Evolution of renal pathology in Fabry disease

Fabry disease is a rare lysosomal storage disorder which results from deficient activity of the enzyme alpha-galactosidase A. The resultant deposition and progressive accumulation of glycosphingolipids in all types of body tissue leads to severe clinical manifestations involving the heart, CNS and kidney. Renal manifestations are observed relatively early in the course of the disease, and progression to end-stage renal failure is common in hemizygous males in the third to fifth decades of life. Renal biopsy specimens reveal evidence of diffuse intracytoplasmic glycosphingolipid accumulation, mainly affecting podocytes and epithelial cells of distal tubules, which are strikingly enlarged and vacuolated. On electron microscopy the deposits appear as typical osmiophilic inclusion bodies in the cytoplasm of all kinds of renal cells, and show a characteristic 'onion skin' or 'zebra' appearance. These pathological features are also evident in heterozygous females. Deposits occur before the development of renal impairment. As patients age, the disease progresses in cells throughout the kidney, and is associated with increasing glycosphingolipid accumulation. CONCLUSION: The age-related evolution of renal pathology in Fabry disease is closely correlated with progressive intracellular deposition of glycosphingolipid and ultimately leads to end-stage renal failure.     

Diagnostic problems in a 17-year-old patient with gastrointestinal manifestations of Fabry disease

Fabry disease is a rare X-linked recessive lysosomal storage disorder caused by deficiency of lysosomal enzyme alpha-galactosidase, which leads to accumulation of globotriasylceramides (GL-3) in visceral tissues and vascular endothelium, causing multi-organ failure. We presenta case of Fabry disease in a 17-year-old patient with mainly gastrointestinal manifestations, diagnosed 10 years after the manifestation of first symptoms. Significant and progressive weight loss with abdominal pain and vomiting, leading to cachexia, were observed in early childhood. The patient was investigated for non-inflammatory bowel diseases, Raynaud syndrome, polimyositis, mitochondrial cytopathies, intestinal lypodystrophies and others. The symptoms of intenstinal pseudo-obstruction syndrome were observed and surgical treatment was instituted because of necrosis of the colon. There was progressive cachexia and parenteral nutrition had to be instituted. Finally, plasma alpha-galactosidase was measured, and its deficit confirmed Fabry disease. In conclusion gastrointestinal symptoms in the course of Fabry disease can obscure other characteristic symptoms, may be prodromal and leading. Heart and renal failure may not occur in children. Unexplained abdominal pain and malnutrition may be gastrointestinal manifestations of metabolic disorders.     

Proteinuria and its consequences in renal disease

Chronic renal diseases that involve proteinuria are typically characterized by an inexorable progression to end-stage renal failure. Many studies suggest that this progression may be the result of factors, such as intraglomerular hypertension and glomerular hypertrophy, that are unrelated to the initial disease. This paper reviews the mechanisms of progression of chronic renal diseases and discusses therapeutic strategies that should prevent or minimize further renal damage and the applicability of these strategies to patients with the rare X-linked lysosomal storage disorder Fabry disease. Renal involvement is a major feature of Fabry disease, which is characterized by vacuolated epithelial cells in the glomerulus and distal tubules, resulting from lipid inclusions within these cells. Although enzyme replacement therapy is the key strategy to halt the progression of Fabry disease, additional therapeutic options include blood pressure control, reduction of proteinuria, lipid control and inhibition of the renin-angiotensin system.
Conclusion : A range of therapeutic options, used in conjunction with enzyme replacement therapy, may have beneficial effects on the renal manifestations of Fabry disease.     

