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

Abstract

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.