​(Fig.3).3). Electron microscopy shows vacuoles filled with a variety of debris, including more or less abundant glycogen particles: for chemical structure instance, glycogen is not very prominent

in the vacuole shown in Figure ​Figure44. Figure 2 Muscle biopsy from a patient with Danon disease. H & E stain reveals small basophilic inclusions in several fibers. Figure 3 Ultrastructure of an autophagic vacuole in the muscle biopsy of a patient with Danon disease. The single membrane-bound vacuole contains various debris but remarkably little glycogen. Figure 4 Immunohistochemistry Inhibitors,research,lifescience,medical of muscle biopsies from a patient with Danon disease upper panel) and from a control (lower panel). Immunoreaction with antibodies to LIMP-1 (left panel) is Inhibitors,research,lifescience,medical more intense in the patient than in the control, whereas immunoreaction with … The precise function of LAMP-2 is not known and the pathogenesis of the “autophagic vacuoles with sarcolemmal features” (AVSF) that are characteristic of Danon disease is likewise unclear (13). In the normal process of autophagy, “isolation membranes” envelop portions of the cytoplasm to form autophagosomes, which fuse with primary lysosomes (containing a battery of acid hydrolases), thus generating autolysosomes, where trapped

cytoplasmic components are digested. In the parallel process of endocytosis, portions of the plasma membrane invaginate to form “early endosomes”, which, after fusing with primary lysosomes, become Inhibitors,research,lifescience,medical “late endosomes” and finally lysosomes. The formation of AVSF in Danon disease, as envisioned by Sugie et al. (13), hypothesizes as a primary (and earlier) phenomenon the formation of LIMP-1-positive autolysosomes,

which are secondarily enveloped by membranes with sarcolemmal features. Alternatively, AVSF may be formed through a dysregulation Inhibitors,research,lifescience,medical of exocytosis (or endocytosis), leading to autophagic vacuoles with sarcolemmal features. However, what exactly this “dysregulation” entails remains to be clarified. Inhibitors,research,lifescience,medical Irrespective of its precise pathogenesis, LAMP-2 deficiency illustrates the importance of rare diseases in helping us understand the normal functioning of the cell, or, to quote William Harvey, “Nature is nowhere accustomed more openly to display her secret mysteries than in cases where she shows tracings of her workings apart from the beaten paths; nor is there any better way to advance the proper Calpain practice of medicine than to give our minds to the discovery of the usual law of nature, by careful investigation of cases of rarer forms of disease”. Acknowledgements Part of this work was supported by grant from the Muscular Dystrophy Association.
Enzyme replacement therapy (ERT) was recently approved for patients with Pompe disease, a devastating disorder affecting both infants and adults (1). The disease is caused by mutations in the acid alpha-glucosidase (GAA) gene, which encodes a lysosomal enzyme responsible for the degradation of glycogen.