Proteinuria and its consequences in renal disease

Chronic renal diseases that involve proteinuria are typically characterized by an inexorable progression to end-stage renal failure. Many studies suggest that this progression may be the result of factors, such as intraglomerular hypertension and glomerular hypertrophy, that are unrelated to the initial disease. This paper reviews the mechanisms of progression of chronic renal diseases and discusses therapeutic strategies that should prevent or minimize further renal damage and the applicability of these strategies to patients with the rare X-linked lysosomal storage disorder Fabry disease. Renal involvement is a major feature of Fabry disease, which is characterized by vacuolated epithelial cells in the glomerulus and distal tubules, resulting from lipid inclusions within these cells. Although enzyme replacement therapy is the key strategy to halt the progression of Fabry disease, additional therapeutic options include blood pressure control, reduction of proteinuria, lipid control and inhibition of the renin-angiotensin system. CONCLUSION: A range of therapeutic options, used in conjunction with enzyme replacement therapy, may have beneficial effects on the renal manifestations of Fabry disease.     

Natural history of the cerebrovascular complications of Fabry disease

Fabry disease is a rare, X-linked lysosomal storage disease caused by an inborn deficiency of alpha-galactosidase A, which results in progressive accumulation of globotriaosylceramide in a range of cells and tissues. Neurological symptoms of Fabry disease, including peripheral neuropathy and cerebrovascular events, are among the most significant clinical aspects. In this paper we present the natural history and mechanisms involved in the cerebrovascular complications of Fabry disease using data reported in FOS-- the Fabry Outcome Survey--and other registries and clinical studies. We discuss ways in which these manifestations can be modified by intervention, including both general measures for cerebrovascular disease and enzyme replacement therapy. Conclusion: Data from FOS have provided important insights into the natural history of the cerebrovascular complications of Fabry disease. Furthermore, the database has demonstrated that significant renal or cardiac disease often co-exists with cerebrovascular disease, and may predispose patients with Fabry disease to neurological disability and stroke.     

Natural history of the cerebrovascular complications of Fabry disease

Fabry disease is a rare, X-linked lysosomal storage disease caused by an inborn deficiency of α-galactosidase A, which results in progressive accumulation of globotriaosylceramide in a range of cells and tissues. Neurological symptoms of Fabry disease, including peripheral neuropathy and cerebrovascular events, are among the most significant clinical aspects. In this paper we present the natural history and mechanisms involved in the cerebrovascular complications of Fabry disease using data reported in FOS – the Fabry Outcome Survey – and other registries and clinical studies. We discuss ways in which these manifestations can be modified by intervention, including both general measures for cerebrovascular disease and enzyme replacement therapy.
Conclusion: Data from FOS have provided important insights into the natural history of the cerebrovascular complications of Fabry disease. Furthermore, the database has demonstrated that significant renal or cardiac disease often co-exists with cerebrovascular disease, and may predispose patients with Fabry disease to neurological disability and stroke.     

Pediatric aspects of Fabry's disease]

Fabry's disease is a rare X-linked inborn error of glycosphingolipid metabolism characterised by an abnormal lipid storage due to a defect of lysozomal alphagalactosidase. The consequence is a storage of glycosphingolipides in all tissues. This storage in vessels's endothelial cells is responsible, in males, for severe ischemic lesions leading to progressive kidney failure, cardiac and cerebral dysfunctions. Similarly, it involves ocular tissues, mainly the cornea, the conjunctiva and the lens. The corneal storage, known as cornea verticillata, is a clinical marker easy to recognize by slit lamp examination of the affected males and carrier females. The enzymatic activity of alphagalactosidase is reduced in tears. Characteristic lamellar bodies can be observed by electron microscopy study of a conjunctival biopsy. Until recently, treatment was limited to symptomatic management of pain, and end-stage complications of renal failure, cardiac or brain disease. Recent studies have demonstrated that enzyme replacement therapy by genetic engineering is now shown to be promising for affected patients.     

