Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “Sphingolipidoses”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 109 records · Page 6Linked to original sources
PubMed1993

Diagnosis and prevention of lysosomal storage diseases in Russia.

A special programme for the diagnosis and prevention of lysosomal storage diseases (LSD) was developed in the former USSR. All the patients from 814 families at risk were investigated using biochemical techniques. In total, 363 patients with mucopolysaccharidoses (MPS), mucolipidoses, glycoproteinoses, sphingolipidoses and other LSD were diagnosed; 55 families at risk sought prenatal diagnosis and 67 fetuses were investigated for MPS (types I, II, IIIA and IIIB, VI), Tay-Sachs disease, Sandhoff disease, GM1-gangliosidosis, metachromatic leukodystrophy, mannosidosis, Gaucher disease and multiple sulphatidosis; 17 affected fetuses were diagnosed and aborted. There was an ethnic distribution of different lysosomal storage diseases in the former USSR.

Amniotic Fluid↗
PubMed1998

Pathological study of mice with total deficiency of sphingolipid activator proteins (SAP knockout mice).

Sphingolipid activator proteins (SAPs) A to D are lysosomal factors required in degradation of sphingolipids with short hydrophilic head groups and are derived from a precursor protein. Sap-B deficiency causes a variant of metachromatic leukodystrophy and sap-C deficiency causes a variant of Gaucher disease. Human total SAP deficiency has been reported in two patients in a single family. In these cases, various inclusions were described in the liver, skin, muscle and peripheral nerves ultrastructurally, but there was no report on the pathological study of the central nervous system (CNS). With targeted disruption of the precursor protein gene, we have generated mice with total SAP deficiency. These mice developed progressive neurological symptoms around day 20 and could not survive beyond day 40. Their cardinal pathology is extensive neurovisceral storage. Neuronal storage was already detected in the dorsal root ganglia as early as postnatal day 1 and diffuse neuronal storage was detected in the CNS after day 10. This storage was immunoreactive with anti-ubiquitin antibody and ultrastructurally appeared as inclusions consisting of numerous concentric lamellar and dense granular structures in the perikarya as well as in dendrites and axons. Axonal spheroids containing electron-dense concentric lamellar bodies and neurofilaments were also conspicuous. The extent of neuronal storage, numbers of storage neurons and axonal spheroids increased with age, accompanied with hypomyelination, astrogliosis and increase of macrophages. After day 30, argyrophilic tangle-like structures, which were immunoreactive with an antibody to phosphorylated neurofilaments, were found in the perikarya of many spinal and some neocortical neurons. Inclusions with various ultrastructural features were also noted in the glial cells, choroid plexus epithelial cells, vascular endothelial cells, Schwann cells, macrophages, fibroblasts, hepatocytes, and renal tubular epithelial cells. Some inclusions in the visceral organs were closely similar to those described in human cases of total SAP deficiency. The ultrastructural features of these inclusions in SAP knockout mice appeared unique and were different from those of other known sphingolipidoses.

Animals↗
PubMed1976

A rapid method for the estimation of beta-galactocerebrosidase, beta-glucocerebrosidase and sphingomyelinase activities in leukocytes.

A method for the assay of leukocyte beta-galactocerebrosidase, beta-glucocerebrosidase and sphingomyelinase activities has been developed, based on the separation of the tritiated sphingolipid substrates from their corresponding radioactive hydrophobic product (ceramide) by thin-layer chromatography on Silica gel H coated microscope slides. For the determination of beta-galactocerebrosidase and beta-glucocerebrosidase activities the silica gel is impregnanted with sodium tetraborate. Each chromatogram is easily divided into two distinct zones and the radioactivity content of each is determined by liquid scintillation counting. The technique described, is rapid, less costly than conventional methods and provides an accurate assessment of sphingolipid hydrolase activity. It is suggested that it should be of considerable value in those areas which require the rapid analysis of large numbers of samples, such as in screening for the sphingolipidoses or for enzyme purification studies.

Chromatography, Gas↗
PubMed1994

[14C]Methylamine accumulation in cultured human skin fibroblasts--a biochemical test for lysosomal storage and lysosomal diseases.

