Here, we report 5 individuals from 2 unrelated families with compound heterozygous variants in ATP6V0A1 presenting with a phenotype of early-onset progressive myoclonus epilepsy (PME) and ataxia and 12 cases with de novo missense variants in the same gene, with severe developmental and epileptic encephalopathy (DEE), resulting from direct impairment of endolysosome acidification and failure of lysosomal functions. Here, ATP6V0A1 is linked to developmental and epileptic encephalopathy.