Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0033687 (proteinuria)
 24,015 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We report here the course and outcomes of 18-month enzyme replacement therapy in two 43 and 41-year-old brothers with Fabry disease. At 18 months of recombinant alpha-galactosidase A (Fabrazyme) infusions, we observed in the older patient: weight gain, decreased proteinuria (from 4 to 1.5 g/d), stabilization of creatinine clearance, much lower frequency and intensity of angina, and in the younger brother: weight gain, stabilization of creatinine clearance and proteinuria, prolongation of PQ interval and improvement of hearing. However, neurologic manifestations deteriorated over treatment period in both patients. No serious infusion-related side effects were observed.
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PMID:[First Polish experience with enzyme replacement therapy in patients with Fabry disease]. 1596 14

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

Enzyme replacement therapy (ERT) with recombinant human alpha-galactosidase A (r-halphaGalA) enhances microvascular globotriaosylceramide clearance and improves clinical symptoms in patients with Fabry disease. We evaluated whether these effects are translated into a long-term benefit of kidney and heart function. We did a single center, prospective, open label study in 26 patients with Fabry disease (one early death, follow-up in 25 patients). r-Alpha-GalA was administered in a dosage of 1 mg/kg body weight every second week. The effect of therapy on clinical end points (death, cardiac and cerebrovascular event, renal failure), cardiac and renal function monitored by Doppler echocardiography, 99Tc-GFR, and proteinuria was investigated. After a mean treatment time of 23 +/- 8 months, nine patients experienced 12 end points, including two deaths. All end points occurred in patients with impaired renal function (n = 16; GFR 71 +/- 17 ml/min/1.73 m2). Despite ERT, renal function deteriorated to 60 +/- 23 ml/min/1.73 m2 (P = 0.04) and left ventricular posterior wall thickness (PWT) did not change (14.0 +/- 2.1 vs 13.4 +/- 2.3 mm). In contrast, patients without impairment of renal function (n = 9) had a more favorable outcome (no clinical events; GFR 115 +/- 18 vs 102 +/- 14 ml/min/1.73 m2, NS; PWT 11.7 +/- 1 and 10.7+/-0.7 mm, P = 0.04). Proteinuria remained unchanged (1.34 +/- 0.94 vs 1.01 +/- 0.97 g/day, n = 10). Patients with impaired renal function have a less favorable outcome and may develop cardiovascular and renal end points despite ERT.
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PMID:Clinical benefit of enzyme replacement therapy in Fabry disease. 1660 85

Fabry disease is a metabolic disorder caused by the genetic deficiency of alpha-galactosidase A. Deposition of glycosphingolipids in podocytes, endothelial cells, and other cell types leads to formation of myelin-like inclusions, which are the hallmark of the disease. In most untreated males, the disorder progresses to end-stage kidney disease. Fabry disease is rare, and no renal biopsy series focusing on pathologic findings has been published in the past 25 years. We retrieved kidney biopsies diagnosed with Fabry disease from our files, and reviewed clinical data as well as the light and electron microscopy. In total, 11 patients were identified: six male subjects aged 17-43 years and five female subjects aged 30-73 years. On average, male patients presented more than 10 years earlier then female patients. A total of 10 patients had proteinuria, two with the nephrotic syndrome. Four male and three female patients had decreased renal function. Light microscopy showed vacuolization of the podocyte cytoplasm and variable glomerular sclerosis. Older patients and males had more advanced glomerular and interstitial sclerosis, but three of the five female patients also had advanced renal disease. Electron microscopy showed the characteristic myelin-like inclusions most prominently in the podocyte cytoplasm. Seven patients also had podocyte foot process effacement. A second type of deposit, unexpected and conspicuous, was identified in three males, and found to be associated with glomerular basement membrane duplications. These deposits were composed of layered membrane-like material, and therefore morphologically distinct from myelin-like inclusions. They probably represent remnants of damaged endothelial cells.
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PMID:Fabry disease: a morphologic study of 11 cases. 1679 80

