Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0002986 (Fabry)
 5,646 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Trihexosylceramide, isolated from human kidney and labelled in the terminal galactose position by oxidation with galactose oxidase and reduction with sodium boro[3H]hydride, was used to study some of the properties of human leucocyte alpha-galactosidase. The enzyme was inactive in the absence of detergent. Of all the detergents tested a crude sodium taurocholate preparation displayed the greatest activity. The optimal detergent concentration varied from 2 to 4 mg/ml depending on the protein concentration and indicating that the enzyme activity was dependent on the protein/detergent ratio. Because of its influence in regulating enzyme activity, it is essential that care must be taken to ensure that the protein/detergent ratio of all incubation mixtures is kept relatively constant whenever the diagnosis of Fabry's disease is attempted.
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PMID:Trihexosylceramide alpha-galactosidase of human leucocytes. 10 20

Angiokeratoma corporis diffusum (Fabry's disease) is an X-linked disorder of glycosphingolipid catabolism. Heterozygous females, although usually asymptomatic, are occasionally as severely afflicted as hemizygous males; recently we identified a heterozygous patient with cardiomyopathy and severe pain in the extremities. In order to elucidate the difference of the clinical features, we analyzed the glycolipid composition of the heart, liver, and kidney obtained from the patient and from a hemizygote. Gas-liquid chromatography revealed that globotriaosylceramide (Gb3) was markedly increased in the heart (32.4 times higher than control) and increased to a lesser extent in the liver and kidney (3.74 and 6.79 times, respectively). The pattern of Gb3 accumulation in the heterozygote, where the highest increases were seen in the heart, was distinct from that in the hemizygote, where elevated levels of Gb3 and Ga2 were found in the kidney. Furthermore, the alpha-galactosidase activity in the heart, liver, and kidney of the heterozygote was 17%, 26%, and 36%, respectively, of normal controls, which correlated well with the accumulation of glycosphingolipid in the heart and with the disease's clinical manifestations. Two other hemizygotic patients, who were identified by low alpha-galactosidase activities, demonstrated the cardiac involvement.
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PMID:Biochemical and clinical analysis of accumulated glycolipids in symptomatic heterozygotes of angiokeratoma corporis diffusum (Fabry's disease) in comparison with hemizygotes. 215 88

Globotriaosylceramide, the natural substrate of alpha-galactosidase A (the enzyme deficient in Fabry's disease) was prepared from human kidney by repeated medium pressure chromatography on Lichroprep Si 60 (E. Merck) before and after peracetylation. The apparently homogeneous preparation migrating as a single band on HPTLC was analysed by fast atom bombardment mass spectrometry and 1H-NMR at 500 MHz. It was found that in this fraction two major molecular species were comigrating: Gal alpha 1-4Gal beta 1-4Glc beta 1-1ceramide with nervonic and lignoceric acid linked to phytosphingosine and Gal beta 1-4Glc beta 1-1 ceramide with palmitic acid linked to sphingosine.
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PMID:The determination of phytosphingosine-containing globotriaosylceramide from human kidney in the presence of lactosylceramide. 216 61

Fabry disease is an X-linked metabolic disorder caused by a deficiency of alpha-galactosidase A (alpha-Gal A). The enzyme defect leads to the systemic accumulation of glycosphingolipids with alpha-galactosyl moieties consisting predominantly of globotriaosylceramide (Gb3). In patients with this disorder, glycolipid deposition in endothelial cells leads to renal failure and cardiac and cerebrovascular disease. Recently, we generated alpha-Gal A gene knockout mouse lines and described the phenotype of 10-week-old mice. In the present study, we characterize the progression of the disease with aging and explore the effects of bone marrow transplantation (BMT) on the phenotype. Histopathological analysis of alpha-Gal A -/0 mice revealed subclinical lesions in the Kupffer cells in the liver and macrophages in the skin with no gross lesions in the endothelial cells. Gb3 accumulation and pathological lesions in the affected organs increased with age. Treatment with BMT from the wild-type mice resulted in the clearance of accumulated Gb3 in the liver, spleen, and heart with concomitant elevation of alpha-Gal A activity. These findings suggest that BMT may have a potential role in the management of patients with Fabry disease.
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PMID:Aging accentuates and bone marrow transplantation ameliorates metabolic defects in Fabry disease mice. 1033 3

