Home > Publications Database > 4-Aminopyridine is a promising treatment option for patients with gain-of-function KCNA2-encephalopathy. > print

001     162807
005     20230915092408.0
024 7 _ |a 10.1126/scitranslmed.aaz4957
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037 _ _ |a DZNE-2021-01462
041 _ _ |a English
082 _ _ |a 500
100 1 _ |a Hedrich, Ulrike B S
|0 P:(DE-HGF)0
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245 _ _ |a 4-Aminopyridine is a promising treatment option for patients with gain-of-function KCNA2-encephalopathy.
260 _ _ |a Washington, DC
|c 2021
|b AAAS
336 7 _ |a article
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336 7 _ |a Journal Article
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336 7 _ |a ARTICLE
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520 _ _ |a 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.
536 _ _ |a 353 - Clinical and Health Care Research (POF4-353)
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588 _ _ |a Dataset connected to CrossRef, PubMed, , Journals: pub.dzne.de
650 _ 7 |a KCNA2 protein, human
|2 NLM Chemicals
650 _ 7 |a Kv1.2 Potassium Channel
|2 NLM Chemicals
650 _ 7 |a 4-Aminopyridine
|0 BH3B64OKL9
|2 NLM Chemicals
650 _ 2 |a 4-Aminopyridine: therapeutic use
|2 MeSH
650 _ 2 |a Brain Diseases
|2 MeSH
650 _ 2 |a Epilepsy
|2 MeSH
650 _ 2 |a Gain of Function Mutation
|2 MeSH
650 _ 2 |a Humans
|2 MeSH
650 _ 2 |a Kv1.2 Potassium Channel: genetics
|2 MeSH
650 _ 2 |a Mutation
|2 MeSH
700 1 _ |a Lauxmann, Stephan
|0 0000-0002-9194-1716
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700 1 _ |a Wolff, Markus
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700 1 _ |a Synofzik, Matthis
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700 1 _ |a Bast, Thomas
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700 1 _ |a Binelli, Adrian
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700 1 _ |a Serratosa, José M
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700 1 _ |a Martínez-Ulloa, Pedro
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700 1 _ |a Allen, Nicholas M
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700 1 _ |a King, Mary D
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700 1 _ |a Gorman, Kathleen M
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700 1 _ |a Zeev, Bruria Ben
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700 1 _ |a Tzadok, Michal
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700 1 _ |a Wong-Kisiel, Lily
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700 1 _ |a Marjanovic, Dragan
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700 1 _ |a Rubboli, Guido
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700 1 _ |a Sisodiya, Sanjay M
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700 1 _ |a Lutz, Florian
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700 1 _ |a Ashraf, Harshad Pannikkaveettil
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700 1 _ |a Torge, Kirsten
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700 1 _ |a Yan, Pu
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700 1 _ |a Bosselmann, Christian
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700 1 _ |a Schwarz, Niklas
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700 1 _ |a Fudali, Monika
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700 1 _ |a Lerche, Holger
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773 _ _ |a 10.1126/scitranslmed.aaz4957
|g Vol. 13, no. 609, p. eaaz4957
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