Hirano et al. define a novel neurological disease spectrum involving the LGI1–ADAM22/23 pathway, based on the identification of ultra-rare biallelic LGI1 variants associated with progressive developmental and epileptic encephalopathy, and a biallelic ADAM23 variant associated with lethal neonatal-onset epilepsy. Here, ADAM22 is linked to Epileptic encephalopathy.