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Articles reporting a histological examination of the CNS were selected. Classic infantile Pompe disease was defined by hypertrophic cardiomyopathy, symptom onset\u2009&lt;\u200912\u00a0months of age, and GAA deficiency, if available.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Of 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\u00a0months (range 1.2\u201317.0) for untreated and 12\u00a0months (range 7.5\u201321.0) 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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Understanding of CNS involvement in classic infantile Pompe disease is rapidly evolving. Histopathological studies from children up to 21\u00a0months 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\u00a0years of age, biomarker changes from around 5\u00a0years, and cognitive decline, reduced processing speed, and background activity slowing on electroencephalogram from approximately 8\u201310\u00a0years 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.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1007\/s00415-026-13991-y","type":"journal-article","created":{"date-parts":[[2026,7,31]],"date-time":"2026-07-31T16:24:56Z","timestamp":1785515096000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Central nervous system histopathological findings in classic infantile Pompe disease: a systematic review with clinical relevance"],"prefix":"10.1007","volume":"273","author":[{"given":"Jan J. 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P., J.M.P. v. d. H. and N.A.M.E van der Beek received funding for research, clinical trials, and\/or as advisor from various industries working on ERT or next-generation therapies in the field of Pompe disease under agreements with Erasmus MC University Medical Center. PWWMP is co-founder and unpaid Chief Scientific Officer of LentiCure, a company developing gene therapy for lysosomal disorders including Pompe disease. The other authors declare no competing interests.","order":1,"name":"Ethics","label":"Conflicts of interest","group":{"name":"EthicsHeading","label":"Declarations"}}],"article-number":"496"}}