Search

Purpose of Review: To deeply investigate one type of intracellular cardiac storage disease, the Fabry disease and one example of extracellular cardiac storage disease, the cardiac amyloidosis, with the aim to collect data about cardiac treatment at the end-stage level and the feasibility of heart transplantation (HTx) in this setting of patients., Recent Findings: Some registry describes that Fabry disease and cardiac amyloidosis showed similar characteristics as hypertrophic cardiomyopathies; thus, their correct diagnosis is often missing or time consuming. A multiorgan approach is mandatory to recognize the main systemic findings of these diseases, involving also the kidneys, the brain, the autonomous system and the skin., Summary: The early diagnosis of these diseases is required to start as soon as possible the correct therapy for the patients affected. However, the end-stage heart failure is common and HTx could be offered to selected patients, especially if affected by light chain cardiac amyloidosis, to allow to perform the autologous stem cell transplantation after the cardiac transplant. Considering the Fabry disease patients, the enzyme recombinant therapy is also mandatory after HTx to avoid potential release of the systemic disease on the donor graft.

Competing Interests: Competing interests: None declared.

Background: Fabry disease is a treatable X-linked condition leading to progressive cardiomyopathy, arrhythmia and premature death. Atrial and ventricular arrhythmias contribute significantly to adverse prognosis; however, guidance to determine which patients require cardiovascular implantable electronic devices (CIEDs) is sparse. We aimed to evaluate indications for implantation practice in the UK and quantify device utilisation., Methods: In this retrospective study, we included demographic, clinical and imaging data from patients in four of the largest UK Fabry centres. Ninety patients with Fabry disease were identified with CIEDs implanted between June 2001 and February 2018 (FD-CIED group). To investigate differences in clinical and imaging markers between those with and without devices, these patients were compared with 276 patients without a CIED (FD-control)., Results: In the FD-CIED group, 92% of patients with permanent pacemakers but only 28% with implantable cardioverter-defibrillators had a class 1 indication for implantation. A further 44% of patients had defibrillators inserted for primary prevention outside of current guidance. The burden of arrhythmia requiring treatment in the FD-CIED group was high (asymptomatic atrial fibrillation:29%; non-sustained ventricular tachycardia requiring medical therapy alone: 26%; sustained ventricular tachycardia needing anti-tachycardia pacing/defibrillation: 28%). Those with devices were older, had greater LV mass, more scar tissue and larger atrial size., Conclusions: Arrhythmias are common in Fabry patients. Those with cardiac devices had high rates of atrial fibrillation requiring anticoagulation and ventricular arrhythmia needing device treatment. These are as high as those in hypertrophic cardiomyopathy, supporting the need for Fabry-specific indications for device implantation., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY. Published by BMJ.)

Fabry's disease is a lysosomal storage disease characterized by intracellular accumulation of ceramide trihexoside resulting from alpha-galactosidase A deficiency. While the heart is often involved, coronary artery disease and its management in Fabry's disease patients are extremely rare clinical entities. We report a case of a 72-year-old man with left main disease in Fabry's disease with special consideration of the arterial wall pathology., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Fabry's disease has cardiac manifestations that may mimic hypertrophic cardiomyopathy, including left ventricular outflow tract (LVOT) obstruction. It is important to distinguish hypertrophic cardiomyopathy from Fabry's disease, which can be treated with enzyme replacement therapy (ERT). However, after adequate ERT, some patients have no resolution of cardiac symptoms; thus, septal myectomy might be considered. We present 2 cases of extended septal myectomy in patients with LVOT obstruction secondary to Fabry's disease., (Copyright © 2013 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Patients with some hereditary nephropathies-including autosomal dominant polycystic kidney disease (ADPKD), Fabry disease and Alport syndrome-can progress to end-stage renal disease (ESRD) and are candidates for kidney transplantation. When considering whether a potential living donor is appropriate for a particular patient, clinicians should be aware of the increased risk of adverse outcomes for the donor and the recipient. Renal transplantation from a living related donor is not contraindicated in most nephropathies that have an autosomal recessive mode of inheritance (for example, autosomal recessive polycystic kidney disease and cystinosis). Renal transplant recipients with ADPKD, however, should only receive a kidney from a related donor if the disease has been excluded in the donor by imaging and/or genetic testing. Potential living related donors for patients with Alport syndrome should be evaluated carefully for the presence of microhematuria and microalbuminuria before a decision is made to perform transplantation, and mothers or heterozygous sisters of affected male recipients with X-linked Alport syndrome should be informed about the possible long-term increased risk of renal dysfunction associated with donation. Most patients with atypical hemolytic uremic syndrome should not receive a kidney transplant from a living donor because there is a high risk of disease recurrence and graft loss.

