4-Aminopyridine is a promising treatment option for patients with gain-of-function <i>KCNA2</i> -encephalopathy

Abstract

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 <i>KCNA2</i>-encephalopathy that the K⁺ channel blocker 4-aminopyridine can antagonize gain-of-function defects caused by variants in the K_V1.2 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 <i>KCNA2</i>-(gain-of-function)–encephalopathy and provide an online tool assisting physicians to select patients with gain-of-function mutations suited to this treatment.