POMPE disease management is evolving as next-generation enzyme replacement, gene therapy, and digital monitoring reshape decisions.
Pompe Disease Pathogenesis: A Wider View
Pompe disease is an autosomal recessive lysosomal storage disorder caused by deficiency of acid alpha glucosidase, leading to progressive glycogen accumulation across multiple tissues. The review describes a spectrum from infantile-onset Pompe disease, often marked by cardiomyopathy and rapid progression, to late-onset Pompe disease, which more commonly features skeletal and respiratory muscle involvement. Beyond lysosomal glycogen storage, the authors highlight mitochondrial dysfunction and impaired autophagic flux as increasingly recognized contributors to disease complications, with downstream oxidative stress and bioenergetic failure.
Central nervous system involvement remains a key unmet need because conventional enzyme replacement approaches do not cross the blood-brain barrier, leaving neurological manifestations incompletely addressed in some patients.
Pompe Disease Management: Screening, Biomarkers, and Next-Generation ERT
Early identification is positioned as critical to preserving function by enabling treatment before irreversible damage occurs. The review discusses practical challenges with dried blood spot newborn screening and summarizes evidence supporting alternative sampling approaches alongside two-tier workflows that pair enzyme activity testing with genetic confirmation to reduce false positives from pseudodeficiency alleles.
On the treatment front, the authors synthesize comparative evidence across available enzyme replacement therapy regimens, including next-generation enzyme replacement options designed to enhance cellular uptake and improve functional outcomes. They also describe a two-component approach that combines an infused enzyme with an oral stabilizer to improve circulating stability and downstream biomarker profiles, while acknowledging limitations in the comparative literature and the ongoing need for long-term data.
Future Directions: Gene Therapy and CNS-Targeted Delivery
Gene therapy is presented as a potential one-time strategy, with progress focused on improving muscle targeting while reducing off-target exposure and dose-related toxicity. The review also highlights transferrin receptor-mediated delivery as an emerging method to move enzyme across the blood-brain barrier, paired with proposed biomarkers and imaging strategies to quantify central glycogen burden and treatment response. Digital health technologies are also emphasized for detecting subtle motor impairment, including in presymptomatic stages, to support earlier intervention and more sensitive monitoring over time.
Reference
Li GR et al. Comprehensive review of recent advances in Pompe disease: pathogenesis, management, and future directions. Frontiers in Neurology. 2026;17:doi:10.3389/fneur.2026.1756935.
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