We report a 16-year-old girl and her one-year-younger sister, both heterozygous for the c.34del24 mutation of the GLA (alpha-galactosidase A) gene, which they inherited from their father who is affected by Fabry disease (FD). Both girls presented with macrohematuria and rapidly progressing proteinuria. Urine analysis revealed glomerular hematuria and a nephrotic range of proteinuria suggesting a concomitant glomerulonephritis. Light microscopy of kidney biopsy was characteristic of IgA nephropathy (IgA deposits in mesangial areas and glomerular capillary loops, and mesangial hypercellularity), whereas electron microscopy showed changes typical of Fabry disease (multiple osmiophilic inclusions in the subendothelial and mesangial areas). These two cases and similar reports in the literature suggest that IgA nephropathy in FD is not merely coincidental.
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PMID:IgA nephropathy in two adolescent sisters heterozygous for Fabry disease. 1683 83

Fabry disease, an inherited deficiency of the lysosomal enzyme alpha-galactosidase A, causes progressive intralysosomal accumulation of globotriaosylceramide (GL-3) and premature death from renal, cardiac, and cerebrovascular manifestations. To determine the long-term safety and efficacy of recombinant human alpha-galactosidase A, an open-label, phase III extension study was conducted, involving 58 patients who had classic Fabry disease and completed a 20-wk, double-blind, randomized, placebo-controlled, phase III study of agalsidase beta and were transitioned to an extension trial to receive biweekly 1 mg/kg agalsidase beta for up to an additional 54 mo. GL-3 accumulation was evaluated in the capillary endothelia of the skin, kidney, and heart. Renal function was assessed. By month 54, all patients with optional kidney biopsies (n = 8) maintained complete GL-3 clearance in renal capillary endothelial cells and multiple cell types. Continued, complete clearance of skin (31 of 36) and heart (six of eight) capillary endothelium was demonstrated. Mean plasma GL-3 levels remained decreased in the normal range. Median serum creatinine and estimated GFR remained stable (normal) in patients with renal data at month 54 (n = 41). Six patients had renal disease progression; most (four of six) were older than 40 yr and had significant proteinuria at baseline and evidence of sclerotic glomeruli pretreatment. Adverse events were generally mild and unrelated to treatment. The most common treatment-related adverse events were infusion-associated reactions, which decreased over time. Long-term agalsidase beta therapy stabilizes renal function in patients without renal involvement at baseline, maintains reduction of plasma GL-3, and sustains GL-3 clearance in capillary endothelial cells and multiple renal cell types.
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PMID:Sustained, long-term renal stabilization after 54 months of agalsidase beta therapy in patients with Fabry disease. 1742 46

Preclinical and phase I/II studies gave the proof of principle of enzyme replacement therapy (ERT) with recombinant alpha-galactosidase A through the demonstration of the clearance of the accumulated subtrate from plasma and tissues. In a multicenter, randomized, placebo-controlled, double-blind phase Ill study, the biological efficacy of recombinant alpha-galactosidose A (agalsidase beta 1 mg/kg/714 days) was demonstrated on the basis of complete clearance of accumulated globotriaosylceramide from the endothelia of the kidney, heart and skin. The phase III extension study data gives additional results: kidney function appears to be stabilized after 54 to 60 months of treatment with agolsidase beta in most patients. Intent-to-treat analysis of a double-blind, randomized, placebo-controlled, phase IV study, showed that, adjusted for on imbalance in baseline proteinuria, agalsidase beta significantly reduces by 53% the risk of a first clinical event (renal, cardiac and cerebrovascular), compared with placebo. Clinical benefits of ERT depend on patients' clinical status at baseline, therefore prompting for onset of ERT before irreversible damage occur and underlying the need to stratify patients' populations to better understand the outcome of ERT.
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PMID:[Development of an orphan drug to treat a genetic disease: the paradigm of agalsidase beta]. 1754 72

