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)

The first patient reported was a 33 years old male with clinical manifestations of Fabry's disease. The diagnosis was confirmed by ophthalmologic, histological and enzymatic studies. Because of inefficacity of treatment with plasma transfusions and of symptomatic therapies, a transplant of cells with normal enzymatic activities was envisioned. In this patient without renal failure, a renal transplant was not justified and a transplant of fetal liver cells was decided. The improvement of extra-renal manifestations of the disease with this new treatment was comparable to that obtained with kidney transplantation. In particular, objective and subjective clinical symptoms were significantly improved: sweating appeared became normal, cutaneous lesions appeared slightly decreased and pains disappeared. This improvement was still persistent 3 years after the fetal liver transplant, the viability of which was initially followed using dosages of circulating alphafoetoprotein. The second case-report is comparable. Fabry's disease was diagnosed in a 26 years old male on the clinical manifestations, the histological lesions and the enzyme deficiency. After failure of one plasma transfusion, the patient received a fetal liver transplant. It is still too early to evaluate the efficacy of the transplant in this second case, especially as the patient had normal sweating and relatively few pains except at the cold season. The mechanism which may be held responsible for possible improvement in our patients, as in recipients of a kidney transplant, is not completely elucidated. The cells, rather than steroids or azathioprine, seemed to support the efficacy. Was the enzyme activity exerted in situ? Was there a "colonization" by lysosomial enzymes? From the results observed after several years will derive the significance of this therapeutic approach in Fabry's disease, more generally, in many diseases associated with a genetic enzyme deficiency.
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PMID:[Fabry's disease: two patients improved by fetal liver cells (author's transl)]. 11 74

Two clones (out of a total of 181 clones tested) derived from the human lymphoblastoid (lymphoid) line F137 after mutagen treatment were found to be deficient in a lysosomal acid hydrolase. The clone N32 derived from EMS-treated F137 is deficient in N-acetyl hexosaminidase A and B but contains normal levels of N-acetyl hexosaminidase C and low levels of an enzyme resembling N-acetyl hexosaminidase S. Thus the enzyme deficiency in this clone appears to resemble the so-called Sandhoff variant of Tay-Sachs disease, a disease inherited as an autosomal recessive condition. The clone G3 derived from MNNG treated F137 is deficient in alpha-galactosidase A. This clone resembles the situation in X-linked Fabry's disease. Karyotype analysis of the clones failed to reveal any chromosome rearrangement or losses of chromosomal material that might have accounted for the mutations and it is suggested that a single point mutation might in each case account for the loss of enzyme activity. No storage of the natural substrates of the two enzymes could be demonstrated in the clones.
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PMID:The deficiency of a lysosomal acid hydrolase in two clones derived from the human lymphoblastoid line F137 after mutagen treatment. 20 Jan 67

We report a new assay for the detection of individuals heterozygous and homozygous for Gaucher's disease which requires relatively small samples of whole blood (0.3 ml), and which determines 4-methylumbelliferyl-beta-D-glucopyranoside:beta-glucosidase activity under conditions optimal for the determination of leukocyte glucocerebroside:beta-glucocereborsidase activity. The procedure involves the preparation of a leukocyte pellet from 50 mul of whole blood by hypotonic lysis of erythrocytes, followed by assay of beta-glucosidase activity at pH 5.5 in the presence of sodium taurocholate (0.6 g/100 ml). The methods described may also prove to be useful for the diagnosis of other diseases of enzyme deficiency which use fluorogenic substrates and leukocytes as a source of enzyme, such as Fabry's disease, Tay-Sachs disease, and generalized gangliosidosis.
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PMID:A microassay for Gaucher's disease. 80 4

The light and electron microscopic findings in the heart of a patient with Fabry's disease are described. The study revealed that all cardiac tissues, including the conducting tissues and the valves, were involved. The latter finding was of particular interest since the patient was known to have mitral insufficiency. The findings of diffuse ballooning of the mitral valve with localized "overshoot" and massive glycolipid storage in the valve substance suggest that the abnormal storage process was itself responsible for the valvular insufficiency. The widespread involvement of the myocardium and conducting tissues is consistent with the elelctrocardiographic changes indicating infarction, although myocardial necrosis was not observed. The findings in this case suggest that the cardiac manifestations in Fabry's disease can be either primary, that is, directly related to the enzyme deficiency, or secondary, that is, evolving with time as a consequence of the disease.
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PMID:Cardiac manifestations of Fabry's disease. Report of a case with mitral insufficiency and electrocardiographic evidence of myocardial infarction. 81 52

