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At least 19 recordsLinked to original sources
PubMed2004

Recent advances in the biochemistry and genetics of sphingolipidoses.

Sphingolipidoses are a subgroup of lysosomal storage diseases. They are defined as disorders caused by a genetic defect in catabolism of sphingosine-containing lipids. Catabolism of these lipids involves enzymes and activator proteins. After the discovery of lysosomes by de Duve and the demonstration of the first defective lysosomal enzyme by Hers in 1963, the first enzyme deficiency for sphingolipidoses was characterized in 1965 and all the defective enzymes were demonstrated in the last three decades. In 1984, the first activator protein was found and it expanded the concept of sphingolipidoses. In the following years, many researches have been undertaken to understand the molecular basis of these diseases, the mechanism of pathogenesis, the mechanism of lysosomal digestion of glycosphingolipids (GSLs) and the functional domains of lysosomal enzymes. New hypotheses and theories have been put forward for the mechanism of lysosomal digestion and pathogenesis. However, although much has been done, the pathogenesis of sphingolipidoses has not been fully elucidated. Mouse models of these diseases have facilitated the elucidation of pathogenesis and the development of therapeutic strategies for these diseases, which are not treatable at present except for Fabry and type 1 Gaucher disease. The purpose of this review is to collect information on the recent researches related to sphingolipidoses. The review includes the hydrolysis of GSLs in lysosome, mechanism of hydrolysis, pathogenesis and genetics of sphingolipidoses, a brief mouse model and therapeutic strategies of these diseases.

Animals↗
PubMed2004

Sphingolipidoses in Turkey.

During the last 5 years 2057 children under the age of 5 with various neurologic symptoms with the suspected diagnosis of lysosomal storage diseases were referred to our hospital from different universities and state hospitals. We were able to separate sphingolipidoses by lysosomal enzyme screening. A total of 300 patients (15%) with sphingolipidoses were diagnosed; there were deficiencies of arylsulfatase A [metachromatic leukodystrophy (MLD)] in 93 (31%), hexosaminidase [Sandhoff disease (SHD)] in 62 (20.7%), hexosaminidase A [Tay-Sachs disease (TSD)] in 15 (5%), beta-galactosidase (GM1 gangliosidosis) in 35 (11.7%), alpha-galactosidase (Fabry disease) in one (0.3%) cerebroside beta-galactosidase (Krabbe disease) in 65 (21.7%) and glucosylceramidase (Gaucher disease) in 29 (9.6%). SHD (20.7%), MLD (31%) and Krabbe disease (21.7%) were common. Prenatal enzymatic diagnosis was made in 70 at risk pregnancies, 64 for TSD and SHD, three for MLD and three for GM1 gangliosidosis by using chorionic villus biopsy in 54, cord blood samples in 12 and cultured amniotic fluid cells in four. Seventeen fetuses were found to be affected. We have calculated the relative frequency and minimum incidence of sphingolipidoses in Turkey. The combined incidence of sphingolipidoses is 4.615 per 100,000 live births. The calculated incidences are 1.43, 0.95, 1, 0.23, 0.54, 0.45, 0.015 per 100,000 live births for MLD, SHD, Krabbe, Gaucher, TSD, GM1 gangliosidosis and Fabry diseases, respectively. The real incidence, which covers all subtypes of this group of diseases, should be greater than this number. The results suggested that, as a group, sphingolipidoses are relatively common and represent an important health problem in Turkey and some rare autosomal recessive diseases of Turkey are due to 'founder effect' created by consanguineous marriages.

Cerebroside-Sulfatase↗
PubMed2003

A historical perspective of the glycosphingolipids and sphingolipidoses.

Glycosphingolipids are a polysaccharide chain between 1 and 40 carbohydrate residues long glycosidically linked to ceramide (a long-chain aliphatic amino-alcohol or sphingoid) that is embedded in the cell plasma membrane with the carbohydrate moiety on the outside. The sphingoid imparts rigidity to the membrane and the carbohydrate tails protect the cell surface and have functions in relation to cell adhesion, growth, regulation, differentiation, cell interaction, recognition and signalling. They provide adhesion sites for pathogens and change during oncogenic transformation. Ceramide is also a component of sphingomyelin. Glycosphingolipids are degraded by lysosomal hydrolysis. The sphingolipidoses are a series of diseases in which mutations affecting the enzymes catalysing the last 11 steps of this process causing abnormal compounds proximal to the metabolic block to accumulate intralysosomally. Thus, they are a sub-group of the lysosomal storage diseases. The degradation of sphingolipids containing three or less carbohydrate residues requires a sphingolipid activator protein and mutations affecting these proteins also cause abnormal glycosphingolipid storage. With one exception (Fabry disease, which is X linked) the sphingolipidoses are inherited autosomally. The phenotypic manifestations of the individual sphingolipidoses are variable although the more severe variants are usually the better known. They have generally been regarded as untreatable but notable therapeutic advances are being made by enzyme replacement therapy and regulating the rate of glycosphingolipid synthesis by inhibiting UDP-glucose-N-acylsphingosine D-glucosyl transferase (CerGlcT), which is the first reaction on the pathway of glycosphingolipid synthesis. The compounds used are N-alkylated iminosugars whose glucose and galactose stereochemistries inhibit CerGlcT. Prenatal and carrier state diagnosis, genetic counselling and the abortion of affected foetuses are reducing the incidence of some of the most severe sphingolipidoses in certain high-incidence populations.