Fabry disease during childhood: clinical manifestations and treatment with agalsidase alfa

Fabry disease is a rare X-linked disorder that leads to widespread and progressive disease manifestations, with patients at risk of premature mortality as a result of renal, cardiovascular or cerebrovascular complications. In recent years there has been a growing awareness that the first signs and symptoms of Fabry disease may begin during childhood. Studies show that clinical manifestations such as pain, hypohidrosis, gastrointestinal disturbances, angiokeratomas, cornea verticillata and acroparaesthesiae may be common in childhood and that such manifestations may become apparent during the first few years of life. Despite the early onset of these signs and symptoms, however, diagnosis is often delayed. Interest is now focused on whether enzyme replacement therapy can slow or prevent the onset of these disease manifestations. Preliminary data from two studies suggest that treatment with agalsidase alfa is well tolerated in children and that it may have beneficial clinical effects; however, further research is needed to determine whether enzyme replacement therapy can prevent the development of disease manifestations. CONCLUSION: The manifestations of Fabry disease first become apparent during childhood. It is well known that disease-associated manifestations are progressive; however, it has yet to be determined whether specific treatment with enzyme replacement therapy can prevent the development of the associated severe and life-threatening complications.     

Sequelae of storage in Fabry disease--pathology and comparison with other lysosomal storage diseases

AIM: To evaluate the sequelae of the lysosomal storage of globotriaosylceramide (Gb3) in a series of patients with Fabry disease. METHODS: Biopsy and post-mortem samples from 12 patients with Fabry disease were examined microscopically, including, in some cases, immunohistochemistry and electron microscopy. Where possible, comparisons were made with other lysosomal storage disorders. RESULTS: Storage of Gb3 in cardiocytes leads commonly to progressive hypertrophy, which is a non-specific phenomenon also observed in other lysosomal storage disorders. Capillary endothelial storage was associated with a tendency for capillary basement membrane multiplication. In the single angiokeratoma studied, the basement membrane was rudimentary. Sinusoids in the adrenal cortex and liver displayed either a slight degree of storage or were unaffected. The glomeruli of the kidney exhibited focal hyalinization starting in the mesangial region. Proximal tubular cells were essentially free of lysosomal accumulation, including protein absorption droplets, despite the presence of proteinuria. In only one case, an autopsied Fabry heterozygote, were the proximal tubular cells loaded with protein absorption droplets. The arterial wall in large muscular arteries (coronary, renal and intrarenal) displayed arteriopathy with pronounced involvement of the smooth muscle cells in the media. Arteriopathy started with storage, followed by cell degeneration and breakdown, extracellular matrix deposition and, often, calcification (confined to the muscular layer). Smooth muscle cells occasionally exhibited shrinkage-type necrosis, with dispersion of the stored lipid into the dense cytoplasmic mass. Intimal and mitral valve fibroblasts exhibited variable storage, which was associated with cell loss and necrosis. Intensive storage was found in Leydig cells and in the epididymal epithelium. CONCLUSION: These long-term sequelae of Gb3 storage are mostly irreversible. Some may interfere with enzyme replacement therapy. It is important, therefore, to consider starting enzyme replacement therapy as early as possible.     

Clinical manifestations of Fabry disease in children: data from the Fabry Outcome Survey

BACKGROUND: Fabry disease is a rare X-linked disorder caused by deficient activity of the enzyme alpha-galactosidase A. This produces progressive lysosomal accumulation of globotriaosylceramide throughout the body, leading to organ failure and premature death. AIM: Here, we present the clinical manifestations of Fabry disease in children enrolled in FOS--the Fabry Outcome Survey--a European database of the natural history of Fabry disease and the effects of enzyme replacement therapy with agalsidase alfa (Replagal). METHODS: Currently, there are 545 patients in FOS, from 11 European countries. We analysed the baseline demographic and clinical characteristics of 82 of these patients (40 boys, 42 girls) who were below 18 y of age. The median age at evaluation (defined as the median age at entry into FOS) was 12.5 and 13.2 y for boys and girls, respectively. RESULTS: The most frequent early clinical manifestations of Fabry disease were neurological (acroparaesthesiae, altered temperature sensitivity) and gastrointestinal symptoms (altered bowel habits and abdominal pain), which were documented in about 80% and 60% of patients, respectively, at the time of evaluation and subsequent entry into FOS. Tinnitus, vertigo, fatigue and angiokeratoma were present in over 40% of patients. Symptoms were noted in early childhood and occurred with similar frequency in boys and girls, although the onset of symptoms was 2-5 y later in girls than in boys. There was an approximately 3-y delay from onset of symptoms to diagnosis, and patients were frequently misdiagnosed. CONCLUSION: Although the life-threatening complications of Fabry disease, such as stroke and renal and heart failure, are not seen in children, the present analysis shows that other symptoms are common and may have an impact on quality of life.     