Fabry's disease is an X-linked recessive disorder that results from the deficiency of alpha-galactosidase A and causes the accumulation of globotriaosylceramide (Gb3) in different tissues. It leads to a rare form of cardiomyopathy which may be complicated by end-stage heart failure and need to heart transplant. Our group described the first case of heart transplant in a woman with cardiomyopathy secondary to Fabry's disease about 12 years ago. There was uncertainty in regards to the possibility of recurrence of the disease as previously documented in kidney transplant recipients and long-term outcomes. In this report, 14 years after transplant, this woman is still alive and there is no evidence of Fabry's disease in any of the endomyocardial biopsies. Heart transplantation can be recommended for Fabry's patients with end-stage cardiomyopathy.

Fabry's disease is an X-linked error of metabolism with deficiency of the enzyme α-glycosidase A, and glycosphingolipid accumulation in multiple tissues. Patients may be asymptomatic and present with advanced disease. We report a case of a 38 year old white male who presented with end stage renal disease of unknown etiology. He received a living-related donor kidney transplant (mother), but lost the graft after 10 years to multiple episodes of rejection. Review of the native renal biopsy with added ultrastructural studies established the diagnosis of Fabry's disease. Evaluation of renal biopsies showing advanced chronic injury should include electron microscopic studies, which may reveal characteristic diagnostic features, as seen in this case of Fabry's disease. Identification of hereditary disorders involving the kidney is important for appropriate treatment and prevention of disease recurrence. Potential living related donors should be screened for genetic involvement.

Background: Fabry disease is a rare but important cause of end-stage renal disease (ESRD) among young men. Postkidney transplantation outcomes among patients with Fabry disease remain controversial., Methods: Using data from Organ Procurement Transplant Network/United Network for Organ Sharing, 197 kidney transplant recipients with ESRD because of Fabry disease from 1987 to 2007 were identified. We compared rates of graft loss and death with those of kidney transplant recipients with other (non-Fabry) causes of ESRD. Fabry patients were then compared with a 10:1 matched cohort of transplant recipients with other causes of ESRD., Results: Five-year graft survival was superior among Fabry patients (74%) compared with those with other causes of ESRD (69%), but was similar to those in the matched cohort (P=0.64). Five-year patient survival among Fabry patients (81%) was similar to those with other causes of ESRD (P=0.33), but was inferior to the matched cohort (90%). Cox multivariate analysis revealed that Fabry patients had a 40% lower risk of returning to dialysis compared with both matched and unmatched cohorts, but had a higher risk of death (2.15; 1.52-3.02) compared with the matched cohort., Conclusion: This analysis of 197 kidney transplant recipients with Fabry indicates that they have superior graft survival and similar patient survival compared with patients with other causes of ESRD. However, Fabry patients had a higher risk of death compared with a matched cohort of patients with other causes of ESRD. This requires further investigation and may suggest a need for further attention to the minimization of cardiovascular death in this group of patients.

Coronary artery bypass grafting was performed in a 54-year-old man affected by untreated Fabry's disease. Left internal mammary artery (LIMA) and saphenous vein grafts were implanted. Surgical samples of LIMA revealed diffuse glycosphyngolipid infiltration of smooth muscle cells, whereas SV was normal. After surgery, the patient received antithrombotic and enzyme replacement therapy. At 1-year follow-up, LIMA graft occluded, whereas saphenous vein graft remained patent. In Fabry's disease, veins, probably because of a low pressure load, seem to be spared from glycosphingolipid accumulation and are more suitable than arteries for grafting. A preventive histology of conduits is suggested before graft selection.

