1. 4-Aminopyridine is a promising treatment option for patients with gain-of-function KCNA2 -encephalopathy.
- Author
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Hedrich UBS, Lauxmann S, Wolff M, Synofzik M, Bast T, Binelli A, Serratosa JM, Martínez-Ulloa P, Allen NM, King MD, Gorman KM, Zeev BB, Tzadok M, Wong-Kisiel L, Marjanovic D, Rubboli G, Sisodiya SM, Lutz F, Ashraf HP, Torge K, Yan P, Bosselmann C, Schwarz N, Fudali M, and Lerche H
- Subjects
- 4-Aminopyridine therapeutic use, Gain of Function Mutation, Humans, Kv1.2 Potassium Channel genetics, Mutation, Brain Diseases, Epilepsy
- 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 KV 1.2 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.- Published
- 2021
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