Cardiac manifestations of Anderson-Fabry disease in children and adolescents

AIM: Fabry disease (Fabry) is a rare X-linked disorder caused by a deficiency of the lysosomal enzyme alpha-galactosidase A. The progressive accumulation of the major substrate, globotriaosylceramide, leads to renal dysfunction and hypertrophic cardiomyopathy, which are reported to become apparent in the third decade. This study was performed to determine if signs of cardiac manifestations of Fabry are seen in younger Fabry patients. METHODS: Twenty children and adolescents of 75th percentile of that in healthy controls. After a mean 26-month follow-up, 12 out of 14 patients (85.7%) showed a mean increase of 7.5+/-3.2 g/m(2.7) in LVM/h(2.7). Heart rate variability (HRV) analyses revealed that male, but not female, Fabry patients had significantly reduced HRV, reflecting a reduction in parasympathetic stimulation of the heart (p<0.05). CONCLUSION: Cardiac involvement in children with Fabry is frequent and may progress even at young age.     

Cardiac involvement in Fabry disease

Fabry disease is a rare X-linked defect of the lysosomal enzyme α-galactosidase A. The disease is characterized by progressive intracellular accumulation of neutral glycosphingolipids. The storage occurs within various tissues and cells, including cardiocytes, the cardiac conduction system, and valvular fibrocytes. Cardiac involvement may be the sole manifestation of the disease, particularly in individuals with residual enzyme activity. In general, hemizygous men are more seriously affected than heterozygous women. The main cardiac manifestations include myocardial hypertrophy, which, in some patients, mimics hypertrophic cardiomyopathy. Conduction system involvement leads to PR shortening or, in later stages, to AV blocks. Arrhythmias presenting with variable severity also appear to be common. Valvular involvement is frequently noted but generally mild and clinically non-significant. Newly available enzyme replacement therapy has produced promising results in preventing further functional deterioration of affected organs and possibly also in reversing impaired function.
Conclusions : With the advent of effective enzyme replacement therapy, early diagnosis of Fabry disease may be crucial for patient prognosis.     

Cardiac involvement in Fabry disease

Fabry disease is a rare X-linked defect of the lysosomal enzyme alpha-galactosidase A. The disease is characterized by progressive intracellular accumulation of neutral glycosphingolipids. The storage occurs within various tissues and cells, including cardiocytes, the cardiac conduction system, and valvular fibrocytes. Cardiac involvement may be the sole manifestation of the disease, particularly in individuals with residual enzyme activity. In general, hemizygous men are more seriously affected than heterozygous women. The main cardiac manifestations include myocardial hypertrophy, which, in some patients, mimics hypertrophic cardiomyopathy. Conduction system involvement leads to PR shortening or, in later stages, to AV blocks. Arrhythmias presenting with variable severity also appear to be common. Valvular involvement is frequently noted but generally mild and clinically non-significant. Newly available enzyme replacement therapy has produced promising results in preventing further functional deterioration of affected organs and possibly also in reversing impaired function. CONCLUSIONS: With the advent of effective enzyme replacement therapy, early diagnosis of Fabry disease may be crucial for patient prognosis.     

