Cation leak: a common functional defect causing developmental and epileptic encephalopathy.

Pathogenic variants in are an established cause of developmental and epileptic encephalopathy (DEE). To date, the stratification of patients with -DEE based on the biophysical consequence on channel function of a given variant has not been possible. Here, we analysed data from eleven patients carrying seven different pathogenic variants located in the transmembrane domains of the protein. All patients were diagnosed with severe disease including epilepsy and intellectual disability. The functional properties of the seven pathogenic variants were assessed using two-electrode voltage-clamp recordings in oocytes. All seven variants showed a significantly larger instantaneous current consistent with cation leak. The impact of each variant on other biophysical properties was variable, including changes in the half activation voltage and activation and deactivation kinetics. These data suggest that cation leak is an important pathogenic mechanism in -DEE. Furthermore, published mouse model and clinical case reports suggest that seizures are exacerbated by sodium channel blockers in patients with variants that cause cation leak. Stratification of patients based on their 'cation leak' biophysical phenotype may therefore provide key information to guide clinical management of individuals with -DEE.