Incorporation of the lysosomotropic amine [14C]methylamine by fibroblasts cultured from patients with lysosomal storage diseases and from controls was used to estimate the size of the lysosomal compartment. All cell lines from patients with infantile and juvenile forms of mucopolysaccharidoses, mucolipidoses and oligosacharidoses showed markedly increased radioactivity compared with the normal range of controls. In cells from patients with sphingolipidoses and adult forms of storage diseases, however, methylamine accumulation was not significantly increased. Experimentally induced lysosomal storage by enzyme inhibitors (leupeptin, suramin) also caused increased methylamine accumulation. When the lysosomal pH was determined with fluorescein isothiocyanate-dextran, it was in the range of normal controls (pH 4.7-5.0) in patients cells. Thus, [14C]methylamine accumulation should depend on the volume rather than differences in acidity of the lysosomal compartment and be a measure of its eventual pathological enlargement. We conclude that the determination of [14C]methylamine accumulation in fibroblasts provides a valuable tool in the screening for a variety of lysosomal storage disorders.

Cells, Cultured↗
PubMed1984

Metabolism of ceramide trihexoside in cultured skin fibroblasts from Fabry's patients, carriers and normal controls.

The metabolism of ceramide trihexoside (CTH) was studied in cultured skin fibroblasts from Fabry's patients, carriers, and controls. The in vitro activities of alpha-galactosidase in fibroblasts using either artificial substrate or CTH led to a clear identification of 4 Fabry's patients, 6 carriers and 8 controls. Normal findings were noted in one carrier. In fibroblasts from Fabry's patients, the residual activities assayed with CTH were less than those with the artificial substrate. In the CTH-loading test, the incorporation and hydrolysis of CTH in the fibroblasts were closely related with the culture time and CTH-concentration in the medium. With 0.5 nmol CTH per flask (25 cm2 growth area, 3 ml of medium), the hydrolysis rate of CTH, based on its incorporation, was 2.1% in fibroblasts from 4 Fabry's patients, 82.0% in 10 controls and 47.1% in 6 out of 7 carriers on the 7th day of culture. The impaired hydrolysis in carriers' fibroblasts differs from the hydrolysis noted in fibroblasts from carriers of autosomal recessive sphingolipidoses with a normal hydrolysis. These findings explain that some of the carriers show clinical symptoms and a mild accumulation of CTH in their tissues, such as seen in Fabry's patients. In one carrier there was a normal hydrolysis of CTH, both in vitro and in the CTH-loading study. This may be explained by Lyon's random X-chromosome inactivation theory.

Cells, Cultured↗
PubMed1994

Free sphingoid bases in tissues from patients with type C Niemann-Pick disease and other lysosomal storage disorders.

The 20-fold increase of free sphingoid bases found in liver from a murine model of Niemann-Pick type C (NPC) combined to the NPC-like phenotype induced by addition of sphinganine to normal fibroblast cultures prompted us to investigate the potential involvement of these compounds in the human disease. The contents of sphingosine and sphinganine were measured in liver, spleen, brain and skin fibroblast cultures by a sensitive HPLC method. In liver and spleen from NPC patients, a 6- to 24-fold elevation of sphingosine and sphinganine already prominent at the fetal stage of the disease was observed, while no clear increase could be evidenced in brain tissue. A significant increase, not modulated by the intralysosomal content of free cholesterol, also occurred in skin fibroblast cultures. To investigate the specificity of these findings, other lysosomal storage disorders were studied. A striking accumulation was found in liver and spleen (24- to 36-fold) from patients with Niemann-Pick disease type A and B (sphingomyelinase-deficient forms), and in cerebral cortex of type A Niemann-Pick disease. A significant storage also occurred in Sandhoff disease, while several other sphingolipidoses showed a moderate elevation. In all cases but Sandhoff disease brain, the sphingosine/sphinganine ratio remained unchanged, suggesting that the accumulated free sphingoid bases derived from sphingolipid catabolism. Formation of complexes between sphingosine and the lipid material accumulated in lysosomes might be a general mechanism in lysosomal lipidoses. In NPC, however, an increase of free sphingoid bases disproportionate to the degree of lysosomal storage and a specific involvement of cultured fibroblasts suggested a more complex or combined mechanism.

Brain Chemistry↗
PubMed2004

Global gene expression in a type 2 Gaucher disease brain.