Effects of enzyme replacement therapy with agalsidase alfa on glomerular filtration rate in patients with Fabry disease: preliminary data

Progressive deposition of globotriaosylceramide results in severe complications involving the kidney, heart and brain in both hemizygous male and heterozygous female patients with Fabry disease. Analysis of renal data from FOS--the Fabry Outcome Survey--suggests that enzyme replacement therapy with agalsidase alfa can significantly improve renal function in patients with Fabry disease, at least in those with a mild decrease in glomerular filtration rate, and may also be able to slow down the natural decline in renal function in patients with a moderate reduction in glomerular filtration rate. CONCLUSION: Initial results from the large cohort of patients within FOS indicate that treatment with agalsidase alfa has beneficial effects on kidney function in patients with Fabry disease.     

Endothelial markers and homocysteine in patients with classic Fabry disease

Aim : Fabry disease is an X-linked inborn error of glycosphingolipid metabolism due to the deficient activity of α-galactosidase A, a lysosomal enzyme. It is a multisystem disorder characterized by progressive renal insufficiency, with added morbidity from cardio- and cerebrovascular involvement. The recent availability of genetically engineered enzyme offers an effective targeted treatment approach, but also emphasizes the need for surrogate markers to delineate organ damage and monitor the efficacy of enzyme replacement therapy (ERT). Methods : Multiple endothelial factors and plasma homocysteine concentrations were investigated in 12 consecutive hemizygous males with classic Fabry disease and 15 controls as part of an exhaustive baseline evaluation prior to ERT. Results : Compared with the controls, plasma concentrations of homocysteine were significantly ( p > 0.01) higher in patients with Fabry disease in the absence of chronic renal failure or vitamin deficiency. Plasma concentrations of vascular cell adhesion molecule-1 were also significantly ( p > 0.05) higher in the patients, and there was a trend for decreased endothelin-1 levels. No difference was found in serum intercellular adhesion molecule-1, plasma P-selectin, serum E-selectin and plasma thrombomodulin between the patients and controls.
Conclusions : The results do not reveal measurable evidence for endothelial and leukocyte activation that could reliably serve as surrogate markers for routine monitoring of the efficacy of ERT in patients with Fabry disease. While the exact origin and clinical significance of hyperhomocysteinaemia in Fabry disease remains to be studied in a larger cohort of patients carefully monitored for their concurrent medications, especially carbamazepine, we suggest that patients may benefit from folic acid or multivitamin therapy to treat this additional vascular risk factor, when present.     

Vascular complications of Fabry disease: enzyme replacement and other therapies

Fabry disease is an X-linked glycosphingolipid storage disorder resulting from deficiency of α-galactosidase A. Storage of globotriaosylceramide ultimately results in multiorgan pathology, including cerebrovascular, cardiovascular and renal disease. Vascular involvement is evident throughout the body but the mechanisms by which storage on a cellular level leads to end-organ pathology are unknown. Here the evidence for abnormal blood flow, vessel architecture and endothelial function will be reviewed and possible models of vascular pathology discussed. The effects of reversal of storage within vessels by enzyme replacement therapy (ERT) and the possibilities for intervention with additional agents will be considered.
Conclusion: The pathology of Fabry disease has an important vascular component, although the underlying pathophysiology is unclear. Preliminary evidence suggests that ERT may have beneficial effects on the vascular component of this multisystem disease.     

Endothelial markers and homocysteine in patients with classic Fabry disease

AIM: Fabry disease is an X-linked inborn error of glycosphingolipid metabolism due to the deficient activity of alpha-galactosidase A, a lysosomal enzyme. It is a multisystem disorder characterized by progressive renal insufficiency, with added morbidity from cardio- and cerebrovascular involvement. The recent availability of genetically engineered enzyme offers an effective targeted treatment approach, but also emphasizes the need for surrogate markers to delineate organ damage and monitor the efficacy of enzyme replacement therapy (ERT). METHODS: Multiple endothelial factors and plasma homocysteine concentrations were investigated in 12 consecutive hemizygous males with classic Fabry disease and 15 controls as part of an exhaustive baseline evaluation prior to ERT. RESULTS: Compared with the controls, plasma concentrations of homocysteine were significantly (p < 0.01) higher in patients with Fabry disease in the absence of chronic renal failure or vitamin deficiency. Plasma concentrations of vascular cell adhesion molecule-1 were also significantly (p < 0.05) higher in the patients, and there was a trend for decreased endothelin-1 levels. No difference was found in serum intercellular adhesion molecule-1, plasma P-selectin, serum E-selectin and plasma thrombomodulin between the patients and controls. CONCLUSIONS: The results do not reveal measurable evidence for endothelial and leukocyte activation that could reliably serve as surrogate markers for routine monitoring of the efficacy of ERT in patients with Fabry disease. While the exact origin and clinical significance of hyperhomocysteinaemia in Fabry disease remains to be studied in a larger cohort of patients carefully monitored for their concurrent medications, especially carbamazepine, we suggest that patients may benefit from folic acid or multivitamin therapy to treat this additional vascular risk factor, when present.     

