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. 2019 Jul;16(3):848-857.
doi: 10.1007/s13311-019-00739-y.

Treatment Responsiveness in KCNT1-Related Epilepsy

Mark P Fitzgerald  1 , Martina Fiannacca  2 , Douglas M Smith  3 , Tracy S Gertler  4 , Boudewijn Gunning  5 , Steffen Syrbe  6 , Nienke Verbeek  7 , Hannah Stamberger  8   9 , Sarah Weckhuysen  8   9 , Berten Ceulemans  10 , An-Sofie Schoonjans  11 , Massimiliano Rossi  12 , Geneviève Demarquay  13 , Gaetan Lesca  12 , Kern Olofsson  2 , D A Koolen  14 , Frauke Hornemann  15 , Stephanie Baulac  16   17   18   19   20 , Guido Rubboli  2   21 , Kelly Q Minks  22 , Bohoon Lee  22 , Ingo Helbig  23 , Dennis Dlugos  23 , Rikke S Møller  2   24 , David Bearden  22
Affiliations

Treatment Responsiveness in KCNT1-Related Epilepsy

Mark P Fitzgerald et al. Neurotherapeutics. 2019 Jul.

Abstract

Pathogenic variants in KCNT1 represent an important cause of treatment-resistant epilepsy, for which an effective therapy has been elusive. Reports about the effectiveness of quinidine, a candidate precision therapy, have been mixed. We sought to evaluate the treatment responsiveness of patients with KCNT1-related epilepsy. We performed an observational study of 43 patients using a collaborative KCNT1 patient registry. We assessed treatment efficacy based upon clinical seizure reduction, side effects of quinidine therapy, and variant-specific responsiveness to treatment. Quinidine treatment resulted in a > 50% seizure reduction in 20% of patients, with rare patients achieving transient seizure freedom. Multiple other therapies demonstrated some success in reducing seizure frequency, including the ketogenic diet and vigabatrin, the latter particularly in patients with epileptic spasms. Patients with the best quinidine response had variants that clustered distal to the NADP domain within the RCK2 domain of the protein. Half of patients did not receive a quinidine trial. In those who did, nearly half did not achieve therapeutic blood levels. More favorable response to quinidine in patients with KCNT1 variants distal to the NADP domain within the RCK2 domain may suggest a variant-specific response.

Keywords: ADNFLE; EIMFS; EOEE; MPSI; Quinidine.

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Conflict of interest statement

The authors declare that they do not have conflicts of interest.

Figures

Fig. 1
Fig. 1
Sustained efficacy of quinidine in KCNT1-related epilepsy. Response to quinidine was considered sustained if it lasted at least 3 months
Fig. 2
Fig. 2
Responsiveness to treatment with quinidine is displayed according to the location of the mutation in the KCNT1 protein. Patients who achieved at least temporary seizure freedom on quinidine lasting > 1 month had mutations that clustered immediately distal to the NADP binding domain within the RCK2 domain. Yellow residues indicate sites with seizure freedom. Purple residues denote sites with responsiveness to quinidine. Red residues denote sites without responsiveness to quinidine. The blue residues denote the locations of the RCK1 and RCK2 domains in the KCNT1 protein, while the green residues denote the location of the NADP binding domain. Patient number (1-20) is listed in parentheses next to responsiveness data. Note: patient 3 had 2 variants in KCNT1 (R428Q and Q651R) and is listed once in the figure
See this image and copyright information in PMC

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