Agalsidase alfa long-term effect on left ventricular hypertrophy in Fabry disease.

INTRODUCTION: Fabry disease (FD) is an X-linked lysosomal storage disorder affecting glycosphingolipid metabolism. Most FD patients have cardiac involvement, mainly manifested as left ventricular hypertrophy (LVH), leading to early death due to complications (arrhythmias, valvular disease, vascular involvement). Early initiation of enzyme replacement therapy (ERT) before fibrosis development has been associated with better cardiac outcomes in terms of left ventricular mass index (LVMI) and functional parameters. METHODS: A retrospective observational study was conducted in patients with FD treated with agalsidase alfa for at least 2 years. The primary objectives were: [a] to assess the annual rate of change in LVMI; [b] to define the overall incidence of stability, regression or progression of LVMI. RESULTS: Forty-nine patients were included in the final analysis, with a median follow-up of 7 years. The overall change in LVMI was 0.38 g/m2.73/year, without significant influence of baseline LVH, gender, age at ERT initiation, LV ejection fraction, body mass index, renal disease, and classical cardiovascular risk factors. Long-term ERT with agalsidase alfa was associated with stabilization of LVMI in 98% of patients with FD and was independent of the same covariables. CONCLUSION: Our results are in line with previous literature of comparable FD populations and probably represent the first study of its kind in Argentina. We here highlight the importance of cardiac morphometric stability as a positive outcome of ERT.

Introducción: La enfermedad de Fabry (EF) es una enfermedad de almacenamiento lisosomal ligada al cromosoma X que afecta el metabolismo de glicoesfingolípidos. La mayoría de pacientes EF tienen afectación cardíaca, manifestada principalmente como hipertrofia ventricular izquierda (HVI), que conduce a muerte prematura secundaria a complicaciones (arritmias, valvulopatías, afectación vascular). El tratamiento de reemplazo enzimático (TRE) precoz, iniciado antes del desarrollo de la fibrosis, se relaciona con mejores resultados cardíacos en términos del índice de masa ventricular izquierda (IMVI) y parámetros funcionales. Métodos: Se realizó un estudio retrospectivo observacional en que se incluyeron pacientes con EF tratados con agalsidasa alfa por al menos 2 años. Los objetivos primarios fueron: [a] evaluar el cambio anual del IMVI; [b] definir la incidencia global de estabilidad, regresión o progresión del IMVI. Resultados: Se incluyeron 49 pacientes, con seguimiento (mediana) de 7 años. El cambio global en el IMVI fue 0.38 g/m2.73/año, sin influencia significativa de HVI basal, sexo, edad de inicio de TRE, fracción de eyección del VI, índice de masa corporal, insuficiencia renal y factores de riesgo cardiovascular clásicos. La TRE a largo plazo con agalsidasa alfa se relacionó con la estabilización del IMVI en el 98% de los pacientes con EF, independientemente de las mismas covariables. Conclusión: Nuestros resultados están en línea con la bibliografía previa de poblaciones comparables y, probablemente, representan el primer estudio de este tipo en Argentina. Se destaca la importancia de la estabilidad morfométrica cardíaca como resultado positivo de la TRE.

Pathogenic pathways of renal damage in Fabry nephropathy: interplay between immune cell infiltration, apoptosis and fibrosis.

BACKGROUND: Fabry nephropathy is a consequence of the deposition of globotriaosylceramide, caused by deficient GLA enzyme activity in all types of kidney cells. These deposits are perceived as damage signals leading to activation of inflammation resulting in renal fibrosis. There are few studies related to immunophenotype characterization of the renal infiltrate in kidneys in patients with Fabry disease and its relationship to mechanisms of fibrosis. This work aims to quantify TGF-ß1 and active caspase 3 expression and to analyze the profile of cells in inflammatory infiltration in kidney biopsies from Fabry naïve-patients, and to investigate correlations with clinical parameters. METHODS: Renal biopsies from 15 treatment-naïve Fabry patients were included in this study. Immunostaining was performed to analyze active caspase 3, TGF-ß1, TNF-α, CD3, CD20, CD68 and CD163. Clinical data were retrospectively gathered at time of kidney biopsy. RESULTS: Our results suggest the production of TNFα and TGFß1 by tubular cells, in Fabry patients. Active caspase 3 staining revealed that tubular cells are in apoptosis, and apoptotic levels correlated with clinical signs of chronic kidney disease, proteinuria, and inversely with glomerular filtration rate. The cell infiltrates consisted of macrophages, T and B cells. CD163 macrophages were found in biopsy specimens and their number correlates with TGFß1 and active caspase 3 tubular expression. CONCLUSIONS: These results suggest that CD163+ cells could be relevant mediators of fibrosis in Fabry nephropathy, playing a role in the induction of TGFß1 and apoptotic cell death by tubular cells. These cells may represent a new player in the pathogenic mechanisms of Fabry nephropathy.