Gaucher disease is a member of a family of inherited disorders called sphingolipidoses that among others includes Tay-Sachs and Sandhoff diseases. It is caused by the accumulation of glucosylceramide (glucocerebroside) due to deficient activity of the enzyme glucosylceramide-beta-glucosidase (glucocerebrosidase). As with other glycosphingolipidoses, severe neurodegeneration is present in types 2 and 3 Gaucher disease. We have used Serial Analysis of Gene Expression (SAGE) to characterize the gene expression profiles in brain of patients with glycosphingolipid storage diseases to understand the molecular details of neurodegeneration. In the current study we have determined the gene expression profile from the brain of a patient with type 2 Gaucher disease, the acute neuronopathic form of the disorder. We found that the expression profile of the type 2 Gaucher brain is significantly altered relative to the normal control brain profile. There were also differences when compared with profiles from Tay-Sachs and Sandhoff patients, in particular in levels of genes related to macrophage activation. Intriguingly we found that gamma-synuclein, a family member of proteins involved the pathogenesis of other neurodegenerative disorders, was elevated in the one Gaucher type 2 patient brain we examined.

Cerebral Cortex↗
PubMed1996

Pseudotumours of hepatic imaging.

The diagnosis of liver tumours with CT depends on differential attenuation coefficients and enhancement patterns. The sensitivity of CT in defining tumours is well established but there remain a variety of conditions that mimic these patterns, presenting a 'pseudotumour' appearance. A common illustrative example is hepatic steatosis, but less well recorded are the sphingolipidoses and intrahepatic arterioportal shunts, either post-traumatic or related to venous outflow block. Alpha-1-antitrypsin deficiency and hereditary tyrosinaemia provide examples in childhood.

Adolescent↗
PubMed1992

Detection of inherited neurometabolic disorders. A practical clinical approach.

The most common neurometabolic disorders to be considered are organic acidurias and amino acid apathies followed by urea cycle disorders, congenital lactic acidosis, peroxisomal disorders, and, less frequently, sphingolipidoses, mucopolysaccharidoses, glycoprotein degradation disorders, fatty acid oxidation disorders, and neuronal ceroid lipofuscinoses.

Adolescent↗
PubMed1975

Mental retardation, hypotonia, and generalized seizures associated with astrocytic "residual" bodies. An ultrastructural study.

Two siblings suffering since birth from convulsions, hypotonia, and mental retardation are presented. In the older sibling (eight and one-half years of age) frontal lobe biopsy revealed abnormal cytosomes with lamellar profiles in astrocytes, macrophages, and to a lesser degree in neurons. Similar cytosomes have not yet been reported in cases of sphingolipidoses or in late infantile-juvenile amaurotic idiocy. These cytosomes stained intensely with silver proteinate, an ultrastructural cytochemical stain for carbohydrate moieties. In contrast, lipofuscin did not stain with silver proteinate. Multilamellar (crescentic curvilinear) cytosomes from a reported case of late infantile amaurotic idocy (Batten-Vogt-Spielmeyer disease) did not stain with silver proteinate. Abnormal cytosomes were not found in blood cells, liver, and peripheral nerve. In the younger sibling (14 months old) postmortem ultrastructural studies of cerebral tissue showed very few abnormal cytosomes. On the basis of the clinical and ultrastructural findings, we conclude that these two cases can be distinguished from those with multilamellar (crescentic-curvilinear) inclusions and from cases of the so-called "neuronal ceroid-lipofuscinosis" syndrome.

Astrocytes↗
PubMedDate not supplied

The Colorado mental retardation and developmental disabilities research center.

The Colorado MRRC was one of the original MRRCs funded and has maintained its focus on genetic and nutritional causes of mental retardation and developmental disabilities. Significant discoveries of the center have included a number of metabolic disorders, including glutaric academia types I and II, electron transport flavoprotein (ETF) deficiency, ETF dehydrogenase deficiency, glycerol kinase deficiency, sphingolipidoses, genetic linkages in dyslexia, phonological deficits in dyslexia, and the importance of the trace mineral Zn in early development. Current research at the center is supported by program of projects grants on inborn errors of metabolism, Down syndrome (DS), autism, and dyslexia.

Academic Medical Centers↗
PubMed1998

Animal models of lysosomal disease: an overview.

