ELP1 (elongator acetyltransferase complex subunit 1) is the largest subunit of the evolutionarily conserved Elongator complex, which catalyzes multiple tRNA wobble base modifications essential for translational regulation 1. ELP1 mediates tRNA binding and catalyzes formation of modified uridines (mcm5U, mcm5s2U, ncm5U) at position 34 in tRNAs 2. The protein regulates α-tubulin acetylation, which controls microtubule-dependent axonal transport in projection neurons 3. Loss-of-function ELP1 variants cause proteome instability through defective tRNA modifications and impaired translational fidelity 1. Germline ELP1 mutations represent the most common genetic predisposition to Sonic Hedgehog medulloblastoma (MBSHH), accounting for ~30% of cases, with somatic loss of chromosome 9 causing biallelic inactivation 1. ELP1 deficiency increases DNA replication stress and compromises p53 signaling in cerebellar progenitors, explaining MBSHH restriction to the SHH-3 subtype 4. Germline mutations also cause familial dysautonomia (HSAN type 3), an autosomal recessive disorder with profound sensory loss, autonomic dysfunction, and neuronal degeneration 5. The Ashkenazi Jewish founder mutation impairs axonal transport through reduced α-tubulin acetylation 3. Disease-modifying therapeutics targeting ELP1 deficiency are advancing toward clinical testing 5.