KCNT1

KCNT1 is a human gene that encodes the Slack (sodium-activated potassium) channel subunit, also known as KNa1.1. This channel is a member of the Slo family of potassium channels. The Slack channel forms homotetrameric channels that are activated by intracellular sodium ions and, to a lesser extent, by intracellular calcium. The channel conducts potassium ions, contributing to the afterhyperpolarization phase of action potentials and shaping neuronal excitability. Slack channels are widely expressed in the brain, including cortex and hippocampus, with functional roles in synaptic transmission and neuronal firing patterns.

Pathogenic variants in KCNT1 are associated with a spectrum of epilepsy and neurodevelopmental disorders. Most disease-causing variants are de novo gain-of-function mutations that increase the potassium current, which paradoxically can destabilize network activity and promote seizures. Core syndromes linked to KCNT1 mutations include malignant migrating partial seizures of infancy (MMPSI), early-infantile epileptic encephalopathy, and various epileptic encephalopathies with variable intellectual disability and motor abnormalities. Some patients present with nocturnal frontal lobe epilepsy or other focal epilepsies.

Diagnosis is usually by genetic testing when epilepsy of early onset is present. Management is challenging; antiseizure medications are often ineffective, though some reports describe seizure improvement with quinidine, a KCNT1 blocker, or with ketogenic diet and other therapies. Ongoing research aims to understand channel regulation and develop targeted therapies.