Temporal Neuropathologic and Behavioral Phenotype of 6^neo/6^neoPompe Disease Mice

Abstract

Pompe disease (glycogen storage disease II) is caused by mutations in the acid α-glucosidase gene. The most common form is rapidly progressive with glycogen storage, particularly in muscle, that leads to profound weakness, cardiac failure, and death by the age of two years. Although usually considered a muscle disease, glycogen storage also occurs in the CNS. We evaluated the progression of neuropathological 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 one 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 three to nine months. These abnormalities were accompanied by progressive behavioral impairment on rotorod, wire hanging and foot fault tests. The extensive neuropathological 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.

Postmortem Findings and Clinical Correlates in Individuals with Infantile-Onset Pompe Disease

“…Accumulation was progressive and included neurons, glia, and pericytes of the cerebral cortex, portions of the basal ganglia, and the brainstem. Early glycogen accumulation was present in the spinal cord, particularly in motor neurons (Sidman et al 2008).…”

CRIM‐negative infantile Pompe disease: 42‐month treatment outcome

“…Muscle weakness significantly improved over the course on ERT, predominantly being limited to facial and neck flexor muscles; however, cognitive testing using Griffith and Bayley scales and SON-R indicated a deviation from age-appropriate development; speech and language development were markedly delayed, and behavioral issues were noted. Behavior impairment in Pompe disease was only reported in a mouse model (Sidman et al 2008).…”

Metabolic signatures of amyotrophic lateral sclerosis reveal insights into disease pathogenesis

“…Reduced α-glucosidase mRNA levels have been reported in laser-captured motor neurons from spinal cords of patients with ALS (13). Deficiency in lysosomal acid α-glucosidase activity leads to Pompe disease, a "neuromuscular" lysosomal storage disease characterized by aberrant glycogen accumulation in both viscera and CNS (22,23). Neutral (endoplasmic reticulum, ER) α-glucosidase trims glucose residues from N-glycans of glycoproteins, which is part of an elaborate and important quality-control system that promotes the proper folding and oligomerization of newly formed proteins and their transport from the ER to their final destination (24).…”