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000162807 041__ $$aEnglish
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000162807 1001_ $$0P:(DE-HGF)0$$aHedrich, Ulrike B S$$b0
000162807 245__ $$a4-Aminopyridine is a promising treatment option for patients with gain-of-function KCNA2-encephalopathy.
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000162807 520__ $$aDevelopmental 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.
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000162807 650_7 $$2NLM Chemicals$$aKCNA2 protein, human
000162807 650_7 $$2NLM Chemicals$$aKv1.2 Potassium Channel
000162807 650_7 $$0BH3B64OKL9$$2NLM Chemicals$$a4-Aminopyridine
000162807 650_2 $$2MeSH$$a4-Aminopyridine: therapeutic use
000162807 650_2 $$2MeSH$$aBrain Diseases
000162807 650_2 $$2MeSH$$aEpilepsy
000162807 650_2 $$2MeSH$$aGain of Function Mutation
000162807 650_2 $$2MeSH$$aHumans
000162807 650_2 $$2MeSH$$aKv1.2 Potassium Channel: genetics
000162807 650_2 $$2MeSH$$aMutation
000162807 7001_ $$00000-0002-9194-1716$$aLauxmann, Stephan$$b1
000162807 7001_ $$00000-0001-5640-0888$$aWolff, Markus$$b2
000162807 7001_ $$0P:(DE-2719)2811275$$aSynofzik, Matthis$$b3$$udzne
000162807 7001_ $$00000-0001-8995-9792$$aBast, Thomas$$b4
000162807 7001_ $$00000-0001-5853-0467$$aBinelli, Adrian$$b5
000162807 7001_ $$00000-0003-2239-8948$$aSerratosa, José M$$b6
000162807 7001_ $$aMartínez-Ulloa, Pedro$$b7
000162807 7001_ $$aAllen, Nicholas M$$b8
000162807 7001_ $$aKing, Mary D$$b9
000162807 7001_ $$00000-0002-5488-1507$$aGorman, Kathleen M$$b10
000162807 7001_ $$00000-0001-6347-2089$$aZeev, Bruria Ben$$b11
000162807 7001_ $$aTzadok, Michal$$b12
000162807 7001_ $$00000-0002-5306-0862$$aWong-Kisiel, Lily$$b13
000162807 7001_ $$00000-0001-9967-7828$$aMarjanovic, Dragan$$b14
000162807 7001_ $$00000-0002-5309-2514$$aRubboli, Guido$$b15
000162807 7001_ $$aSisodiya, Sanjay M$$b16
000162807 7001_ $$00000-0002-3778-3286$$aLutz, Florian$$b17
000162807 7001_ $$00000-0001-6842-916X$$aAshraf, Harshad Pannikkaveettil$$b18
000162807 7001_ $$aTorge, Kirsten$$b19
000162807 7001_ $$aYan, Pu$$b20
000162807 7001_ $$00000-0002-1596-5599$$aBosselmann, Christian$$b21
000162807 7001_ $$00000-0002-4064-3073$$aSchwarz, Niklas$$b22
000162807 7001_ $$00000-0002-9922-9942$$aFudali, Monika$$b23
000162807 7001_ $$0P:(DE-HGF)0$$aLerche, Holger$$b24
000162807 773__ $$0PERI:(DE-600)2518839-2$$a10.1126/scitranslmed.aaz4957$$gVol. 13, no. 609, p. eaaz4957$$n609$$peaaz4957$$tScience translational medicine$$v13$$x1946-6242$$y2021
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