Fabry disease: detection of undiagnosed hemodialysis patients and identification of a "renal variant" phenotype

BACKGROUND: Fabry disease is an X-linked recessive lysosomal storage disease resulting from deficient alpha-galactosidase A (alpha-Gal A) activity. Renal failure is a major debilitating complication in classically affected males. To determine if this disorder is underdiagnosed in patients with end-stage renal disease (ESRD), the frequency of unrecognized males with Fabry disease on chronic hemodialysis was determined. METHODS: Plasma alpha-Gal A activity was measured in 514 consecutive males with ESRD on hemodialysis. Patients with low alpha-Gal A activity were evaluated clinically and their alpha-Gal A mutations were determined. RESULTS: Six (1.2%) of 514 hemodialysis patients had low plasma alpha-Gal A activities and a previously identified (E66Q, A97V, M296I) or novel (G373D) missense mutation. At ages 30 to 68 years, five patients lacked the classic manifestations of angiokeratoma, acroparesthesias, hypohidrosis, and ocular opacities, while the sixth lacked angiokeratoma and ocular changes. Five had left ventricular hypertrophy (LVH). CONCLUSION: The clinical spectrum of Fabry disease includes a "renal variant" phenotype in patients without classic symptoms who develop ESRD. Affected males undergoing hemodialysis or renal transplantation can be readily diagnosed by plasma alpha-Gal A assays. These patients and their family members may benefit from enzyme replacement therapy for the later, life-threatening cardiovascular and cerebrovascular complications of Fabry disease.     

Henoch-Schoenlein nephritis in adults-clinical features and outcomes in Finnish patients

Fabry disease, an X-linked lysosomal storage disease, results from the deficient activity of the enzyme alpha-galactosidase A (alpha-Gal A) and the progressive accumulation of globotriaosylceramide (GL-3) and related glycosphingolipids. In classically affected males with this inherited nephropathy, early and marked GL-3 deposition in the podocytes leads to proteinuria in childhood or adolescence. With increasing age, GL-3 deposition in renal microvascular endothelial cells, and to a lesser extent in interstitial and mesangial cells, leads to renal insufficiency in the third to fifth decades of life. Recently identified "renal variants" who lack the classical disease manifestations of acroparesthesias, angiokeratoma, hypohidrosis, and characteristic corneal/lenticular opacities also develop renal failure. In contrast, "cardiac variants" who also lack the classical phenotype, develop proteinuria in adulthood, but survive a normal lifespan without developing renal failure. Here, we review the renal involvement and pathology in the classical, renal and cardiac variant phenotypes, and present highlights of the preclinical studies and clinical trials that demonstrated the safety and effectiveness of recombinant alpha-Gal A replacement for this inherited nephropathy.     

A nonsense mutation (R220X) in the alpha-galactosidase A gene causes typical Fabry disease in both genders

BACKGROUND: Fabry disease is an X-linked recessive disorder resulting from a deficiency of lysosomal alpha-galactosidase A (alpha-Gal A). Chronic renal failure is an important cause of death in patients with Fabry disease. We report on patients with Fabry disease (a hemizygous male and his mother) due to a nonsense mutation (R220X) in the alpha-Gal A gene. METHODS: The proband, a 41-year-old man, and his 71-year-old mother presented with renal and cardiac manifestations of Fabry disease. Histological examination and molecular analysis of the alpha-Gal A gene were performed. RESULTS: Typical histological findings of Fabry disease were observed in a renal biopsy specimen from the proband and in renal and myocardial necropsy specimens from the mother. Sequencing of a full-length alpha-Gal A cDNA from the proband indicated a C-T transition at codon 220, resulting in substitution of the predictable termination for arginine (R220X). Examination of genomic alpha-Gal A DNA revealed that the proband was a hemizygote and the mother was a heterozygous carrier for the mutation. CONCLUSION: This is the first detailed report of family members with Fabry disease due to a nonsense mutation (R220X) in the alpha-Gal A gene. Our study indicates that this mutation causes the typical disease in both genders.     