Fabry disease is an X-linked inborn error of glycosphingolipid catabolism resulting from a deficiency of lysosomal alpha-galactosidase activity. Globotriaosylceramide accumulates predominantly in lysosomes of various tissues. Former studies have clarified the nature of this disease, and the accumulated materials in the lysosomes have been analyzed using biochemical techniques. In the present study, transmission electron microscopy was used to reveal the fine structure of these lysosomal deposits, and sugar residues in the lysosomal deposits in Fabry disease were examined by lectin histochemistry combined with enzyme digestion. This is the first report to describe the lysosomal sugar residues in Fabry disease analyzed using lectin histochemistry at the ultrastructural level. With these techniques, we were able to detect alpha-galactosyl, beta-galactosyl and glucosyl sugar residues in the lysosomal deposits. The experimental procedures used in this study have considerable potential for use in investigations of glycolipid and glycoprotein storage diseases without the need for complex methodology and expensive materials.
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PMID:Fabry disease: ultrastructural lectin histochemical analyses of lysosomal deposits. 1066 60

Fabry disease is a compelling target for gene therapy as a treatment strategy. A deficiency in the lysosomal hydrolase alpha-galactosidase A (alpha-gal A; EC ) leads to impaired catabolism of alpha-galactosyl-terminal lipids such as globotriaosylceramide (Gb3). Patients develop vascular occlusions that cause cardiovascular, cerebrovascular, and renal disease. Unlike for some lysosomal storage disorders, there is limited primary nervous system involvement in Fabry disease. The enzyme defect can be corrected by gene transfer. Overexpression of alpha-gal A by transduced cells results in secretion of this enzyme. Secreted enzyme is available for uptake by nontransduced cells presumably by receptor-mediated endocytosis. Correction of bystander cells may occur locally or systemically after circulation of the enzyme in the blood. In this paper we report studies on long-term genetic correction in an alpha-gal A-deficient mouse model of Fabry disease. alpha-gal A-deficient bone marrow mononuclear cells (BMMCs) were transduced with a retrovirus encoding alpha-gal A and transplanted into sublethally and lethally irradiated alpha-gal A-deficient mice. alpha-gal A activity and Gb3 levels were analyzed in plasma, peripheral blood mononuclear cells, BMMCs, liver, spleen, heart, lung, kidney, and brain. Primary recipient animals were followed for up to 26 weeks. BMMCs were then transplanted into secondary recipients. Increased alpha-gal A activity and decreased Gb3 storage were observed in all recipient groups in all organs and tissues except the brain. These effects occurred even with a low percentage of transduced cells. The findings indicate that genetic correction of bone marrow cells derived from patients with Fabry disease may have utility for phenotypic correction of patients with this disorder.
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PMID:Long-term enzyme correction and lipid reduction in multiple organs of primary and secondary transplanted Fabry mice receiving transduced bone marrow cells. 1084 53

Fabry disease is a lysosomal storage disorder caused by a deficiency of the lysosomal enzyme alpha-galactosidase A (alpha-gal A). This enzyme deficiency leads to impaired catabolism of alpha-galactosyl-terminal lipids such as globotriaosylceramide (Gb3). Patients develop painful neuropathy and vascular occlusions that progressively lead to cardiovascular, cerebrovascular, and renal dysfunction and early death. Although enzyme replacement therapy and bone marrow transplantation have shown promise in the murine analog of Fabry disease, gene therapy holds a strong potential for treating this disease in humans. Delivery of the normal alpha-gal A gene (cDNA) into a depot organ such as liver may be sufficient to elicit corrective circulating levels of the deficient enzyme. To investigate this possibility, a recombinant adeno-associated viral vector encoding human alpha-gal A (rAAV-AGA) was constructed and injected into the hepatic portal vein of Fabry mice. Two weeks postinjection, alpha-gal A activity in the livers of rAAV-AGA-injected Fabry mice was 20-35% of that of the normal mice. The transduced animals continued to show higher alpha-gal A levels in liver and other tissues compared with the untouched Fabry controls as long as 6 months after treatment. In parallel to the elevated enzyme levels, we see significant reductions in Gb3 levels to near normal at 2 and 5 weeks posttreatment. The lower Gb3 levels continued in liver, spleen, and heart, up to 25 weeks with no significant immune response to the virus or alpha-gal A. Also, no signs of liver toxicity occurred after the rAAV-AGA administration. These findings suggest that an AAV-mediated gene transfer may be useful for the treatment of Fabry disease and possibly other metabolic disorders.
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PMID:Adeno-associated viral vector-mediated gene transfer results in long-term enzymatic and functional correction in multiple organs of Fabry mice. 1122 98

