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)

Globotriaosylceramide is a neutral glycolipid containing the trihexoside Gal(alpha1-4)Gal(ss1-4)Glc(ss1-1') covalently bound to N-acylsphingosine. It was identified as the main storage substance in the kidney of patients with Fabry disease, an X-linked deficiency of lysosomal alpha-galactosidase A which can significantly be ameliorated by enzyme replacement therapy. Unlike hemizygote males, affected heterozygote females cannot be identified by enzyme assays and therefore may remain untreated. A quantitation of urinary globotriaosylceramides was proposed as an alternative method for their diagnosis. However, the required studies on physiological and pathological variations in the excretion of trihexosides so far have been prevented by a lack of suitable methods. A validated, robust and quick high-throughput method for the quantitative analysis of globotriaosylceramide isoforms using stable-isotope-dilution/internal standardization and electrospray ionization mass spectrometry (ESI-MS) was developed. An internal standard, stearoyl-d35-globotriaosylceramide, was synthesized by enzymatic coupling of d35-stearic acid to the corresponding lyso-ceramidetrihexoside. Glycolipid isoforms of high purity were obtained from a 5-mL urine portion by extraction on C18 solid-phase columns and a novel washing protocol. ESI-MS analysis was performed in full and neutral loss scan modes. Urinary trihexosyl- and some of the di- and monohexosylceramide isoforms can be quantified within a single experiment. All glycolipid isoforms were above detection limit in healthy male and female subjects (n = 63). Prominent elevations of tetracosanoyl-(C24:0 plus C24:1)-globotriaosylceramides were found in urines from female (>2.5-fold above normals) or male Fabry patients (>5.8-fold above normals), but not among controls. Globotriaosylceramide isoforms shall now be analyzed in Fabry patients, non-genetic kidney disease and healthy subjects to define the conditions for a safe diagnosis of heterozygotes.
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PMID:Rapid determination of urinary globotriaosylceramide isoform profiles by electrospray ionization mass spectrometry using stearoyl-d35-globotriaosylceramide as internal standard. 1588 Jun 67

Fabry disease (FD) is an X-linked inborn error of glycosphingolipid (GSL) metabolism, caused by a deficiency of the lysosomal alpha-galactosidase A, which results in high levels in lysosomes and biological fluids of globotriaosylceramide (Gb3) and digalactosylceramide (Ga2), also known as galabiosylceramide. We report here a detailed study of the molecular species of GSLs in urinary samples obtained from hemizygous and heterozygous patients by use of matrix-assisted laser desorption ionisation and tandem mass spectrometry (MALDI-MS-MS). Twenty-two and fifteen molecular species were identified in the globotriaosylceramide and digalabiosylceramide series, respectively. The major sphingoid base was sphingosine (d18:1), and dihydrosphingosine (C18:0) and sphingadienine (d18:2) were also present. The molecular profiles obtained by MALDI-TOF-MS enabled us to show significant differences between GSLs composition for young, adult or atypic hemizygote and heterozygote patients. Thus, MALDI-TOF-MS and MS-MS proved a powerful tool for screening a population of patients with clinical signs suggestive of FD by direct and rapid GSL fingerprinting and identification, and for study of the biological processes occurring in glycosphingolipid accumulation.
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PMID:Fast fingerprinting by MALDI-TOF mass spectrometry of urinary sediment glycosphingolipids in Fabry disease. 1595 71

Fabry disease is an X-linked inherited loss of alpha-galactosidase A (alpha-Gal A). Affected patients experience complications that include neuropathy, renal failure, and cardiovascular disease. Although the genetic and biochemical basis of this sphingolipidosis is well studied, the basis for the vascular disease remains poorly understood. In an attempt to create a suitable in vitro model of this disease, conditions for the growth of primary cultures of aortic endothelial cells from wild-type and alpha-Gal A -/0 mice were established. The cultured cells demonstrated CD-31 expression by flow cytometry and LDL binding by immunofluorescence. The glycolipid expression patterns were compared between wild-type and alpha-Gal A null cells. Importantly, cells from alpha-Gal A -/0 mice but not alpha-Gal A +/0 mice expressed high levels of the globo-series glycosphingolipid globotriaosylceramide (Gb3). The age-dependent elevation in Gb3 was measured. By 4 mo of age, alpha-Gal A -/0 mouse aortic endothelial cells achieved their peak Gb3 levels. The ability to lower Gb3 levels pharmacologically was assessed next. The glucosylceramide synthase inhibitor ethylenedioxyphenyl-P4 significantly lowered but did not eliminate Gb3 levels by 96 h of treatment. Gb3 synthesis was completely blocked as measured by [14C]galactose labeling. Recombinant alpha-Gal A more significantly lowered Gb3 levels by 48 h but had a more limited effect on de novo synthesis. Together, both agents eliminated detectable Gb3. In summary, primary cultures of aortic endothelial cells from Fabry mice retain the phenotype of elevated globo-series glycosphingolipids. These cells provide a useful model for comparing pharmacologic agents used for glycolipid reduction.
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PMID:An in vitro model of Fabry disease. 1603 56

