PubMed Health⌕ Search

SEARCH · PubMed Health

Results for “Sphingolipidoses”

Explore indexed PubMed citations for clinical trials, systematic reviews and public health research. Read source abstracts and follow each citation to its original PubMed record.

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

At least 271 records · Page 15Linked to original sources
PubMed1982

Diagnosis of metachromatic leukodystrophy, Krabbe disease, and Farber disease after uptake of fatty acid-labeled cerebroside sulfate into cultured skin fibroblasts.

[(14)C]Stearic acid-labeled cerebroside sulfate (CS) was presented to cultured skin fibroblasts in the media. After endocytosis into control cells 86% was readily metabolized to galactosylceramide, ceramide, and stearic acid, which was reutilized in the synthesis of the major lipids found in cultured fibroblasts. Uptake and metabolism of the [(14)C]CS into cells from typical and atypical patients and carriers of metachromatic leukodystrophy (MLD), Krabbe disease, and Farber disease were observed. Cells from patients with late infantile MLD could not metabolize the CS at all, while cells from an adult MLD patient and from a variant MLD patient could metabolize approximately 40 and 15%, respectively, of the CS taken up. These results are in contrast to the in vitro results that demonstrated a severe deficiency of arylsulfatase A in the late infantile and adult patient and a partial deficiency (21-27% of controls) in the variant MLD patient. Patients with Krabbe disease could metabolize nearly 40% of the galactosylceramide produced in the lysosomes from the CS. This is in contrast to the near zero activity for galactosylceramidase measured in vitro. Carriers of Krabbe disease with galactosylceramidase activity near half normal in vitro and those with under 10% of normal activity were found to metabolize galactosylceramide in cells significantly slower than controls. This provides a method for differentiating affected patients from carriers with low enzyme activity in vitro. Cells from patients with Farber disease could catabolize only approximately 15% of the ceramide produced from galactosylceramide. This technique provides a method for the identification of typical and atypical patients and carriers of three genetic diseases using one substrate.

Amidohydrolases↗
PubMed1983

Concentrations of an activator protein for sphingolipid hydrolysis in liver and brain samples from patients with lysosomal storage diseases.

The hydrolysis of sphingolipids by lysosomal enzymes requires the presence of additional proteins, which have been called activator proteins. The number of activator proteins, their specificity, exact mechanism of action, and response to a storage process all remain to be determined. In this study, antibodies to an activator protein known to bind sphingolipids and activate the enzymatic hydrolysis of GM1 ganglioside and sulfatide were used to estimate the concentration of this activator protein in small samples of liver and brain from patients with lysosomal storage diseases. By using rocket immunoelectrophoresis, the concentration of cross-reacting material (CRM) was determined. Control livers had an average of 0.95 +/- 0.18 (mean +/- 1 SD) microgram CRM/mg protein in the extracts, and control brains had an average of 0.25 +/- 0.14 microgram CRM/mg protein. Extremely high levels of CRM were found in extracts of livers from patients with type 1 GM1 gangliosidosis (15.1 and 16.9), and type A Niemann-Pick disease (10.7). Extracts of brain samples revealed a large amount of CRM in type 1 GM1 gangliosidosis (14.8), Tay-Sachs disease (5.3 and 8.7), and Sandhoff disease (13.5). Significantly elevated CRM was also measured in brain samples from patients with type 2 GM1 gangliosidosis, type A Niemann-Pick disease, metachromatic leukodystrophy, and Krabbe disease. The highest levels are found in those genetic diseases where the lipids stored, primarily or secondarily to the genetic defect, bind to this activator protein. This activator protein may have an important function in regulating intralysosomal lipid catabolism, and changes in its concentration in certain genetic diseases may be the cause of clinical, biochemical, and pathological heterogeneity found in the patients.

Adolescent↗
PubMed2004

Cerebral glycolipidoses: clinical characteristics of 41 pediatric patients.

A retrospective clinical and biochemical analysis of 41 pediatric patients with cerebral lipidoses seen between 1995 to 2003 was performed at a tertiary referral center for neurologic disorders in southern India. Enzyme assays in serum and leukocytes, including histopathology, neuroimaging, and neurophysiology studies, were performed. There were 20 cases of metachromatic leukodystrophy (infantile,14; juvenile, 6), 12 cases of Tay-Sachs disease (infantile, 9; late G(M2-M3) gangliosidoses, 3), 8 cases of Sandhoff's disease, and 1 male case with multiple sulfatase deficiency. Consanguinity was present in 51.2% of cases. The male-to-female ratio was 23:17. Similar illness in the families was noted in 24.4%. The prominent clinical features in sulfatide lipidoses were regression of motor and mental milestones, seizures, and speech impairment, and in G(M2) gangliosidoses, the features were delayed milestones, startle myoclonus, seizures, and the presence of cherry-red spots. The case with multiple sulfatase deficiency had low levels of arylsulfatase A and B. This study indicates that these autosomal recessive inherited disorders are indeed prevalent in India.

Adolescent↗
PubMed1976

Ultrastructural studies in fetal I-cell disease.