The relative rarity of human lysosomal disorders, extremely heterogeneous genetic background and ethical restrictions make well-controlled studies difficult with human patients. Genetically authentic animal models complement human patients with their ready availability, homogeneous genetic background and the relatively flexible experimental designs. Spontaneous animal models of human lysosomal disorders are rare, particularly among small laboratory animals. However, the homologous recombination and embryonic stem cell technology has so far enabled us to duplicate almost all known human sphingolipidoses, two mucopolysaccharidoses and aspartylgly-cosaminuria in mice and more disorders are expected in the near future. This technology also allows generation of mouse mutants that are not known or are highly unlikely to exist in humans, such as 'double-knockouts'. Studies of lysosomal disease have come to the half-way turning point of the marathon race from clincopathological descriptions, identification of affected compounds, enzymology, to the present gene-level inquiries. The animal models will play an important role in our long journey from nucleic acids back to biology. While the utility of these mouse models is obvious, species differences in the brain development and metabolic pathways must be always remembered if the ultimate goal of the study is application to human patients. After all, the mouse is not human.

Animals↗
PubMed1998

Twenty five years of the "psychosine hypothesis": a personal perspective of its history and present status.

Twenty five years ago in 1972, a hypothesis was introduced to explain the pathogenetic mechanism underlying the unusual cellular and biochemical characteristics of globoid cell leukodystrophy (Krabbe disease). It postulated that galactosylsphingosine (psychosine), which cannot be degraded due to the underlying genetic defect, is responsible for the very rapid loss of the oligodendrocytes and the consequent paradoxical analytical finding, the lack of accumulation of the primary substrate, galactosylceramide, in patients' brain. It took nearly ten years before the actual accumulation of psychosine was demonstrated in human Krabbe patients and also in the brain of twitcher mice, an equivalent murine mutant. Meanwhile this "psychosine hypothesis" has been extended to Gaucher disease and then to a more general hypothesis encompassing all sphingolipidoses that the "lyso-derivatives" of the primary sphingolipid substrates of the defective enzymes in respective disorders play a key role in their pathogenesis. Some of these extensions not only remain speculative without conclusive factual evidence but may eventually turn out to be an overstretching. This article attempts, from my personal perspective, at tracing historical development of the "psychosine hypothesis" and examining its current status and possible future directions.

Animals↗
PubMed1999

Sphingosylphosphorylcholine in Niemann-Pick disease brain: accumulation in type A but not in type B.

A study of brain lipids in patients with the sphingomyelinase-deficient types of Niemann-Pick disease demonstrated that abnormal accumulation of sphingomyelin occurs only in the brain of neuronopathic type A patients but not in the non-neuronopathic type B. Additional lipid abnormalities were present in the type A brain. In contrast, the brain lipid profile was normal in type B patients. Since lysosphingolipids have been implicated in the biochemical pathogenesis of other genetic lysosomal sphingolipidoses, the occurrence of sphingosylphosphorylcholine (lysosphingomyelin) was specifically investigated in brain and extraneural tissues, using an HPLC method with fluorescent detection of orthophtalaldehyde derivatives. Levels close to or below the limit of detection (10 pmol/mg tissue protein) were observed in normal and pathological controls. A striking accumulation was observed in brain of two Niemann-Pick type A patients (830 and 430 pmol/mg protein in 27-and 16-month-old children with severe and milder neurological course, respectively), which was not present at the fetal stage of the disease. No significant increase was found in brain tissue from a 3.5 year-old type B patient. In liver and spleen, abnormally high sphingosylphosphorylcholine levels were observed in both types of the disease, with indication of a progressive increase during development. This study establishes the integrity of brain tissue in Niemann-Pick disease type B and suggests that the lysocompound sphingosylphosphorylcholine could play a role in the pathophysiology of brain dysfunction in the neuronopathic type A.

Brain↗
PubMed1995

Mouse models of Tay-Sachs and Sandhoff diseases differ in neurologic phenotype and ganglioside metabolism.

Tay-Sachs and Sandhoff diseases are clinically similar neurodegenerative disorders. These two sphingolipidoses are characterized by a heritable absence of beta-hexosaminidase A resulting in defective GM2 ganglioside degradation. Through disruption of the Hexa and Hexb genes in embryonic stem cells, we have established mouse models corresponding to each disease. Unlike the two human disorders, the two mouse models show very different neurologic phenotypes. Although exhibiting biochemical and pathologic features of the disease, the Tay-Sachs model showed no neurological abnormalities. In contrast, the Sandhoff model was severely affected. The phenotypic difference between the two mouse models is the result of differences in the ganglioside degradation pathway between mice and humans.

Animals↗
PubMed1998

[Uveitis masquerade syndrome in Gaucher disease. Causal treatment by alglucerase substitution therapy].

