Treatment Responsiveness in KCNT1-Related Epilepsy
Mark Fitzgerald
(1, 2)
,
Martina Fiannacca
(3)
,
Douglas Smith
(4)
,
Tracy Gertler
(5)
,
Boudewijn Gunning
(6)
,
Steffen Syrbe
(7)
,
Nienke Verbeek
(8)
,
Hannah Stamberger
(9, 10, 11)
,
Sarah Weckhuysen
(11, 10, 9)
,
Berten Ceulemans
(9, 11)
,
An-Sofie Schoonjans
(12, 13)
,
Massimiliano Rossi
(14)
,
Geneviève Demarquay
(15, 16)
,
Gaetan Lesca
(14)
,
Kern Olofsson
(3)
,
D.A. Koolen
(17)
,
Frauke Hornemann
,
Stephanie Baulac
(18, 19)
,
Guido Rubboli
(3, 20)
,
Kelly Minks
(21)
,
Bohoon Lee
(21)
,
Ingo Helbig
(1, 2)
,
Dennis Dlugos
(1, 2)
,
Rikke Møller
(22, 3)
,
David Bearden
(21)
1
CHOP -
Children’s Hospital of Philadelphia
2 Perelman School of Medicine
3 The Danish Epilepsy Centre Filadelfia [Dianalund, Denmark]
4 Minnesota Epilepsy Group
5 Ann & Robert H. Lurie Children's Hospital of Chicago
6 SEIN - Stichting Epilepsie Instellingen Nederland
7 Heidelberg University Hospital [Heidelberg]
8 UMCU - University Medical Center [Utrecht]
9 UA - University of Antwerp
10 VIB - Vlaams Instituut voor Biotechnologie [Ghent, Belgique]
11 UZA - Antwerp University Hospital [Edegem]
12 VUB - Vrije Universiteit Brussel [Bruxelles]
13 UZ Brussel - Universitair Ziekenhuis Brussel = University Hospital of Brussels
14 CRNL-GENDEV - Genetics of Neurodevelopment
15 CRNL - Centre de recherche en neurosciences de Lyon - Lyon Neuroscience Research Center
16 HCL - Hospices Civils de Lyon
17 Radboud University Medical Center [Nijmegen]
18 ICM - Institut du Cerveau = Paris Brain Institute
19 CHU Pitié-Salpêtrière [AP-HP]
20 UCPH - University of Copenhagen = Københavns Universitet
21 URMC - University of Rochester Medical Center
22 SDU - University of Southern Denmark
2 Perelman School of Medicine
3 The Danish Epilepsy Centre Filadelfia [Dianalund, Denmark]
4 Minnesota Epilepsy Group
5 Ann & Robert H. Lurie Children's Hospital of Chicago
6 SEIN - Stichting Epilepsie Instellingen Nederland
7 Heidelberg University Hospital [Heidelberg]
8 UMCU - University Medical Center [Utrecht]
9 UA - University of Antwerp
10 VIB - Vlaams Instituut voor Biotechnologie [Ghent, Belgique]
11 UZA - Antwerp University Hospital [Edegem]
12 VUB - Vrije Universiteit Brussel [Bruxelles]
13 UZ Brussel - Universitair Ziekenhuis Brussel = University Hospital of Brussels
14 CRNL-GENDEV - Genetics of Neurodevelopment
15 CRNL - Centre de recherche en neurosciences de Lyon - Lyon Neuroscience Research Center
16 HCL - Hospices Civils de Lyon
17 Radboud University Medical Center [Nijmegen]
18 ICM - Institut du Cerveau = Paris Brain Institute
19 CHU Pitié-Salpêtrière [AP-HP]
20 UCPH - University of Copenhagen = Københavns Universitet
21 URMC - University of Rochester Medical Center
22 SDU - University of Southern Denmark
Mark Fitzgerald
- Fonction : Auteur
- PersonId : 806936
- ORCID : 0000-0002-7121-0705
Gaetan Lesca
- Fonction : Auteur
- PersonId : 769268
- ORCID : 0000-0001-7691-9492
- IdRef : 124685811
Frauke Hornemann
- Fonction : Auteur
Résumé
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.