One of the functionally characterized mutations affecting the VSM, namely the de novo E1211K mutation, affecting a highly-conserved residue in the DIII-S1 and found in a patient affected with intractable seizures and developmental delay, revealed complex alterations in the biophysical properties of Nav1.2 channels, including a hyperpolarization of both the half-activation and half-inactivation potentials and a delay in the recovery from inactivation, therefore leading to unpredictable results on mutation-dependent pathogenetic mechanisms. This evidence concerns the gene SCN2A and Global developmental delay.