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

Hedrich, UBS; Lauxmann, S; Wolff, M; Synofzik, M; Bast, T; Binelli, A; Serratosa, JM; ... Lerche, H; + view all (2021) 4-Aminopyridine is a promising treatment option for patients with gain-of-function KCNA2-encephalopathy. Science Translational Medicine , 13 (609) , Article eaaz4957. 10.1126/scitranslmed.aaz4957. Green open access

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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 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.

Type: Article
Title: 4-Aminopyridine is a promising treatment option for patients with gain-of-function KCNA2-encephalopathy
Open access status: An open access version is available from UCL Discovery
DOI: 10.1126/scitranslmed.aaz4957
Publisher version: https://doi.org/10.1126/scitranslmed.aaz4957
Language: English
Additional information: This version is the author accepted manuscript. For information on re-use, please refer to the publisher’s terms and conditions.
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology > Clinical and Experimental Epilepsy
URI: https://discovery.ucl.ac.uk/id/eprint/10137729
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