eliglustat-tartrate and Heart-Diseases

Fabry disease is an X-linked metabolic storage disorder due to the deficiency of lysosomal alpha-galactosidase A, and the subsequent accumulation of glycosphingolipids, primarily globotriaosylceramide, throughout the body. Males with classical Fabry disease develop early symptoms including pain and hypohidrosis by the second decade of life reflecting disease progression in the peripheral and autonomic nervous systems. An insidious cascade of disease processes ultimately results in severe renal, cardiac, and central nervous system complications in adulthood. The late complications are the main cause of late morbidity, as well as premature mortality. Disease presentation in female heterozygotes may be as severe as in males although women may also remain asymptomatic. The recent introduction of enzyme replacement therapy to address the underlying pathophysiology of Fabry disease has focused attention on the need for comprehensive, multidisciplinary evaluation and management of the multi-organ system involvement. In anticipation of evidence-based recommendations, an international panel of physicians with expertise in Fabry disease has proposed guidelines for the recognition, evaluation, and surveillance of disease-associated morbidities, as well as therapeutic strategies, including enzyme replacement and other adjunctive therapies, to optimize patient outcomes.

Topics: Adult; alpha-Galactosidase; Child; Fabry Disease; Female; Gastrointestinal Diseases; Heart Diseases; Humans; Isoenzymes; Kidney Diseases; Lung Diseases; Male; Nervous System Diseases; Organ Specificity; Otorhinolaryngologic Diseases; Practice Guidelines as Topic

Anderson-Fabry disease is an X-linked recessive lysosomal storage disease resulting from deficient alpha-galactosidase A activity. The conception of the disease has changed within the last decade. Studies of the last years have shown that the disease is not limited to the classical full-blown manifestation in affected males, which is well known since more than a century, but may also occur in carrier females. The phenomenology may differ in severity and kind of organ manifestation. Cardiac and renal variants with solely disease manifestation of these organs have also been described in an increasing number. It is likely that a spectrum exists regarding alpha-galactosidase A activity in both genders on the one hand, and an additional one regarding the severity and the number of organs affected on the other. The purpose of this review is to sharpen physicians' perception of this disease. Early and accurate diagnosis is mandatory considering that this disorder is now, after introduction of the novel enzyme replacement therapy, a treatable disease.

Topics: alpha-Galactosidase; Eye Diseases; Fabry Disease; Female; Heart Diseases; Humans; Isoenzymes; Kidney Diseases; Male; Pain

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 multisystemic disorder of lipid metabolism secondary to X-chromosome alterations and is frequently associated with cardiac manifestations such as left ventricular (LV) hypertrophy, gradually leading to an alteration in cardiac performance. The purpose of this study was to monitor, using magnetic resonance imaging (MRI), any changes produced by enzyme replacement therapy with agalsidase beta at the cardiac level in patients with Anderson-Fabry disease.. Sixteen (ten men, six women) patients with genetically confirmed Anderson-Fabry disease underwent cardiac MRI before starting enzyme replacement therapy (baseline study) and after 48 months of treatment with agalsidase beta at the dose of 1 mg/kg (follow-up study).. After 48 months of treatment, a significant reduction in LV mass and wall thickness was observed: 187±59 g vs. 149±44 g, and 16±3 mm vs. 13±3 mm, respectively. A significant reduction in T2 relaxation time was noted at the level of the interventricular septum (81±3 ms vs. 67±7 ms), at the apical level (80±8 ms vs. 63±6 ms) and at the level of the lateral wall (82±8 ms vs. 63±10 ms) (p<0.05). No significant variation was observed in ejection fraction between the two studies (65±3% vs. 64±2%; p>0.05) (mean bias 1.0); however, an improvement was noted in the New York Heart Association (NYHA) class of the majority of patients (12/16) (p<0.05).. In patients with Anderson-Fabry disease undergoing enzyme replacement therapy with agalsidase beta, MRI documented a significant reduction in myocardial T2 relaxation time, a significant decrease in maximal myocardial thickness and in total LV mass. MRI did not reveal significant improvements in LV global systolic function; however, improvement in NYHA functional class was noted, consistent with improved diastolic function.

Topics: Adult; alpha-Galactosidase; Enzyme Replacement Therapy; Fabry Disease; Female; Heart Diseases; Humans; Isoenzymes; Magnetic Resonance Imaging, Cine; Male; Risk Factors; Vectorcardiography

Topics: Adolescent; alpha-Galactosidase; Biomarkers; Child; Fabry Disease; Female; Fibrosis; Heart Diseases; Humans; Isoenzymes; Male; Myocardium; Sex Characteristics

Clinical Fabry's disease is due to any of multiple mutations in the X-linked alpha-galactosidase gene. These mutations are kindred-specific, often spontaneous, and produce varying degrees of functional enzyme deficiency resulting in deposits of specific glycosphingolipid (cerumide), especially in the vasculature, kidneys, heart and reticuloendothelial tissue. Disease frequency has probably been over-estimated at 1/40,000; so few centres have developed clinical experience of the disease, though the disease has been identified in all major racial groups.

Topics: alpha-Galactosidase; Australia; Clinical Trials as Topic; Fabry Disease; Female; Heart Diseases; Humans; Isoenzymes; Kidney Diseases; Male

Fabry disease is an inherited lysosomal storage disorder caused by deficiency of the enzyme alpha-galactosidase A. The enzyme deficiency results in accumulation of glycosphingolipids in the lysosomes n nearly all cell types and tissues leading to a multisystem disease. MANIFESTATIONS include painful crisis, angiokeratomas, corneal dystrophy, and hypohydrosis. The severe renal, cerebrovascular, and cardiac involvement is predominantly responsible for premature mortality in Fabry patients. The disease is X-linked and manifests primarily in hemizygous males but also heterozygous females can be affected. CARDIAC INVOLVEMENT is frequent in Fabry disease. Patients develop hypertrophic cardiomyopathy, arrhythmias, conduction abnormalities, and valvular abnormalities. Although Fabry disease leads to a complex clinical syndrome, there are studies indicating that manifestations can be limited to the heart. The isolated cardiac variant of Fabry disease seems to be more common than previously thought: around 3-6% of male patients with left ventricular hypertrophy seem to suffer from this disease variant.. Recent advances in molecular biology and genetic engineering have enabled the development of enzyme replacement therapy in Fabry disease. Results from two independent therapy studies are indeed promising: Infusion of the enzyme preparation seems to be well tolerated and effective in catabolizing the lipid deposits. This enzyme replacement therapy could be one of the first examples for causal treatment of left ventricular hypertrophy. Therefore, early diagnosis of hypertrophy patients with the cardiac variant of Fabry disease is important.

Topics: Adolescent; Adult; alpha-Galactosidase; Angina Pectoris; Animals; Arrhythmias, Cardiac; Cardiomyopathy, Hypertrophic; Cell Line; Child; Cricetinae; Diagnosis, Differential; Electrocardiography; Fabry Disease; Female; Genetic Engineering; Heart Diseases; Heart Valve Diseases; Heterozygote; Homozygote; Humans; Hypertrophy, Left Ventricular; Isoenzymes; Male; Randomized Controlled Trials as Topic; Sex Factors; Time Factors