%0 Journal Article
%A Hedrich, Ulrike B S
%A Lauxmann, Stephan
%A Wolff, Markus
%A Synofzik, Matthis
%A Bast, Thomas
%A Binelli, Adrian
%A Serratosa, José M
%A Martínez-Ulloa, Pedro
%A Allen, Nicholas M
%A King, Mary D
%A Gorman, Kathleen M
%A Zeev, Bruria Ben
%A Tzadok, Michal
%A Wong-Kisiel, Lily
%A Marjanovic, Dragan
%A Rubboli, Guido
%A Sisodiya, Sanjay M
%A Lutz, Florian
%A Ashraf, Harshad Pannikkaveettil
%A Torge, Kirsten
%A Yan, Pu
%A Bosselmann, Christian
%A Schwarz, Niklas
%A Fudali, Monika
%A Lerche, Holger
%T 4-Aminopyridine is a promising treatment option for patients with gain-of-function KCNA2-encephalopathy.
%J Science translational medicine
%V 13
%N 609
%@ 1946-6242
%C Washington, DC
%I AAAS
%M DZNE-2021-01462
%P eaaz4957
%D 2021
%X 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.
%K 4-Aminopyridine: therapeutic use
%K Brain Diseases
%K Epilepsy
%K Gain of Function Mutation
%K Humans
%K Kv1.2 Potassium Channel: genetics
%K Mutation
%K KCNA2 protein, human (NLM Chemicals)
%K Kv1.2 Potassium Channel (NLM Chemicals)
%K 4-Aminopyridine (NLM Chemicals)
%F PUB:(DE-HGF)16
%9 Journal Article
%$ pmid:34516822
%R 10.1126/scitranslmed.aaz4957
%U https://pub.dzne.de/record/162807