Pompe disease (glycogen storage disease II) is caused by mutations in the acid 
alpha-glucosidase gene. The most common form is rapidly progressive with 
glycogen storage, particularly in muscle, which leads to profound weakness, 
cardiac failure, and death by the age of 2 years. Although usually considered a 
muscle disease, glycogen storage also occurs in the CNS. We evaluated the 
progression of neuropathologic and behavioral abnormalities in a Pompe disease 
mouse model (6neo/6neo) that displays many features of the human disease. 
Homozygous mutant mice store excess glycogen within large neurons of hindbrain, 
spinal cord, and sensory ganglia by the age of 1 month; accumulations then 
spread progressively within many CNS cell types. "Silver degeneration" and 
Fluoro-Jade C stains revealed severe degeneration in axon terminals of primary 
sensory neurons at 3 to 9 months. These abnormalities were accompanied by 
progressive behavioral impairment on rotorod, wire hanging, and foot fault 
tests. The extensive neuropathologic alterations in this model suggest that 
therapy of skeletal and cardiac muscle disorders by systemic enzyme replacement 
therapy may not be sufficient to reverse functional deficits due to CNS glycogen 
storage, particularly early-onset, rapidly progressive disease. A better 
understanding of the basis for clinical manifestations is needed to correlate 
CNS pathology with Pompe disease manifestations.