Classic infantile Pompe disease, the most severe phenotype of Pompe disease, is characterized by involvement of the central nervous system (CNS). The condition is typically treated with enzyme replacement therapy (ERT), but patients continue to experience substantial unmet medical needs even after treatment, creating a need for new therapeutic approaches. In particular, therapies that can cross the blood-brain barrier may help address CNS involvement in the disease.
In a systematic review published in the Journal of Neurology, Jan J. A. van den Dorpel, of University Medical Center Rotterdam in The Netherlands, and colleagues reviewed histopathological findings in classic infantile Pompe disease. To identify original research articles that reported a histological examination of the CNS, they searched the Embase, MEDLINE Ovid, Web of Science, and Cochrane Central databases through December 16, 2025. Classic infantile Pompe disease was defined by hypertrophic cardiomyopathy, symptom onset prior to 12 months of age, and GAA deficiency, when available.
The review included approximately 40 articles, representing 49 patients up to 21 months of age. Seven patients were treated with ERT. The results showed histologic abnormalities throughout the CNS, with the cerebral and cerebellar white matter, globus pallidus, dentate nucleus, motor nuclei of the brainstem, and anterior horn cells most affected. Glycogen accumulation was severe in astrocytes and in neurons of the globus pallidus. Meanwhile, subcortical structures were involved more frequently than cortical ones, while cortical neurons were affected with greater variability.
The researchers noted a temporal gap between the extensive abnormalities observed at autopsy in infancy and the later radiological, biochemical, and clinical manifestations of the disease. For example, they describe how white matter pathology is prominent in infants, while abnormalities on magnetic resonance imaging tend to only emerge around 2 to 3 years, with biomarker changes not observed until around 5 years. Meanwhile, symptoms like cognitive decline and reduced processing speed, along with activity slowing on electroencephalogram, don’t typically emerge until around 8 to 10 years.
Overall, the authors note that these findings indicate that CNS disease evolves gradually in classic infantile Pompe disease, providing a basis for hypotheses on the pathogenesis of CNS involvement. However, they add that direct clinicopathological correlations remain limited, while the knowledge of the mechanisms linking glycogen accumulation to neurological manifestations of the disease is still limited.