Fabry disease: diagnosis and treatment

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.     

Long-term therapy with agalsidase alfa for Fabry disease: safety and effects on renal function in a home infusion setting.

BACKGROUND: Fabry disease is an X-linked disorder of glycosphingolipid catabolism that is the result of an intracellular deficiency in the lysosomal enzyme alpha-galactosidase A (alpha-Gal A). This enzymatic defect results in the accumulation of globotriaosylceramide (Gb(3)) within cells and causes progressive neurological, cardiovascular and renal dysfunction. Our objective is to describe the safety and renal effects of long-term enzyme replacement therapy. METHODS: This was a single centre, prospective open-label treatment trial in 25 adult male Fabry patients who had completed a 6-month randomized placebo-controlled study and subsequently enrolled in an open-label extension study. Patients were treated every other week with agalsidase alfa (0.2 mg/kg) infused intravenously over 40 min. The main outcome measures were safety, antibody response and renal glomerular filtration rate (GFR). RESULTS: During the 4-4.5 years of enzyme replacement therapy, all eligible subjects were able to transition to home therapy. Eight patients developed persistent IgG antibodies to agalsidase alfa, but IgE antibodies were not detected in any patient. The development of IgG antibodies appeared not to affect any clinical end points. Estimated GFR remained stable in subgroups of patients with Stage I (GFR >90 ml/min) or Stage II (GFR 60-89 ml/min) chronic kidney disease at baseline. In contrast, in the subgroup of patients with Stage III chronic kidney disease (GFR 30-59 ml/min), the slope of the decline in GFR was reduced compared with comparable historical controls, suggesting that enzyme replacement therapy was slowing the decline of renal function in this susceptible population. CONCLUSIONS: Long-term enzyme replacement therapy with agalsidase alfa is safe and may slow the progressive decline in renal function that was commonly observed in adult males with Fabry disease.     

alpha-Galactosidase A deficiency in Dutch patients on dialysis: a critical appraisal of screening for Fabry disease.

INTRODUCTION: Fabry disease or alpha-galactosidase A (alpha-Gal A) deficiency is an X-linked lysosomal storage disorder that often leads to renal insufficiency in males and occasionally in females. The disease is rare, but its prevalence may be underestimated due to its variable clinical picture. Enzyme supplementation therapy with rHu-alphaGal A is currently available. Limited experience has so far shown that therapy may at best stabilize renal function. Despite these preliminary findings, much effort is being put into screening high-risk groups for undiagnosed alpha-Gal A deficiency. We studied the prevalence of alpha-Gal A deficiency in a Dutch dialysis cohort to establish possible underdiagnosis. We discuss the benefits of screening for Fabry disease. METHODS: Activity of alpha-Gal A in whole blood was measured in a group of 508 male Dutch dialysis patients. RESULTS: Of the 508 patients studied only one patient, already known with Fabry disease, had a alpha-Gal A deficiency, a prevalence of 0.22% (95 CI 0-1.1%). CONCLUSIONS: No undiagnosed Fabry patients were found, indicating that in our studied cohort there is no large-scale underestimation of its prevalence. Even though screening of dialysis patients for Fabry disease might identify patients who remain otherwise unrecognized, screening of high-risk populations for alpha-Gal A deficiency should be carried out with caution since long-term efficacy of treatment is currently unknown.     

