4-Aminopyridine is a promising treatment option for patients with gain-of-function KCNA2 -encephalopathy
| Autor: | José M. Serratosa, Kathleen M. Gorman, Dragan Marjanovic, Adrian Binelli, Niklas Schwarz, Kirsten Torge, Guido Rubboli, Monika Fudali, Harshad Pannikkaveettil Ashraf, Sanjay M. Sisodiya, Ulrike B. S. Hedrich, Matthis Synofzik, Mary D. King, Lily C. Wong-Kisiel, Pu Yan, Bruria Ben Zeev, Pedro Martínez-Ulloa, Holger Lerche, Michal Tzadok, Stephan Lauxmann, Christian Bosselmann, Thomas Bast, Markus Wolff, Florian Lutz, Nicholas M. Allen |
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| Rok vydání: | 2021 |
| Předmět: |
Brain Diseases
Pediatrics medicine.medical_specialty Epilepsy business.industry Encephalopathy genetics [Kv1.2 Potassium Channel] Treatment options General Medicine medicine.disease therapeutic use [4-Aminopyridine] Gain of function Gain of Function Mutation Mutation Mutation (genetic algorithm) Intellectual disability KCNA2 protein human Kv1.2 Potassium Channel medicine Humans Gain of function mutation ddc:500 4-Aminopyridine business |
| Zdroj: | Science translational medicine 13(609), eaaz4957 (2021). doi:10.1126/scitranslmed.aaz4957 |
| ISSN: | 1946-6242 1946-6234 |
| DOI: | 10.1126/scitranslmed.aaz4957 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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