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PubMed1992

Angiokeratoma corporis diffusum in a patient with normal enzyme activities and Turner's syndrome.

A case of angiokeratoma corporis diffusum (ACD) involving the skin of a 26-year-old patient with Turner's syndrome presenting with normal physical and mental development is reported. The unusual nature of this association confirms the theory that ACD presenting with skin lesions alone is a rare but specific clinical entity which differs from the hereditary sphingolipidoses like Fabry's disease.

Adult↗
PubMed1980

Nomenclature of GM2-gangliosidoses.

As a supplement to the recently proposed systematic nomenclature for the genotypes and phenotypes of GM2-gangliosidoses (O'Brien 1978b), it is suggested that guidelines be adopted for the use of eponyms and type designations in connection with this group of sphingolipidoses. The biochemical genetics of the lysosomal beta-hexosaminidase system in man are briefly reviewed, and recommendations are proposed for the use of eponyms and type designations based upon a locus-oriented framework.

Hexosaminidases↗
PubMed1992

Novel procedure for measuring psychosine derivatives by an HPLC method.

We developed a sensitive and simple method to determine galactosylsphingosine and glucosylsphingosine as a 4-fluoro-7-nitrobenzofurazan autofluorescent compound, using HPLC equipped with a Showdex sugar column. Amounts of galactosylsphingosine were successfully measured in the picomole range. This novel procedure is more stable and simpler than the previous method using o-phthalaldehyde. It was applied to tissues from the twitcher mouse, an animal model of human globoid cell leukodystrophy. The amount of galactosylsphingosine was 34-102 micrograms/kg of wet tissues in control cerebrum and cerebellum, whereas in twitcher mice the range was 2,251-4,228 micrograms/kg of wet tissues. The psychosine concentration was also increased in the liver and kidney of twitcher mice, respectively, 1,513 micrograms and 1,106 micrograms/kg of wet tissue (normal liver, 125 micrograms; normal kidney, 74 micrograms/kg of wet tissue). This novel procedure is useful for the pathochemical evaluation of lysosphingolipids in various sphingolipidoses as well as in other neuropathological and cellular conditions.

4-Chloro-7-nitrobenzofurazan↗
PubMed2005

A new turning point in glycosphingolipid research.

Research on glycosphingolipids has advanced with the finding of their involvement in sphingolipidoses, blood group- and differentiation-related antigens, and receptors for bacteria and viruses. Recently, the molecular cloning of genes for the synthesis of glycosphingolipids has been performed extensively, and mice without sugar transferase-genes have been generated. These transferase-null mice have shown that the complex carbohydrate structures of glycosphingolipids are not essential for the embryogenesis, morphogenesis or development of animals, but that the accumulation of an intermediate, such as GM3 or ceramide, causes significant failure of neural development in knockout mice as to the GM2, GD3 and GlcCer synthase genes. On the other hand, the nonreducing terminal carbohydrates in either glycosphingolipids or glycoproteins have been confirmed to be related to carbohydrate-mediated phenomena using the same gene-manipulation technique, indicating that glycosphingolipids are some of the carriers for functionally important carbohydrates. Glycosphingolipids are certainly small molecules with hydrophobic ceramides, which carry both donor and acceptor groups of the hydrogen-bonding region with the potential ability to interact with several proteins on the raft structure in biomembranes, and their dynamic movement in the membranes was revealed by the flip-flop regulation of their synthesis in the Golgi apparatus and the transformation-associated alteration in the reactivity of the carbohydrate moiety with several ligands. Thus, research on the functional significance of glycosphingolipids should be carried out again regarding their physicochemical properties.

Animals↗
PubMed1998

Mouse models of human lysosomal diseases.