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.

Hematopoietic cell transplantation can impact lysosomal storage disorders (LSDs) and will be enhanced by gene therapy. Transduced cells in LSDs often secrete the therapeutic hydrolase, which can be used by bystander cells. However, toxicity associated with myeloablative transplant preparative regimens limits many applications of this approach in gene therapy. We hypothesized that reduced-intensity (RI) conditioning regimens would allow stable engraftment of therapeutically transduced cells and allow correction of Fabry disease. We transplanted transduced cells into Fabry mice receiving eight different clinically relevant chemotherapy- and/or radiotherapy-based RI conditioning regimens generating modest and transient lymphoid/myeloid cell depletion. Two comprehensive transplantation Protocols were performed. Firstly, transplantation of 0.38 x 10(6) gene-modified stem/progenitor cells was nominally effective; none of the RI regimens led to stable alpha-galactosidase A (alpha-gal A) correction. Secondly, transduced cells were preselected for functional transgene expression and transplanted at a higher dose (0.72 x 10(6) cells). Each RI regimen yielded engraftment of functional transgene-positive cells through 180 days along with increased plasma alpha-gal A activity. Importantly, the RI regimens mediated broad organ enzyme correction and were not associated with immune responses against alpha-gal A. RI conditioning thus has an important role in gene therapy for LSDs; a variety of regimens can be effective in this context.

Background: Fabry's disease (FD) is an inborn error of glycosphingolipid catabolism with progressive systemic deposition of globotriaosylceramide thereby leading to renal and cardiac failure. Current therapy involves symptomatic medical management, dialysis, enzyme replacement therapy, kidney transplantation (KTx), and more recently gene therapy. Case fatalities occur in the fourth decade of life resulting from uremia unless dialysis or KTx is undertaken., Study Design: This is a retrospective study aimed at determining the effect of KTx on the long-term outcome of patients with FD., Results: Between 1964 and 1998, ten patients with FD received KTx at our institutions. Actuarial patient and graft survivals were 100% and 90% at 5 years; 76% and 66% at 10 years. One kidney graft was lost due to rejection. Patient survival data compared favorably at 5 years with survival of FD patients on hemodialysis alone (41%, P < .05). Five patients are alive at the time of this study, and five patients died with median survival time after KTx of 128 months (range: 74-160 months)., Conclusions: This study demonstrates an excellent outcome in patients with FD in the first decade after KTx. In the absence of a severe contraindication, we advocate KTx to improve the overall prognosis of patients with renal failure due to FD. Based on the data, enzyme replacement therapy after KTx seems indicated, as FD progresses posttransplant, leading to case fatalities in the second decade after KTx.

Anderson-Fabry disease (AFd) is an X-linked metabolic disease with clinical manifestations secondary to accumulation of glycosphingolipids in various tissues. We report the first case in which a patient with renal variant of AFd and chronic renal failure developed bilateral conventional renal cell carcinoma. His metabolic disorder was diagnosed only after histopathologic study of the kidney specimen resected because of the tumoral lesion. There is no clear etiologic relation between the metabolic and neoplastic disease. As AFd is not common or well known and its clinical manifestations tend to be nonspecific, the disorder is often unrecognized, misdiagnosed, or diagnosed late in life. The pathologist should be aware of this disorder when evaluating a kidney specimen from patients with chronic renal failure of unknown cause.