Renal involvement in Anderson-Fabry disease

Anderson-Fabry disease (AFd) is a rare X-linked lisosomal storage disorder of glycosphingolipid (GL) metabolism, caused by a deficiency of the activity of alpha-galactosidase A (alpha-gal A). The progressive accumulation of GL in tissues results in the clinical manifestations of the disease, that are more evident in hemizygous males, and include characteristic skin lesions (angiokeratomas), neurological symptoms (acroparesthesia), ocular features (cornea verticillata), cardiac involvement (left ventricular enlargement, conduction abnormalities), cerebrovascular manifestations (thromboses, hemorrhage, etc.), and kidney involvement with progression to end-stage renal failure (ESRF). ESRF is a common manifestation in hemizygous males (3rd-5th decade) and death occurs around the 5th decade of life because of severe cardiac and/or cerebrovascular complications. Heterozygous females have an attenuated form of this systemic disease. In the kidney, accumulation of GL occurs in the endothelial cells of every vessel, in the epithelial cells of every tubular segment, and in all kinds of glomerular cells. The broad spectrum of renal lesions is a pathophysiological continuum with progressive impairment in the renal function related to continuous intracellular deposition of GL. Electron microscopic study of renal biopsies shows typical osmiophilic inclusion bodies in the cytoplasm of all kind of renal cells, characterized by concentric lamellation of clear and dark layers (35-50 A of periodicity). ESRF is treated by dialysis and kidney transplantation: neither treatment modifies the progression of the cardiovascular and cerebrovascular lesions due to progressive GL deposition. The outcome of kidney transplantation seems to be similar to that found in other non-diabetic patients, but the survival rate on dialysis is lower than in patients with other causes of ESRF. Nowadays, treatment with enzyme replacement infusion with purified alpha-Gal A, produced by a genetically engineered human cell line or Chinese hamster ovocytes, seems to be effective and safe.     

Kidney transplantation and enzyme alpha-galactosidase A therapy in patient with Fabry disease: a case report

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.     

Diagnosis and management of kidney involvement in Fabry disease

Interest in the diagnosis and treatment of Fabry disease has been greatly stimulated by the availability of Food and Drug Administration-approved, effective enzyme replacement therapy. This review will update the progress in this area since enzyme replacement therapy has become available. Fabry disease is often associated with proteinuric chronic kidney disease (CKD), and it appears that the treatment paradigms that have proven to be so effective in diabetes mellitus and other forms of proteinuric kidney disease are also effective in conjunction with enzyme replacement therapy for treating the kidney manifestations of Fabry disease. As such, Fabry disease represents an interesting example of progressive proteinuric kidney disease in which the usual blood pressure is lower than in other forms of CKD. This makes the use of effective antiproteinuric therapy challenging, especially considering the autonomic dysfunction that appears to be part of the disease. Comprehensive therapy for Fabry disease includes enzyme replacement therapy and all of the adjunctive therapies that are currently used to treat all forms of proteinuric CKD. It is anticipated that this approach will preserve kidney function and also benefit the cardiac and cerebrovascular systems in patients with Fabry disease.     

Enzyme replacement therapy in Fabry's disease: recent advances and clinical applications

Fabry's disease is a rare X-linked recessive disorder resulting from deficient lysosomal enzyme, alpha-galactosidase A (alpha-Gal A) activity. The deficiency leads to progressive glycosphingolipid globotriaosylceramide (Gb3) accumulation in fluids and tissues, including vascular endothelium, connective tissue, kidney, heart, brain and peripheral nerves. Classic Fabry's disease in hemizygous males has high morbidity and mortality due to end-stage renal disease (ESRD) requiring hemodialysis (HD) or kidney transplantation, myocardial involvement and central nervous system (CNS) complications. Most heterozygous females can also suffer from this severe disease deterioration. Until recently, Fabry's disease management consisted of symptomatic and palliative treatment, but this has changed with the availability of the recombinant human alpha-Gal A enzyme, agalsidase. Two different agalsidase formulations have been obtained: one from human fibroblast (agalsidase alpha), and one from Chinese hamster ovary (CHO) cells (agalsidase beta). Both preparations underwent clinical trials that documented the feasibility, efficacy and safety of the treatment. In addition, several clinical observations have proved that agalsidase reduces the storage of the substrate from several organs and tissues and, consequently, improves signs and symptoms of Fabry's disease. Additional clinical experiences have confirmed the initial clinical trial results, but further studies are needed to evaluate the long-term outcome of enzyme replacement therapy (ERT). We reviewed the clinical trial observations, as well as subsequent clinical experiences with ERT in patients with Fabry's disease.     