[Guidelines for diagnosis, monitoring and treatment of Fabry disease]. / Guía para el diagnóstico, seguimiento y tratamiento de la enfermedad de Fabry.

Fabry disease is an X-linked hereditary lysosomal storage disorder caused by deficiency of the enzyme alpha-galactosidase A. Knowledge about this disease, and its medical management, has made remarkable progress in the last decade, including the development of its specific treatment. This guide was developed by medical professionals from various specialties involved in the care of patients with Fabry disease. The discussion and analysis of the available scientific evidence, coupled with the experience of each of the participants, has allowed us to develop the concepts included in this guide in order to provide a useful tool for all professionals who care for patients with Fabry disease.

Major cardiovascular adverse events in Fabry disease patients receiving agalsidase alfa.

Cardiovascular mortality (CVM) has become the major contributor to overall Fabry disease (FD) mortality in the enzyme replacement therapy (ERT) era. Our objectives were to describe causes and potential predictors of mortality in FD adult patients in Argentina, and to assess risk of major adverse cardiovascular events (MACE) in the ERT era. We retrospectively studied 93 consecutive patients treated with alphagalactosidase A (median follow up: 9.5 years from start of ERT). Mean age at ERT starting was 35 ± 16.3 years. Prevalence of cardiomyopathy and renal disease reached 47% and 41%, respectively. Eleven subjects (11.8%, 95% CI: 5-18%) died during follow up (1.24/100 patient-years). Mean overall survival was 71 years (95% CI: 66-75 years). Seven cases were considered as CVM; main causes were sudden death and stroke. Risk of MACE was 14% (95% CI: 6.9-21.1%; 1.47 events/100 patient-years from start of ERT). All but 2 subjects had at least one comorbid cardiovascular risk factor; however, 86% of patients remained free of MACE during follow-up. CVM remained low and our study was underpowered for detection of predictors of mortality, but it is worth noting that age at diagnosis and ERT starting, left ventricular mass index and renal disease trended to correlate with CVM. Prevalence of hypertension, diabetes and dyslipidemia were lower in FD patients when compared to population level data. As in the Argentinean general population, CVM was the leading cause of mortality among this cohort of consecutive FD patients treated with agalsidase alfa.

La mortalidad cardiovascular (MCV) se ha convertido en el principal contribuyente a la mortalidad general por enfermedad de Fabry (EF) en la era de la terapia de reemplazo enzimático (TRE). Nuestros objetivos fueron describir las causas y posibles predictores de mortalidad en pacientes adultos con EF en la Argentina, y evaluar el riesgo de eventos cardiovasculares mayores (MACE) en la actual era de TRE. Se estudiaron 93 pacientes consecutivos tratados con agalsidasa-alfa por una mediana de 9.5 años tras iniciar TRE. La edad al inicio de TRE fue 35 ± 16.3 años. La prevalencia de cardiomiopatía y enfermedad renal alcanzó 47% y 41%, respectivamente. Once sujetos (11.8%; IC95%: 5-18%) murieron durante el seguimiento (1.24/100 pacientes/año). La supervivencia global fue 71 años (IC95%: 66-75 años). Siete casos fueron considerados como MCV; las principales causas fueron muerte súbita e ictus. El riesgo de MACE fue 14% (IC95%: 6.9-21.1%; 1.47 eventos/100 pacientes/año desde la ERT). Todos menos 2 sujetos tenían al menos un factor de riesgo cardiovascular, pero el 86% permaneció libre de MACE. Los eventos de MCV fueron escasos. El estudio tuvo reducido poder estadístico para detectar predictores de mortalidad, pero la edad al diagnóstico y al iniciar la TRE, índice de masa ventricular izquierda y enfermedad renal tendieron a correlacionarse con MCV. La prevalencia de hipertensión, diabetes y dislipidemia fue menor en comparación con la población general. Como ocurre con la población general en Argentina, los eventos cardiovasculares fueron la principal causa de muerte en esta cohorte de pacientes consecutivos con EF tratados con agalsidasa-alfa.