Background: We sought to assess the safety and efficacy of enzyme replacement therapy (ERT) with recombinant human-alpha-galactosidase A (rh-alpha-Gal A) in kidney transplant recipients with Fabry disease, a previously unstudied population., Methods: Three male kidney transplant recipients with biochemically, genetically, and histologically confirmed Fabry disease and documented Fabry myocardiopathy received the rh-alpha-Gal A, agalsidase beta, 1 mg/kg of body weight every 2 weeks by intravenous infusion and were monitored biochemically, clinically, and electrocardiographically and echocardiographically for 18 months., Results: Patients showed biochemical, clinical/functional, and morphologic response to ERT. Plasma globotriaosylceramide decreased 23% to 50%. Extremity pain resolved within 2 months in the patient with this manifestation. On echocardiography, left ventricular mass, end diastolic diameter (EDD), and cardiac contractility, shown by ejection fraction (EF), improved in 2 of the 3 patients receiving essentially all planned infusions. EDD and EF remained basically stable, but cardiac morphologic abnormalities progressed in the other patient, who had a 5-month interruption in ERT after the initial month. Mild mitral insufficiency persisted in all patients, as did atrial fibrillation in the affected individual. After a combined total of 116 infusions, no treatment-related adverse event, intolerance, or seroconversion was seen. Renal function remained stable and the immunosuppression regimen unchanged in all patients., Conclusion: Our pilot study provides preliminary evidence that ERT with agalsidase beta, 1 mg/kg every 2 weeks, is safe and often effective against extra-renal manifestations in kidney transplant patients with Fabry disease. Studies with longer courses of this and higher doses of ERT are merited in this population.

Introduction: Fabry's disease is an X-linked error of glycosphingolipid metabolism. Clinical manifestations of the disease are secondary to accumulation of glycosphingolipids in various tissues. Renal failure and vascular complications are common. There are conflicting reports regarding the outcomes of patients with Fabry's disease after renal transplantation., Methods: We reviewed the United States Renal Data System Registry database from 1988 and 1998, and found 93 patients with Fabry's disease who had received a renal transplant. Case-matched patients were identified to serve as controls., Results: Patients with Fabry's disease demonstrated equivalent 5-year patient and graft survival, compared with controls (83% and 75%, respectively, for those with Fabry's disease vs. 82% and 67% for controls)., Conclusion: Despite their high risk for cardiovascular complications, patients with Fabry's disease have excellent outcomes after renal transplantation.

Fabry's disease is a rare cause of cardiomyopathy. There are no previous reported cases of cardiac transplantation for end-stage cardiomyopathy secondary to Fabry's disease. Recurrence of disease in allografts following renal transplantation has been documented, but the course following heart transplantation is not known. A 53-year-old female presented with congestive heart failure and was found to have end-stage restrictive cardiomyopathy secondary to Fabry's disease, as diagnosed by endomyocardial biopsy. She underwent cardiac transplantation. Eight weeks post-transplantation, electron microscopy of an endomyocardial biopsy specimen showed concentric lamellar inclusions within myocytes similar to inclusions seen in the preoperative biopsy and the explanted heart. However, subsequent biopsies up to one year after heart transplantation did not show any such inclusions. There has been no clinical evidence of Fabry's cardiomyopathy. Heart transplantation is a viable option for end-stage Fabry's cardiomyopathy. However, long term follow-up is required to determine clinical outcome.

A case of Fabry's disease in a renal transplant recipient with a follow-up period of 11 years is reported. The patient suffered from renal, skin, peripheral nerve lesions, and asymptomatic cardiomegaly. Fabry's disease symptoms disappeared after transplantation. Improvement of renal function was rapidly observed, and it remained satisfactory during the whole posttransplantation period. The patient died of a severe, uncontrolled infection and of biliary peritonitis. Autopsy showed a polyvisceral accumulation of sphingolipids deposits. The engrafted kidney was histologically free of disease. Ultrastructurally, it revealed numerous sphingolipid inclusions in the endothelial cells of capillaries. The explanation of this complication could be attributed to: (1) high circulating levels of plasma substrates locally overwhelming the enzymatic capability of the graft endothelial cells; and (2) the endothelial cells originated from the recipient but not from the donor, an occurrence that has been described after transplantation. Rejection and the newly formed deposits in the endothelial cells may lead to the loss of the engrafted organ. As a consequence of the increasing possibility of organ transplantation, this complication should be detected by studying the blood vessels ultrastructurally in order to evaluate the condition of the transplant.

