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 cardiovascular abnormalities were investigated in two unrelated hemizygous males with Fabry disease who had clinical mitral insufficiency. Postmortem examination of their hearts revelaed anatomic, ultrastructural and biochemical abnormalities resulting from defective activity of the lysosomal enzyme, alpha-galactosidase A. The ultrastructural and biochemical studies demonstrated the marked accumulation of the major glycosphingolipd substrate, trihexosyl ceramide, in the lyosomes of all the cardiac tissues examined; the greatest concentrations were found in the mitral valve and elft ventricular myocardium. Intriguingly, digalactosyl ceramide, a glycosphingolipid substrate not detectable in normal lung, vessel or cardiac tissues, was found increased only in the lung and right heart tissues. Morphologic and chemical examination of cardiac and systemic vessels demonstrated accumulation of trihexosyl ceramide in lysosomes of the vascular endothelium. These studies demonstrate that the progressive accumulation of trihexosyl ceramide in the lysosomes of the cardiac structures and vascular system leads to the multiple cardiovascular manfiestation of Fabry disease.
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PMID:Cardiac valvular anomalies in Fabry disease. Clinical, morphologic, and biochemical studies. 82 66

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

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

Skeletal muscle is involved symptomatically in two lysosomal storage diseases, acid maltase deficiency and a similar condition in which enzyme levels are normal. Asymptomatic storage in skeletal muscle cells is found in Batten-Kufs' disease (ceroid lipofuscinosis), Fabry's disease, and mannosidosis, as well as in rare patients with an unidentified storage disease. Other cell types (vascular endothelium, smooth muscle, fibroblasts, satellite cells) within the confines of the biopsy specimen may reveal storage in other diseases. The differential diagnosis involves predominantly both normal and abnormal conditions in which acid phosphatase activity is prominent in cells.
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PMID:Lysosomal storage in human skeletal muscle. 308 57

Late graft histology after renal transplantation for Fabry's disease has only once been previously reported. Clinical data and kidney biopsy findings in a case of Fabry's disease before and eight years after successful kidney transplantation are presented. The graft maintains normal function. Graft histology in light microscopy showed no abnormalities reminiscent of the diseased native kidney. Electron microscopy revealed occasional small myelin figures which were present only in the vascular endothelium. Their significance and a review of conflicting reports and opinions from the literature are discussed.
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PMID:Renal biopsy in Fabry's disease eight years after successful renal transplantation. 310 60

Therapeutic administration of amiodarone, an antiarrhythmic drug, to eight patients resulted in the formation of vortex-like figures within the anterior cornea. Clinical examination disclosed no visual loss or other ocular abnormality attributable to the drug. In one patient, light and transmission electron microscopy of corneal epithelium, bulbar conjunctiva, and cataractous lens revealed complex lipid deposits within lysosome-like intracytoplasmic inclusions in corneal, conjunctival, and lens epithelium, conjunctival fibrocytes, and conjunctival vascular endothelium. Amiodarone keratopathy is compared clinically and morphologically with the corneal alterations seen in Fabry's disease and in chloroquine use as an example of a drug-induced lipid storage disorder.
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PMID:Amiodarone keratopathy: drug-induced lipid storage disease. 625 44

Fabry disease is characterized by a deficiency of lysosomal alpha-galactosidase (alpha-Gal) and the accumulation of glycosphingolipid (e.g. predominantly globotriaosylceramide) in various tissues, mainly in lysosomes of the vascular endothelium. This disorder is currently classified into two clinical phenotypes; classical severe type and atypical variant type. Classical form patients, with clinical manifestations of generalized angiopathy of early onset, usually show no detectable alpha-Gal activity. Recently, there are also atypical form patients with residual alpha-Gal activity and late-onset cardiomyopathy without other systemic manifestations. So far, we identified a number of alpha-Gal gene mutations including partial gene deletions, splicing mutations, nonsense mutations and missense mutations. They were heterogeneous and more than half of them were missense mutations. To clarify the molecular mechanism causing the enzyme defect in the patient, various missense mutations were expressed in COS-1 cells. At least, two groups have been identified; one expressing a mutant enzyme without catalytic activity (non-functional type), and the other expressing catalytically active but unstable mutant enzyme (fragile type). The fragile type mutants were widely present in the different clinical phenotypes from classical severe type to atypical milder type including subclinical Fabry hemizygote, and the mutant enzymes were posttranslationally inactivated and degraded in the cells. The inactivation and degradation were prevented by the addition of substrate analogue; galactose or melibiose. These findings provided us with significant informations on the molecular pathology of the enzyme defect in Fabry disease, and suggested the possibility of a new therapeutic approach for this disease.
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PMID:[alpha-Galactosidase gene mutation and its expression product in Fabry disease (alpha-galactosidase deficiency)]. 912 Sep 96

