EIF2B3 encodes the gamma subunit of eukaryotic translation initiation factor 2B (eIF2B), a guanine nucleotide exchange factor that catalyzes GDP-to-GTP exchange on the eIF2 complex gamma subunit 123. This exchange is essential for initiating protein synthesis by delivering methionyl-initiator tRNA to the ribosome. The eIF2B complex's activity is negatively regulated when eIF2 alpha subunit becomes phosphorylated, resulting in global translation repression 13. Biallelic EIF2B3 mutations cause vanishing white matter disease (VWM), a severe autosomal recessive leukodystrophy characterized by progressive white matter rarefaction and cerebrospinal fluid replacement 45. Clinical manifestations include ataxia, spasticity, optic atrophy, and cognitive decline 6. EIF2B3 mutations impair oligodendrocyte development and myelin formation 4, with altered protein expression including reduced crystallins and increased proteases 7. Mutant oligodendrocytes demonstrate reduced endoplasmic reticulum stress tolerance due to depressed autophagy flux, contributing to cell apoptosis 8. While most cases present in childhood with rapid progression, rare antenatal-onset cases with mild symptoms and extended survival have been documented 9. Adult-onset EIF2B3 variants occur with female predominance and progressive neurological decline 610.