We have developed a series of inhibitors of glucosylceramide synthase that are structurally based on the parent compound D-threo-1-phenyl-2-decanoylamino-3-morpholino-1-propanol (PDMP). These inhibitors provide useful tools for manipulating glycosphingolipid levels in cells and for elucidating questions associated with sphingolipid signaling. Recently, two highly active glucosylceramide synthase inhibitors, D-threo-3', 4'-ethylenedioxy-1-phenyl-2-palmitoylamino-3- pyrrolidino-1-propanol and D-threo-4'-hydroxy-1-phenyl-2-palmitoylamino-3- pyrrolidino-1-propanol, were designed, synthesized, and studied. These inhibitors markedly reduced glycosphingolipid levels in MDCK cells without any accumulation of intracellular ceramide and associated growth inhibition. Subsequently, each inhibitor was evaluated for its ability to lower glycolipid levels in virally transformed lymphoblasts from a patient with alpha-galactosidase A deficiency. Both compounds significantly reduced neutral glycosphingolipid levels in the lymphoblasts without any morphological changes and growth inhibition. Furthermore, the inhibitors were applied to a mouse knockout model of Fabry disease. Inhibitor treatment blocked accumulation of globotriaosylceramide (Gb3) in the kidney, liver and heart of mice. In contrast to another glucosylceramide synthase inhibitor, N-butyldeoxynojirimycin, this treatment was not associated with any significant change in body weight or organ weight and without immunodepletion. These results suggest that these newest PDMP homologues are promising as therapeutic agents for the treatment of glycosphingolipid storage disorders.
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PMID:Agents for the treatment of glycosphingolipid storage disorders. 1151 34

Fabry disease is an X-linked lysosomal disorder characterized by deficient alpha-galactosidase A activity and intracellular accumulations of glycosphingolipids, mainly globotriaosylceramide (Gb3). Clinically, patients occasionally present CNS dysfunction. To examine the pathophysiology underlying brain dysfunction, we examined glucose utilization (CMR(glc)) and cerebral blood flow (CBF) globally and locally in 18 brain structures in the alpha-galactosidase A gene knockout mouse. Global CMR(glc) was statistically significantly reduced by 22% in Fabry mice (p < 0.01). All 18 structures showed decreases in local CMR(glc) ranging from 14% to 33%. The decreases in all structures of the diencephalon, caudate-putamen, brain stem, and cerebellar cortex were statistically significant (p < 0.05). Global cerebral blood flow (CBF) and local CBF measured in the same 18 structures were lower in Fabry mice than in control mice, but none statistically significantly. Histological examination of brain revealed no cerebral infarcts but abundant Gb3 deposits in the walls of the cerebral vessels with neuronal deposits localized to the medulla oblongata. These results indicate an impairment in cerebral energy metabolism in the Fabry mice, but one not necessarily due to circulatory insufficiency.
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PMID:Local and global cerebral blood flow and glucose utilization in the alpha-galactosidase A knockout mouse model of Fabry disease. 1175 62

Fabry disease is a rare X-linked disorder, characterized by deficient activity of the lysosomal enzyme alpha-galactosidase A. This leads to systemic accumulation of the glycosphingolipid globotriaosylceramide (Gb3) in all body tissues and organs, including the kidney. Renal manifestations are less evident in female heterozygotes than in male hemizygotes, according to the Lyon hypothesis. Accumulation of Gb3 occurs mainly in the epithelial cells of Henle's loop and distal tubule, inducing early impairment in renal concentrating ability; involvement of the proximal tubule induces Fanconi syndrome. All types of glomerular cells are involved, especially podocytes, and glomerular proteinuria may occur at a young age. The evolution of renal Fabry disease is characterized by progressive deterioration of renal function to end-stage renal failure (ESRF). Ultrastructural study of kidney biopsies reveals typical bodies in the cytoplasm of all types of renal cells, characterized by concentric lamellation of clear and dark layers with a periodicity of 35-50 A. Management of progressive renal disease requires dietetic and therapeutic strategies, usually indicated in developing chronic renal failure, with dialysis and renal transplantation required for patients with ESRF. The recent development of enzyme replacement therapy, however, should make it possible to prevent or reverse the progressive renal dysfunction associated with Fabry disease.
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PMID:Renal pathological changes in Fabry disease. 1175 81


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