Longitudinal characterization of Gaa c.1826dupA mouse reveals cardiac, myopathic, biochemical phenotypes of Pompe disease

Pompe disease (PD) is a rare autosomal recessive disorder caused by acid α-glucosidase (GAA) deficiency, leading to lysosomal glycogen accumulation. Pathogenic GAA variants result in enzyme dysfunction and glycogen storage in cardiac, skeletal, and smooth muscle, as well as in the central nervous system, driving both systemic and neurological manifestations. We previously characterized a transgenic knock-in (KI) mouse carrying the Gaa c.1826dupA variant to 12 weeks of age, showing it recapitulates key biochemical and phenotypic features of PD. Here, we extend this analysis to present a long-term characterization of the Gaa c.1826dupA KI model using physiological, behavioral, biochemical, and histopathological assessments. KI mice exhibited early-onset hypertrophic cardiomyopathy with significant cardiac functional decline, reduced body mass, impaired skeletal muscle strength, locomotion, coordination, and balance. Biochemically, KI mice showed decreased GAA activity and increased lysosomal glycogen accumulation in the heart, diaphragm, gastrocnemius, and brain. Despite these abnormalities, survival did not differ from wild-type mice—a divergence from severe human PD but consistent with other murine models. Collectively, these findings support this KI model as a translational platform for therapeutic evaluation in PD.