The skin, brain, lung, liver, and kidney from a 20-week-old fetus who was diagnosed as having fetal I-cell disease by amniocentesis at 14 weeks of gestation were examined by light and electron microscopy. In addition, cultured fibroblasts from the skin were also observed microscopically. Cytoplasmic inclusions with dense polymorphic contents appeared commonly in the capillary endothelial cells in the skin, lung, glomerulus of the kidney, and the epithelial cells of proximal tubules of the kidney, and sometimes in the hepatocytes of the liver and the nerve and glial cells of the brain. Erythropoietic cells in the liver and circulating erythrocytes contained dense inclusions varying in developmental stages. Fibroblasts of the skin had several clear vacuoles, and cultured fibroblasts were filled with dense inclusions. The dense cytoplasmic inclusions in fetal I-cell disease were light and electron microscopically similar to the residual bodies which are commonly observed in the phagocytic cells.

Adult↗
PubMed2006

Difficulty in recognizing multiple sulfatase deficiency in an infant.

We describe the difficulty in recognizing multiple sulfatase deficiency (MSD; Online Mendelian Inheritance in Man [OMIM] database No. 272200) in an infant. MSD is a rare autosomal recessive disorder that affects the posttranslational activation of various sulfatase enzymes. It is both biochemically and clinically variable. Currently, there are 12 known sulfatases in humans, and the clinical presentation of MSD is a unique composite of those individual enzyme defects. Here we report a black girl who presented with bilateral broad thumbs and great toes, both with angulation deformities at birth. Rubinstein-Taybi syndrome (OMIM No. 180849) was considered initially. The detection of inclusion bodies in her white blood cells at 37 months of age led to the appropriate diagnostic workups for lysosomal storage diseases. Elevation of urine mucopolysaccharides provided additional clues, and the fibroblast enzyme assays finally established the diagnosis. Broad thumbs and great toes are rare features of MSD, and to the best of our knowledge such a bilateral congenital anomaly with angulation deformities has never been reported before to be associated with MSD.

Diagnosis, Differential↗
PubMed2006

A chaperone-mediated approach to enzyme enhancement as a therapeutic option for the lysosomal storage disorders.

Enzyme activity can be deficient in the lysosome because certain newly synthesised mutation-bearing proteins are unstable and prone to misfolding. These structurally defective proteins are detected by the quality control system in the endoplasmic reticulum and subsequently diverted to cellular pathways of degradation. Recent studies have shown that low molecular weight ligands that are competitive inhibitors for some of these lysosomal enzymes can, in subinhibitory concentrations, act as 'chaperones' and rescue the mutant proteins, leading to the reconstitution of their hydrolytic activity within the lysosome. The potential of these agents as a therapeutic option will be dependent on their safety and tolerability profile, and the absence of toxic metabolic byproducts resulting from their use; there should be no or minimal nonspecific interference with other physiological or adaptive cellular activities. Compared with enzyme replacement therapy, the plausible advantages of using small molecule chaperones derive from the ease of oral administration, lack of immunogenicity and the possibility of delivery across the blood-brain barrier; and thus the potential to treat neurodegenerative clinical variants. The major challenges in developing therapies for rare diseases, such as the lysosomal storage disorders (LSDs), include recruitment of a sufficient number of suitable study patients and establishment of the optimal (dose/frequency) regimen to achieve a meaningful outcome. Multiple therapeutic approaches for the LSDs will provide patients with a range of options, which may be adequate as singular strategies or when given in combination. This review examines the characteristics of select agents that represent current candidates for a chaperone-mediated approach to the treatment of a subgroup of the LSDs, specifically the glycosphingolipidoses. Clinical trial experience with the use of these drugs will clarify their position in the management algorithm, which currently has enzyme replacement therapy as its linchpin. A major therapeutic goal would be improved physical and functional wellbeing, leading to increased meaningful survival.

Animals↗
PubMed2005

Role of ceramides in barrier function of healthy and diseased skin.

Stratum corneum intercellular lipids play an important role in the regulation of skin water barrier homeostasis and water-holding capacity. Modification of intercellular lipid organization and composition may impair these properties. Patients with skin diseases such as atopic dermatitis, psoriasis, contact dermatitis, and some genetic disorders have diminished skin barrier function. Lipid composition in diseased skin is characterized by decreased levels of ceramide and altered ceramide profiles. To clarify mechanisms underlying ceramides as a causative factor of skin disease, investigators have examined the activity of enzymes in the stratum corneum on ceramide production and degradation. The activities of ceramidase, sphingomyelin deacylase, and glucosylceramide deacylase are increased in epidermal atopic dermatitis. Investigators have also compared the expression levels of sphingolipid activator protein in the epidermis of normal and diseased skin. A decreased level of prosaposin has been identified in both atopic dermatitis and psoriasis. These results indicate that decreased ceramide level is a major etiologic factor in skin diseases. Hence, topical skin lipid supplementation may provide opportunities for controlling ceramide deficiency and improving skin condition.

Administration, Topical↗
PubMed1987

Farber's disease: a fine structural study.

A 1-week-old baby boy presented with hepatosplenomegaly, coarse facial features, and cloudy corneas. A metabolic storage disease was considered and he underwent cutaneous and liver biopsy. By light microscopy the skin was normal. Kupffer cells were enlarged and had foamy cytoplasm. Ultrastructural examination of skin and liver demonstrated features compatible with Farber's disease: curvilinear and "banana" bodies, zebra-like structures, and concentric lamellar bodies. A deficiency of lysosomal acid ceramidase was subsequently demonstrated in cultured fibroblasts and in liver tissue corroborating the ultrastructural findings.

Acid Ceramidase↗