The latter energetic hypothesis is supported by the

notion that GAA activity normally “returns” to the cytoplasm the end product of lysosomal glycogen digestion, glucose. It is also telling that in muscle from patients with the infantile form of GSD II most glycogen is free in the cytoplasm, probably released by “burst Inhibitors,research,lifescience,medical lysosomes” (13). A more compelling scenario for the pathogenesis of GSD II, as well as other lysosomal storage disorders (16), involves a disruption of the vital autophagic process, with accumulation of autophagosomes resulting from defective autophagosome-lysosome fusion (16, 17). In fact, Nishino Inhibitors,research,lifescience,medical and colleagues went as far as stating that “Pompe disease can no longer be viewed simply as a glycogen storage disease,” but rather as a problem in handling excessive numbers of autophagosomes (13). A unique feature of GSD II is the availability of a generally effective – and now widely utilized – enzyme replacement therapy (ERT) with recombinant human GAA (rhGAA). There is already Inhibitors,research,lifescience,medical a vast literature on the Cilengitide mw subject (10), and a few problems have emerged, such as the immune reaction to rhGAA in infants with null mutations and no GAA protein (i.e. no cross-reactive immunological material, CRIM) (18). Assumption of rhGAA

into lysosomes is probably hindered by the more general autophagic

dysfunction mentioned above and Inhibitors,research,lifescience,medical several stratagems have been proposed to improve uptake, including conjugation of rhGAA with a synthetic oligosaccharide harboring mannose-6-phosphate (19), combining ERT with chaperones (20), and inhibition of glycogen synthesis (21, 22). One final clinical note: besides skeletal muscle, smooth muscle must also be affected in late-onset GSD II because there have been a few reports of cerebral arteriopathies, Inhibitors,research,lifescience,medical often affecting the basilar artery (23, 24). GSD III (debrancher enzyme deficiency; Cori-Forbes disease) The debrancher is a “double duty” enzyme, with two Rutecarpine catalytic functions, oligo-1,4-1,4-glucantransferase and amylo-1,6-glucosidase. Once phosphorylase has shortened the peripheral chains of glycogen to about four glucosyl units (this partially digested glycogen is called phosphorylase-limit dextrin, PLD), the debrancher enzyme removes the residual stumps in two steps. First, a maltotriosyl unit is transferred from a donor to an acceptor chain (transferase activity), leaving behind a single glucosyl unit, which is then hydrolyzed by the amylo-1- ,6-glucosidase, at which point the branch is off. A singlecopy gene, AGL, encodes the debrancher enzyme.