Thornton, B. T.; Hardinger, A. G.; Pence, L.; Prem Kumar, P.; Connolly, N.; Weir, S. J.; Vivian, J. L.

Background: Vici syndrome (VS) is a rare pediatric genetic disorder characterized by profound developmental delay, seizures, immune deficits, cardiomyopathy, and progressive motor dysfunction, with a median survival of approximately 42 months. This devastating condition is caused by pathogenic variants in the EPG5 gene, which encodes a key regulator of autophagy. Loss of EPG5 function leads to the accumulation of toxic intracellular material and widespread cellular dysfunction. Currently, there are no effective treatments for VS. The underlying cellular mechanisms driving the progressive neurological decline in VS remain poorly understood. Although previous studies using Epg5 knockout models have demonstrated severe neurological phenotypes, these models have not been comprehensively characterized for molecular and cellular deficits within the central nervous system. Methods: We report the generation and analysis of novel genetically engineered mouse models of VS, including a strain harboring a truncating mutation that recapitulates a pathogenic variant identified in a VS patient and a strain with an Epg5 null allele. These mutant models were used to further understand the underlying molecular deficits of the nervous system. Results: These novel Epg5 mutant mouse models exhibited incompletely penetrant perinatal lethality and neurological deficits were detectable by six weeks of age, which worsen over time. Histological analysis revealed widespread expansion of microglia and astrocytes throughout the central nervous system (CNS). Transcriptomic profiling of CNS tissue revealed robust neuroinflammatory signatures, implicating the activation of both microglia and astrocytes. Notably, the molecular profiles of Epg5-deficient mice share features with disease-associated microglia observed in other models of neurological disease and injury. Conclusions: The analysis of these novel mouse models of Vici syndrome suggest a critical role for neuroglial activation in the pathogenesis of VS. These novel in vivo models will be a valuable platform for preclinical evaluation of therapeutic strategies targeting autophagy-related neurodegeneration in congenital disorders of autophagy.