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)

Apparent deficiency of alpha-galactosidase A was observed in a 51-year-old, clinically healthy male, with no clinical symptoms of Fabry disease, and without excess urinary excretion of ceramide trihexoside. The deficiency, which was similar to that found in Fabry disease patients, could be demonstrated using both synthetic and natural substrates. This pseudodeficiency was transmitted in his family by classical X-linked inheritance. His wife showed enzyme activity in the normal range, two daughters were heterozygotes for this mutation as demonstrated by hair root assay, and three sons showed normal alpha-galactosidase activity. Kinetic studies in cultured skin fibroblasts indicated a five-fold increase in the apparent Km and a greater heat stability of the residual alpha-galactosidase activity when compared to controls. These data indicate that the residual enzyme activity in this mutation behaves similarly to that observed in Fabry disease patients but does not cause any clinical abnormalities.
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PMID:Pseudodeficiency of alpha-galactosidase A. 627 39

The endocytosis of alpha-galactosidase A was studied in cultured fibroblasts from patients with Fabry disease. Alpha-galactosidase A was purified from human placenta by chromatography on concanavalin A-Sepharose, DEAE-cellulose, and N-epsilon-aminocaproyl-alpha-D-galactosylamine-Sepharose. Separation of the high-uptake form of the enzyme from the low-uptake form was accomplished by chromatography on ECTEOLA-cellulose. With the high-uptake form of the enzyme, the uptake was linear at low concentrations of enzyme and had a Kuptake of 0.01 U/ml of medium that corresponds to a Km of 5.0 x 10(-9) M. At high concentrations of enzyme, it became saturated. The high-uptake form could be converted to the low-uptake form by treatment with acid phosphatase. Mannose-6-P strongly inhibited the active uptake of the enzyme. Once taken up into the lysosomes of Fabry disease fibroblasts, alpha-galactosidase A activity was rapidly lost in the first 2 days of incubation at 37 degrees C, but was fairly stable for the next 6 days. The half-life of internalized alpha-galactosidase A activity was calculated to be 4 days. Crosslinking of the enzyme with hexamethylene diisocyanate did not increase the intracellular stability of alpha-galactosidase A activity.
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PMID:Endocytosis of lysosomal alpha-galactosidase A by cultured fibroblasts from patients with Fabry disease. 628 97

Single cells were sorted from cultured fibroblasts of five carriers of Fabry's disease using a cell sorter (FACS II). The alpha-galactosidase A activity in the single fibroblasts was assayed in nanoliter droplets with the help of quantitative microfluorimetric techniques. Two populations of fibroblasts were present in the carriers, one showing an alpha-galactosidase-A activity comparable to that of Fabry patients, and another with normal alpha-galactosidase-A activity. This provides evidence of X-inactivation at the alpha-galactosidase-A locus. Since X-inactivation occurs at random, a high number of single cells has to be assayed to increase the clinical reliability for carrier detection. The methodology as presented enables such an approach.
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PMID:Detection of Fabry's disease heterozygotes by enzyme analysis in single fibroblasts after cell sorting. 630 50

Cultured fibroblasts from a patient with Fabry's disease were treated with alpha-galactosidase A. The cells internalized the enzyme via a receptor-mediated transport system, resulting in the uptake of enzyme to 50% of the activity of normal cells. Following uptake of the enzyme and incubation for 9 days, a loss of electron-dense lamellar material within membrane-bound residual bodies was detected by electron microscopy. Morphometric analysis of electron micrographs showed that the percentage volume of cytoplasm occupied by electron-dense lamellar material in Fabry's disease fibroblasts decreased to near normal after treatment with enzyme. These results indicate that the ultrastructural abnormalities of Fabry's disease cells can be corrected by enzyme replacement, at least in cultured fibroblasts.
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PMID:Loss of electron-dense lamellar material from Fabry's disease fibroblasts after enzyme replacement. 631 65