Misdiagnosis in Fabry disease.

OBJECTIVE: To evaluate the most frequent diagnostic errors in patients with Fabry disease and the types of specialists most often consulted before diagnosis. STUDY DESIGN: We evaluated 45 consecutive symptomatic patients with Fabry disease confirmed by enzymatic tests in males and genetic studies in females. We interviewed the patients, their mothers, or both regarding symptoms, age at onset, medical consultations, and recommended treatments. RESULTS: Neuropathic pain was the most frequent initial complaint, and rheumatic fever was the most common diagnosis. Seven patients were treated with penicillin for many years. Ten patients sought medical consultation because of abdominal pain and were diagnosed with food intoxication or nonspecific pain. Six patients sought consultation because of anhidrosis, considered of unclear cause, and angiokeratomas diagnosed as petechiae. Internists and pediatricians were the most frequently consulted specialists. The correct diagnosis was obtained after a mean of 19.7 years. CONCLUSIONS: Pediatricians as well as internists commonly misdiagnose Fabry disease. Neuropathic pain, hypohidrosis, and recurrent abdominal pain in childhood or adolescence should include Fabry disease in the differential diagnosis to facilitate earlier diagnosis and treatment of these patients.

Major cardiovascular adverse events in Fabry disease patients receiving agalsidase alfa / Eventos cardiovasculares mayores en pacientes con enfermedad de Fabry tratados con agalsidasa alfa

Abstract Cardiovascular mortality (CVM) has become the major contributor to overall Fabry disease (FD) mortality in the enzyme replacement therapy (ERT) era. Our objectives were to describe causes and potential predictors of mortality in FD adult patients in Argentina, and to assess risk of major adverse cardio vascular events (MACE) in the ERT era. We retrospectively studied 93 consecutive patients treated with alpha-galactosidase A (median follow up: 9.5 years from start of ERT). Mean age at ERT starting was 35±16.3 years. Prevalence of cardiomyopathy and renal disease reached 47% and 41%, respectively. Eleven subjects (11.8%, 95%CI: 5-18%) died during follow up (1.24/100 patient-years). Mean overall survival was 71 years (95%CI: 66-75 years). Seven cases were considered as CVM; main causes were sudden death and stroke. Risk of MACE was 14% (95%CI: 6.9-21.1%; 1.47 events/100 patient-years from start of ERT). All but 2 subjects had at least one comorbid cardiovascular risk factor; however, 86% of patients remained free of MACE during follow-up. CVM remained low and our study was underpowered for detection of predictors of mortality, but it is worth noting that age at diagnosis and ERT starting, left ventricular mass index and renal disease trended to correlate with CVM. Prevalence of hypertension, diabetes and dyslipidemia were lower in FD patients when compared to population level data. As in the Argentinean general population, CVM was the leading cause of mortality among this cohort of consecutive FD patients treated with agalsidase alfa.

