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)

[6-2H2]Glucose was used as a tracer for a comparative study on the metabolism of the neutral glycosylceramides in plasma of a control subject and a patient with Fabry's disease. The incorporation of the tracer into the glucosyl and galactosyl moieties of the glycosphingolipids was measured by gas chromatography-mass spectrometry of the tetra-0-acetyl methyl glycoside derivatives. Experiments on the precision and accuracy for measurements of [6,6-2H2]hexose in a sample demonstrated that incorporation of 0.2% or more of [6,6-2H2]glucose could be detected with a 95% confidence limit of +/-0.16%. The labeled substrate (35g) was infused into each subject with a 5-g priming dose and the remainder administered at a constant rate of 3 g/hour over a 10-hour period. During the infusion, the plasma glucose of each subject attained a concentration of about 30% [6,6-2H2]glucose which diminished rapidly after the administration of substrate was complete. A concentration of 0.8% [6,6-2H2]glucose was observed in glucosylceramide (GL-la) from plasma of both subjects between 48 and 72 hours after the infusion began. The label disappeared from this lipid at a logarithmic rate and 0.2% or less of the molecules were labeled 9 days after the experiment began. In contrast to the results with GL-la, the maximum incorporation of [6,6-2H2]hexose into lactosylceramide (galactosyl-(beta1 leads to 4)-glucosylceramide) was 2-fold higher in the Fabry patient (1.6%) than in the control (0.8%). The trihexosylceramide (galactosyl-(alpha1 leads to 4)-galactosyl-(beta1 leads to 4)-glucosylceramide, GL-3a) from plasma of the control reached a maximum of 0.4% [6,6-2H2]hexose in both the glucosyl and galactosyl moieties whereas the GL-3a from the Fabry patient was not significantly labeled. The maximal labeling of the GL-4a fraction (N-acetyl-galactosaminyl-galactosyl-galactosyl-glucosylceramide) was slightly depressed in the Fabry patient (0.4%) as compared to the control (0.7%). Turnover times for the glycosphingolipids of plasma were calculated to be from 4 to 8 days and the turnover rates were from 1 to 6 mumol/day.
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PMID:Metabolism of neutral glycosphingolipids in plasma of a normal human and a patient with Fabry's disease. 80 41

Human lymphoid cell lines established by Epstein-Barr viral transformation of peripheral B-lymphocytes from normal subjects and from Fabry patients, were investigated for their ability to biosynthesize neutral glycosphingolipids from [14C]galactose and [14C]glucose as precursors. Galactose was taken up in the presence of high concentrations of glucose and selectively utilised by the cells in the synthesis of galactosphingolipids. The pattern of neutral glycosphingolipids labelled from [14C]galactose was slightly modified with time of labelling in either lymphoid cell line: the first labelled glycosphingolipid was lactosylceramide (LacCer) in the normal line and globotetraosylceramide (GbOse4Cer) in the Fabry line. After labelling for 96 h, a steady state was reached and the percentage of every type of labelled glycosphingolipid was stable in each cell line; however, differences in the neutral sphingolipid composition appeared between the various cell lines. When using radiolabelled glucose as precursor, the major part of the radioactivity was incorporated into neutral lipids and phospholipids; neutral sphingolipids were much less labelled than when using galactose. Catabolism of endogeneous labelled glycosphingolipids (synthesized by the cells during the 'pulse') was studied after cultivating the cells without radiolabelled precursors ('chase'). In the cells from normal subjects, all the neutral glycosphingolipids were slowly degraded (half-life time around 15-25 days for LacCer and GbOse3Cer). In contrast, in a lymphoid line from a Fabry patient, no appreciable degradation of GbOse3Cer occurred during 30 days. This block in the catabolism of GbOse3Cer is in good agreement with the previously reported deficiency of alpha-galactosidase A activity in this Fabry lymphoid cell line [Salvayre, R. et al. (1981) Biochim. Biophys. Acta 659, 445-456] and demonstrates that alpha-galactosidase B does not hydrolyze GbOse3Cer in the living cell (in contrast to the situation in vitro).
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PMID:[Neutral glycosphingolipids of Fabry's disease lymphoblastoid lines established by Epstein-Barr virus transformation]. 298 12

