Using a mouse model of Glucose Transporter 1 (Glut1) haploinsufficiency which faithfully replicates the core characteristics of De Vivo disease, a human Glut1 Deficiency Syndrome (Glut1DS), we found an early and pronounced decrease in brain glucose, lactate, and glycogen levels. To elucidate the cellular and molecular mechanisms underlying Glut1DS, we conducted an RNA-sequencing analysis on the somatosensory and motor cerebral cortex of a mouse model for Glut1DS.Our analysis revealed 195 up-regulated and 71 down-regulated genes in Glut1-deficient mice compared to wild type controls. Gene set analysis of these differentially expressed genes highlighted their involvement in myelin structure and myelination processes. Notably, the expression of genes coding for Proteolipid protein 1, myelin and lymphocyte protein and myelin associated glycoprotein was significantly decreased in the cerebral cortex of Glut1 deficient mice. Together, these results indicate that Glut1 deficiency causes alteration of myelin gene expression in the mouse brain. Myelin alteration in the cerebral cortex could be a factor contributing to the locomotor deficits observed in Glut1-deficient mice. Further characterization of the cellular and molecular mechanisms affected by SLC2A1 disease causing mutations should improve our understanding of the causes of De Vivo disease symptoms and contribute to the development of targeted and effective therapies.