Journal Article

DZNE-2021-01462

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png 4-Aminopyridine is a promising treatment option for patients with gain-of-function KCNA2-encephalopathy.

Hedrich, U. B. S. ; Lauxmann, S. ; Wolff, M. ; Synofzik, M.DZNE* ; Bast, T. ; Binelli, A. ; Serratosa, J. M. ; Martínez-Ulloa, P. ; Allen, N. M. ; King, M. D. ; Gorman, K. M. ; Zeev, B. B. ; Tzadok, M. ; Wong-Kisiel, L. ; Marjanovic, D. ; Rubboli, G. ; Sisodiya, S. M. ; Lutz, F. ; Ashraf, H. P. ; Torge, K. ; Yan, P. ; Bosselmann, C. ; Schwarz, N. ; Fudali, M. ; Lerche, H.

2021
AAAS Washington, DC

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Please use a persistent id in citations: doi:10.1126/scitranslmed.aaz4957

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.

Keyword(s): 4-Aminopyridine: therapeutic use (MeSH) ; Brain Diseases (MeSH) ; Epilepsy (MeSH) ; Gain of Function Mutation (MeSH) ; Humans (MeSH) ; Kv1.2 Potassium Channel: genetics (MeSH) ; Mutation (MeSH) ; KCNA2 protein, human ; Kv1.2 Potassium Channel ; 4-Aminopyridine

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Contributing Institute(s):

1. Parkinson Genetics (AG Gasser 1)

Research Program(s):

1. 353 - Clinical and Health Care Research (POF4-353) (POF4-353)

Appears in the scientific report 2021

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Database coverage:
; BIOSIS Previews ; Biological Abstracts ; Clarivate Analytics Master Journal List ; Essential Science Indicators ; IF >= 15 ; JCR ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection

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