eliglustat-tartrate and Heart-Failure

Anderson-Fabry disease is an X-linked lysosomal storage disorder resulting from the deficiency of the hydrolytic enzyme alpha galactosidase A, with consequent accumulation of globotrioasoyl ceramide in cells and tissues of the body, resulting in a multi-system pathology including end organ failure. In the classical phenotype, cardiac failure, renal failure and stroke result in a reduced median life expectancy. The current causal treatment for Fabry disease is the enzyme replacement therapy (ERT): two different products, Replagal (agalsidase alfa) and Fabrazyme (agalsidase beta), have been commercially available in Europe for almost 10 years and they are both indicated for long-term treatment. In fact, clinical trials, observational studies and registry data have provided many evidences for safety and efficacy of ERT in improving symptoms of pain, gastrointestinal disturbances, hypohidrosis, left ventricular mass index, glomerular filtration rate and quality of life. Few data are available on comparison of the two treatments and on the clinical course of the disease. This article reviews the published evidence for clinical efficacy of the two available enzyme preparations.

Topics: Adult; alpha-Galactosidase; Clinical Trials as Topic; Enzyme Replacement Therapy; Fabry Disease; Female; Galactosidases; Heart Failure; Humans; Isoenzymes; Male; Recombinant Proteins; Renal Insufficiency; Stroke; Trihexosylceramides

Topics: Adrenergic beta-Antagonists; alpha-Galactosidase; Angiotensin-Converting Enzyme Inhibitors; Cardiac Pacing, Artificial; Chromosomes, Human, X; Fabry Disease; Heart Failure; Humans; Isoenzymes; Recombinant Proteins

Anderson Fabry disease is a life threatening, X-linked inborn metabolic defect of the lysosomal enzyme áalpha-galactosidase A. The deficiency of alpha-galactosidase A leads to a progressive accumulation of globotriaosylceramide (Gb(3)), the major glycosphingolipid substrate of the enzyme, within vulnerable cells, tissues, and organs, including the cardiovascular system. Cardiac involvement is frequent and patients with cardiac affection develop progressive hypertrophic infiltrative cardiomyopathy, valvular abnormalities, arrhythmias, and conduction abnormalities and may develop coronary heart disease. Hemizygous male patients have no detectable alpha-galactosidase A activity, while affected heterozygous females may have normal level of alpha-galactosidase A activity. Death occurs in male patients at 45 to 50 years, about 15 to 20 years earlier than in female patients due to a vicious circle from chronic renal insufficiency, arterial hypertension, atherosclerotic lesions and cerebrovascular hemorrhage or insults, and cardiomyopathy. Cardiac involvement in hetero- and hemizygotes will be discussed as well as the influence of enzyme replacement of alpha-galactosidase A.

Topics: Adult; alpha-Galactosidase; Animals; Arrhythmias, Cardiac; Biopsy; Cardiomyopathy, Hypertrophic; Cell Line; Child; Clinical Trials as Topic; Coronary Disease; Cricetinae; Diagnosis, Differential; Echocardiography; Electrocardiography; Endocardium; Enzyme Therapy; Fabry Disease; Female; Galactose; Heart Diseases; Heart Failure; Heart Valve Diseases; Humans; Hypertrophy, Left Ventricular; Incidence; Infant, Newborn; Infusions, Intravenous; Isoenzymes; Magnetic Resonance Imaging; Male; Middle Aged; Mitral Valve Prolapse; Myocardium; Sex Factors; Smoking

Anderson-Fabry disease is a rare X-linked lysosomal storage disease caused by α-galactosidase A (α-GalA) gene variants and characterized by a large genotypic and phenotypic spectrum. Enzyme replacement therapy (ERT) using recombinant α-GalA has been approved for > 10 years as a specific therapy for the disease. However, the long-term clinical efficacy for cardiac manifestations has been equivocal because it depends on several factors such as genotype, sex, age, and disease severity at the initiation of ERT. We report the differences in the clinical effects of ERT continued for > 10 years in three patients with the same genotype. Left ventricular hypertrophy and myocardial dysfunction progressed in the heterozygote proband even under ERT, although disease progression was prevented in two sons of Case 1.

Topics: Adult; alpha-Galactosidase; Atrial Fibrillation; Disease Progression; Echocardiography; Electrocardiography; Enzyme Replacement Therapy; Fabry Disease; Female; Heart Failure; Humans; Hypertrophy, Left Ventricular; Isoenzymes; Magnetic Resonance Imaging; Male; Treatment Outcome

The well-described histologic and electron microscopic findings in Fabry disease cardiomyopathy are hypertrophic vacuolated cells with electron dense concentric lamellar bodies. We present altered findings in an endomyocardial biopsy from a patient with treated Fabry disease. A 51-year-old male with Fabry disease, treated with recombinant alpha-galactosidase enzyme replacement therapy for over 18 months, underwent an endomyocardial biopsy for heart failure. The histologic changes showed widespread hypertrophy and vacuolization with rare eosinophilic bodies. Electron microscopy failed to reveal the characteristic globotriaosylceramide concentric lamellar bodies (myelin figures) in the sarcoplasm. Instead, extensive aggregates and single tubular crystalline structures, giant secondary lysosomes as well as abnormal branched chain glycogen were present. This is the first histologic description of long-standing treated Fabry disease in cardiac myocytes.

Topics: alpha-Galactosidase; Biopsy; Fabry Disease; Follow-Up Studies; Heart Failure; Humans; Isoenzymes; Male; Middle Aged; Myocardium; Myocytes, Cardiac; Time Factors; Treatment Outcome