Vascular complications of Fabry disease: enzyme replacement and other therapies

Fabry disease is an X-linked glycosphingolipid storage disorder resulting from deficiency of alpha-galactosidase A. Storage of globotriaosylceramide ultimately results in multiorgan pathology, including cerebrovascular, cardiovascular and renal disease. Vascular involvement is evident throughout the body but the mechanisms by which storage on a cellular level leads to end-organ pathology are unknown. Here the evidence for abnormal blood flow, vessel architecture and endothelial function will be reviewed and possible models of vascular pathology discussed. The effects of reversal of storage within vessels by enzyme replacement therapy (ERT) and the possibilities for intervention with additional agents will be considered. Conclusion: The pathology of Fabry disease has an important vascular component, although the underlying pathophysiology is unclear. Preliminary evidence suggests that ERT may have beneficial effects on the vascular component of this multisystem disease.     

Effects of enzyme replacement therapy with agalsidase alfa on glomerular filtration rate in patients with Fabry disease: preliminary data

Progressive deposition of globotriaosylceramide results in severe complications involving the kidney, heart and brain in both hemizygous male and heterozygous female patients with Fabry disease. Analysis of renal data from FOS - the Fabry Outcome Survey - suggests that enzyme replacement therapy with agalsidase alfa can significantly improve renal function in patients with Fabry disease, at least in those with a mild decrease in glomerular filtration rate, and may also be able to slow down the natural decline in renal function in patients with a moderate reduction in glomerular filtration rate.
Conclusion : Initial results from the large cohort of patients within FOS indicate that treatment with agalsidase alfa has beneficial effects on kidney function in patients with Fabry disease.     

Fabry disease in children and the effects of enzyme replacement treatment

Fabry disease is a rare, X-linked inborn error of glycosphingolipid catabolism caused by a deficiency in the activity of the lysosomal enzyme, α-galactosidase A. In affected patients, the enzyme substrate, globotriaosylceramide (Gb3), accumulates in cells of various tissues and organs. Lysosomal accumulation of Gb3 begins in utero, and signs and symptoms of Fabry disease emerge in childhood and adolescence. The earliest presenting symptoms are typically neuropathic pain and gastrointestinal problems, which can have a substantial impact on health-related quality of life. Life-threatening major organ involvement is rare in young patients, but signs of kidney dysfunction (e.g., proteinuria), left ventricular hypertrophy, and stroke have been reported in children. There are two enzyme preparations for therapy: agalsidase alfa and beta. In two clinical trials of enzyme replacement therapy (ERT) with agalsidase alfa, including 37 children, boys demonstrated reductions in plasma Gb3 levels, and both boys and girls reported reductions in neuropathic pain and in the use of neuropathic pain medications. Heart rate variability, which is reduced in boys with Fabry disease, was statistically significantly improved with 6 months of agalsidase alfa treatment. In a single clinical study of agalsidase beta in children (n =16), skin Gb3 deposits and plasma Gb3 levels were reduced in boys. Differences exist in the administration and the safety profile of these two enzyme formulations. Follow-up of these cohorts and additional studies will be necessary to fully evaluate long-term efficacy of ERT in children with Fabry disease.