The authors detected on necropsy in a 63-year-old woman with the clinical diagnosis of hypertension, atherosclerosis of the coronary and peripheral arteries, thromboembolism into the cerebral circulation and impaired cardiac conductivity lysosomal storage identified by histochemical and electronoptic analyses along with lipid chromatography as Fabry's disease. The stored lipids were neutral glycosphingolipids of the globo series globotriaosylceramide) and of the gala- series (galabiosylceramide) which accumulated as a result of deficient activity of the degrading enzyme alpha galactosidase A. Marked accumulation of these specific lipids was found in cardiomyocytes, in smooth muscles (of the media in arteries of the heart, kidneys, liver, spleen, lungs) in podocytes and mesangial cells of renal glomeruli, in epithelia of Henle's loop and in the distal tubules. In the vascular endothelium the storage was at the borderline of detectability. Accumulation did not lead to detectable organ disorders with the exception of the heart where it participated, no doubt, significantly in the cardiocyte hypertrophy. Examination of relatives revealed in the proband's son (age 41 years) a combination of renal, cardiac and skin changes typical for Fabry's disease which, however was not clinically diagnosed. The diagnosis was confirmed by proving of alpha-galactosidase A deficiency in the peripheral leucocytes and point mutation L293X in the VIth exon of the appropriate gene. In a granddaughter (age 15 years) biochemical and molecular genetic methods revealed the heterozygous state of Fabry's disease in preclinical stage.
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PMID:[Postmortem diagnosis of Fabry disease in a female heterozygote leading to the detection of undiagnosed manifest disease in the family]. 1074 23

Fabry disease results from deficient alpha-galactosidase A (alpha-Gal A) activity and the pathologic accumulation of the globotriaosylceramide (GL-3) and related glycosphingolipids, primarily in vascular endothelial lysosomes. Treatment is currently palliative, and affected patients generally die in their 40s or 50s. Preclinical studies of recombinant human alpha-Gal A (r-halphaGalA) infusions in knockout mice demonstrated reduction of GL-3 in tissues and plasma, providing rationale for a phase 1/2 clinical trial. Here, we report a single-center, open-label, dose-ranging study of r-halphaGalA treatment in 15 patients, each of whom received five infusions at one of five dose regimens. Intravenously administered r-halphaGalA was cleared from the circulation in a dose-dependent manner, via both saturable and non-saturable pathways. Rapid and marked reductions in plasma and tissue GL-3 were observed biochemically, histologically, and/or ultrastructurally. Clearance of plasma GL-3 was dose-dependent. In patients with pre- and posttreatment biopsies, mean GL-3 content decreased 84% in liver (n=13), was markedly reduced in kidney in four of five patients, and after five doses was modestly lowered in the endomyocardium of four of seven patients. GL-3 deposits were cleared to near normal or were markedly reduced in the vascular endothelium of liver, skin, heart, and kidney, on the basis of light- and electron-microscopic evaluation. In addition, patients reported less pain, increased ability to sweat, and improved quality-of-life measures. Infusions were well tolerated; four patients experienced mild-to-moderate reactions, suggestive of hypersensitivity, that were managed conservatively. Of 15 patients, 8 (53%) developed IgG antibodies to r-halphaGalA; however, the antibodies were not neutralizing, as indicated by unchanged pharmacokinetic values for infusions 1 and 5. This study provides the basis for a phase 3 trial of enzyme-replacement therapy for Fabry disease.
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PMID:A phase 1/2 clinical trial of enzyme replacement in fabry disease: pharmacokinetic, substrate clearance, and safety studies. 1117 18

Fabry disease is an X-linked lysosomal storage disorder that results from a deficiency of the enzyme alpha-galactosidase A (alpha-Gal A). The lack of alpha-Gal A causes an intracellular accumulation of glycosphingolipids, mainly globotriaosyceramide (GL3). Affected organs include, among others, the vascular endothelium, heart, brain, and kidneys, leading to end-stage renal disease (ESRD). Since Fabry disease cannot be cured at present, clinical management is symptomatic. Enzyme replacement therapy (ERT) with recombinant alpha-Gal A has been introduced as a new therapeutic option for the treatment of Fabry patients. Short-term (one year) clinical studies have positively correlated ERT with improvement of clinical symptoms and microvascular endothelial cell clearance. Treatment outcome concerning severe organ manifestations such as proteinuria and renal function impairment, left ventricular hypertrophy, and heart failure in the long run has yet to be shown. In our studies we used sensitive and noninvasive techniques such as ultrasound-based strain rate imaging and magnetic resonance imaging (MRI), combined with MR-spectroscopy (MR-S), for the quantification of functional abnormalities at an early stage of the disease and during long-term follow-up. Future issues should determine the appropriate timing to start therapy and how children and heterozygous females should be managed. Given the diagnostic and therapeutic potential today, it is of importance to identify patients at an early stage and to start therapeutic intervention before progression of organ damage is inevitable.
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PMID:Fabry disease: diagnosis and treatment. 1269 40


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