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)

Fabry disease is an X-linked inborn error of metabolism resulting from the deficient activity of the lysosomal hydrolase, alpha-galactosidase A (alpha-Gal A; alpha-D-galactoside galactohydrolase, EC 3.2.1.22). To investigate the structure, organization, and expression of alpha-Gal A, as well as the nature of mutations in Fabry disease, a clone encoding human alpha-Gal A was isolated from a lambda gt11 human liver cDNA expression library. To facilitate screening, an improved affinity purification procedure was used to obtain sufficient homogeneous enzyme for production of monospecific antibodies and for amino-terminal and peptide microsequencing. On the basis of an amino-terminal sequence of 24 residues, two sets of oligonucleotide mixtures were synthesized corresponding to adjacent, but not overlapping, amino acid sequences. In addition, an oligonucleotide mixture was synthesized based on a sequence derived from an alpha-Gal A internal tryptic peptide isolated by reversed-phase HPLC. Four positive clones were initially identified by antibody screening of 1.4 X 10(7) plaques. Of these, only one clone (designated lambda AG18) demonstrated both antibody binding specificity by competition studies using homogeneous enzyme and specific hybridization to synthetic oligonucleotide mixtures corresponding to amino-terminal and internal amino acid sequences. Nucleotide sequencing of the 5' end of the 1250-base-pair EcoRI insert of clone lambda AG18 revealed an exact correspondence between the predicted and known amino-terminal amino acid sequence. The insert of clone lambda AG18 appears to contain the full-length coding region of the processed, enzymatically active alpha-Gal A, as well as sequences coding for five amino acids of the amino-terminal propeptide, which is posttranslationally cleaved during enzyme maturation.
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PMID:Fabry disease: isolation of a cDNA clone encoding human alpha-galactosidase A. 299 89

An endothelial cell line has been established from the umbilical vein obtained after abortion of a male fetus suffering from Fabry disease. This X-linked inborn error of glycosphingolipid catabolism results from deficiency of the lysosomal hydrolase alpha-galactosidase A. The clinical manifestations of the disease are mainly caused by glycosphingolipid depositions in the endothelium of all vessels. The hemizygous cell line and eight endothelial cell lines originating from the umbilical cords of normal newborns were grown for more than 10 passages. They had a short generation time that allowed us to get sufficient cells for qualitative and quantitative investigations of alpha-galactosidase. The enzyme in normal endothelial cells had a similar thermostability and isoelectric focusing pattern as that in fibroblasts, but the activity was essentially higher in endothelial cells. The hemizygous endothelial cells were deficient in alpha-galactosidase A. It is concluded that endothelial cell lines are an important alternative to fibroblasts for in vitro studies of the lysosomal storage diseases.
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PMID:Lysosomal alpha-galactosidase in endothelial cell cultures established from a Fabry hemizygous and normal umbilical veins. 300 54

Two lysosomal storage diseases, cystinosis and Fabry disease, were diagnosed clinically in different members of a single sibship. The possibility that the affected sister and brother might have related disorders with disparate manifestations was pursued. The four principal family members were tested for heterozygote status with respect to serum and leukocyte alpha-galactosidase A activity, urinary trihexosylceramide excretion, and the capacity to engage in cystine counter-transport across leukocyte lysosome membranes. Results were consistent with classical autosomal recessive inheritance in the case of cystinosis and X-linked inheritance for Fabry disease, confirming that this family represents an example of two rare disorders occurring in the same sibship.
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PMID:Biochemical phenotyping of a single sibship with both cystinosis and Fabry disease. 302 48

The synthesis and processing of the human lysosomal enzyme alpha-galactosidase A was examined in normal and Fabry fibroblasts. In normal cells, alpha-galactosidase A was synthesized as an Mr = 50,500 precursor, which contained phosphate groups in oligosaccharide chains cleavable by endoglucosaminidase H. The precursor was processed via ill-defined intermediates to a mature Mr 46,000 form. Processing was complete within 3-7 days after synthesis. In the presence of NH4Cl and in I-cell fibroblasts, the majority of newly synthesized alpha-galactosidase A was secreted as an Mr = 52,000 form. For comparison, the processing and stability of alpha-galactosidase A were examined in fibroblasts from five unrelated patients with Fabry disease, which is caused by deficient alpha-galactosidase A activity. In one cell line, synthesis of immunologically cross-reacting polypeptides was not detectable. In another, the synthesis, processing, and stability of alpha-galactosidase A was indistinguishable from that in normal fibroblasts. In a third Fabry cell line, the mutation retarded the maturation of alpha-galactosidase A. Finally, in two cell lines, alpha-galactosidase A polypeptides were synthesized that were rapidly degraded following delivery to lysosomes. These results clearly indicate that Fabry disease comprises a heterogeneous group of mutations affecting synthesis, processing, and stability of alpha-galactosidase A.
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PMID:Synthesis and processing of alpha-galactosidase A in human fibroblasts. Evidence for different mutations in Fabry disease. 302 62