A pilot trial of enzyme replacement using splenic and plasma forms of alpha-galactosidase A was undertaken in 2 brothers with Fabry disease, an X-linked glycosphingolipid storage disease. Partially purified preparations of alpha-galactosidase A from human spleen and plasma Cohn fraction IV-1 were prepared aseptically for in vivo administration. The disappearance of enzymatic activity from plasma, levels of circulating substrate, and potential immune response were evaluated following IV administration of 6 unentrapped doses (2,000 U/kg) of each enzyme form to the respective recipient during a 117-day period. Repeated injections were well tolerated. The circulating half-life of the splenic form was about 10 min whereas that for the plasma form was approximately 70 min. No immune response was detected by skin and immunodiffusion tests or by alterations in the maximal activity or clearance kinetics for either enzyme following successive administrations. After each dose of the splenic form, the concentration of the accumulated circulating substrate globotriaosylceramide, decreased maximally (approximately 50% of initial values) in 15 min and returned to preinfusion levels by 2-3 hr. In marked contrast, injection of the plasma form decreased the circulating substrate levels 50-70% by 2-6 hr; the concentrations of globotriaosylceramide gradually returned to preinfusion values by 36-72 hr. Two consecutive doses of the plasma form, administered on days 1 and 3, reduced the circulating substrate concentration to normal levels. Prior to the 6th enzyme administration, circulating substrate was stable-isotope labeled by the infusion of dideutero-glucose, and the effects of each enzyme form on circulating substrate degradation and reaccumulation were determined. The results of this study indicated that labeled (newly synthesized) substrate reaccumulated following injection of the splenic enzyme whereas both unlabeled (previously stored?) and labeled substrate reaccumulated in the circulation after administration of the plasma form. These studies demonstrated the differential disappearance kinetics of the splenic and plasma forms of alpha-galactosidase A, their differential effects on circulating substrate degradation and reaccumulation, as well as the lack of an immune response to repeated administrations of these homologous, unentrapped enzymes.
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PMID:Enzyme therapy XVII: metabolic and immunologic evaluation of alpha- galactosidase A replacement in Fabry disease. 625 19

We report renal lesions and functional alterations in a 32-year-old man with Fabry's disease (ceramidetrihexosidase deficiency). By light microscopy of a renal biopsy specimen, distinctive "foamy" cytoplasmic alterations were observed in renal glomerular, tubular, vascular, and interstitial cells. Histochemical analysis of vacuolated epithelial cells showed glycolipid- and phospholipid-like material. Ultrastructurally, dense osmiophilic as well as stacked and concentric laminated profiles were observed within these epithelial cells. In addition, glomerular endocapillary, parietal, and vascular epithelial cells contained opaque osmiophilic granular deposits with paracrystalline arrays. Renal function studies indicated a glomerular filtration rate of 86.1 mL/min/1.73 sq m, effective renal plasma flow of 415 mL/min/1.73 sq m, tubular reabsorption of glucose of 356 mg/min/100 glomerular filtration rate, and maximal urinary concentrating and diluting ability of 568 and 46 mOsm/kg, respectively. Serum ceramide hexosidase activity was 0.18 nmole/hr/mL (normal, 8 to 15). We conclude that renal dysfunction associated with Fabry's disease is associated mainly with accumulation of glycolipid and phospholipid compounds in the walls of blood vessels and distal nephrons.
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PMID:Clinicopathologic, enzymatic, and genetic features in a case of Fabry's disease. 676 61

The content of glycosphingolipids (GSL) was studied in the urinary sediments (24-hr specimens) from seven normal subjects, a patient with Fabry's disease, and five homozygotes with familial hypercholesterolemia (FH). Normal urinary sediments contained very small amounts of GalCer, GlcCer, GaOse(2)Cer, LacCer, GbOse(3)Cer, and GbOse(4)Cer. In Fabry urinary sediment, the levels (nmole glucose/24 hr) of GaOse(2)Cer and of GbOse(3)Cer were 389 and 550, respectively. In urinary sediments from the FH subjects, the mean contents (nmol glucose/mg protein per 24 hr) of GlcCer, GalCer, and LacCer were 2.7, 1.9, and 15.8 times higher, respectively, than in normals. The mean contents ( micro g/mg protein per 24 hr) of total cholesterol and phospholipid in the urinary sediment of FH (1.1 and 224, respectively) and normals (0.8 and 220) were similar. The mean contents of GlcCer, GalCer, and LacCer, expressed in terms of the cholesterol content of urinary sediment (nmol glucose/ micro g cholesterol per 24 hr), were increased 3.4-, 1.6-, and 5.4-fold, respectively, in the FH homozygotes. Of the five FH homozygotes, only one, who had undergone a portacaval shunt and was also receiving lipid-lowering therapy, had a normal value of LacCer. The other four FH homozygotes had levels of LacCer that were 3- to 55-fold higher (nmol glucose/mg protein per 24 hr) and 5.5- to 7.3-fold higher (nmol glucose/ micro g cholesterol per 24 hr) than the mean of the normals. One homozygote underwent plasma exchange therapy that reduced both the baseline urinary (nmol glucose/24 hr) and plasma (nmol/100 ml) LacCer levels from 86 to 7 and from 1491 to 852, respectively. Eleven days after plasma exchange, the urinary LacCer levels approached pre-exchange levels (59 nmol glucose/24 hr). The data indicate that there is an abnormality of GSL metabolism associated with familial hyper-cholesterolemia and that the urinary excretion of GSL can be modified by plasma exchange therapy.-Chatterjee, S., C. S. Sekerke, and P. O. Kwiterovich, Jr. Increased urinary excretion of glycosphingolipids in familial hypercholesterolemia.
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PMID:Increased urinary excretion of glycosphingolipids in familial hypercholesterolemia. 680 69

