Pompe disease, also referred to as glycogen storage disease type 2 (GSD2) is a rare, progressive, and heterogeneous neuromuscular disorder. It results from deficiency of the lysosomal enzyme acid α-glucosidase (GAA), caused by pathogenic variants in the GAA gene located on chromosome 17q25.2–q25.3.

We describe a 12-year-old male from Chihuahua, Mexico, presenting with progressive proximal muscle weakness and exercise intolerance. His history was notable for an EBV infection three months prior to symptom onset. Over three years, he developed increasing lower limb weakness, myalgias, and early fatigue without sensory, cardiac, or respiratory symptoms. Examination revealed proximal lower limb weakness (iliopsoas 4+/5, quadriceps 4+/5, hamstrings 4−/5), mild hypotrophy, and macroglossia. Serum CK was persistently elevated (2239 U/L). Differential diagnoses included inflammatory, dystrophic, and metabolic myopathies. Negative autoimmune serology and the presence of macroglossia and rapid progression favored a metabolic etiology. Enzymatic testing confirmed markedly reduced GAA activity (0.21 nmol/ml/hr; ref. 1.29–25.7). Genetic analysis identified compound heterozygosity for GAA variants c.2480_2426del (p.Gln803Profs*39) and c.-32-13T>G, confirming late-onset Pompe disease (LOPD).

Functional assessment showed a six-minute walk distance (6MWD) of 285 m (58.7% predicted) and reduced maximal inspiratory pressure (59% predicted), indicating diaphragmatic weakness. Echocardiography was normal. Enzyme replacement therapy (ERT) with avalglucosidase alfa (20 mg/kg every two weeks) was initiated. At follow-up, 6MWD improved to 320 m (49.4% predicted), though oxygen desaturation (6%) and fatigue persisted, indicating partial therapeutic benefit.

This case exemplifies the diagnostic and therapeutic complexity of pediatric late-onset Pompe disease, reinforcing the importance of early recognition in adolescents with insidious proximal weakness and sustained hyperCKemia. Integrating enzymatic, genetic, and functional assessments enables precise characterization of disease phenotype. Timely initiation of enzyme replacement therapy, complemented by structured multidisciplinary follow-up, may reshape the natural history of LOPD, optimizing long-term neuromuscular and respiratory outcomes.