In response to various cellular stress stimuli, eIF2α kinases (PERK, HRI, GCN2, PKR) are selectively activated and phosphorylate eIF2α, resulting in the inhibition of eIF2B GEF activity and suppression of global translation. The translation of ISR effector mRNAs such as ATF4 is up-regulated promoting stress response gene expression. If stress is overcome GADD34 promotes dephosphorylation of eIF2α restoring homeostatic translation. VWM mutations can decrease eIF2B GEF activity, complex formation or eIF2B body formation, resulting in ISR dysregulation including increased ATF4 expression and decreased eIF2α phosphorylation. ISRIB and Guanabenz modulate ISR signalling through increasing eIF2B complex formation and decreasing dephosphorylation of eIF2α respectively, highlighting therapeutic potential for the treatment of VWM.