Genetically authentic animal models of human lysosomal diseases occur spontaneously in many mammalian species. However, most are among larger domestic or farm animals with only two well-defined genetic lysosomal diseases known among rodents. This status changed dramatically in recent years with the advent of the combined homologous recombination and embryonic stem cell technology, which allows directed generation of mouse models that are genetically equivalent to human diseases. Almost all known human sphingolipidoses, two mucopolysaccharidoses and aspartylglycosaminuria have so far been duplicated in mice and more 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." These animal models will play an important role in studies of the pathogenesis and treatment of these disorders. While the utility of these mouse models is obvious, species differences in brain development and metabolic pathways must be always remembered, if the ultimate goal of the study is application to human patients.

Animals↗
PubMed1967

Diagnosis of gaucher's disease and niemann-pick disease with small samples of venous blood.

Enzymes which catalyze the hydrolysis of glucocerebroside and sphingomyelin have been demonstrated in preparations of washed human white blood cells. The level of activity of these respective enzymes is markedly decreased in leukocyte preparations obtained from patients with Gaucher's and Niemann-Pick diseases. Assay of these enzymes may be useful in the differential diagnosis of the sphingolipidoses.

Adolescent↗
PubMed1989

Inborn errors of metabolism. Sensitivity of screening tests in high risk patients.

We estimated the sensitivity of a screening procedure (SP) for inborn errors of metabolism (IEM) in 566 referred, high-risk patients. The 143 (25.3% of the total sample) patients with initial abnormal results in at least one screening test (ST) were recalled for further investigations. An IEM was diagnosed in 40.6 percent of the 106 patients who came for reevaluation. In 114 of the remaining 423 patients who had normal initial ST, an IEM was still suspected on basis of clinical, radiological, and/or laboratory findings and was confirmed in 30 of such patients (5.3% of the total sample and 7.1% of the patients with normal results in the SP). The sensitivity of the SP was estimated maximally as 67.4 percent and the efficiency as 80.4 percent. Twenty-five of the 30 cases undetected with the SP were patients with sphingolipidoses. The simple inclusion of thin-layer chromatography of urinary oligosaccharides in the SP should allow the detection of at least one half of these cases, increasing its sensitivity by 14.1 percent and its efficiency by 4.6 percent. In at least 7.1 percent of patients with an initial normal ST, an IEM was detected. These would have remained undiagnosed if the limitations of the SP employed had not been fully understood.

Child↗
PubMed2002

Glucosylceramide modulates membrane traffic along the endocytic pathway.

Glycosphingolipids are endocytosed and targeted to the Golgi apparatus, but are mistargeted to lysosomes in numerous sphingolipidoses. Substrate reduction therapy utilizes imino sugars to inhibit glucosylceramide synthase and potentially abrogate the effects of storage. Gaucher disease is a hereditary deficiency in glucocerebrosidase leading to glucosylceramide accumulation; however, Gaucher fibroblasts exhibited normal Golgi transport of lactosylceramide. To better understand the effects of glycosphingolipid accumulation on intracellular trafficking and the use of imino sugar inhibitors, we studied sphingolipid endocytosis in fibroblast and macrophage models for Gaucher disease. Treatment of fibroblasts or RAW macrophages with conduritol B epoxide, an inhibitor of lysosomal glucocerebrosidase, resulted in a change in the endocytic targeting of lactosylceramide from the Golgi to the lysosomes. Co-treatment of macrophages with conduritol B-epoxide and 12-25 microM N-butyldeoxygalactonojirimycin, an inhibitor of glycosphingolipid biosynthesis, prevented the mistargeting of lactosylceramide to the lysosomes and restored trafficking to the Golgi. Surprisingly, higher doses (>25 microM) of NB-DGJ induced targeting of lactosylceramide to the lysosomes, even in the absence of conduritol B-epoxide. These data demonstrate that both increases and decreases in glucosylceramide levels can dramatically alter the endocytic targeting of lactosylceramide and suggest a role for glucosylceramide in regulation of membrane transport.

Biological Transport↗
PubMed2000

Glucosylsphingosine accumulation in mice and patients with type 2 Gaucher disease begins early in gestation.

