acid Phosphatase↗
PubMedDate not supplied

[Enzyme diagnostics in lysosomal diseases with emphasis on sphingolipidoses].

The authors describe the conditions and results of the enzymatic diagnosis in various sphingolipidoses, based on their personal experience. A precise diagnosis can be presently made on white blood cells, cultured fibroblasts or amniotic cells, and in some cases on serum or urine. In most cases the use of artificial substrates allows a relatively simple diagnosis. The methods are quantitative or qualitative (especially cellulose acetate electrophoresis, of which a few pictures are shown). The results are particularly clear in Tay-Sachs disease and its variants. Despite the fatal prognosis of most sphingolipidoses it is important to ensure a precise and precocious diagnosis. This is of prime value when a prenatal detection of the disease is considered in case of a future pregnancy.

Amniotic Fluid↗
PubMed1971

Sphingolipidoses.

Sphingolipidoses are an heterogeneous group of inherited disorders of lipid metabolism affecting primarily the central nervous system. These disorders occur chiefly in the pediatric population, and the degenerative nature of the disease processes is generally characterized by diffuse and progressive involvement of neurones (gray matter) with psychomotor retardation and myoclonus or of fiber tracts (white matter) with weakness and spasticity. Biochemical research has identified the defects in the sphingolipidoses to specific lysosomal enzymes. For example, Niemann-Pick disease lacks sphingomyelinase; Krabbe's disease lacks galactocerebrosidase; Gaucher's disease lacks beta-D-glucosidase; metachromatic leukodystrophy lacks sulfatase; Tay-Sachs disease lacks hexosaminidase A; and generalized gangliosidosis lacks beta-galactosidase. Although there are no currently available modes of rendering corrective therapy in these disorders, a definitive diagnosis is possible both antepartum as well as postpartum. This information provides a sound and accurate basis for genetic counseling.

Brain↗
PubMed1978

Diagnosis of the sphingolipidoses with labelled natural substrates.

The genetic heterogeneity of sphingolipidoses is underlined and the desirability of using natural labelled substrates for the diagnoses of each new index case strongly emphasized. Recent studies of our Scandinavian Krabbe families (more than 50) have repeatedly shown that there is no method developed which can be used for the detection of carriers of the mutant gene in leukocytes or lymphocytes. Also described are enzymic studies in two forms of Gaucher disease which further demonstrate the importance of natural substrates for the diagnoses of the disease in leukocytes and cultivated amniotic fluid cells.

Acetylglucosaminidase↗
PubMed1979

Basic findings and current developments in sphingolipidoses.

Sphingolipidoses are caused by recessively inherited deficiencies of lysosomal hydrolases. The clinical backgrounds of and current biochemical and genetic approaches to the different forms and variants of gangliosidoses, trihexosylceramidosis (Fabry's disease), galactosylceramidosis (Krabbe's disease), sulfatidoses (metachromatic leukodystrophies), glucosylceramidosis (Gaucher's disease), sphingomyelinoses (Niemann-Pick disease) and ceramidosis (Farber's disease) are presented.

Fabry Disease↗
PubMed1975

Experimental polymer storage disease in rabbits. An approach to the histogenesis of sphingolipidoses.

Water-soluble polymer compound, polyvinyl alcohol(PVA), and water-insoluble polymer compounds, polyvinyl acetate (PVAc) and polystylol (PS), were administered in 297 rabbits. When high polymerized PVA, PVAc or PS were continuously injected intravenously for a long period of time, lesions resembled to those of Gaucher and Niemann-Pick diseases were developed. From these experimental results, pathological development of various sphingolipidoses found in the human body was discussed and pathological findings were analysed polymer-chemically from the chemical properties of the substances stored.

Animals↗
PubMed1987

Lysosphingolipids inhibit protein kinase C: implications for the sphingolipidoses.

Lysosphingolipids potently and reversibly inhibited protein kinase C activity and binding of phorbol dibutyrate in vitro and in human platelets. As with activation of protein kinase C by phosphatidylserine and sn-1,2-diacylglycerol, inhibition was subject to surface dilution. Accordingly, inhibition in mixed micelle assays was dependent on the molar percentage of lysosphingolipids rather than the bulk concentration. Lysosphingolipids inhibited protein kinase C activity at molar percentages similar to those required for activation by phosphatidylserine and sn-1,2-diacylglycerol. Since lysosphingolipids accumulate in Krabbe's disease, Gaucher's disease, and other sphingolipidoses, the hypothesis that lysosphingolipid inhibition of protein kinase C represents the missing functional link between the accumulation of sphingolipids and the pathogenesis of these disorders appears to unify existing data. The accumulation of lysosphingolipids would cause progressive dysfunction of signal transduction mechanisms vital for neural transmission, differentiation, development, and proliferation and would eventually lead to cell death.

Blood Platelets↗
PubMed1978

Clinical and biochemical pathophysiology of ataxia in the sphingolipidoses.

The sphingolipidoses are best defined as lysosomal storage disorders. Their manifestations can be explained on the basis of a few key principles that should all be verified before making a diagnosis. A genetic mutation may reduce the activity of a lysosomal hydrolase. Mutations of the hydrolases, respecting the active site, would not compromise their activity as tested in vitro but might interfere with the lysosomal functions. The undegraded substrates accumulate in the tissues where they are normally synthesized or taken up. The site and rate of storage define the clinical expression of the defect, which may include ataxia. Detailed, comprehensive, multidisciplinary studies emphasize the great complexity of the lysosomal storage disorders and the nonspecificity of single clinical, pathological, ultrastructural, or biochemical criteria. The possibility of inducing storage by chemical means points to aspects of the lysosomal physiology that have been neglected so far but that might also have genetic expression. Lysosomal hydrolases function in a controlled environment dependent on the lysosomal membrane, pH, and hypothetical dispersing agents. Any of these factors conceivably may be genetically impaired and give rise to apparently nonspecific storage.

Ataxia↗
PubMed1978

[Clinical, preclinical and prenatal diagnosis of congenital sphingolipidoses by determining lysosomal hydrolases (author's transl)].

Sphingolipidoses in infancy and adulthood and associated metabolic disturbances are caused by a recessively inherited, circumscribed lysosomal enzyme deficiency in the catabolism of various structural tissue substances. After presenting detailed methods for the quantitative assay of activities of lysosomal hydrolytic enzymes in leukocytes, serum , fibroblasts, urine and organ tissue with the aid of synthetic chromogenic and fluorescent substrates the signigicance of these methods for clinical diagnosis, for the detection of homozygote persons before developing clinical symptoms (preclinical diagnosis), for the preventive prenatal diagnosis and forthe detection of heterozygote carriers is described for the following diseases: Deficiency of hexosaminidase A and B, deficiency of beta-glucosidase, deficiency or arylsulfatase A, deficiency of alpha-galactosidase, deficiency of alpha-glucosidase.

Clinical Enzyme Tests↗
PubMed1989

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.

Consanguinity↗