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's disease is a lipid storage disease found in children and adults. The lipid is stored as a myelin-figure-like whorl of membranes in endothelial and smooth muscle cells, myocardium, fibroblasts, and epithelial cells of the glomerulus. The lipid deposits are identifiable by light microscopy, but are much easier to demonstrate by electron microscopy. The disease leads to vascular insufficiency because of narrowing and thrombosis of arteries and arterioles. The resultant vascular insufficiency leads to peripheral neuritis, myocardial infarction, peripheral infarction and cerebral infarction. Corneal clouding due to lipid deposits is also seen. Renal involvement is widespread, but renal failure occurs late.
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PMID:Fabry's disease. Primary diagnosis by electron microscopy. 11 41

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's disease is a lipid storage disease caused by an X-linked hereditary deficiency of alpha-galactosidase. The enzymatic defect causes progressive deposition of ceramide trihexoside (CTH) in various tissues, leading to renal failure, premature myocardial infarction, and stroke, with a high rate of mortality in younger patients. Among the complications associated with Fabry's disease, a few cases involving avascular necrosis (AVN) of the femoral head have been reported. However, direct evidence of deposition of CTH in bone marrow in the femoral head has not been demonstrated. This report describes a 58-year-old man who underwent total hip arthroplasty for femoral head AVN associated with Fabry's disease. The accumulation of CTH was examined by chemical analysis of the sphingolipid extracted from the femoral head, using delayed-extraction matrix-assisted laser desorption ionization-time-of-flight mass spectrometry. This is the first report confirming the presence of CTH in the sphingolipid fraction from normal and necrotic bone of a patient with Fabry's disease.
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PMID:Avascular necrosis of the femoral head in a patient with Fabry's disease: identification of ceramide trihexoside in the bone by delayed-extraction matrix-assisted laser desorption ionization-time-of-flight mass spectrometry. 1212 77

Fabry disease (FD, OMIM 301500) is an X-linked inherited disorder of metabolism due to mutations in the gene encoding alpha-galactosidase A, a lysosomal enzyme. The enzymatic defect leads to the accumulation of neutral glycosphingolipids throughout the body, particularly within endothelial cells. Resulting narrowing and tortuosity of small blood vessels lead to tissue ischaemia and infarction. Inability to prevent the progression of glycosphingolipid deposition causes significant morbidity (acroparesthesia, angiokeratoma, autonomic dysfunction, cardiomyopathy and deafness), and mortality from early onset strokes, heart attack and renal failure in adulthood. Demonstration of alpha-galactosidase A deficiency in leukocytes or plasma is the definitive method for the diagnosis of affected hemizygous males. Most heterozygotes present with a cardiac, renal or neurological symptomatology, although to a lesser extent than what is observed in hemizygotes. Due to random X-chromosomal inactivation, enzymatic detection of carriers is often inconclusive. Molecular testing of possible carriers is therefore mandatory for accurate genetic counselling. The GLA gene has been cloned and more than 200 mutations have been identified. Medical management is symptomatic and consists of partial pain relief with analgesic drugs (gabapentin, carbamazepine), whereas renal transplantation or dialysis is available for patients experiencing end-stage renal failure. However, the ability to produce high doses of alpha-galactosidase A in vitro has opened the way to clinical studies and enzyme replacement therapy has recently been validated as a therapeutic agent for FD patients in clinical trials. Long term safety and efficacy of replacement therapy are currently being investigated.
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PMID:[Fabry's disease (alpha-galactosidase-A deficiency): physiopathology, clinical signs, and genetic aspects]. 1236 Jul 45

Fabry disease is an X-linked inherited disorder of metabolism due to mutations in the gene encoding alpha-galactosidase A, a lysosomal enzyme. The enzymatic defect leads to the systemic accumulation of incompletely metabolised glycosphingolipids, primarily globotriaosylceramide, in plasma and lysosomes within various tissues. Inability to prevent the progression of glycosphingolipid deposition causes significant morbidity, associated with significant impact on quality of life and diminished lifespan from early onset strokes, heart attack and progressive renal failure. The disease manifests primarily in hemizygous males; however, there is increasing recognition that heterozygous (carrier) females may also develop disease-related complications. Indeed, most heterozygotes present with cardiac, renal or neurological symptoms, although with later-onset and to a lesser extent than is observed in hemizygotes. Until recently, medical management was symptomatic, consisting of partial pain relief with analgesic drugs (carbamazepin, gabapentin), kidney and vascular protection with angiotensin-converting enzyme inhibitors, statins and folic acid, whereas renal transplantation or dialysis is available for patients experiencing end stage renal failure. The ability to produce high doses of alpha-galactosidase A has opened the way to preclinical studies, and enzyme replacement therapy has recently been validated as a therapeutic agent in clinical trials. Long-term safety and efficacy of replacement therapy are currently being investigated. Increasing knowledge of the natural history of Fabry disease and greater experience with enzyme therapy should enable optimal patient care. The complexity and relative rarity of Fabry disease necessitates a multi-disciplinary team approach that may be facilitated by a disease registry.
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PMID:Fabry disease: recent advances in enzyme replacement therapy. 1238 6