Fabry disease is a rare X-linked lysosomal storage disorder caused by deficient activity of alpha-galactosidase A (alpha-Gal A) resulting in the storage of glycosphingolipids, especially globotriaosylceramide (Gb3), in cells throughout the body, causing life-threatening renal, cardiac, and cerebrovascular complications in hemizygous males and some heterozygous females. Disease manifestations in heterozygotes are being recognized increasingly, but quantitative prospective data on their extent and severity are limited. Prospective clinical and laboratory assessments were performed in a 7-day study of 61 women with signs and symptoms of Fabry disease. Analyses included medical history and physical, neurologic, cardiac, and ophthalmologic assessments; laboratory assessments; renal function tests; magnetic resonance imaging (MRI) and magnetic resonance angiography (MRA) of the head; and Fabry-related blood and urine tests, including Gb3 levels in blood and urine, skin biopsies, and DNA genotype analysis of the alpha-Gal A gene to identify causative mutations. Quality of life, pain and concomitant medication were documented using validated questionnaires and diaries. All patients had normal Gb3 levels in plasma; only 1 patient had visible storage material in the superficial dermal vascular endothelial cells. Cardiac, renal, or cerebrovascular abnormalities were documented in 52 of the 57 patients (91%) with confirmed Fabry genotypes. These included electrocardiographic abnormalities in 38 of 52 patients (73%), echocardiographic abnormalities in 8 of 57 (14%), proteinuria (>150 g protein/24-h urine) in 23 of 38 (61%), low estimated glomerular filtration rate (<90 mL/min per 1.73 m) in 24 of 57 (42%), abnormal MRI in 4 of 54 (7%), and abnormal MRA in 10 of 50 patients (20%). Angiokeratomas and corneal epitheliopathy were documented in 63% and 82% of the 57 patients, respectively. Despite the virtual absence of storage material in plasma and skin vascular endothelial cells, this population of women with Fabry disease exhibited a wide spectrum of clinical abnormalities. Useful outcome measures for assessment of specific therapies need to be developed. Studies limited to homogeneously affected subjects may be possible.
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PMID:The relationship of vascular glycolipid storage to clinical manifestations of Fabry disease: a cross-sectional study of a large cohort of clinically affected heterozygous women. 1614 26

Fabry disease is an inherited lysosomal storage disorder characterized by a pathological intracellular glycosphingolipid deposition. The disease is caused by a deficit in the lysosomal enzyme alpha-galatosidase A, the gene for which is located in the X chrosomal region Xq 22. Globotriaosylceramide (Gb3) accumulate progressively in multi-organ vulnerable cells throughout the body, including cardiovascular, renal, and cerebrovascular systems. The present manuscript is to review cardiovascular and renal manifestations of Fabry disease and the new diagnostic procedures for earlier detection and the therapeutic assessments of this disease. We are applying noninvasive cardiovascular and microcirculation analysis methods and novel cardiac biomarkers. Novel therapeutic strategies for this disease have been developing in recent years, which include the clinically introduced enzyme infusion replacement therapy and experimentally developing gene-transfer therapy. We have reported that AAV-mediated muscule-directed gene transfer is very effective for long-term systemic delivery of alpha-gal A (25% of normal mice enzyme activity), resulting in complete clearance of multi-organs Gb3 accumulation. Echocardiographic and immunohistochemical examination demonstrated structural improvement of cardiac hypertrophy. When and to whom the novel therapeutic strategies should be applied to obtain the maximum efficacy and safety remain to be established.
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PMID:Cardiovascular manifestations of Fabry disease and the novel therapeutic strategies. 1624 24

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

Fabry disease is a lysosomal storage disorder caused by deficiency of alpha-galactosidase A (alpha-Gal A) resulting in lysosomal accumulation of glycosphingolipid globotriosylceramide Gb3. Misfolded alpha-Gal A variants can have residual enzyme activity but are unstable. Their lysosomal trafficking is impaired because they are retained in the endoplasmic reticulum (ER) by quality control. Subinhibitory doses of the competitive inhibitor of alpha-Gal A, 1-deoxygalactonojirimycin (DGJ), stabilize mutant alpha-Gal A in vitro and correct the trafficking defect. We showed by immunolabeling that the chaperone-like action of DGJ significantly reduces the lysosomal Gb3 storage in human Fabry fibroblasts harboring the novel mutations T194I and V390fsX8. The specificity of the DGJ effect was proven by RNA interference. Electron microscopic morphometry demonstrated a reduction of large-size, disease-associated lysosomes and loss of characteristic multilamellar lysosomal inclusions on DGJ treatment. In addition, the pre-Golgi intermediates were decreased. However, the rough ER was not different between DGJ-treated and untreated cells. Pulse-chase experiments revealed that DGJ treatment resulted in maturation and stabilization of mutant alpha-Gal A. Genes involved in cell stress signaling, heat shock response, unfolded protein response, and ER-associated degradation show no apparent difference in expression between untreated and DGJ-treated fibroblasts. The DGJ treatment has no apparent cytotoxic effects. Thus our data show the usefulness of a pharmacological chaperone for correction of the lysosomal storage in Fabry fibroblasts harboring different mutations with residual enzyme activity. Pharmacological chaperones acting on misfolded, unstable mutant proteins that exhibit residual biological activity offer a convenient and cost-efficient therapeutic strategy.
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PMID:Pharmacological chaperone corrects lysosomal storage in Fabry disease caused by trafficking-incompetent variants. 1653 66

