KCNT1 gain-of-function mutations linked to human epilepsy are modulated by quinidine

Abstract

Epilepsy of infancy with migrating focal seizures (EIMFS) and a severe form of autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) are strikingly different epilepsy syndromes, which have very recently been associated with mutations in the same gene. EIMFS is a rare early infantile epileptic encephalopathy characterised by heterogeneous migrating focal seizures, and associated with arrest or regression of development resulting in profound disability. In contrast, ADNFLE begins in mid-childhood and is characterized by clusters of motor seizures arising from sleep and is associated with major comorbidities of intellectual disability and psychiatric features. Whole exome sequencing of patients with EIMFS and severe ADNFLE has revealed a number of KCNT1 mutations with 100% penetrance, many of which are de novo . KCNT1 , widely expressed in the mammalian central nervous system, encodes a potassium channel that is activated by large elevations in intracellular sodium, which occur during normal physiological signalling in the nervous system. While KCNT1 channels are thought to play important roles in regulating neuronal excitability, their precise contribution to electrical activity differs in different neuronal cell types. KCNT1 disorders are resistant to standard anti-epileptic drugs and have a severe prognosis, creating an urgent need for novel therapies. Several studies have demonstrated that antiarrhythmic compounds, such as quinidine, bepridil and clofilium are effective blockers of KCNT1 channels and despite their known adverse effect profile our recent study suggests that they may hold promise as effective therapies in EIMFS. This research highlight describes this study, evaluating the electrophysiological and pharmacological gain-of-function phenotype of KCNT1 mutations in vitro and examining the neurodevelopmental time frame for the potential contribution of this channel to neuronal excitability in vivo .