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

Ulrike B.S. Hedrich, Stephan Lauxmann, Markus Wolff, Matthis Synofzik, Thomas Bast, Adrian Binelli, José M. Serratosa, Pedro Martínez-Ulloa, Nicholas M. Allen, Mary D. King, Kathleen M. Gorman, Bruria Ben Zeev, Michal Tzadok, Lily Wong-Kisiel, Dragan Marjanovic, Guido Rubboli, Sanjay M. Sisodiya, Florian Lutz, Harshad Pannikkaveettil Ashraf, Kirsten TorgePu Yan, Christian Bosselmann, Niklas Schwarz, Monika Fudali, Holger Lerche

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish (US)
Article numbereaaz4957
JournalScience translational medicine
Issue number609
StatePublished - Sep 1 2021

ASJC Scopus subject areas

  • General Medicine


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