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Fabry Disease Management - largest and longest examination of ERT with agalsidase alfa
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Professor Christoph Kampmann, MD
Centre for Lysosomal Storage Diseases, Children's Hospital of the University, Johannes Gutenberg University , Mainz , Germany

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Fabry disease is an inherited and multi system inherited, X-linked disease, caused by a deficiency of the lysosomal enzyme Alpha-galactosidase A, resulting in a widely distributed accumulation of Gb3 (globotriaosylceramide), the main storage product. The clinical features are including angiokeratoma, cataract, renal failure and cardiomyopathy. Among them, cardiac disease was the main cause of death in both males (34%) and females (57%) by FOS (the Fabry Outcome Survey). Importance of renal diseases as a cause of death in patients with Fabry disease is decreasing with improvements in the management of renal disease, while the importance of cardiac disease is increasing.

Incidence of hypertrophic cardiomyopathy (HCM) is 1/500 males over 40 years old and 1-9 in 100 of unrelated HCM patients have Fabry disease. Clinical symptoms of Fabry cardiomyopathy are angina pectoris, dyspnea, palpitations, fatigue, syncope, and fibrosis in severe cases. Fabry cardiomyopathy is progressive and the prevalence of cardiomyopathy increases age dependently, leading to increasing LV mass and premature death. In Fabry cardiomyopathy, the intracellular aggregation of Gb3 leads to a swelling of the cell and therefore a progressive loss of cell integrity and cell function.

Treatment and management of heart failure in Fabry cardiomyopathy includes the increase enzyme activity (ERT; enzyme replacement therapy and chaperone), concomitant therapy (antiarrhythmics, ACE, ARB, anti-anginal) and in case of failure heart transplantation.
Potential effects of ERT are, stop of progression of disease, reduction of cardiomyopathy, normalization of left ventricular mass, avoiding development of disease related alterations and changing the natural course of the disease.
There are two different ERTs available. One is Agalsidase alfa (Replagal; TKT/Shire HGT; produced in a human cell line after virus-free gene activation) and the other is Agalsidase beta (Fabrazyme; Genzyme, recombinant and produced in a CHO cell line).

We conducted and contributed to several studies with agalsidase alfa in male and female patients and in children. In children treated for more than 4 years, urine Gb3 decreases to normal level within 1.5 year which indicates clearence of Gb3 from the body. Pain index decreases within 1.5 year but after that the index is stable. Autonomic cardiac control becomes normal after 6 months. No IgE antibodies ever detected during the study. Only 6% of children develop IgG antibodies, but the titres increase within the first year of treatment and thereafter stabilized. Based on the results of these trials, ERT with agalsidase alfa is recommended in all males as early as possible and in all females with symptoms, although guidelines for children have not been established so far.

Agalsidase alfa and beta are believed to be similar in structure and functionally equivalent. Is efficacy dose dependent (high dose is recommended)? No publication or study has ever been able to prove this hypothesis so far, although several studies tried to compare alfa or beta or both on Fabry disease.

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