Resumen La mortalidad cardiovascular (MCV) se ha convertido en el principal contribuyente a la mortalidad general por enfermedad de Fabry (EF) en la era de la terapia de reemplazo enzimático (TRE). Nuestros objetivos fueron describir las causas y posibles predictores de mortalidad en pacientes adultos con EF en la Argentina, y evaluar el riesgo de eventos cardiovasculares mayores (MACE) en la actual era de TRE. Se estudiaron 93 pacientes consecutivos tratados con agalsidasa-alfa por una mediana de 9.5 años tras iniciar TRE. La edad al inicio de TRE fue 35 ± 16.3 años. La prevalencia de cardiomiopatía y enfermedad renal alcanzó 47% y 41%, respectivamente. Once sujetos (11.8%; IC95%: 5-18%) murieron durante el seguimiento (1.24/100 pacientes/año). La supervivencia global fue 71 años (IC95%: 66-75 años). Siete casos fueron considerados como MCV; las principales causas fueron muerte súbita e ictus. El riesgo de MACE fue 14% (IC95%: 6.9-21.1%; 1.47 eventos/100 pacientes/año desde la ERT). Todos menos 2 sujetos tenían al menos un factor de riesgo cardiovascular, pero el 86% permaneció libre de MACE. Los eventos de MCV fueron escasos. El estudio tuvo reducido poder estadístico para detectar predictores de mortalidad, pero la edad al diagnóstico y al iniciar la TRE, índice de masa ventricular izquierda y enfermedad renal tendieron a correlacionarse con MCV. La prevalencia de hipertensión, diabetes y dislipidemia fue menor en comparación con la población general. Como ocurre con la población general en Argentina, los eventos cardiovasculares fueron la principal causa de muerte en esta cohorte de pacientes consecutivos con EF tratados con agalsidasa-alfa.

Treatment of fabry disease: current and emerging strategies.

Fabry disease is an X-linked lysosomal storage disorder (LSD) due to deficiency of the enzyme α-galactosidase A (GLA). Absent or reduced enzyme activity leads to impaired catabolism of neutral glycosphingolipids, particularly globotriaosylceramide (Gb3), resulting in intracellular deposition of such lipids. Clinical manifestations in hemizygote males include angiokeratoma, hypohydrosis, acroparesthesia, abdominal pain, proteinuria, renal insufficiency, left ventricular hypertrophy and cerebrovascular accidents. Heterozygote women may present with mild to severe signs and symptoms. Since year 2001, enzyme replacement therapy (ERT) is the only specific treatment for Fabry disease. The beneficial effect of ERT on different organs/systems has been extensively evaluated, and an improvement in renal function, cardiac mass and quality of life has been reported. Different treatment approaches are currently on development. One of them implies the use of the active-site-specific chaperone 1-deoxygalactonojirimycin that acts facilitating folding of mutant GLA in the endoplasmic reticulum and increasing its lysosomal residual activity. Reduction of Gb3 deposits has been shown in lymphoblasts from Fabry patients with missense mutations and transgenic mouse model expressing a missense mutation GLA. Gene therapy has been also developed as a potential option for treatment of Fabry disease. This review will discuss these novel therapeutic options along with their advantages and limitations.

Guía para el diagnóstico, seguimiento y tratamiento de la enfermedad de Fabry / Guidelines for diagnosis, monitoring and treatment of Fabry disease

La enfermedad de Fabry es un trastorno de almacenamiento lisosomal hereditario ligado al cromosoma X, ocasionado por el déficit de la enzima alfa galactosidasa A. El conocimiento sobre esta patología, y en particular su manejo médico, ha progresado notablemente en la última década, incluyendo el desarrollo de su tratamiento específico. La presente guía fue desarrollada por profesionales médicos de diversas especialidades involucrados en la atención de pacientes con enfermedad de Fabry. La discusión y análisis de las evidencias científicas disponibles, sumado a la experiencia de cada uno de los participantes, ha permitido desarrollar los conceptos vertidos en esta guía con el objetivo de brindar una herramienta útil para todos los profesionales que asisten a pacientes con enfermedad de Fabry.

Fabry disease is an X-linked hereditary lysosomal storage disorder caused by deficiency of the enzyme alpha-galactosidase A. Knowledge about this disease, and its medical management, has made remarkable progress in the last decade, including the development of its specific treatment. This guide was developed by medical professionals from various specialties involved in the care of patients with Fabry disease. The discussion and analysis of the available scientific evidence, coupled with the experience of each of the participants, has allowed us to develop the concepts included in this guide in order to provide a useful tool for all professionals who care for patients with Fabry disease.