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)

We report a rare heterozygous status for Fabry's gene with severe kidney involvement and normal alpha-galactosidase A activity, together with the intrafamilial variations in the clinical expression of the disease. The random X inactivation hypothesis seems to explain such a variable expression of the alpha-galactosidase gene in our cases.
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PMID:[Fabry's disease: kidney insufficiency in heterozygous patient]. 256 53

Originally described as a dermatologic curiosity by Fabry in 1898 and independently by Anderson in the same year, Fabry disease is now recognized as an inborn error of glycosphingolipid metabolism resulting from the defective activity of the lysosomal enzyme, alpha-galactosidase A (see Desnick and Sweeley for a comprehensive review). The enzymatic defect, transmitted by an X-linked recessive gene, leads to the accumulation of neutral glycosphingolipids with terminal alpha-galactosyl residues in the plasma and in the lysosomes of endothelial, perithelial, and smooth muscle cells of the cardiovascular-renal system and, to a lesser extent, in reticuloendothelial, myocardial, and connective tissue cells. Epithelial cells in the kidney, cornea, and other tissues contain the lysosomal depositions, as do the ganglia and perineural cells of the autonomic nervous system. The major accumulated substrate is globotriaosylceramide [galactosyl-(alpha 1----4)-galactosyl-(beta 1----4)-glucosyl-(beta 1----1')-ceramide]; another substrate, galabiosylceramide [galactosyl-(alpha 1----4)-galactosyl-(beta 1----1')-ceramide] is deposited primarily in renal lysosomes. The clinical manifestations of Fabry disease are the sequelae of the anatomical and physiologic alterations produced by progressive glycosphingolipid deposition. Clinical onset of the disease in hemizygous males usually occurs during childhood or adolescence, with periodic crises of severe pain in the extremities (acroparesthesias), the appearance of the vascular cutaneous lesions (angiokeratoma), hypohidrosis, and the characteristic corneal dystrophy. With increasing age, the major morbid symptoms of the disease result from the progressive infiltration of glycosphingolipid in the cardiovascular-renal system. Death usually occurs from renal, cardiac, or cerebral complications of the vascular disease. Prior to the availability of treatment by renal transplantation or dialysis, the average age at death for affected males was about 40 years. Heterozygous females, who may exhibit the disease in an attenuated form, are most likely to have only corneal opacities. Previously, the diagnosis of affected hemizygous males and heterozygous females was based on clinical findings and the levels of alpha-galactosidase A activity in easily obtained sources, e.g., plasma and isolated lymphocytes or granulocytes. Because the gene encoding alpha-galactosidase A undergoes random X-inactivation, the expressed level of enzymatic activity in females heterozygous for the disease gene may vary significantly, thereby making accurate carrier detection difficult.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Fabry disease: molecular genetics of the inherited nephropathy. 256 47

Fabry disease, an X-linked inborn error of glycosphingolipid catabolism, results from the deficient activity of the lysosomal hydrolase, alpha-galactosidase A. Previously, the diagnosis of affected hemizygous males and heterozygous females was based on clinical findings and the levels of alpha-galactosidase A activity in easily obtained sources such as plasma and isolated lymphocytes or granulocytes. Since the gene encoding alpha-galactosidase A undergoes random X-inactivation, the expressed level of enzymatic activity in females heterozygous for the disease gene may vary significantly, thereby making accurate carrier detection difficult. The recent cloning and characterization of the full-length cDNA encoding human alpha-galactosidase A now permits the accurate diagnosis of affected hemizygotes and heterozygous females. In families with gene rearrangements or an altered restriction endonuclease cleavage site, precise diagnosis can be accomplished by Southern hybridization analysis using the alpha-galactosidase A cDNA as probe. In families with normal restriction patterns, two restriction fragment length polymorphisms have been identified in and adjacent to the alpha-galactosidase A gene which also allow precise hemizygote and heterozygote diagnosis. In addition, the recent identification of polymorphic, random DNA sequences (DXS17 and DXS87) located near the alpha-galactosidase A locus permits molecular diagnosis in informative families. Further evaluation of DXS17, DXS87 and other closely linked random DNA probes is required in order to determine their informativeness, proximity to the alpha-galactosidase A locus and, hence, accuracy for molecular diagnosis.
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PMID:Fabry disease: molecular diagnosis of hemizygotes and heterozygotes. 283 Oct 42