Gaucher disease, the most common of the sphingolipidoses, results from the inherited deficiency of the enzyme glucocerebrosidase (EC 3.2.1.45). Although type 2 (acute neuronopathic) Gaucher disease is associated with rapidly progressive and fatal neurologic deterioration, the pathophysiologic mechanisms leading to the neurologic symptoms and early demise remain uncharacterized. While the pathology encountered in Gaucher disease has been attributed to glucocerebroside storage, glucosylsphingosine (Glc-sph), a cytotoxic compound, also accumulates in the tissues. Elevations of brain Glc-sph have been reported in patients with types 2 and 3 Gaucher disease. In this study, Glc-sph levels were measured using HPLC in tissues from mice with type 2 Gaucher disease created with a null glucocerebrosidase allele. Compared with unaffected littermates, homozygous mice with type 2 Gaucher disease had approximately a 100-fold elevation of Glc-sph in brain, as well as elevated levels in other tissues. This accumulation was detected in utero by E 13 and increased progressively throughout gestation. Similarly, elevated Glc-sph levels were seen in human fetuses with type 2 Gaucher disease, indicating that therapy initiated after birth may be too late to prevent the sequelae of progressive neurologic damage that begins early in gestation. These findings suggest that the accumulation of Glc-sph may be responsible for the rapid demise of mice with type 2 Gaucher disease and the devastating clinical course seen in patients with type 2 Gaucher disease.

Animals↗
PubMed1977

Galactocerebrosidase activity in canine globoid leukodystrophy.

In an investigation of canine globoid leukodystrophy, cerebroside beta-galactosidase activities were assayed in 24 brains from neonatal and older dogs and in 90 canine leukocyte pellets from nine samplings. The neonatal brains had significantly less enzyme activity than the brains of older dogs, which indicates a potential complication in making neonatal and fetal enzymatic diagnoses. For leukocytes, heterozygous activities averaged 51 percent and globoid leukodystrophy activities 18 percent of mean enzyme activity of normal leukocytes. Variability of leukocyte enzyme activities among the nine samplings was large, but within each sample, variability per genotypic category was moderate. A statistical model was developed to facilitate enzyme diagnosis in the dog and, by implication, in human globoid leukodystrophy and other sphingolipidoses.

Animals↗
PubMed2001

Depletion of rafts in late endocytic membranes is controlled by NPC1-dependent recycling of cholesterol to the plasma membrane.

In mammalian cells, cholesterol is thought to associate with sphingolipids to form lateral membrane domains termed rafts. Increasing evidence suggests that rafts regulate protein interactions, for example, during signalling, intracellular transport and host-pathogen interactions. Rafts are present in cholesterol-sphingolipid-enriched membranes, including early and recycling endosomes, but whether rafts are found in late endocytic organelles has not been analyzed. In this study, we analyzed the association of cholesterol and late endosomal proteins with low-density detergent-resistant membranes (DRMs) in normal cells and in cells with lysosomal cholesterol-sphingolipid accumulation. In normal cells, the majority of [(3)H]cholesterol released from [(3)H]cholesterol ester-LDL associated with detergent-soluble membranes, was rapidly transported to the plasma membrane and became increasingly insoluble with time. In Niemann-Pick C1 (NPC1) protein-deficient lipidosis cells, the association of LDL-cholesterol with DRMs was enhanced and its transport to the plasma membrane was inhibited. In addition, the NPC1 protein was normally recovered in detergent-soluble membranes and its association with DRMs was enhanced by lysosomal cholesterol loading. Moreover, lysosomal cholesterol deposition was kinetically paralleled by the sequestration of sphingolipids and formation of multilamellar bodies in late endocytic organelles. These results suggest that late endocytic organelles are normally raft-poor and that endocytosed LDL-cholesterol is efficiently recycled to the plasma membrane in an NPC1-dependent process. The cholesterol-sphingolipid accumulation characteristic to NPC disease, and potentially to other sphingolipidoses, causes an overcrowding of rafts forming lamellar bodies in the degradative compartments.