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.
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PMID:Fabry disease in mice is associated with age-dependent susceptibility to vascular thrombosis. 1253 29

In Fabry disease, deficiency of alpha-galactosidase A induces glycolipid storage that accounts for neuropathy, renal failure, myocardial infarction and stroke. Vascular crises may be precipitated by stressful conditions. To evaluate pathomechanisms of overall organ versus microvessel perfusion in response to ischemic challenge, we assessed resting and postischemic forearm and skin blood flow in Fabry patients. In 14 Fabry patients and 15 healthy controls, we measured resting and postischemic forearm blood flow by means of venous occlusion plethysmography and superficial index finger skin blood flow using laser Doppler flowmetry. At rest, arterial inflow into the limb was averaged from eight venous occlusion measurements and expressed as % volume change/minute. Postischemic plethysmographic inflow was determined from the peak influx during the first venous occlusion following three minutes of ischemia. Transcutaneous oxygen and carbon dioxide partial pressures at the forearm were monitored continuously. At rest, plethysmographic forearm perfusion was 15% lower in patients than in controls (p < 0.05) while skin blood flow did not differ between patients and controls. After ischemia, forearm hyperperfusion was less pronounced in patients than in controls (p < 0.05), while skin perfusion almost doubled in patients but increased only slightly in controls. Transcutaneous oxygen and carbon dioxide pressures did not differ between both groups. We conclude that the reduced overall limb perfusion at rest and after ischemia is likely to be due to lipid deposition with increased rigidity, decreased distensibility and lowered diameter of the vasculature. The exaggerated skin perfusion after ischemia might be attributable to the small fiber neuropathy of Fabry patients with deficient vasoconstrictor tone and enhanced vasodilatation due to hypersensitivity of denervated intracutaneous nerve fibers towards ischemia.
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PMID:Postischemic cutaneous hyperperfusion in the presence of forearm hypoperfusion suggests sympathetic vasomotor dysfunction in Fabry disease. 1292 18

Fabry disease is an under-recognized X-linked recessive lysosomal storage disorder resulting from the deficient activity of the enzyme alpha-galactosidase A (alpha-Gal A). The first case of Fabry disease in Slovenia was diagnosed in 1991. This 46 year-old male was referred for dermatologic evaluation of a purpura on his abdomen. He was being treated for proteinuria and cardiac symptoms. The diagnosis of angiokeratoma corporis diffusa (Fabry disease) was made clinically and confirmed by demonstration of the deficient leukocyte alpha-Gal A activity. The patient subsequently developed cerebrovascular symptoms, coronary disease, and renal failure, and died from a recurrent myocardial infarction. Family studies identified several other affected males and carrier female relatives with this X-linked recessive disorder. This case illustrates the typical multi-manifestations of this inherited disease which now can be safely and effectively treated by enzyme replacement therapy. Early diagnosis is important for the most effective treatment of this disease.
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PMID:Fabry disease. A case report. 1581 41

Fabry disease is an inherited metabolic disease caused by the deficiency of the lysosomal enzyme alpha-Galactosidase A. In consequence, globotriaosylceramide (Gb3) accumulates in nearly all tissues and body fluids. Typically, the disease manifestation is in childhood with acroparaesthesia of burning character in hands and feet. Angioceratoma, cornea verticillata and proteinuria may be found as well at an early stage of the disease. With ongoing age vital organs are increasingly affected. Major causes for death are cerebrovascular events, myocardial infarction, and progressive renal insufficiency. Enzyme replacement therapy (ERT) offers an efficient treatment of Fabry disease. On the basis of newly diagnosed patients we describe the clinical picture, diagnosis and principles of ERT.
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PMID:[Fabry disease--a provocation for pediatrics]. 1643 75

We report two cases of heterozygous Fabry disease with severe organ damage. Case 1 was a 47-year-old woman. In April 1977, at the age of 27 years, she had proteinuria and edema around the 26th week of her second pregnancy and was diagnosed as toxicosis of pregnancy. She had proteinuria after the delivery. In 1990, a renal biopsy showed zebra bodies under electron microscopic findings, and the patient was diagnosed as Fabry disease. In 1998, a myocardial biopsy showed identical findings. The patient developed severe hypertension and decreased renal function, and alpha-galactosidase enzyme replacement therapy was initiated. However, despite treatment, she was started on dialysis in 2004. Case 2 was a 40-year-old woman. In March 2003, the patient presented with severe hypertension. The patient had cerebral infarction, cardiac hypertrophy, old myocardial infarction and renal failure without diabetes mellitus, hyperlipidemia and collagen disease. The patient was diagnosed as Fabry disease from persistent numbness and pain in the four extremities, a family history of mortality due to heart disease, and skin biopsy findings. She is currently undergoing enzyme replacement therapy. It is generally known that female Fabry disease patients are asymptomatic or mildly symptomatic, as were the present two patients, but some can have marked organ disorders. Hence, even in female patients, it is necessary to consider Fabry disease as a causative disease of chronic renal failure.
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PMID:[Two cases of heterozygous Fabry disease]. 1691 64


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