Human alpha-galactosidase A (alpha-D-galactoside galactohydrolase; EC 3.2.1.22) is a lysosomal hydrolase encoded by a gene localized to the chromosomal region Xq22. The deficient activity of this enzyme results in Fabry disease, an X chromosome-linked recessive disorder that leads to premature death in affected males. For studies of the structure and function of alpha-galactosidase A and for characterization of the genetic lesions in families with Fabry disease, the full-length cDNA was isolated, sequenced, and used to screen human genomic libraries. The 1393-base-pair full-length cDNA had a 60-nucleotide 5' untranslated region and encoded a precursor peptide of 429 amino acids including a signal peptide of 31 residues. Three overlapping lambda clones spanning 32 kilobases were identified that contained the entire approximately equal to 12-kilobase chromosomal gene as well as approximately equal to 9 and approximately equal to 11 kilobases of 5' and 3' flanking sequence, respectively. The gene had seven exons. The genomic exonic and full-length cDNA sequences were identical. All intron-exon splice junctions conformed to the GT/AT consensus sequence. The 5' flanking region of this lysosomal housekeeping gene contained Sp1 and CCAAT box promoter elements as well as sequences corresponding to the activator protein 1 (AP1), octanucleotide ("OCTA"), and "core" enhancer elements. There was an upstream "HTF" island (Hpa II tiny fragments) followed by four direct repeats of the "chorion box" enhancer. The unique lack of a 3' untranslated sequence in the alpha-galactosidase A cDNA was confirmed by sequencing additional cDNA clones and the genomic 3' region.
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PMID:Structural organization of the human alpha-galactosidase A gene: further evidence for the absence of a 3' untranslated region. 283 63

Endothelial cells are of particular interest for therapeutic strategies in Fabry's disease, because the accumulation of glycosphingolipids in the vascular endothelium as a result of alpha-galactosidase A (alpha-galA) deficiency is responsible for the major clinical manifestations of the disease. Electron microscopical observations of cultured endothelial cells obtained from the umbilical vein of a hemizygous Fabry fetus showed that the glycosphingolipids are deposited as lamellar material in the lysosomes, as has been found previously for cultured fibroblasts and many different tissues. Mannose 6-phosphate (man 6-P)-receptor mediated and Concanavalin A (ConA)-mediated uptake of purified alpha-galA was attempted in the endothelial cells as well as in cultured fibroblasts from the same fetus. Our results on high-uptake alpha-galA indicate that the endothelial cells do not internalize alpha-galA via the man 6-P receptor. Immunofluorescence studies after addition of the receptor antibody to the cells support the theory that they have no or very few man 6-P receptors on the surface. Morphological studies did not show lysosomal changes which could suggest that the enzyme is taken up into the endothelial cells; however, we found reproducible modifications of the lysosomes in Fabry fibroblasts after incubation with high-uptake alpha-galA. Cell-associated alpha-galA activity was found in both cell types, when the enzyme was added to cells preincubated with ConA; but the lectin treatment by itself induced considerable ultrastructural changes in the cytoplasm, which obscured a possible effect by the enzyme.
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PMID:Enzyme replacement in Fabry endothelial cells and fibroblasts: uptake experiments and electron microscopical studies. 283 53

