TY  - JOUR
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
TI  - 4-Aminopyridine is a promising treatment option for patients with gain-of-function KCNA2-encephalopathy.
JO  - Science translational medicine
VL  - 13
IS  - 609
SN  - 1946-6242
CY  - Washington, DC
PB  - AAAS
M1  - DZNE-2021-01462
SP  - eaaz4957
PY  - 2021
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.
KW  - 4-Aminopyridine: therapeutic use
KW  - Brain Diseases
KW  - Epilepsy
KW  - Gain of Function Mutation
KW  - Humans
KW  - Kv1.2 Potassium Channel: genetics
KW  - Mutation
KW  - KCNA2 protein, human (NLM Chemicals)
KW  - Kv1.2 Potassium Channel (NLM Chemicals)
KW  - 4-Aminopyridine (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:34516822
DO  - DOI:10.1126/scitranslmed.aaz4957
UR  - https://pub.dzne.de/record/162807
ER  -