Pompe disease is a systemic metabolic disorder characterized by lack of 
acid-alpha glucosidase (GAA) resulting in ubiquitous lysosomal glycogen 
accumulation. Respiratory and ambulatory dysfunction are prominent features in 
patients with Pompe yet the mechanism defining the development of muscle 
weakness is currently unclear. Transgenic animal models of Pompe disease 
mirroring the patient phenotype have been invaluable in mechanistic and 
therapeutic study. Here, we demonstrate significant pathological alterations at 
neuromuscular junctions (NMJs) of the diaphragm and tibialis anterior muscle as 
prominent features of disease pathology in Gaa knockout mice. Postsynaptic 
defects including increased motor endplate area and fragmentation were readily 
observed in Gaa(-/-) but not wild-type mice. Presynaptic neuropathic changes 
were also evident, as demonstrated by significant reduction in the levels of 
neurofilament proteins, and alterations in axonal fiber diameter and myelin 
thickness within the sciatic and phrenic nerves. Our data suggest the loss of 
NMJ integrity is a primary contributor to the decline in respiratory and 
ambulatory function in Pompe and arises from both pre- and postsynaptic 
pathology. These observations highlight the importance of systemic phenotype 
correction, specifically restoration of GAA to skeletal muscle and the nervous 
system for treatment of Pompe disease.