Fabry disease (FD), the second most common type of lysosomal storage disease (LSD), is one of 41 disorders characterized by accumulation of substances normally degraded within lysosomes. It is an X-linked recessive disorder characterized by a deficiency of lysosomal alpha-galactosidase A (alpha-Gal A). The locus for human alpha-Gal A is located on the Xq22 chromosome. Most FD mutations are confined to a single family. Although FD is an X-linked disorder, up to one third of female carriers develop clinical manifestations of the disease. It typically presents during infancy or adolescence with crisis of neuropathic pain (acroparesthesia), angiokeratomas, and asymptomatic corneal lesions. As Gb3 deposition progresses, clinical manifestations occur in other organs. Patients typically die in the fourth or fifth decade of life due to cardiac, renal or cerebrovascular complications. Usually, there is diffuse deposition of glycosphingolipid in the renal glomeruli, tubules, interstitium, and vasculature. Clinically, the renal disease manifests with hypertension, microscopic hematuria (rare), moderate proteinuria, which can be in the nephrotic range, and lipiduria. End-stage renal disease can be treated with either dialysis or transplantation. Thegene for (x-Gal A was cloned and sequenced, which eventually led to production of enzyme for therapeutic use by either recombinant DNA technology or gene activation.
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PMID:Fabry kidney disease. 1765 9

Fabry disease, an X-linked recessive glycolipid storage disease, is caused by a deficiency of the lysosomal enzyme alpha-galactosidase A (alpha-Gal A), which cleaves a fatty substance called globotriaosylceramide (GL3). The abnormal storage of GL3 in blood vessel walls leads to ischemia and necrosis, particularly in blood vessels of the skin, kidneys, heart, brain, and nervous system. The aim of our study was to present the results of cadaveric kidney transplantation with enzyme alpha-Gal A therapy in a patient with Fabry disease. The patient was diagnosed with Fabry disease at the age of 33 years, based on enzymatic tests. Renal manifestations occurred a year later as proteinuria. At the age of 35 years, the glomerular filtration rate (GFR) was within the normal range. The patient received supplemental enzyme treatment with alpha-Gal (1 mg/kg every 2 weeks). At 3 months after starting supplementation, renal function worsened with serum creatinine levels at 1.7 to 1.8 mg/dL. The following months of supplementation (alpha-Gal 1 mg/kg) concurred with progressive renal dysfunction. After 27 months of supplementation at 37 years, with a creatinine value of 5.5 mg/dL, hemodialysis began and months later the patient received a cadaveric kidney graft. The patient no longer required dialysis. On postoperative day 5 the serum creatinine was 3.9 mg/dL; on day 7, 2.2 mg/dL; on day 14, 1.5 mg/dL. Enzyme supplementation began on posttransplant day 13. Renal graft function has been good during 5 months of observation with creatinine levels at 1.2 to 1.3 mg/dL. The treatment does not interfere with tacrolimus metabolism. Simultaneous chronic enzyme supplementation is the optimal treatment in the fifth stage of end-stage renal disease in Fabry disease.
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PMID:Kidney transplantation and enzyme alpha-galactosidase A therapy in patient with Fabry disease: a case report. 1802 18

Fabry disease (FD) is an X-linked lysosomal storage disease caused by alpha-galactosidase A deficiency. The Fabry Registry is a global clinical effort to collect longitudinal data on FD. In the past, most "carrier" females were usually thought to be clinically unaffected. A systematic effort has been made to enroll all FD females, regardless of symptomology. Of the 1077 enrolled females in the Registry, 69.4% had symptoms and signs of FD. The median age at symptom onset among females was 13 years, and even though 84.1% had a positive family history, the diagnosis was not made until a median age of 31 years. Twenty percent experienced major cerebrovascular, cardiac, or renal events, at a median age of 46 years. Among adult females with estimated glomerular filtration rate (eGFR) data (N=638), 62.5% had an eGFR <90 ml/min/1.73 m2 and 19.0% had eGFR <60 ml/min/1.73 m2. Proteinuria 300 mg/day was present in 39.0% of females, and 22.2% had >1 gram/day. Quality of life (QoL), as measured by the SF-36((R)) survey, was impaired at a later age than in males, but both genders experience significantly impaired QoL from the third decade of life onward. Thus, females with FD have a significant risk for major organ involvement and decreased QoL. Females should be regularly monitored for signs and symptoms of FD, and considered for enzyme replacement therapy.
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PMID:Females with Fabry disease frequently have major organ involvement: lessons from the Fabry Registry. 1803 17


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