Pompe Disease: A Review of Diagnosis, Molecular Genetics, and Treatment Management

Pompe disease, a rare autosomal recessive lysosomal storage disorder, results from mutations in the GAA gene that lead to deficient acid alpha-glucosidase activity and glycogen accumulation in various tissues.

This review employs the diagnostic approach to the disease, encompassing enzymatic assays and molecular genetics, with a focus on genotype-phenotype correlations and regionspecific mutations.

Over 500 mutations in the GAA gene, including missense, nonsense, insertions, deletions, and splicing defects, contribute to varying levels of enzyme deficiency, accounting for the diverse clinical manifestations of Pompe disease.

Current therapies, including Enzyme replacement therapy (ERT), are the cornerstone treatments for Pompe disease, utilizing recombinant human alpha-glucosidase to restore enzyme activity and reduce glycogen accumulation in lysosomes. While ERT significantly improves survival, cardiomyopathy, and respiratory function, its limited uptake in skeletal muscle and immunogenicity pose challenges. Innovations include immune tolerance protocols and nextgeneration enzymes to enhance skeletal muscle delivery. Gene therapy emerges as a promising alternative, leveraging viral vectors to deliver functional GAA genes, thereby enabling sustained endogenous enzyme production and addressing limitations of ERT. Preclinical and early-phase trials demonstrate efficacy, reduced immunogenicity, and enhanced skeletal muscle uptake; however, challenges, such as vector immunogenicity and cost, remain. Thus, genetic counseling is essential for family planning and managing emotional and psychosocial challenges related to this disease.

This article highlights advances and challenges in the diagnosis, management, and treatment of Pompe disease, providing a comprehensive resource for clinicians and researchers.