TY - JOUR
T1 - 4-Aminopyridine is a promising treatment option for patients with gain-of-function KCNA2-encephalopathy
AU - Hedrich, Ulrike B.S.
AU - Lauxmann, Stephan
AU - Wolff, Markus
AU - Synofzik, Matthis
AU - Bast, Thomas
AU - Binelli, Adrian
AU - Serratosa, José M.
AU - Martínez-Ulloa, Pedro
AU - Allen, Nicholas M.
AU - King, Mary D.
AU - Gorman, Kathleen M.
AU - Zeev, Bruria Ben
AU - Tzadok, Michal
AU - Wong-Kisiel, Lily
AU - Marjanovic, Dragan
AU - Rubboli, Guido
AU - Sisodiya, Sanjay M.
AU - Lutz, Florian
AU - Ashraf, Harshad Pannikkaveettil
AU - Torge, Kirsten
AU - Yan, Pu
AU - Bosselmann, Christian
AU - Schwarz, Niklas
AU - Fudali, Monika
AU - Lerche, Holger
N1 - Publisher Copyright:
Copyright © 2021 The Authors, some rights reserved;
PY - 2021/9/1
Y1 - 2021/9/1
N2 - 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.
AB - 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.
UR - https://www.scopus.com/pages/publications/85114836330
U2 - 10.1126/scitranslmed.aaz4957
DO - 10.1126/scitranslmed.aaz4957
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C2 - 34516822
AN - SCOPUS:85114836330
SN - 1946-6234
VL - 13
JO - Science Translational Medicine
JF - Science Translational Medicine
IS - 609
M1 - eaaz4957
ER -