title: Temporal neuropathologic and behavioral phenotype of 6neo/6neo Pompe disease mice.
abstract: 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.
authors.affiliation: Department of Neurology (RLS), Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA. richard_sidman@hms.harvard.edu
authors.forename: Richard L
authors.initials: RL
authors.lastname: Sidman
authors.forename: Tatyana
authors.initials: T
authors.lastname: Taksir
authors.forename: Jonathan
authors.initials: J
authors.lastname: Fidler
authors.forename: Michael
authors.initials: M
authors.lastname: Zhao
authors.forename: James C
authors.initials: JC
authors.lastname: Dodge
authors.forename: Marco A
authors.initials: MA
authors.lastname: Passini
authors.forename: Nina
authors.initials: N
authors.lastname: Raben
authors.forename: Beth L
authors.initials: BL
authors.lastname: Thurberg
authors.forename: Seng H
authors.initials: SH
authors.lastname: Cheng
authors.forename: Lamya S
authors.initials: LS
authors.lastname: Shihabuddin
mesh_terms: D000367:Age Factors; D000818:Animals; D001522:Behavior, Animal / Q000502:physiology*; D002490:Central Nervous System / Q000473:pathology* / Q000648:ultrastructure; D004195:Disease Models, Animal; D018450:Disease Progression; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D006003:Glycogen / Q000378:metabolism; D006009:Glycogen Storage Disease Type II / Q000235:genetics / Q000473:pathology* / Q000503:physiopathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D046529:Microscopy, Electron, Transmission / Q000379:methods; D009043:Motor Activity / Q000502:physiology; D053580:Muscle Strength / Q000502:physiology; D018482:Muscle, Skeletal / Q000473:pathology / Q000503:physiopathology; D010641:Phenotype; D011597:Psychomotor Performance / Q000502:physiology; D011930:Reaction Time / Q000502:physiology; D000520:alpha-Glucosidases / Q000172:deficiency
chemical_list: D005904:Glial Fibrillary Acidic Protein; D006003:Glycogen; D000520:alpha-Glucosidases