We present a rare case of priapism in a child, ten years old, in association with Fabry's disease. The child had a history of disseminated nodular enlargement, crises of fever, intermittent pain in the extremities and ten hours persistent painful erection of the penis. We don't obtain pain or erection relief with sedation, epidural block and irrigation of the corporal bodies. A saphenous-cavernous shunt, in the Grayhack fashion made, being results satisfactory. In the follow-up, the child had sporadic pain in the extremities and no erection of the penis. The cavernosography showed the shunt open. Fabry's disease was confirmed by nodular biopsy and the demonstration of deficient alpha-galactosidase.

Fabry's disease, which is characterized by alpha-galactosidase A (AG) deficiency, causes early renal failure. Kidney transplants do not reliably supply the deficient enzyme. To assess both urinary excretion of AG by the transplant and the relationship between urine and serum hydrolase activity, acute and chronic acid-base studies were performed in normal control subjects and in the patient with Fabry's disease who had undergone renal transplantation. For the acute studies, alkalosis was induced by intravenous infusion of sodium bicarbonate and acidosis was induced by ingestion of ammonium chloride. The chronic study involved long-term ingestion of NH4Cl by only the patient with Fabry's disease. The results show that AG is secreted by the renal graft. Urinary hydrolase excretion was increased by acute alkalinization and decreased by acute acidification. Acute, but not chronic, acidification increased the patient's serum AG activity, indicating that long-term acidification is not useful for treating Fabry's disease after transplantation. The large changes in hydrolyase excretion induced by acute and chronic acid-base changes show the difficulty of using lysosomal enzymuria as a diagnostic marker for renal disorders without knowledge of acid-base conditions.

A case of Fabry's disease in a 52-year-old man is reported. At the age of 45 the patient developed uremia, and nephrectomy and kidney transplantation were performed. The follow-up is described and compared to other published cases. Up to now no single therapy is known, but kidney transplantation appears to be justified.

A family in the north-east of England with Anderson--Fabry's disease is presented. Alpha-galactosidase activity in plasma and white cells was significantly reduced in three adult male members of the family. One of them had an abnormal chromosome karyotype pattern with an extra Y chromosome (47,XYY) and he was clinically less severely affected than his brothers. Coincidentally five other members of the family suffered from a form of familial spastic paraplegia.

Late graft histology after renal transplantation for Fabry's disease has only once been previously reported. Clinical data and kidney biopsy findings in a case of Fabry's disease before and eight years after successful kidney transplantation are presented. The graft maintains normal function. Graft histology in light microscopy showed no abnormalities reminiscent of the diseased native kidney. Electron microscopy revealed occasional small myelin figures which were present only in the vascular endothelium. Their significance and a review of conflicting reports and opinions from the literature are discussed.

Plasma neutral glycolipid levels and plasma and leukocyte alpha-galactosidase activities were measured serially before and after renal allotransplantation in two men, aged 47 and 45 years, with renal failure due to Fabry's disease. The patients were followed posttransplantation for 92 and 64 weeks, respectively. No significant elevation of plasma or leukocyte alpha-galactosidase activities above levels in untreated men with Fabry's disease or decrease in the levels of trihexosyl ceramide was observed in either patient. The results do not support the use of renal allotransplantation for enzyme replacement in Fabry's disease.

In a patient with Fabry's disease who had undergone kidney transplantation to correct uremia, the neutral glycosphingolipids and alpha-galactosidase activity have been measured in plasma and urine and, 9 months later, after the death of the patient, in autopsy material. After transplantation, there was no significant increase in alpha-galactosidase activity in plasma; the activity found never exceeded 3% of the mean control value. A striking parallelism was found during the follow-up period in the increase and decrease of trihexosylceramide and globoside and also of glucosylceramide and dihexosylceramide. The alpha-galactosidase activity in spleen and liver was as low as that observed in untreated Fabry hemizygotes. These data and those obtained from autopsy material provide evidence that renal transplantation does not lead to a specific enzymic breakdown of trihexosylceramide in Fabry patients. However, no trihexosylceramide accumulation was observed in the transplanted kidney.