Sustained, long-term renal stabilization after 54 months of agalsidase beta therapy in patients with Fabry disease

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.     

Fabry disease: diagnosis and management, with emphasis on the renal manifestations

PURPOSE OF REVIEW: Interest in the diagnosis and treatment of Fabry disease has been greatly stimulated by the availability of Food and Drug Administration-approved, effective enzyme-replacement therapy. This review will update the progress in this area over the last 18 months that effective enzyme-replacement therapy has become available. RECENT FINDINGS: Fabry disease is often associated with proteinuric chronic kidney disease, and it appears that the treatment paradigms that have proven to be so effective in diabetes mellitus and other forms of proteinuric renal disease are also effective, in conjunction with enzyme-replacement therapy for treating the renal manifestations of Fabry disease. As such, Fabry disease represents an interesting example of progressive proteinuric renal disease in which the usual blood pressure is lower than in other renal diseases. This makes the use of effective anti-proteinuric therapy challenging, especially considering the autonomic dysfunction that appears to be part of the disease. Recent advances are considered in this review, with emphasis on the role of kidney biopsy, effective dosing and maximal comprehensive therapy of Fabry disease. SUMMARY: Maximal, comprehensive therapy for Fabry disease includes effective enzyme-replacement therapy and all of the adjunctive therapies that are currently used to treat all forms of proteinuric chronic kidney disease. It is anticipated that this approach will preserve kidney function and also benefit the cardiac and cerebrovascular systems in patients with Fabry disease.     

An in vitro model of Fabry disease

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.     

Update on Fabry disease: kidney involvement, renal progression and enzyme replacement therapy

Fabry disease is an X-linked lysosomal storage disorder which is caused by a deficiency of the lysosomal enzyme alpha-galactosidase A. The lack of enzyme causes a progressive intracellular accumulation of glycosphingolipids, mainly globotriaosylceramide (GL3). Affected organs are, among others, the vascular endothelium, heart, brain and kidneys, as well as the central and peripheral nervous system. With the approval of enzyme replacement therapy (ERT) in 2001, a specific treatment approach was opened for the first time. Randomized and placebo-controlled trials have shown the safety and efficacy of ERT with improvement of clinical symptoms and microvascular endothelial cell clearance. Long-term treatment outcomes in patients with severe organ manifestations, in particular proteinuria and renal function impairment, are still critical and warrant further investigation. Besides ERT being an optimized adjunctive therapy, timely initiation of ERT is important to assure optimal medical care. Subsequent follow-up assessments should be carried out in all patients on a regular basis to evaluate treatment outcomes.     

Identification of Fabry's disease by the screening of alpha-galactosidase A activity in male and female hemodialysis patients

BACKGROUND: Although previous studies reported that the prevalence of Fabry's disease was 0.16 - 1.2% in hemodialysis (HD) patients based on measurement of a-galactosidase A (alpha-Gal A) activity, few reports detected female patients by the screening for alpha-Gal A. Here we determined the prevalence of Fabry's disease not only in male but also in female HD patients by measuring alpha-Gal A. METHODS: Plasma alpha-Gal A was measured in 696 consecutive males (n = 401) and females (n = 295) on HD. Patients with low plasma alpha-Gal A were examined for leukocyte alpha-Gal A, and patients with low leukocyte alpha-Gal A underwent alpha-Gal A gene sequence analysis for possible mutations, and family survey. RESULTS: Among 15 patients with low plasma alpha-Gal A activity, 4 male patients with low leukocyte alpha-Gal A and 1 female patient revealing low plasma alpha-Gal A were detected in 696 HD patients (0.7% of total patients). 3 of these 5 patients were already diagnosed to have the classical type of Fabry's disease. The other 2 patients were newly diagnosed as Fabry's disease, and did not have typical manifestations of Fabry's disease other than renal failure and left ventricular hypertrophy. DNA analysis of these 2 newly diagnosed patients revealed that each had an alpha-Gal missense mutation, previously identified (E66Q, M2961). CONCLUSION: Fabry's disease should be considered in the etiology of unexplained end-stage renal disease. Not only affected males but also affected females undergoing HD patients can be readily diagnosed by alpha-Gal A activities and gene analysis. These patients and their family members may benefit from enzyme replacement therapy for Fabry's disease.     

