Central nervous system histopathological findings in classic infantile Pompe disease: a systematic review with clinical relevance.

introductionClassic infantile Pompe disease is the most severe phenotype within the clinical spectrum of Pompe disease and is characterized by central nervous system (CNS) involvement.

methodsA systematic review on histopathological findings in classic infantile Pompe disease was conducted using Embase, Medline Ovid, Web of science and Cochrane central databases for original research articles until 16-12-2025. Articles reporting a histological examination of the CNS were selected. Classic infantile Pompe disease was defined by hypertrophic cardiomyopathy, symptom onset < 12 months of age, and GAA deficiency, if available.

resultsOf the 3734 records identified, 39 articles were included in the study, comprising 49 patients, 7 of whom treated with enzyme replacement therapy. The median age at autopsy was 6 months (range 1.2-17.0) for untreated and 12 months (range 7.5-21.0) for treated patients. Histologic abnormalities were found throughout the CNS. The cerebral and cerebellar white matter (WM), globus pallidus, dentate nucleus, motor nuclei of the brainstem, and anterior horn cells were most frequently affected. Glycogen accumulation was severe in astrocytes and in neurons of the globus pallidus. Cortical neurons were affected with greater variability, and subcortical structures were more frequently involved than cortical ones.

conclusionsUnderstanding of CNS involvement in classic infantile Pompe disease is rapidly evolving. Histopathological studies from children up to 21 months demonstrate early and widespread CNS pathology. Notably, there is a marked temporal gap between the extensive abnormalities observed at autopsy in infancy and later radiological, biochemical, and clinical manifestations. While white matter pathology is already prominent in young patients, abnormalities on magnetic resonance imaging typically emerge from 2 to 3 years of age, biomarker changes from around 5 years, and cognitive decline, reduced processing speed, and background activity slowing on electroencephalogram from approximately 8-10 years onward. These observations suggest a gradual evolution of CNS disease, although direct clinicopathological correlations remain limited. Epilepsy has been reported later in the disease course, and we have observed upper motor neuron signs in older patients, suggesting progressive gray and white matter involvement that may contribute to cognitive decline. The mechanisms linking glycogen accumulation to neurological manifestations remain incompletely understood. Taken together, these observations form the basis for several hypotheses on the pathogenesis of CNS involvement in classic infantile Pompe disease.