Some KCNQ2 mutations found in the S4 and pore regions have a more severe dominant-negative effect and lead to neonatal-onset EE, and KCNQ2 mutation variants in the S4 domain can affect channel gating and increase the threshold for channel activation38,53, but the mutations in the S4 domain do not significantly impair surface protein expression53. This evidence concerns the gene KCNQ2 and ethylmalonic encephalopathy.