A nationwide blood spot screening study for Fabry disease in the Czech Republic haemodialysis patient population.

BACKGROUND: Fabry disease (FD) is a genetic disorder characterized by accumulation of trihexosylceramide in lysosomes of various tissues leading to multiorgan manifestations, including progressive renal disease. Previous screening studies have shown that a non-neglectable proportion of haemodialysis(HD) patients have unsuspected FD. An extensive FD screening study, the largest to date, has been conducted in HD patients in Czech Republic. We aimed to uncover previously undiagnosed FD patients, to enable them to benefit from cause-specific therapeutic intervention with enzyme replacement therapy (ERT). METHODS: Large-scale screening was executed using a convenient automated enzymatic (alpha-galactosidose A, alpha-Gal A) dried blood spot on filter paper fluorescence method. RESULTS: In total, 3370 (45.1% males, 54.9% females) out of 4058 HD patients (83%) in Czech Republic participated in this blood spot screening (BSS) study. Abnormal low fluorescence readings were obtained in 117 patients (3.5%). Subsequent determination of plasma alpha-Gal A activity identified four males and three females with deficient plasma enzyme activity. Determination of alpha-Gal A activity in peripheral blood leucocytes and confirmatory molecular analysis resulted in four newly diagnosed Fabry males and one female. Subsequent family screening identified 10 family members with genotypically proven FD. Based on these screening results, ERT could be offered to five male FD patients. CONCLUSIONS: BSS represents a promising screening tool that has proven to be convenient and effective in uncovering unrecognized FD patients among the chronic HD population in Czech Republic.     

Complete Atrioventricular Block After Kidney Transplantation in a Patient With Fabry Disease Receiving Enzyme Replacement Therapy: A Case Report

Fabry disease (FD) is a rare X-linked lysosomal storage disorder that results from the deficient activity of the lysosomal enzyme α-galactosidase A (α-Gal A) enzyme. Kidney transplantation is an option for treating end-stage renal disease in patients with FD. However, only a few cases of kidney transplantation have been reported involving patients with FD and end-stage renal disease and cardiomyopathy after enzyme replacement therapy. A 53-year-old man who underwent peritoneal dialysis was referred to our department because his brother was diagnosed with FD. The diagnosis of FD was also confirmed in our patient on account of the reduced leukocyte α-Gal A enzyme activity and mutation in the α-galactosidase A gene (p.Arg301Gln). Though our patient had end-stage renal disease, he received enzyme replacement therapy with 1 mg/kg agalsidase-β every 2 weeks (Fabrazyme; Genzyme Co, Mass, USA) owing to markedly diffuse cardiac hypertrophy. Six years later, he underwent successful deceased-donor kidney transplantation. The post-transplantation course was uneventful, 4 months after transplantation. However, though he showed T-cell-mediated rejection on kidney biopsy, lamellar lysosomal inclusions were not present in vascular endothelial cells. After several months, a permanent pacemaker was inserted owing to a complete atrioventricular block; the patient died of sepsis and candidemia 1 year later. Deceased-donor kidney transplantation was successfully performed in an FD patient with sustained enzyme replacement therapy. However, owing to high cardiac morbidity and infection risks even after enzyme replacement therapy, close monitoring of these risks is essential for increasing patient survival after kidney transplantation.     