Carbohydrate Sequence↗
PubMed1998

Recent advances in the biochemistry of sphingolipidoses.

Glycosphingolipids are ubiquitous membrane components of eukaryotic cells. They participate in various cell recognition events and can regulate enzymes and receptors within the plasma membrane. Sphingolipidoses are due to an impaired lysosomal digestion of these substances. Glycosphingolipids are degraded by the action of exohydrolases, which are supported, in the case of glycosphingolipids with short oligosaccharide chains, by sphingolipid activator proteins. Five sphingolipid activator proteins are known so far, the GM2-activator and the SAPs, SAP-A to D (also called saposins). Degradation of glycosphingolipids requires endocytic membrane flow of plasma membrane derived glycosphingolipids into the lysosomes. Recent research focused on the topology of this process and on the mechanism and physiological function of sphingolipid activator proteins. Limited knowledge is available about enzymology and topology of glycosphingolipid biosynthesis. Recently, intermediates of this metabolic pathway have been identified as novel signalling molecules. Inhibition of glycosphingolipid biosynthesis has been shown to be beneficial in the animal model of Tay-Sachs disease. Mice with disrupted genes for lysosomal hydrolases and activator proteins are useful models for known human diseases and are valuable tools for the study of glycosphingolipid metabolism, the pathogenesis of sphingolipidoses and novel therapeutic approaches.

Animals↗
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↗
PubMed1998

Therapy for the sphingolipidoses.

Sphingolipidoses are human metabolic storage disorders characterized by the accumulation of harmful quantities of glycosphingolipids and phosphosphingolipids. These lipids have in common a hydrophobic portion of their structure called ceramide. In glycosphingolipids, various oligosaccharides are linked to ceramide through glycosidic bonds. An example is glucocerebroside, composed of ceramide and 1 molecule of glucose. Large quantities of glucocerebroside accumulate in tissues in patients with Gaucher disease. Higher oligosaccharide homologues contain additional neutral and acidic oligosaccharides. Among these are gangliosides that have 1 or more molecules of N-acetylneuraminic acid. A ganglioside called G(M2) accumulates in Tay-Sachs disease. Sphingomyelin is a phosphosphingolipid that accumulates in patients with Niemann-Pick disease.

Humans↗
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↗
PubMed2001

Gaucher disease: understanding the molecular pathogenesis of sphingolipidoses.

Gaucher disease is a typical lysosomal storage disease, resulting from an inborn deficiency of glucocerebrosidase. This leads to the accumulation of glycolipids in macrophages, particularly those in the liver, bone marrow, spleen and lung. In addition, disease of the nervous system can arise as a result of the accumulation of endogenous glycosphingolipid metabolites in brain tissue. About 150 mutations of the glucocerebrosidase gene have been identified in patients with Gaucher disease, some of which are predictive of phenotype. However, even patients and siblings with the same mutation, including monozygotic twins, may exhibit marked variability in disease expression and severity, illustrating our lack of understanding of the phenotype-genotype relationship in the sphingolipidoses. Massive organomegaly, particularly of the spleen, is a frequent feature of the disease. Although the liver and spleen may increase greatly in size, the amount of pathological lipid stored in the affected macrophages (Gaucher cells) accounts for less than 2% of the additional tissue mass. It is therefore clear that an inflammatory response occurs in affected individuals and that the clinical phenotype is due to an effect of macrophage storage beyond the physical presence of the Gaucher cells. Factors released by Gaucher cells, including pro-inflammatory cytokines and perhaps cathepsins, provide a mechanistic link between lysosomal storage and the diverse clinical manifestations of Gaucher disease. Emerging proteomic technology and gene expression profiling should not only improve our understanding of pathogenesis but also offer the prospect of identifying novel biomarkers that can be used as surrogate measures of disease activity and responses to treatment.

Gaucher Disease↗
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↗
PubMed1981

[Phenotypes in heteroglycanoses and sphingolipidoses (author's transl)].

Sphingolipidoses and heteroglycanoses are inborn errors of the carbohydrate metabolism. Biochemically and clinically hetero-glycanoses are sub-divided into mucopolysaccharidoses, oligosaccharidoses and mucolipidoses. These disorders of complex carbohydrate metabolism are due to the inborn defect of one or more lysosomal enzymes which in turn cause an intracellular accumulation of not-degraded complex carbohydrates corresponding to a wide pattern of clinical expression and symptomatology ranging from psychomotor retardation without any dysmorphic signs to severe features of a storage disease with dwarfism, peculiar facial appearance, organomegaly and skeletal changes. Investigations of recent years revealed that there is tremendous phenotypic variation even within diseases caused by a deficiency of the same enzyme. On the other hand, clinically indistinguishable phenotypes may be caused by the defect of different enzymes.

Adolescent↗