FABRY CARDIOMYOPATHY: METABOLIC IMPACT OF ENZYME-REPLACEMENT THERAPY

Fabry disease is caused by deficit of an enzyme contained in lysosomes responsible for glycosphingolipids degradation. This deficit cause progressive accumulation of glycosphingolipids inside cells of different tissue different tissues, including skin, kidneys, vascular endothelium, ganglion cells of peripheral nervous system and heart with loss of function of the organs involved. Cardiac involvement is characterized by progressive left ventricular hypertrophy that finally evolves in heart failure. It is the most important cause of death not only in hemizygote males but also in female heterozygote carriers, with a reduction of life-expectancy of approximately 20 and 15 years respectively. Recently enzyme-replacement therapy has been revealed effective in reducing glycosphyngolipids accumulation and in clearing existing deposits with improvement and even regression of the cardiomyopathy. Initial experience with enzyme-replacement therapy has shown that some patients fail to respond with worsening of cardiac and other involved organs damage. With this study we intend to define the mechanisms leading to enzyme-replacement failure assessing through endomyocardial biopsies and blood samples collection before and after acute and chronic enzyme administration, the effective amount of enzyme entering myocardial cells and the effective enzymatic activity restored in myocardial tissue and the amount of glycosphyngolipids eliminated. This approach could clarify the limiting factor in patients not responding to enzyme-replacement and provide suggestions to ameliorate the treatment by modifyng the synthetic enzyme or by the adjunction of additive treatments. Furthermore, comparing clinical, genetic and pathological features of patients responding and not responding to treatment we could identify the markers predicting a poor response thus allowing an early modification of treatment.