S2.1 Enzyme replacement therapy (ERT) in Glycogen Storage Disease Type II: the first treatment developed

Since 2006 ERT is available in Europe and numerous studies were reported both in infantile and in juvenile - adult patients that demonstrated variable efficacy (1, 2). We have followed infants treated with ERT either early in the first year or later. In one child with onset at birth, diagnosed in the third day of life we observed an excellent long-term clinical response on severe bradycardia and reduction of left ventricular mass index in cardiomyopathy (3) while in another child where the therapy was post-pond no such response was observed: in this second case a large connective tissue replacement was present in the biopsy after ERT. In juvenile and late onset cases a large experience was collected by the Italian group of GSDII (4) and will be soon reported in full. Beside the clinical follow-up we also did a repeated second biopsy after ERT in two cases after 6 months in a 17 year old juvenile case and after 36 months of ERT in a 63 year ventilator dependent woman and we observed less degree of vacuolization in muscle fibers. We documented that ERT improves muscle fiber trophism and decreases PAS positivity, as well as the extensive muscle autophagic vacuolization. We did observe that ERT is effective in both infantile and late-onset GSDII cases, but at a different extent. To explain the difference of ERT in late onset cases we suppose that fiber sarcolemmal membrane compartimentalization around autophagosomes might contribute to the different response in infants and adults; in fact we previously reported (5) that there is a greater degree of fiber sarcolemmal membranes around vacuoles in muscle fibers of late-onset GSDII, versus classical infantile Pompe patients. This protective mechanism may influence the delivery of ERT in adult cases. Furthermore a high antibody titer against recombinant enzyme has been observed (1, 6) both in infants and in adults and might influence ERT efficacy. Finally body composition (I.e fat and connective tissue) and the different mannose receptor density in various tissues (heart, skeletal muscle, diaphragm) has to be considered. ERT is the first treatment developed for GSDII, but it needs further refinements. Several trials are in fact exploring new avenues of treatment (chaperons, new compounds with different affinity for mannose receptor, immunotherapy, etc.).