BACKGROUND: Gaucher's disease, a sphingolipidose transmitted by autosomal-recessive inheritance, is caused by a deficiency of the lysosomal enzyme beta-glucocerebrosidase which is responsible for hydrolysation of glucocerebroside to ceramid and glucose. Thus glucocerebroside is accumulated in the reticuloendothelial cells of spleen, liver and bone marrow and pathognomonic Gaucher's cells are formed. CASE REPORT: In May 1997 a 42-year-old female patient presented with left-sided intermediate uveitis of unknown origin and decreasing visual acuity to perception of hand movements and intact projection of light since September 1996. To exclude a systemic disease a thorough medical examination--showing hepatoslpenomegaly, anemia, thrombocytopenia and bone lesions--was initiated and revealed advanced M. Gaucher (Type I) by bone marrow punction. Intravenous therapy with alglucerase was administered promptly. After five months of treatment vitreous opacities resolved almost completely and visual acuity increased to 0.7. CONCLUSIONS: The dramatic improvement occurred under treatment with alglucerase after no response to steroid treatment. Thus intermediate uveitis with severe vitritis can be interpreted as uveitis masquerade syndrome with M. Gaucher. To the best of our knowledge, this is the first case of M. Gaucher presenting initially as intermediate uveitis and showing successful clinical improvement during administration of alglucerase.

Adult↗
PubMed2026

A human lysosomal storage disorder toolkit for decoding proteome landscapes in cortical-like and dopaminergic-like induced neurons.

Lysosomes maintain cellular homeostasis by degrading proteins delivered via endocytosis and autophagy and by recycling building blocks for organelle biogenesis. Lysosomal storage disorders (LSDs) comprise a group of diseases affecting diverse lysosomal functions. To facilitate molecular phenotyping across diverse LSD gene classes, we are developing a library of human embryonic stem cells engineered to lack individual LSD genes as a resource for the field. Here, we report our initial stem cell toolkit lacking one of 23 LSD genes, including the majority of genes associated with sphingolipidoses and neuronal ceroid lipofuscinoses, and its use in the generation of a proteomic resource for induced cortical-like and midbrain dopaminergic-like neurons. In-depth abundance and correlation profiling across organelles and suborganelle components revealed potential vulnerabilities that reflect distinct patterns of proteome alterations across both genotypes and neuronal cell types. We characterize alterations in the mitochondrial proteome associated with GBA1 and ASAH1 deficiency and identify synaptic and mitochondrial defects in ASAH1-/- induced neurons that correlate with defects in neuronal firing rates. Moreover, we developed an informatic pipeline for proteome-wide identification of individual protein-protein interactions and protein complexes that may be disrupted as a result of LSD gene deficiency. Finally, we visualized structural alterations of ASAH1-deficient endolysosomes in situ using cryoelectron tomography, revealing swollen organelles that were largely devoid of dense internal membranes characteristic of wild-type cells, but containing numerous intralumenal vesicle compartments. This toolkit and associated proteomic landscapes provide a resource for defining molecular signatures associated with LSD gene dysfunction and organelle vulnerability.

Humans↗
PubMed2003

Biosynthesis and degradation of mammalian glycosphingolipids.

Glycolipids are a large and heterogeneous family of sphingolipids that form complex patterns on eukaryotic cell surfaces. This molecular diversity is generated by only a few enzymes and is a paradigm of naturally occurring combinatorial synthesis. We report on the biosynthetic principles leading to this large molecular diversity and focus on sialic acid-containing glycolipids of the ganglio-series. These glycolipids are particularly concentrated in the plasma membrane of neuronal cells. Their de novo synthesis starts with the formation of the membrane anchor, ceramide, at the endoplasmic reticulum (ER) and is continued by glycosyltransferases of the Golgi complex. Recent findings from genetically engineered mice are discussed. The constitutive degradation of glycosphingolipids (GSLs) occurs in the acidic compartments, the endosomes and the lysosomes. Here, water-soluble glycosidases sequentially cleave off the terminal carbohydrate residues from glycolipids. For glycolipid substrates with short oligosaccharide chains, the additional presence of membrane-active sphingolipid activator proteins (SAPs) is required. A considerable part of our current knowledge about glycolipid degradation is derived from a class of human diseases, the sphingolipidoses, which are caused by inherited defects within this pathway. A new post-translational modification is the attachment of glycolipids to proteins of the human skin.

Animals↗