Androstenes↗
PubMed1991

Lipid-laden macrophages in bone marrow of leprosy patients.

While conducting a study to observe bone marrow cytomorphological changes in multibacillary leprosy, lipid laden macrophages as seen in sphingolipidoses were noted. The present study was planned to observe the occurrence and morphological characterization of these macrophages in various types of leprosy. Bone marrow records from 48 cases of paucibacillary and 72 cases of multibacillary leprosy were analysed. The macrophages accounting at the most for 3.5% of marrow cells were observed in 5 cases of paucibacillary and 43 cases of multibacillary leprosy with a maximum incidence being observed in patients with ENL (16/17). The lipid present in the cytoplasm of these cells could be derived from the lipid of the cell wall of Mycobacterium leprae. To the best of our knowledge, these cells have not been reported in leprosy so far.

Bone Marrow↗
PubMed2001

Apoptosis of Neuro2a cells induced by lysosphingolipids with naturally occurring stereochemical configurations.

Lysosphingolipids, which lack the fatty acid moiety of sphingolipids, are known to be accumulated in some variants of sphingolipid storage diseases. Here, we report that lysosphingolipids with naturally occurring stereochemical configurations induce apoptosis in mouse neuroblastoma Neuro2a cells. The intracellular dehydrogenase activity and [3H]thymidine incorporation of Neuro2a cells were strongly suppressed by the addition of lysosphingolipids in a dose-dependent manner, whereas the parental sphingolipids had no effect. Intranucleosomal DNA fragmentation, chromatin condensation, and phosphatidylserine externalization, which are typical features of apoptosis, were observed when the cells were cultured with 40-80 microM of lysosphingolipids for 24-48 h in the presence of 5% fetal calf serum. Activation of caspase-3-like enzyme occurred after addition of lysosphingolipids followed by incubation at 37 degrees C for 24 h. The addition of an inhibitor of caspases, ZVAD-fmk, to the Neuro2a cell culture completely inhibited the elevation of caspase-3 activity but not the DNA fragmentation. These results may indicate that a caspase-3 independent signaling pathway is involved in the lysosphingolipid-induced apoptosis and suggest that accumulation of lysosphingolipids, but not parental sphingolipids, triggers the apoptotic cascade in neuronal cells of patients with sphingolipidoses.

Amidohydrolases↗
PubMed2003

Cutaneous variant of angiokeratoma corporis diffusum.

A case of angiokeratoma corporis diffusum (ACD) involving the skin of a 22-year-old patient presenting with normal physical and mental development is reported. ACD presenting with skin lesions alone is a rare but specific clinical entity, which differs from hereditary sphingolipidoses such as Fabry's disease.

Adult↗
PubMed1992

[Strategies for the diagnosis of lysosomal storage diseases: symptoms, methods and samples].

Lysosomal diseases are a group of about 30 genetic defects with a total incidence of 3 to 4 cases/10,000 newborns. Their clinical appearance is very heterogeneous and comprises infantile, as well as juvenile or adult forms. Our concept for their diagnosis has now been in use for eight years and entails the following strategy: The three main symptom groups coarse facial features, visceromegaly and/or psychomotor retardation should be examined for their typical expression and for the occurrence of specific "key symptoms". Thereafter, biochemical analysis of urine for oligosaccharides, mucopolysaccharides and in some cases, of sphingolipids or direct enzyme assays in serum, peripheral leucocytes or skin fibroblasts are performed. The selection of appropriate methods is usually the domain of the biochemist and greatly depends on the available samples and the quality of clinical information. The diagnostic value and the limitations of methods and samples are discussed in detail. Finally, evidence of defects in the expression of relevant gene products, such as enzymes, activator proteins or transport proteins can be obtained and used for genetic counselling and/or for prenatal diagnosis in chorionic villi or cultured amniotic fluid cells. Our results confirm the data on the high incidence of mucopolysaccharidoses I and III A. In addition, a comparatively high number of otherwise rare diseases, such as fucosidosis or sialic acid storage disease was found. Among the group of sphingolipidoses, special attention should be paid to juvenile or adult forms.

