Treatment Responsiveness in KCNT1-Related Epilepsy

Mark P. Fitzgerald*, Martina Fiannacca, Douglas M. Smith, Tracy S. Gertler, Boudewijn Gunning, Steffen Syrbe, Nienke Verbeek, Hannah Stamberger, Sarah Weckhuysen, Berten Ceulemans, An Sofie Schoonjans, Massimiliano Rossi, Geneviève Demarquay, Gaetan Lesca, Kern Olofsson, D. A. Koolen, Frauke Hornemann, Stephanie Baulac, Guido Rubboli, Kelly Q. MinksBohoon Lee, Ingo Helbig, Dennis Dlugos, Rikke S. Møller, David Bearden

*Kontaktforfatter for dette arbejde

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

Resumé

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.

OriginalsprogEngelsk
TidsskriftNeurotherapeutics
Vol/bind16
Udgave nummer3
Sider (fra-til)848-857
ISSN1933-7213
DOI
StatusUdgivet - jul. 2019

Fingeraftryk

Quinidine
NADP
Vigabatrin
Registries

Citer dette

Fitzgerald, M. P., Fiannacca, M., Smith, D. M., Gertler, T. S., Gunning, B., Syrbe, S., ... Bearden, D. (2019). Treatment Responsiveness in KCNT1-Related Epilepsy. Neurotherapeutics, 16(3), 848-857. https://doi.org/10.1007/s13311-019-00739-y
Fitzgerald, Mark P. ; Fiannacca, Martina ; Smith, Douglas M. ; Gertler, Tracy S. ; Gunning, Boudewijn ; Syrbe, Steffen ; Verbeek, Nienke ; Stamberger, Hannah ; Weckhuysen, Sarah ; Ceulemans, Berten ; Schoonjans, An Sofie ; Rossi, Massimiliano ; Demarquay, Geneviève ; Lesca, Gaetan ; Olofsson, Kern ; Koolen, D. A. ; Hornemann, Frauke ; Baulac, Stephanie ; Rubboli, Guido ; Minks, Kelly Q. ; Lee, Bohoon ; Helbig, Ingo ; Dlugos, Dennis ; Møller, Rikke S. ; Bearden, David. / Treatment Responsiveness in KCNT1-Related Epilepsy. I: Neurotherapeutics. 2019 ; Bind 16, Nr. 3. s. 848-857.
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title = "Treatment Responsiveness in KCNT1-Related Epilepsy",
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",
author = "Fitzgerald, {Mark P.} and Martina Fiannacca and Smith, {Douglas M.} and Gertler, {Tracy S.} and Boudewijn Gunning and Steffen Syrbe and Nienke Verbeek and Hannah Stamberger and Sarah Weckhuysen and Berten Ceulemans and Schoonjans, {An Sofie} and Massimiliano Rossi and Genevi{\`e}ve Demarquay and Gaetan Lesca and Kern Olofsson and Koolen, {D. A.} and Frauke Hornemann and Stephanie Baulac and Guido Rubboli and Minks, {Kelly Q.} and Bohoon Lee and Ingo Helbig and Dennis Dlugos and M{\o}ller, {Rikke S.} and David Bearden",
year = "2019",
month = "7",
doi = "10.1007/s13311-019-00739-y",
language = "English",
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pages = "848--857",
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Fitzgerald, MP, Fiannacca, M, Smith, DM, Gertler, TS, Gunning, B, Syrbe, S, Verbeek, N, Stamberger, H, Weckhuysen, S, Ceulemans, B, Schoonjans, AS, Rossi, M, Demarquay, G, Lesca, G, Olofsson, K, Koolen, DA, Hornemann, F, Baulac, S, Rubboli, G, Minks, KQ, Lee, B, Helbig, I, Dlugos, D, Møller, RS & Bearden, D 2019, 'Treatment Responsiveness in KCNT1-Related Epilepsy', Neurotherapeutics, bind 16, nr. 3, s. 848-857. https://doi.org/10.1007/s13311-019-00739-y

Treatment Responsiveness in KCNT1-Related Epilepsy. / Fitzgerald, Mark P.; Fiannacca, Martina; Smith, Douglas M.; Gertler, Tracy S.; Gunning, Boudewijn; Syrbe, Steffen; Verbeek, Nienke; Stamberger, Hannah; Weckhuysen, Sarah; Ceulemans, Berten; Schoonjans, An Sofie; Rossi, Massimiliano; Demarquay, Geneviève; Lesca, Gaetan; Olofsson, Kern; Koolen, D. A.; Hornemann, Frauke; Baulac, Stephanie; Rubboli, Guido; Minks, Kelly Q.; Lee, Bohoon; Helbig, Ingo; Dlugos, Dennis; Møller, Rikke S.; Bearden, David.

I: Neurotherapeutics, Bind 16, Nr. 3, 07.2019, s. 848-857.

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

TY - JOUR

T1 - Treatment Responsiveness in KCNT1-Related Epilepsy

AU - Fitzgerald, Mark P.

AU - Fiannacca, Martina

AU - Smith, Douglas M.

AU - Gertler, Tracy S.

AU - Gunning, Boudewijn

AU - Syrbe, Steffen

AU - Verbeek, Nienke

AU - Stamberger, Hannah

AU - Weckhuysen, Sarah

AU - Ceulemans, Berten

AU - Schoonjans, An Sofie

AU - Rossi, Massimiliano

AU - Demarquay, Geneviève

AU - Lesca, Gaetan

AU - Olofsson, Kern

AU - Koolen, D. A.

AU - Hornemann, Frauke

AU - Baulac, Stephanie

AU - Rubboli, Guido

AU - Minks, Kelly Q.

AU - Lee, Bohoon

AU - Helbig, Ingo

AU - Dlugos, Dennis

AU - Møller, Rikke S.

AU - Bearden, David

PY - 2019/7

Y1 - 2019/7

N2 - 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.

AB - 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.

KW - ADNFLE

KW - EIMFS

KW - EOEE

KW - MPSI

KW - Quinidine

U2 - 10.1007/s13311-019-00739-y

DO - 10.1007/s13311-019-00739-y

M3 - Journal article

C2 - 31054119

AN - SCOPUS:85065321375

VL - 16

SP - 848

EP - 857

JO - Neurotherapeutics

JF - Neurotherapeutics

SN - 1933-7213

IS - 3

ER -

Fitzgerald MP, Fiannacca M, Smith DM, Gertler TS, Gunning B, Syrbe S et al. Treatment Responsiveness in KCNT1-Related Epilepsy. Neurotherapeutics. 2019 jul;16(3):848-857. https://doi.org/10.1007/s13311-019-00739-y