The Evolution of Pompe disease From Fatal Infantile Disorder to Treatable Myopathy

April 15 marks International Pompe Day, an international awareness day for Pompe disease, a rare genetic neuromuscular disorder. Historically described as a fatal metabolic myopathy of infancy, Pompe disease has undergone significant clinical and scientific redefinition over the past century. Advances in molecular biology, diagnostic methodologies, and targeted therapies have contributed to its current classification as a treatable, though still complex, neuromuscular disorder. Its historical trajectory reflects broader developments in rare disease research and the application of precision medicine in neurology.

First described in 1932 by Johannes Cassianus Pompe, the disease was identified in an infant presenting severe cardiomegaly and early mortality. Postmortem evaluation demonstrated extensive glycogen accumulation in cardiac and skeletal muscle, leading to its initial classification as a glycogen storage disorder. In the decades that followed, Pompe disease was further categorized as glycogen storage disease type II, although the precise enzymatic defect remained unclear through the mid-20th century, limiting both diagnostic specificity and therapeutic development.^1,2

A major advance occurred in the 1960s with the identification of acid alpha-glucosidase (GAA) deficiency as the underlying cause of the disease. This discovery coincided with the emerging understanding of lysosomal function and helped establish Pompe disease as a prototypical member of Lysosomal storage disorders. Subsequent work clarified that impaired glycogen degradation within lysosomes leads to progressive accumulation, resulting in cellular dysfunction, particularly in cardiac and skeletal muscle tissue. These mechanistic insights provided the foundation for later therapeutic development.^3,4

Over time, the recognized clinical spectrum of Pompe disease expanded. Early reports emphasized the infantile-onset form, characterized by hypertrophic cardiomyopathy, hypotonia, and high mortality, often within the first year of life. By the late 20th century, clinicians increasingly recognized a late-onset phenotype, with presentation ranging from adolescence to adulthood and typically involving progressive limb-girdle weakness and respiratory insufficiency. This broadened phenotypic understanding contributed to increased recognition of Pompe disease within the differential diagnosis of neuromuscular disorders in adult neurology practice.⁴

Diagnostic approaches have also evolved substantially. Muscle biopsy, once central to diagnosis due to its demonstration of vacuolar myopathy with glycogen accumulation, has largely been supplemented by enzyme activity assays using dried blood spots, leukocytes, or cultured fibroblasts. The identification of pathogenic variants in the GAA gene in the 1990s enabled molecular confirmation of disease and improved diagnostic precision. More recently, the adoption of newborn screening programs, first implemented in Taiwan and subsequently expanded to other regions, including parts of the United States, has allowed for earlier detection, including in presymptomatic individuals.^5,6

A notable turning point occurred in 2006 with the approval of enzyme replacement therapy (ERT) using alglucosidase alfa.⁷ This therapy represented the first disease-specific treatment for Pompe disease and was associated with a shift in clinical outcomes, particularly in infantile-onset cases. Clinical studies demonstrated improvements in survival, reductions in cardiomegaly, and achievement of motor milestones in treated infants. In late-onset disease, ERT has been associated with stabilization or modest improvements in motor and respiratory function, although variability in treatment response has been observed across patient populations.⁸

Despite these advances, several limitations of ERT remain. These include immune responses to the recombinant enzyme, limited uptake in skeletal muscle, and the need for lifelong intravenous administration. As a result, research has increasingly focused on next-generation strategies, including modified enzyme formulations with improved tissue targeting, adjunctive therapies to enhance delivery, and gene-based approaches. The application of gene therapy is currently under investigation as a potential method to achieve sustained enzyme expression and reduce treatment burden.⁹

Pompe disease is now frequently cited as an example of the translation of molecular insights into targeted therapeutic strategies for rare neurologic conditions. Its history highlights the importance of early diagnosis, particularly in the context of newborn screening, in influencing clinical outcomes. At the same time, ongoing challenges underscore the need for continued therapeutic innovation.⁵

For neurologists, evolving understanding of Pompe disease has implications for clinical practice, including increased awareness of late-onset presentations, use of genetic and enzymatic testing in evaluation, and familiarity with available and emerging therapies. Continued research is expected to further define its management within the broader field of neuromuscular and metabolic disorders.

REFERENCES
1. Pompe JC. Over idiopathische hypertrophie van het hart. NedTijdschr Geneeskd. 1932;76:304-311.
2. Hirschhorn R, Reuser AJJ. Glycogen storage disease type II: acid α-glucosidase (acid maltase) deficiency. In: Valle D, ed. The Metabolic and Molecular Bases of Inherited Disease. 8th ed. McGraw-Hill; 2001:3389-3420.
3. Hers HG. α-Glucosidase deficiency in generalized glycogen-storage disease (Pompe’s disease). Biochem J. 1963;86(1):11-16. doi:10.1042/bj0860011
4. van der Ploeg AT, Reuser AJJ. Pompe’s disease. Lancet. 2008;372(9646):1342-1353. doi:10.1016/S0140-6736(08)61555-X
5. Chien YH, Hwu WL, Lee NC. Pompe disease: early diagnosis and early treatment make a difference. Pediatr Neonatol. 2013;54(4):219-227. doi:10.1016/j.pedneo.2013.03.009
6. Kemper AR, Comeau AM, Green NS, et al. Evidence report: newborn screening for Pompe disease. Genet Med. 2007;9(5):267-290. doi:10.1097/GIM.0b013e31804a7d5a
7. Kishnani PS, Steiner RD, Bali D, et al. Pompe disease diagnosis and management guideline. Genet Med. 2006;8(5):267-288. doi:10.1097/01.gim.0000218152.87434.f3
8. van der Ploeg AT, Clemens PR, Corzo D, et al. A randomized study of alglucosidase alfa in late-onset Pompe’s disease. N Engl J Med. 2010;362(15):1396-1406. doi:10.1056/NEJMoa0909859
9. Mendelsohn NJ, Messinger YH, Rosenberg AS, Kishnani PS. Elimination of antibodies to recombinant enzyme in Pompe’s disease. N Engl J Med. 2009;360(2):194-195. doi:10.1056/NEJMc0806809