Abnormalities, Multiple↗
PubMed1990

Pathology of the central nervous system with special reference to the lipids.

The historical background of lipid research with particular reference to the nervous system is outlined. Attention is called to the early studies of Swedish investigators on the morphology and physical properties of the lipid rich myelin sheath. The pioneering research of the late Gunnar Brante on quantitative topical lipid chemistry of the human nervous system in health and disease is pointed out. A selection of lipid histochemical methods for various spingolipids is presented. Results are reported of their application to cases of four genetically determined sphingolipidoses. The morphological changes characterizing these diseases are interpreted in terms of histochemistry and biochemistry. The recently developed method by Dowson for the characterization of autofluorescence emission spectra from neuronal lipopigment in various ceroidoses (ceroid-lipofuscinosis) has been applied to cases of Sanfilippo's syndrome and Salla disease. The results are briefly commented upon.

Brain Diseases, Metabolic↗
PubMedDate not supplied

[Hereditary lysosomal diseases. I. Initial results of a diagnostic program in Mexico].

Results obtained by the Lysosome Storage Disease Diagnostic Program are described as well as the criteria used for the selection of patients to be studied. This program was started in 1983 and is sponsored by the National Reference Center for the Detection and Diagnosis of Inborn Errors of Metabolism in Mexico City. Laboratory tests include chemical determinations of urinary glycosaminoglycans and enzymatic assays of 15 lysosomal enzymes that allow the identification of 25 of the 35 lysosomal storage diseases known. A total of 259 patients with clinical phenotypes suggesting a lysosomal storage disease, and 47 individuals at risk for the carrier state were studied. The disease diagnosed were 35 patients with mucopolysaccharidoses, 27 with sphingolipidoses, 5 with mucolipidoses and 7 with glycogenoses; the most common lysosomal storage disease was Gaucher followed in decreasing frequency by Morquio, Hunter and glycogenoses Ia. The carrier state was confirmed in 29 of close relatives, one of them confirmed prenatally.

Genetic Carrier Screening↗
PubMed1986

Myoclonus in neuronal storage and Lafora diseases.

Genetic storage diseases with prominent myoclonus include classic infantile Tay-Sachs disease and juvenile neuropathic Gaucher's disease among the sphingolipidoses, most of the variants of the sialidoses and ceroid-lipofuscinoses, and Lafora disease. The character of the myoclonus differs from disease to disease and often changes as the disease runs its course. For example, massive myoclonic jerks to sound with rapid habituation and a prolonged refractory period are characteristic of the early stages of Tay-Sachs disease; children with late infantile ceroid-lipofuscinosis are most sensitive to light flashes below 3 Hz, those with juvenile Gaucher's disease at 6 to 10 Hz, and those with Lafora disease at 15 to 20 Hz, whereas young adults with sialidosis are not sensitive to either light or sound but are highly sensitive to somatosensory stimulation and movement. Some patients with sialidosis were found to have two distinct types of myoclonus: (a) a stimulus-insensitive facial myoclonus without EEG correlate that persisted in slow-wave sleep and (b) stimulus-sensitive massive jerks associated with vertex positive EEG spikes on which sleep had the paradoxic effect of suppressing jerks while stimulating spikes. Systematic EEG and event-related potential studies, including backward averaging from jerks and detailed anatomic studies of postmortem specimens with modern histochemical techniques, may help illuminate these intriguing differences. New modalities are needed to treat the myoclonus of these diseases since it generally responds poorly to currently available pharmacologic agents.

Adolescent↗