The first part of this review deals with the new biochemical and genetical data concerning alpha-galactosidase and alpha-N-acetylgalactosaminidase. Molecular forms of these both enzymes can be classified into two groups following their physical, enzymatic and genetical properties: - the 3 forms of the alpha-galactosidase A group differ by the number of sialyl residues and their isoelectric point. All the forms of this group are heat-labile, hydrolyse only alpha-galactosides and proceed from the same alpha-GalA, X-linked gene. - alpha-galactosidase B is an alpha-N-acetylgalactosaminidase with broad substrate specificity, in vitro, is heat-stable and proceed from the alpha- GalB or alpha- NAGA gene of the chromosome 22. Structural and enzymatic data concerning these enzymes and their functions in the catabolism of glycosphingolipids and glycoproteins are reviewed. The second part deals with the pathophysiology of Fabry disease. The more prominent genetical and biochemical data and their diagnostic uses are reported: isozymic determination, cell cloning, quantitative determination of accumulated glycolipids. At last, were pointed the new developments of the research on Fabry disease: cultured cells as experimental model (fibroblasts, lymphoid cell lines) and therapeutic attempts.
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PMID:[Alpha-galactosidases and alpha-N-acetylgalactosaminidase. Biochemical bases of Fabry's disease]. 632 22

Percutaneous renal biopsy was performed in a surface coal miner with radiographic and histopathologic pulmonary changes consistent with acute silicolipoproteinosis who developed proteinuria and hematuria. Electron microscopic evaluation of the renal tissue specimen revealed a diffusely thickened glomerular basement membrane, foot process effacement, and dense lamellar inclusions in swollen glomerular epithelial cells, similar to those seen in Fabry's disease. However, normal levels of plasma alpha-galactosidase A, normal urinary sediment glycosphingolipids and the absence of the clinical characteristics of Fabry's disease excluded this diagnosis. This case illustrates that electron-dense lamellar inclusions, similar to those seen in Fabry's disease, may be seen in other entities such as nephropathy associated with silicosis.
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PMID:Silicon nephropathy mimicking Fabry's disease. 641 69

Although the accumulation of neutral glycosphingolipid (GSL), principally globotriaosylceramide ( GbOse3Cer ), in the kidney of patients with Fabry's disease is well documented, little is known about the type and quantity of lipid present in the renal tubular cells shed in the urine. Using a variety of cytologic technics, the authors examined exfoliated cells found in the urine specimens of patients hemizygous and heterozygous for alpha-galactosidase A deficiency. Renal tubular cells contained periodic acid- Shiff positive material that could be identified easily by Papanicolaou stain. A fluorescein-labeled antibody specific for GbOse3Cer localized this lipid to the cytoplasm. Electron microscopy showed numerous electron-dense multilamellar membranous inclusions within phagolysosomes and electronlucent material within lysosomes of tubular cells. Based on immunofluorescence, heterozygote individuals had similar distribution but less quantity of cytoplasmic GSL. The authors conclude that in Fabry's disease GSL accumulates probably in lysosomes of renal tubular cells. These cells are exfoliated and can be identified specifically in voided urine specimens. Examination of renal tubular cells in urine using the fluorescein antibody technic described here affords a noninvasive means of diagnosing and following the effect of therapy in patients with Fabry's disease.
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PMID:Immunohistochemical localization of glycosphingolipid in urinary renal tubular cells in Fabry's disease. 643 64

Fabry's disease results from deficient activity of the enzyme alpha-galactosidase A. Cardiac abnormalities result from glycosphingolipid deposition in the myocardium, valvular tissue, and vessel walls. A noninvasive method to examine these abnormalities would be useful in the evaluation of patients. We examined the echocardiograms of 32 patients, 25 hemizygous and seven heterozygous, for Fabry's disease. The aortic root diameter was measured in each hemizygote. In nine patients under 26 years it was 33.2 +/- 1.2 mm. and in two it was dilated. In 16 patients over 26 years it was 38.8 +/- 1.2 mm. (p < 0.01), and in 12 it was dilated. The left ventricular posterior wall was measured in the echocardiogram of 21 normotensive hemizygotes. The difference in thickness between nine patients under 26 years (9.6 +/- 1.3 mm.) and 12 patients over 26 years (12.4 +/- .07 mm.) was not statistically significant. Only two of the nine younger patients had left ventricular wall thickness greater than normal compared to eight of the 12 older patients. The mean left ventricular shortening fraction of 22 hemizygous patients was normal. One hemizygote had echocardiographic evidence of mitral valve prolapse. Four of the seven heterozygotes had normal echocardiograms. Among the other three, one had increased left ventricular wall thickness, a second had disproportionate ventricular septal thickness, and a third had both abnormalities. The echocardiographic aortic root size was normal in each heterozygote. Abnormal echocardiographic findings were more common in older hemizygous patients, a distribution similar to that of the age of onset of cardiac dysfunction. Increased left ventricular wall thickness probably reflects glycosphingolipid deposition in the myocardium. Dilatation of the aortic root may result from degenerative changes of the aortic media. Abnormalities of mitral valve echoes were uncommon.
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PMID:The M-mode echocardiogram in Fabry's disease. 677 85

