4-Aminopyridine is a promising treatment option for patients with gain-of-function -encephalopathy.

Michal Tzadok, Holger Lerche, Monika Fudali, Niklas Schwarz, Christian Bosselmann, Pu Yan, Kirsten Torge, Harshad Pannikkaveettil Ashraf, Florian Lutz, Sanjay M Sisodiya, Guido Rubboli, Dragan Marjanovic, Lily Wong-Kisiel, Ulrike B S Hedrich, Bruria Ben Zeev, Kathleen M Gorman, Mary D King, Nicholas M Allen, Pedro Martínez-Ulloa, José M Serratosa, Adrian Binelli, Thomas Bast, Matthis Synofzik, Markus Wolff, Stephan Lauxmann

Journal: Science translational medicine 2021;13(609):eaaz4957

PMID: 34516822

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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 -encephalopathy that the K channel blocker 4-aminopyridine can antagonize gain-of-function defects caused by variants in the K1.2 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 -(gain-of-function)–encephalopathy and provide an online tool assisting physicians to select patients with gain-of-function mutations suited to this treatment.

Address: Department of Neurology and Epileptology, Hertie Institute for Clinical Brain Research, University of Tuebingen, 72076 Tuebingen, Germany.; Department of Pediatric Neurology and Developmental Medicine, University Children's Hospital, 72076 Tuebingen, Germany.; Department of Pediatric Neurology, Vivantes-Klinikum Neukölln, 12351 Berlin, Germany.; Department of Neurology and Neurodegenerative Diseases, Hertie-Institute for Clinical Brain Research, University of Tuebingen, 72076 Tuebingen, Germany.; German Center for Neurodegenerative Diseases (DZNE), 72076 Tübingen, Germany.; Epilepsy Center Kork, 77694 Kehl-Kork, Germany.; Medical Faculty of the University of Freiburg, 79110 Freiburg, Germany.; Department of Pediatric Neurology, Elizalde Children's Hospital, C1270 Buenos Aires, Argentina.; Neurology Laboratory and Epilepsy Unit, Department of Neurology, IIS- Fundacio'n Jime'nez Dı'az, UAM, 28040 Madrid, Spain.; Centro de Investigacio'n Biome'dica en Red de Enfermedades Raras (CIBERER), 28029 Madrid, Spain.; Department of Paediatrics, Clinical Sciences Institute, National University of Ireland Galway, Galway H91 TK33, Ireland.; Department of Neurology and Neurophysiology, Children's Health Ireland at Temple Street, Dublin DO1 YC67, Ireland.; School of Medicine and Medical Science, University College Dublin, Dublin DO4 V1W8, Ireland.; Sackler School of Medicine Tel Aviv University, Tel Aviv 6997801, Israel.; Pediatric Neurology Unit, Edmond and Lilly Safra Pediatric Hospital, Sheba Medical Center, 5265601 Ramat Gan, Israel.; Divisions of Child Neurology & Division of Epilepsy, Department of Neurology, Mayo Clinic College of Medicine, 200 First Street SW, Rochester, MN 55905, USA.; Danish Epilepsy Center, Filadelfia, 4293 Dianalund, Denmark.; University of Copenhagen, 1165 Copenhagen, Denmark.; Department of Clinical and Experimental Epilepsy, UCL Queen Square Institute of Neurology, London WC1N 3BG, UK.; Chalfont Centre for Epilepsy, Bucks SL9 0RJ, UK.; Department of Neurosurgery, University of Tuebingen, 72076 Tuebingen, Germany.

DOI: 10.1126/scitranslmed.aaz4957

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MeSH Terms: 4-Aminopyridine, Brain Diseases, Epilepsy, Gain of Function Mutation, Humans, Kv1.2 Potassium Channel, Mutation