Fabry disease in the era of enzyme replacement therapy: a renal perspective

Fabry disease, the second most prevalent lysosomal storage disorder after Gaucher disease, is caused by mutations of the gene encoding the lysosomal hydrolase, -galactosidase A. The enzymatic defect is inherited in an X-linked recessive fashion and leads to systemic glycosphingolipid deposition, resulting in profound dysfunction of neurological, renal, cardiac, and cerebrovascular systems. Although symptoms typically appear in childhood in hemizygous males and some heterozygous females, the diagnosis is often delayed or unrecognized, owing to variable presentations and low incidence. The initial phase begins in childhood or adolescence and is characterized by neuropathic pain, angiokeratomas, and ocular deposits. The later phase is distinguished by progressive cardiac, cerebral, and renal involvement, leading to multi-organ dysfunction and death. Recently published clinical trials have demonstrated the efficacy of enzyme replacement therapy in decreasing neuropathic pain and substrate deposition in target organs. Pediatricians have a key role to play in making the diagnosis, so that therapy can be initiated before irreversible tissue injury develops. Further research is required to determine optimal dosing protocols for treatment and to establish whether therapy can retard the progression of organ dysfunction, or even prevent these complications altogether.     

Fabry disease

Fabry disease resulting from a deficiency of α-galactosidase A leads to the accumulation of globotriaosylceramide in various organs. Because the disease is an X-linked recessive disorder, males tend to develop more symptoms and more severe symptoms than females. There are also some variants of Fabry disease, and cardiac variant (cardiac Fabry disease) has the dysfunctions only in heart. Cardiac manifestations in Fabry disease are initially symmetrical and concentric left ventricular hypertrophy, and later progressive cardiac dysfunction with localized thinning of the basal posterior wall. In recent years, enzyme replacement therapy has been performed as a treatment for Fabry disease, and the initiation of this therapy is expected before the cardiac fibrosis develops. Therefore, early diagnosis of Fabry disease is essential, and echocardiography is an indispensable tool for clinical practice of this disease. Then, it is necessary to remember this disease as a differential diagnosis when encountering unexplained left ventricular hypertrophy.     

Globotriaosylceramide accumulation in the Fabry kidney is cleared from multiple cell types after enzyme replacement therapy

BACKGROUND: Fabry disease, a lysosomal storage disease caused by deficient lysosomal alpha-galactosidase A activity, is characterized by globotriaosylceramide (GL-3) accumulation in multiple cell types, particularly the vasculature, leading to end organ failure. Accumulation in the kidney is responsible for progressive decline in renal function in male patients with the classical phenotype, resulting in renal failure in their third to fifth decades of life. With the advent of recombinant protein synthesis technology, enzyme replacement therapy has become a viable alternative to dialysis or renal transplantation, previously the only available treatment options for end-stage renal disease. METHODS: The pre- and post-treatment renal biopsies were analyzed from fifty-eight Fabry patients enrolled in a Phase 3 double-blind, randomized, placebo-controlled trial followed by a six-month open label extension study of the recombinant human enzyme, alpha-galactosidase A (r-halphaGalA), administered IV at 1 mg/kg biweekly. The purpose of this investigation was to detail the pathologic changes in glycosphingolipid distribution and the pattern of post-treatment clearance in the kidney. RESULTS: Baseline evaluations revealed GL-3 accumulations in nearly all renal cell types including vascular endothelial cells, vascular smooth muscle cells, mesangial cells and interstitial cells, with particularly dense accumulations in podocytes and distal tubular epithelial cells. After 11 months of r-halphaGalA treatment there was complete clearance of glycolipid from the endothelium of all vasculature as well as from the mesangial cells of the glomerulus and interstitial cells of the cortex. Moderate clearance was noted from the smooth muscle cells of arterioles and small arteries. Podocytes and distal tubular epithelium also demonstrated evidence for decreased GL-3, although this clearance was more limited than that observed in other cell types. No evidence of immune complex disease was found by immunofluorescence despite circulating anti-r-halphaGalA IgG antibodies. CONCLUSIONS: These findings indicate a striking reversal of renal glycosphingolipid accumulation in the vasculature and in other renal cell types, and suggest that long-term treatment with r-halphaGalA may halt the progression of pathology and prevent renal failure in patients with Fabry disease.