Fabry disease, an X-linked inborn error of glycosphingolipid catabolism, results from mutations in the alpha-galactosidase A (alpha-Gal A) gene at Xq22.1. To determine the nature and frequency of the molecular lesions causing the classical and milder-variant Fabry phenotypes, and for precise carrier detection in Fabry families, the alpha-Gal A transcripts or genomic sequences from unrelated Fabry hemizygotes were analyzed. In patients with the classical phenotype, 18 new mutations were identified: N34S, C56G, W162R, R227Q, R227X, D264V, D266V, S297F, D313Y, G328A, W340X, E398X, IVS2+2, IVS5 delta-2,3, 773 delta 2, 954 delta 5, 1016 delta 11, and 1123 delta 53. Unrelated asymptomatic or mildly affected patients with symptoms confined to the heart had a missense mutation, N215S, that expressed residual enzymatic activity. Related, moderately affected patients with late-onset cardiac and pulmonary manifestations had a small deletion, 1208 delta 3, that predicted the in-frame deletion of arginine 404 near the terminus of the 429 residue enzyme polypeptide. In addition, five small gene rearrangements involving exonic sequences were identified in unrelated classically affected patients. Two small deletions and one small duplication had short direct repeats at their respective breakpoint junctions and presumably resulted from slipped mispairing. A deletion occurred at a potential polymerase alpha arrest site, while the breakpoints of another deletion occurred at an inverted tetranucleotide repeat. Screening of unrelated Fabry patients with allele-specific oligonucleotides for seven mutations revealed that these were private, with the notable exception of N215S, R227Q, and R227X, which were each found in several unrelated families from different ethnic backgrounds. The CpG dinucleotide at codon 227 was the most common site of mutation, having been altered in 5% of the 148 unrelated Fabry alleles. These studies revealed that most alpha-Gal A lesions were private, that codon 227 was a mutational hot spot, and that certain mutations predicted a milder disease phenotype.
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PMID:Nature and frequency of mutations in the alpha-galactosidase A gene that cause Fabry disease. 750 5

Fabry disease, an X-linked inborn error of glycosphingolipid catabolism, results from mutations in the alpha-galactosidase A gene at Xq22.1. To determine the nature and frequency of the molecular lesions causing the classical and milder variant Fabry phenotypes, and for precise carrier detection in Fabry families, the alpha-galactosidase A coding and flanking intronic sequences from 23 unrelated Fabry hemizygotes were analyzed. In patients with the classic phenotype, 16 new missense and nonsense mutations and four small exonic gene rearrangements were identified: C52S, C56F, E59K, L89R, R100K, R112H, L131P, A143P, G144V, C172Y, D244N, N272K, A288D, W81X, Q99X, Q157X, R301X, 25del1, 333del18, 358del6, and 1020del1. The R112H mutation at a CpG dinucleotide resulted in residual activity and a mild variant phenotype while the R112C lesion caused the classic disease manifestations, defining a genotype/phenotype correlation for sense and antisense mutations at the same CpG dinucleotide. In addition, two complex rearrangements, each involving two mutational events, occurred in classic hemizygotes. Both rearrangements resulted in missense mutations that did not change the reading frame. Notably, three of the deletions occurred within 11 codons in exon 2, thereby defining a 'hot-spot' for deletions. These studies revealed that most mutations in the alpha-galactosidase A gene causing Fabry disease were private, that codons 111-122 defined a deletion hot-spot, and that different substitutions of the same codon resulted in markedly different disease phenotypes.
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PMID:Fabry disease: twenty-three mutations including sense and antisense CpG alterations and identification of a deletional hot-spot in the alpha-galactosidase A gene. 753 40


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