LAUSR

Description 4-Aminopyridine is a potential therapeutic option for a subgroup of patients with KCNA2-encephalopathy and gain-of-function variants. Targeting the K+ey current Gain-of-function (GOF) mutations in the potassium channel Kv1.2 cause a subtype of developmental KCNA2-encephalopathy, characterized by the occurrence of seizures, cerebellar ataxia, and intellectual disabilities. The available treatments are mostly ineffective. Here, Hedrich et al. showed that the potassium channel blocker 4-aminopyridine (4-AP) corrected electrophysiological abnormalities in neurons in vitro. 4-AP was effective in reducing symptoms in 9 of 11 patients carrying GOF Kv1.2 mutations. Seizure reduction and improvements in movements and cognition were reported for the majority of the treated patients, without causing severe side effects. The results suggest that blocking potassium channels could be an effective approach for treating patients with GOF in Kv1.2. Developmental and epileptic encephalopathies are devastating disorders characterized by epilepsy, intellectual disability, and other neuropsychiatric symptoms, for which available treatments are largely ineffective. Following a precision medicine approach, we show for KCNA2-encephalopathy that the K+ channel blocker 4-aminopyridine can antagonize gain-of-function defects caused by variants in the KV1.2 subunit in vitro, by reducing current amplitudes and negative shifts of steady-state activation and increasing the firing rate of transfected neurons. In n-of-1 trials carried out in nine different centers, 9 of 11 patients carrying such variants benefitted from treatment with 4-aminopyridine. All six patients experiencing daily absence, myoclonic, or atonic seizures became seizure-free (except some remaining provoked seizures). Two of six patients experiencing generalized tonic-clonic seizures showed marked improvement, three showed no effect, and one worsening. Nine patients showed improved gait, ataxia, alertness, cognition, or speech. 4-Aminopyridine was well tolerated up to 2.6 mg/kg per day. We suggest 4-aminopyridine as a promising tailored treatment in KCNA2-(gain-of-function)–encephalopathy and provide an online tool assisting physicians to select patients with gain-of-function mutations suited to this treatment.