Sisters with atypical Fabry's disease with complete atrioventricular block.
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A 56 year old woman with severe right heart failure and complete atrioventricular block was referred to hospital for further examination. Symptoms and signs suggestive of Fabry's disease, such as corneal opacities, acroparaesthesias, hypohidrosis, and angiokeratoma, were not noted. Echocardiography showed a diffuse hypertrophic left ventricular wall and paradoxical movement of the interventricular septum. Cardiac catheterisation showed restrictive-type ventricular dysfunction. Left ventricular endomyocardial biopsy showed central vacuolar degeneration of myocytes with inclusion bodies, which had a concentric lamellar configuration under electron microscopy. This finding is specific for Fabry's disease. The patient's elder sister had experienced an almost identical clinical course and histological findings of myocardial cells on necropsy. In conclusion, two sisters were encountered displaying interesting cases of atypical Fabry's disease. Symptoms began with complete atrioventricular block and histological myocardial findings were specific for Fabry's disease. (+info)
Fabry disease with few clinical signs and symptoms.
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We describe a 25-year-old man with Fabry disease who remained undiagnosed until progressive renal involvement had begun, because of few clinical signs or symptoms except intermittent acroparesthesia. He had non-nephrotic proteinuria and normal renal function. Renal biopsy revealed focal and segmental glomerular sclerosis with vacuolated podocytes. Electron microscopy demonstrated characteristic lamellated bodies. Alpha-galactosidase A (alpha-galA) activity was markedly decreased. Early diagnosis of Fabry disease is becoming important because of the prospect of recombinant alpha-galA replacement therapy. Careful history taking, physical examinations, and renal histology with electron microscopy are essential for the diagnosis in the course of the disease. (+info)
Production in yeast of alpha-galactosidase A, a lysosomal enzyme applicable to enzyme replacement therapy for Fabry disease.
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A mammalian-like sugar moiety was created in glycoprotein by Saccharomyces cerevisiae in combination with bacterial alpha-mannosidase to produce a more economic enzyme replacement therapy for patients with Fabry disease. We introduced the human alpha-galactosidase A (alpha-GalA) gene into an S. cerevisiae mutant that was deficient in the outer chains of N-linked mannan. The recombinant alpha-GalA contained both neutral (Man(8)GlcNAc(2)) and acidic ([Man-P](1-2)Man(8)GlcNAc(2)) sugar chains. Because an efficient incorporation of alpha-GalA into lysosomes of human cells requires mannose-6-phosphate (Man-6-P) residues that should be recognized by the specific receptor, we trimmed down the sugar chains of the alpha-GalA by a newly isolated bacterial alpha-mannosidase. Treatment of the alpha-GalA with the alpha-mannosidase resulted in the exposure of a Man-6-P residue on a nonreduced end of oligosaccharide chains after the removal of phosphodiester-linked nonreduced-end mannose. The treated alpha-GalA was efficiently incorporated into fibroblasts derived from patients with Fabry disease. The uptake was three to four times higher than that of the nontreated alpha-GalA and was inhibited by the addition of 5 mM Man-6-P. Incorporated alpha-GalA was targeted to the lysosome, and hydrolyzed ceramide trihexoside accumulated in the Fabry fibroblasts after 5 days. This method provides an effective and economic therapy for many lysosomal disorders, including Fabry disease. (+info)
Fabry disease in mice is associated with age-dependent susceptibility to vascular thrombosis.
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Fabry disease is an X-linked lysosomal storage disorder due to deficiency of alpha-galactosidase A (GLA) activity that results in the widespread accumulation of neutral glycosphingolipids. Renal failure, neuropathy, premature myocardial infarction, and stroke occur in patients with this condition primarily due to deposition of glycosphingolipids in vascular endothelial cells. The clinical consequences of Fabry disease suggest that vascular thrombosis may play a prominent role in the pathogenesis of this disease; however, the vasculopathy associated with Fabry disease has not been extensively studied. To determine if mice genetically deficient in Gla are susceptible to vascular thrombosis, a photochemical carotid injury model was used to induce occlusive thrombosis. In this model, Gla-/0 mice displayed a progressive age-dependent shortening of the time to occlusive thrombosis after vascular injury that correlated with progressive accumulation of globotriasylceramide (Gb3) in the arterial wall. Bone marrow transplantation from Gla-/0 to Gla+/0 mice and from Gla+/0 to Gla-/0 mice did not change the thrombotic phenotype of the host. These studies reveal a potent vascular prothrombotic phenotype in Gla-deficient mice and suggest that antithrombotic therapies as well as therapies designed to reduce the vascular accumulation of Gb3 may have beneficial effects on thrombotic complications in patients with Fabry disease. (+info)
Long-term correction of globotriaosylceramide storage in Fabry mice by recombinant adeno-associated virus-mediated gene transfer.