Anderson Fabry disease is an X-linked lysosomal storage disorder caused by alpha-galactosidase A deficiency. Hemizygous males and some heterozygous females develop renal failure and cardiovascular complications in early adult life. We have investigated six large UK families to assess the possible linkage of five polymorphic DNA probes to the Anderson Fabry locus, previously localised to Xq21-24. No recombination was found between Anderson Fabry disease and DXS87, DXS88 and DXS17, which gave lodmax = 6.4, 6.4 and 5.8 respectively at theta = 0.10, (upper confidence limit 0.10). DXS3 gave lodmax 2.9 at theta = 0.10 (upper confidence limit 0.25). DXYS1 was excluded from linkage. The best fit map (DXYS1/DXS3) theta = 0.192 (DXS17/DXS87/DXS88/Anderson Fabry locus) provided no information about the order of loci in parentheses due to the absence of recombinants. The close linkage of DXS17, DXS87 and DXS88, together with alpha-galactosidase A estimation, can be used for antenatal diagnosis and carrier detection until the application of a gene specific probe has been evaluated.
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PMID:Anderson Fabry disease, a close linkage with highly polymorphic DNA markers DXS17, DXS87 and DXS88. 289 May 70

We have isolated and characterized a human genomic clone for a lysosomal enzyme gene. The start point of transcription was identified using primer extension of poly(A)+ mRNA. This genomic clone is specific for human alpha-galactosidase A, and it includes sequences for the promoter, complete signal peptide, first exon, and part of the first intron. Direct and inverted repeat elements of 10, 11, 16, 19, and 22 nucleotides (nt) flank the promoter site. A (GA)n repeat element of approx. 60 nt with strong homology to similar elements identified in several species is located upstream from the promoter. A GGGCGG site specific for DNA-binding protein Sp1 is located near a CAAT box, and the CCGCCC inverted repeat of the Sp1 binding sequence is located by the TATA box. The sequence immediately flanking the ATG start codon of the human alpha-galactosidase A is highly homologous to sequences flanking the ATG start codons of the other human lysosomal hydrolases for which sequence information is available (beta-glucocerebrosidase, cathepsin B, cathepsin D, and beta-hexosaminidase alpha chain), but not for any of the other 133 human signal peptides examined. Our analysis also reveals that conversion of the propeptide to the mature enzyme involves cleavage of a C-terminal rather than an N-terminal fragment. This information about the normal alpha-galactosidase A gene will be useful for comparison to data obtained from patients with Fabry disease, who are characterized by a deficiency of this enzyme. This is the first genomic clone described to date for any lysosomal enzyme, and it establishes a reference for future analyses of the molecular events that mediate the expression of this important class of enzymes.
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PMID:A genomic clone containing the promoter for the gene encoding the human lysosomal enzyme, alpha-galactosidase A. 289 62

Anderson-Fabry disease is an X-linked lysosomal storage disorder due to alpha-galactosidase A deficiency. In affected males there is a high mortality in early adult life due to renal failure and cardiovascular complications. We describe our preliminary results from genetic linkage studies in five families using two polymorphic DNA probes, DXS17 and DXYS1, mapping to an area on the long arm of the X chromosome between Xq13-22. DXS17 identified a Taql polymorphism closely linked to the disease locus in three families (lodmax Z = 4.23. at a recombination fraction decreases theta = 0.0). Restriction fragment length polymorphisms detected by DXYS1 were not linked.
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PMID:Anderson-Fabry disease--family linkage studies using two polymorphic X-linked DNA probes. 290 72

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

Fabry's disease (angiokeratoma corporis diffusum) is an X-linked recessive inherited metabolic defect due to the lack of the enzyme alpha-galactosidase A. We reviewed the Argentine literature on the subject, the main features of the disease and its differential diagnosis. Two patients aged ten and fifteen are described showing the characteristic clinical picture of the disease since ages four and nine respectively. Skin and conjunctival ultrastructural studies showed intracytoplasmatic granules with a lamellar appearance in the endothelial cells, pericytes and fibroblasts. Plasma levels of alpha-galactosidase activity were sharply decreased in the two patients studied and partially decreased in their heterozygous mothers.
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PMID:[Angiokeratoma corporis diffusum (Fabry's disease). Update. Apropos of 2 cases]. 299 36


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