We have shown that the ABC transporter, multiple drug resistance protein 1 (MDR1, P-glycoprotein) translocates glucosyl ceramide from the cytosolic to the luminal Golgi surface for neutral, but not acidic, glycosphingolipid (GSL) synthesis. Here we show that the MDR1 inhibitor, cyclosporin A (CsA) can deplete Gaucher lymphoid cell lines of accumulated glucosyl ceramide and Fabry cell lines of globotriaosyl ceramide (Gb3), by preventing de novo synthesis. In the Fabry mouse model, Gb3 is increased in the heart, liver, spleen, brain and kidney. The lack of renal glomerular Gb3 is retained, but the number of verotoxin 1 (VT1)-staining renal tubules, and VT1 tubular targeting in vivo, is markedly increased in Fabry mice. Adult Fabry mice were treated with alpha-galactosidase (enzyme-replacement therapy, ERT) to eliminate serum Gb3 and lower Gb3 levels in some tissues. Serum Gb3 was monitored using a VT1 ELISA during a post-ERT recovery phase +/- biweekly intra peritoneal CsA. After 9 weeks, tissue Gb3 content and localization were determined using VT1/TLC overlay and histochemistry. Serum Gb3 recovered to lower levels after CsA treatment. Gb3 was undetected in wild-type liver, and the levels of Gb3 (but not gangliosides) in Fabry mouse liver were significantly depleted by CsA treatment. VT1 liver histochemistry showed Gb3 accumulated in Kupffer cells, endothelial cell subsets within the central and portal vein and within the portal triad. Hepatic venule endothelial and Kupffer cell VT1 staining was considerably reduced by in vivo CsA treatment. We conclude that MDR1 inhibition warrants consideration as a novel adjunct treatment for neutral GSL storage diseases.
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PMID:Treatment of neutral glycosphingolipid lysosomal storage diseases via inhibition of the ABC drug transporter, MDR1. Cyclosporin A can lower serum and liver globotriaosyl ceramide levels in the Fabry mouse model. 1672 20

Anderson-Fabry disease is a rare inherited X-linked lysosomal storage disease caused by deficiency of the enzyme alpha-galactosidase A. The deficiency of alpha-galactosidase activity leads to progressive, abnormal accumulation of neutral glycosphingolipids in the lysosome. With increasing age globotriaosylceramide (Gb3) progressively accumulates in different cells, tissues and organs throughout the body. The overall prevalence of Anderson-Fabry disease is 1:117.00 or 1: 40.000 in (male) population. Typically, the clinical onset of Anderson-Fabry disease occurs during childhood or adolescence, with early symptoms of neuropathic pain (recurrent episodes of severe pain in the extremities), angiokeratomas (characteristic cutaneous lesions), oedematous upper eyelids, peripheral vasospasm and ophthalmological abnormalities. The disease progresses through adulthood and by the age of 30-40 years several major organ systems may be affected; cardiac disease, renal insufficiency, cerebrovascular attacks and neurologic findings are common. Death usually occur secondary to renal, cardiac or cerebrovascular complications during the fourth or fifth decade of life. Enzyme replacement therapy is a major advance in the treatment of rare diseases. In 2001 two formulations have been approved by the European Medical Evaluation Agency, agalsidase alpha and agalsidase beta. Agalsidase alpha is produced on the human fibroblast cell line, and agalsidase beta from the Chinese hamster ovary cell line.
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PMID:[Anderson-Fabry disease]. 1680 73

The neurological manifestations of Fabry disease include both peripheral and central nervous system involvement caused by a deficiency of alpha-galactosidase A and accumulation of alpha-D-galactosyl moieties, particularly globotriosylceramide accumulation (Gb3). These are found in Schwann cells and dorsal root ganglia together with deposits in central nervous system neurons. Involvement of the peripheral nervous system affect mainly small Adelta and C fibers and are likely causally related to the altered autonomic function and neuropathic pain found in this disorder. Other related abnormalities to be discussed are hypohidrosis and other abnormalities attributed to autonomic nervous system dysfunction. The function of the peripheral nervous system is somewhat improved by ERT with reduction in neuropathic pain and an improvement of the detection threshold for cold and warm sensation in the hand and foot. Improvement in sweating and heat tolerance is also noted following ERT. Despite those positive results, ERT does not normalize the function of the peripheral nervous system.
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PMID:Neuropathy and Fabry disease: pathogenesis and enzyme replacement therapy. 1689 55


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