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@ARTICLE{Hedrich:162807,
      author       = {Hedrich, Ulrike B S and Lauxmann, Stephan and Wolff, Markus
                      and Synofzik, Matthis and Bast, Thomas and Binelli, Adrian
                      and Serratosa, José M and Martínez-Ulloa, Pedro and Allen,
                      Nicholas M and King, Mary D and Gorman, Kathleen M and Zeev,
                      Bruria Ben and Tzadok, Michal and Wong-Kisiel, Lily and
                      Marjanovic, Dragan and Rubboli, Guido and Sisodiya, Sanjay M
                      and Lutz, Florian and Ashraf, Harshad Pannikkaveettil and
                      Torge, Kirsten and Yan, Pu and Bosselmann, Christian and
                      Schwarz, Niklas and Fudali, Monika and Lerche, Holger},
      title        = {4-{A}minopyridine is a promising treatment option for
                      patients with gain-of-function {KCNA}2-encephalopathy.},
      journal      = {Science translational medicine},
      volume       = {13},
      number       = {609},
      issn         = {1946-6242},
      address      = {Washington, DC},
      publisher    = {AAAS},
      reportid     = {DZNE-2021-01462},
      pages        = {eaaz4957},
      year         = {2021},
      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.},
      keywords     = {4-Aminopyridine: therapeutic use / Brain Diseases /
                      Epilepsy / Gain of Function Mutation / Humans / Kv1.2
                      Potassium Channel: genetics / Mutation / KCNA2 protein,
                      human (NLM Chemicals) / Kv1.2 Potassium Channel (NLM
                      Chemicals) / 4-Aminopyridine (NLM Chemicals)},
      cin          = {AG Gasser 1},
      ddc          = {500},
      cid          = {I:(DE-2719)1210000},
      pnm          = {353 - Clinical and Health Care Research (POF4-353)},
      pid          = {G:(DE-HGF)POF4-353},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:34516822},
      doi          = {10.1126/scitranslmed.aaz4957},
      url          = {https://pub.dzne.de/record/162807},
}