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

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.
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PMID:A historical perspective of the glycosphingolipids and sphingolipidoses. 1280 32

Fabry disease is an X-linked disorder associated with early onset stroke. We previously found a significantly elevated cerebral blood flow (CBF) in patients with Fabry disease. We set to determine whether elevated resting CBF in Fabry disease is primarily a cerebrovascular abnormality or is secondary to enhanced neuronal metabolism. The relationship of cerebral metabolism and blood flow to Fabry leukoencephalopathy was also investigated. We measured the global and regional cerebral metabolic rate of glucose using 18-fluoro-deoxyglucose (FDG) and PET in 16 patients with Fabry disease (7 patients with leukoaraiotic lesions and 9 without) and in 7 control subjects. MRI fluid attenuated inversion recovery (FLAIR) studies were also performed in the patient and control groups. All control subjects had normal MRI FLAIR studies with no high-signal deep white matter lesions (WML). Patients were partitioned into FLAIR lesion and non-FLAIR lesion groups. We found no evidence of cerebral glucose hypermetabolism in Fabry disease. On the contrary, significantly decreased regional cerebral glucose metabolism (rCMRGlu) was found particularly in the deep white matter in the Fabry non-lesion group and exacerbated in the lesion group. Lesion-susceptible regions were relatively hyperperfused in non-lesion patients compared to the control group. We conclude that the elevated rCBF and decreased white matter rCMRGlu indicates a dissociation between metabolism and blood flow suggesting chronic deep white matter metabolic insufficiency.
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PMID:White matter lesions in Fabry disease occur in 'prior' selectively hypometabolic and hyperperfused brain regions. 1469 56

Corneal clouding is uncommon in infants and children but when present in this age group, it is often associated with mucopolysaccharidoses or Fabry disease. This report describes the case of an 11-year-old male who demonstrated poor weight gain, short stature, segmental myoclonus, and learning problems from 5 years of age followed by general weakness and extremely poor balance. Corneal clouding was evident as a result of a blurred vision complaint at 9 years of age. Both urine metabolic screening for mucopolysaccharidoses and analysis of lysosomal enzymes displayed negative findings. Clinical conditions worsened, including ptosis, progressive weakness, and positive Gowers' sign. Oral glucose lactate stimulation test was positive, therefore a muscle biopsy was performed at 11 years of age. Light microscopy of muscle biopsy disclosed abundant ragged red fibers; electron microscopy revealed abnormal mitochondria in terms of tubular cristae, concentrated cristae, stacking cristae, and round granular patterns of inclusion bodies in the matrix. Thus mitochondrial disease was diagnosed. We conclude that mitochondrial disease should be added to the list of differential diagnosis of corneal clouding in children, especially in cases with normal urine metabolic screening for mucopolysaccharidoses or when assays of lysosomal enzymes appear normal.
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PMID:Corneal clouding: An infrequent ophthalmic manifestation of mitochondrial disease. 1676 25

An optical sensor for detection of glucose is implemented by incorporating a carbohydrate sensitive hydrogel as a Fabry-Perot cavity at the end of optical fiber for high sensitivity readout of the gel length. The glucose sensing functionality was achieved by incorporating boronic acid moieties into an acrylamide-based hydrogel. The interaction between glucose and boronic acid changes the driving forces for gel swelling thus inducing a glucose sensitive hydrogel swelling. The effects on the carbohydrate swelling response, with respect to sensitivity and selectivity, by incorporation of a cationic monomer, dimethyl-aminopropyl acrylamide, into the boronic acid functionalized responsive gels were determined. The linear gel swelling response in aqueous solutions at aqueous 2.5mM carbohydrates were determined to -1760nm/mM for glucose whereas mannose, sucrose, fructose and galactose displayed a response of about 10% of the glucose response for the hydrogels containing 10mol% dimethylaminopropyl acrylamide. This gel composition with 10mol% dimethylaminopropyl acrylamide is the most promising for detection of glucose at physiological pH and ionic strength. A mechanism where carbohydrate specific stabilisation of the boronic acid group and possible carbohydrate mediated additional crosslinking of the elastically active polymer chains is suggested.
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PMID:Glucose sensors based on a responsive gel incorporated as a Fabry-Perot cavity on a fiber-optic readout platform. 1906 67


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