Fabry's disease is an X-linked recessive genetic deficiency of the enzyme alpha-galactosidase A, which leads to the pathologic deposition of neutral glycosphingolipids in lysosomes of the vascular endothelium of the heart, brain and kidney. The disease is progressive in hemizygous male patients, with increasing involvement of the major organs leading to death. Because cardiac involvement is a constant feature, echocardiograms were performed on 35 patients with Fabry's disease, 23 hemizygotes (aged 28.6 +/- 14 years) and 12 heterozygotes (aged 31.6 +/- 6 years), to determine whether cardiac involvement could be detected noninvasively. The results demonstrated that hemizygous male patients had a greater aortic root diameter, thicker interventricular septum and greater ventricular mass than did heterozygous female patients. Left ventricular mass per square meter of body surface area correlated well with clinical disease severity (r = 0.68, p less than 0.05), suggesting progressive glycosphingolipid deposition. Older heterozygotes (greater than 25 years old) had more severe evidence of cardiac disease than did younger male patients. Although mitral valve prolapse was identified in 12 (54%) of 23 male hemizygotes and in 7 (58%) of 12 female heterozygotes its presence did not correlate with clinical disease severity or other echocardiographic variables. Therefore, echocardiographic evidence of Fabry's disease appears to correlate with age-related disease severity and may be a useful noninvasive marker to follow disease progression and possible regression when appropriate therapy becomes available.
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PMID:Echocardiographic abnormalities and disease severity in Fabry's disease. 308 58

A number of metabolic disorders are characterized by generalized angiokeratomas and neurologic dysfunction. Fabry's disease (angiokeratoma corporis diffusum universale) is an X-linked recessive disorder caused by a deficiency of alpha-galactosidase A. Fucosidosis is an autosomal recessive disorder caused by a lack of fucosidase. Sialidosis with deficiencies of neuraminidase and beta-galactosidase is the third important association.
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PMID:Metabolic disorders characterized by angiokeratomas and neurologic dysfunction. 311 2

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

A simple and sensitive fluorometric method has been described for the differential determination of the activity of lysosomal alpha-galactosidase A and alpha-galactosidase B. The procedure employs 4-methylumbelliferyl-alpha-D-galactopyranoside as substrate and N-acetylgalactosamine as an inhibitor of alpha-galactosidase B, but not of alpha-galactosidase A to differentiate the two activities. This method was shown to be applicable in the differentiation of the two enzyme activities in human tissues and in the diagnosis of the heterozygous and hemizygous genotypes for Fabry's disease in cultured skin fibroblasts.
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PMID:Differential assay for lysosomal alpha-galactosidases in human tissues and its application to Fabry's disease. 626 21

The diagnosis of Fabry's disease (angiokeratoma corporis diffusum universale) is usually confirmed by demonstrating typical cytoplasmic inclusions in a renal biopsy specimen, in conjunction with typical skin and ocular lesions and deficient alpha-galactosidase A activity in a male patient. Affected men are usually associated with carrier female family members. Electron microscopy of the urine sediment from two patients with Fabry's disease demonstrated typical laminated cytoplasmic inclusions within exfoliated epithelial cells. This method may be useful in the diagnosis of Fabry's disease and in screening of kin for hemizygotes and female carriers.
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PMID:Cytoplasmic inclusions of Fabry's disease. Ultrastructural demonstration of their presence in urine sediment. 626 85

The identification of female carriers of Fabry's disease is important for genetic counselling since prenatal diagnosis of affected fetuses is possible. The activities of either total alpha-galactosidase or alpha-galactosidase A in cultured fibroblasts were similar in Fabry carriers and controls and cannot therefore be used for carrier detection. Better discrimination between carriers and controls was found when total alpha-galactosidase activity was expressed as a ratio to beta-galactosidase activity, but overlap still occurred. However, there was complete discrimination between the ratio of alpha-galactosidase A to beta-galactosidase in cultured fibroblasts from five carriers of Fabry's disease and either 11 controls, seven hemizygote affected males or two of their female relatives.
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PMID:Fibroblast alpha-galactosidase A activity for identification of Fabry's disease heterozygotes. 627 49


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