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Fabry disease is an X-linked recessive inborn metabolic disorder characterized by systemic and vascular accumulation of globotriaosylceramide (Gb(3)) caused by a deficiency of the lysosomal enzyme alpha-galactosidase A (alpha-gal A). The condition is associated with an increased morbidity and mortality due to renal failure, cardiac disease, and early onset of stroke. Hemizygous males are primarily affected clinically with variable expression in heterozygous females. Gene-therapy trials have been initiated recently in alpha-gal A knockout mouse models of Fabry disease by using a variety of viral vectors. In the present investigation we administered single i.v. injections of 1 x 10(10) genomes of recombinant adeno-associated virus (rAAV) encoding the human alpha-gal A gene driven by a modified chicken beta-actin (CAG) promoter to alpha-gal A knockout (Fabry) mice. Transgenic mice were analyzed for expression of alpha-gal A activity and Gb(3) levels in liver, kidney, heart, spleen, small intestine, lung, and brain. Administration of the rAAV-CAG-hAGA vector resulted in stable expression of alpha-gal A in organs of the Fabry mice for >6 months. alpha-Gal A activity in the organs became equal to or higher than that of wild-type mice. Accumulated Gb(3) in the liver, heart, and spleen was reduced to that of wild-type mice with lesser but significant reductions in kidney, lung, and small intestine. Injection of the rAAV-CAG-hAGA construct into skeletal muscle did not result in expression of alpha-gal A in it or in other tissues. This study provides a basis for a simple and efficient gene-therapy approach for patients with Fabry disease and is indicative of its potential for the treatment of other lysosomal storage disorders. (+info)
A biochemical and pharmacological comparison of enzyme replacement therapies for the glycolipid storage disorder Fabry disease.
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Fabry disease is a lysosomal storage disease arising from deficiency of the enzyme alpha-galactosidase A. Two recombinant protein therapeutics, Fabrazyme (agalsidase beta) and Replagal (agalsidase alfa), have been approved in Europe as enzyme replacement therapies for Fabry disease. Both contain the same human enzyme, alpha-galactosidase A, but they are produced using different protein expression systems and have been approved for administration at different doses. To determine if there is recognizable biochemical basis for the different doses, we performed a comparison of the two drugs, focusing on factors that are likely to influence biological activity and availability. The two drugs have similar glycosylation, both in the type and location of the oligosaccharide structures present. Differences in glycosylation were mainly limited to the levels of sialic acid and mannose-6-phosphate present, with Fabrazyme having a higher percentage of fully sialylated oligosaccharides and a higher level of phosphorylation. The higher levels of phosphorylated oligomannose residues correlated with increased binding to mannose-6-phosphate receptors and uptake into Fabry fibroblasts in vitro. Biodistribution studies in a mouse model of Fabry disease showed similar organ uptake. Likewise, antigenicity studies using antisera from Fabry patients demonstrated that both drugs were indistinguishable in terms of antibody cross-reactivity. Based on these studies and present knowledge regarding the influence of glycosylation on protein biodistribution and cellular uptake, the two protein preparations appear to be functionally indistinguishable. Therefore, the data from these studies provide no rationale for the use of these proteins at different therapeutic doses. (+info)
Cutaneous variant of angiokeratoma corporis diffusum.
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A case of angiokeratoma corporis diffusum (ACD) involving the skin of a 22-year-old patient presenting with normal physical and mental development is reported. ACD presenting with skin lesions alone is a rare but specific clinical entity, which differs from hereditary sphingolipidoses such as Fabry's disease. (+info)
Early detection of Fabry cardiomyopathy by tissue Doppler imaging.
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BACKGROUND: Fabry cardiomyopathy is diagnosed by detection of left ventricular hypertrophy (LVH) in patients with alpha-Galactosidase A deficiency. Conventional noninvasive tools are unable to provide a preclinical diagnosis allowing prompt institution of enzymatic therapy. METHODS AND RESULTS: We studied three groups of patients: 10 patients with causal mutations for Fabry disease and LVH, 10 mutation-positive patients without LV, and 10 healthy relatives without causal mutations and no LVH. All patients with LVH and 6 patients with Fabry disease without LVH with complex repetitive ventricular arrhythmias underwent biventricular endomyocardial biopsy to assess cardiac involvement. In all patients 2-dimensional echocardiography with tissue Doppler analysis in the pulsed Doppler mode was performed: systolic (Sa), early diastolic (Ea), and late diastolic (Aa) velocities were measured, and the Ea/Aa ratio and the dimensionless parameter E/Ea were computed at both corners of the mitral annulus. Histology and electron microscopy studies showed glycosphingolipid deposits in all cases. All mutation-positive patients had significant reduction of Sa, Ea, and Aa velocities at both corners of the mitral annulus compared with normal control subjects. Ea/Aa ratio was significantly lower and E/Ea ratio significantly higher in mutation-positive patients than in control subjects. Patients with LVH showed significantly lower contraction and relaxation tissue Doppler velocities, lower Ea/Aa ratio, and higher E/Ea ratio in comparison with mutation-positive patients with no LVH. CONCLUSIONS: Fabry cardiomyopathy is characterized by reduced myocardial contraction and relaxation tissue Doppler velocities, detectable even before development of LVH. Tissue Doppler imaging can provide a preclinical diagnosis of Fabry cardiomyopathy, allowing early institution of enzyme replacement therapy. (+info)