The inherited lysosomal storage diseases are a distinct group of inborn errors of metabolism characterised by deficiencies in specific lysosomal enzymes. As many as 40 such disorders have now been described in man. We have measured the activities of up to 16 lysosomal acid hydrolases in plasma and/or extracts of leucocytes and cultured skin fibroblasts from 198 patients referred from throughout Ireland. These 16 assays allowed the biochemical diagnosis of 20 lysosomal storage diseases. Activities were compared with reference ranges to determine homozygotes and heterozygotes. Of the 44 patients with positive results, 15 were diagnosed as being homozygous for a specific lysosomal enzyme deficiency, 4 were identified as having multiple enzyme deficiencies (mucolipidosis Type II/I-cell disease) and 25 had heterozygote (carrier) enzyme levels. Of the latter, 24 were either parents (obligate heterozygotes) or siblings of homozygotes and one was a heterozygote for the X-linked recessively inherited Fabry's disease.
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PMID:The biochemical diagnosis of lysosomal storage diseases--a review of five years experience. 228 77

Fabry's disease is one of the sphingolipidoses which results from the enzyme deficiency, alpha-galactosidase-A. It is a rare, hereditary, multiorgan disorder affecting the eye, skin, kidney, gastrointestinal system, heart, reticuloendothelial system, and central nervous system. Because all affected males and 90% of affected females exhibit ocular abnormalities, optometrists may be the first health care practitioners to identify these individuals.
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PMID:Fabry's disease (angiokeratoma corporis diffusum universale): ocular and associated findings. 641 87

Two cases of angiokeratoma corporis diffusum with mental retardation and some features of a mucopolysaccharidosis have been investigated biochemically, histopathologically, and by electron microscopy. It is submitted, on this evidence, that they are examples of a hitherto undescribed form of lysosomal enzyme deficiency disease.
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PMID:Angiokeratoma corporis diffusum with features of a mucopolysaccharidosis. 676 48

Fabry disease is a disorder of glycosphingolipid metabolism caused by deficiency of lysosomal alpha-galactosidase A (alpha-Gal A), resulting in renal failure along with premature myocardial infarction and strokes. No effective treatment of this disorder is available at present. Studies of residual activities of mutant enzymes in many Fabry patients showed that some of them had kinetic properties similar to those for normal alpha-Gal A, but were significantly less stable, especially in conditions of neutral pH (refs. 3-5). The biosynthetic processing was delayed in cultured fibroblasts of a Fabry patient, and the mutant protein formed an aggregate in endoplasmic reticulum, indicating that the enzyme deficiency in some mutants was mainly caused by abortive exit from the endoplasmic reticulum, leading to excessive degradation of the enzyme. We report here that 1-deoxy-galactonojirimycin (DGJ), a potent competitive inhibitor of alpha-Gal A, effectively enhanced alpha-Gal A activity in Fabry lymphoblasts, when administrated at concentrations lower than that usually required for intracellular inhibition of the enzyme. DGJ seemed to accelerate transport and maturation of the mutant enzyme. Oral administration of DGJ to transgenic mice overexpressing a mutant alpha-Gal A substantially elevated the enzyme activity in some organs. We propose a new molecular therapeutic strategy for genetic metabolic diseases of administering competitive inhibitors as 'chemical chaperons' at sub-inhibitory intracellular concentrations.
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PMID:Accelerated transport and maturation of lysosomal alpha-galactosidase A in Fabry lymphoblasts by an enzyme inhibitor. 988 49

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

Alpha-N-acetylgalactosaminidase (alpha-NAGA) deficiency with angiokeratoma corporis diffusum (AKCD) is one of the lysosomal storage diseases. GalNAc(alpha))1-O-Ser/Thr (Tn) is theoretically deposited in lysosomes, but substances with attached galactose and neuraminic (sialic) acid (T and sialosyl Tn, respectively) are excreted in patients' urine. In this study, in two Japanese cases we analyzed the material accumulated in lysosomes using immunoelectron microscopy with mouse antibodies to Tn, sialosyl Tn and T (Thomsen-Friedenreich) antigens in order to find out what substance(s) is really deposited in lysosomes. We found that only GalNAc(alpha)1-O-Ser/Thr (Tn) was actually accumulated in vacuolated lysosomes of vascular endothelial cells, eccrine sweat gland cells, fibroblasts and pericytes. Galactosylation and sialylation of Tn appears to occur in cells other than those in the skin. The results suggest that this disease is caused by a single enzyme deficiency.
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PMID:Immunoelectron microscopic analysis of lysosomal deposits in alpha-N-acetylgalactosaminidase deficiency with angiokeratoma corporis diffusum. 1200 20


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