Seizure worsening and sodium channel blockers in HCN1-related epilepsies: A case series

Pathogenic variants in HCN1 are associated with a spectrum of epilepsies, including drug-resistant developmental and epileptic encephalopathies. However, evidence to guide antiseizure medication (ASM) selection in HCN1-related epilepsies remains limited. In this intentionally selected, retrospective case series, we identified seven patients with confirmed pathogenic or likely pathogenic HCN1 variants associated with gain-of-function effects. In all cases, treatment with sodium-channel-blocking ASMs including phenytoin, lamotrigine, oxcarbazepine, and lacosamide was associated with seizure worsening, with clinical improvement after drug discontinuation. These findings identify a clinically actionable gene–drug interaction in HCN1-related epilepsies and support a mechanism-based approach to ASM selection. Our data provide translational evidence to inform precision treatment strategies and help avoid potentially harmful therapies in affected children.