An emerging phenotype of central nervous system involvement in Pompe disease: from bench to bedside and beyond

Pompe disease (PD) is a lysosomal storage disorder caused by deficiency of the lysosomal enzyme acid-alpha glucosidase (GAA). Pathogenic variants in the GAA gene lead to excessive accumulation of lysosomal glycogen primarily in the cardiac, skeletal, and smooth muscles. There is growing evidence of central nervous system (CNS) involvement in PD. Current research is focused on determining the true extent of CNS involvement, its effects on behavior and cognition, and effective therapies that would correct the disease in both muscle and the CNS. This review article summarizes the CNS findings in patients, highlights the importance of research on animal models, explores the probable success of gene therapy in reversing CNS pathologies as reported by some breakthrough preclinical studies, and emphasizes the need to follow patients and monitor for CNS involvement over time. Lessons learned from animal models (bench) and from the literature available to date on patients will guide future clinical trials in patients (bedside) with PD. Our preliminary studies in infantile PD show that some patients are susceptible to early and extensive CNS pathologies, as assessed by neuroimaging and developmental assessments. This article highlights the importance of neuroimaging which could serve as useful tools to diagnose and monitor certain CNS pathologies such as white matter hyperintense foci (WMF) in the brain. Longitudinal studies with large sample sizes are warranted at this time to better understand the emergence, progression and consequences of CNS involvement in patients with PD.