Dysregulated metabolism in neurodevelopmental disorders: From glycolytic gene variants to metabolic reprogramming and therapeutic perspectives

This is the authors' abstract. We don't add key points for this paper.

Proper neurodevelopment requires precisely coordinated energy metabolism, with glycolysis serving as a central pathway in supporting neuronal growth, differentiation, and synaptic connectivity. While an increasing number of mutations in glycolysis-related genes to have been linked to neurodevelopmental disorders (NDDs), the precise pathogenic mechanisms remain largely elusive. This review systematically summarizes the clinical phenotypes associated with glycolytic gene variants and dissects their impact on brain metabolism. We further highlight cell type-specific metabolic reprogramming in neurons, astrocytes, microglia and oligodendrocytes, emphasizing how these cells adapt glycolysis flux under pathological conditions. We also discuss current and emerging therapeutic strategies targeting glycolysis-targeted therapies, including metabolic supplementation, enzyme stabilization, and gene therapy. By integrating genetic, metabolic, and therapeutic insights, this review provides a comprehensive framework to understand how glycolysis governs brain development and presents new avenues for treating NDDs through metabolic intervention.