Developmental and Epileptic Encephalopathy: Pathogenesis of Intellectual Disability Beyond Channelopathies

Developmental and epileptic encephalopathies (DEEs) are a group of neuropediatric diseases associated with epileptic seizures, severe delay or regression of psychomotor development, and cognitive and behavioral deficits. What sets DEEs apart is their complex interplay of epilepsy and developmental delay, often driven by genetic factors. These two aspects influence one another but can develop independently, creating diagnostic and therapeutic challenges. Intellectual disability is severe and complicates potential treatment. Pathogenic variants are found in 30-50% of patients with DEE. Many genes mutated in DEEs encode ion channels, causing current conduction disruptions known as channelopathies. Although channelopathies indeed make up a significant proportion of DEE cases, many other mechanisms have been identified: impaired neurogenesis, metabolic disorders, disruption of dendrite and axon growth, maintenance and synapse formation abnormalities -synaptopathies. Here, we review recent publications on non-channelopathies in DEE with an emphasis on the mechanisms linking epileptiform activity with intellectual disability. We focus on three major mechanisms of intellectual disability in DEE and describe several recently identified genes involved in the pathogenesis of DEE.