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Neurotherapeutics

, Volume 16, Issue 3, pp 848–857 | Cite as

Treatment Responsiveness in KCNT1-Related Epilepsy

  • Mark P. FitzgeraldEmail author
  • 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. Minks
  • Bohoon Lee
  • Ingo Helbig
  • Dennis Dlugos
  • Rikke S. Møller
  • David Bearden
Original Article

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.

Key Words

Quinidine EIMFS MPSI ADNFLE EOEE 

Notes

Acknowledgments

Steffen Syrbe received funding from a grant from the Dietmar-Hopp-Stiftung (23011236 to S.S.)

• Tracy Gertler received funding from an National Center for Advancing Translational Sciences grant (KL2TR001424 to T.G.)

• Ingo Helbig was supported by intramural funds by the University of Kiel and through grants by the German Research Foundation (DFG, HE5415/5-1, HE 5415/6-1, HE 5415/7-1) within the framework of the EuroEPINOMICS-RES project through the Eurocores program of the European Science Foundation (ESF).

• David Bearden received funding from and served as a consultant for Q-State Biosciences

Compliance with Ethical Standards

Conflict of Interest

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

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Disclosure forms provided by the authors are available with the online version of this article.

Supplementary material

13311_2019_739_MOESM1_ESM.pdf (1.2 mb)
ESM 1 (PDF 1224 kb)

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Copyright information

© The American Society for Experimental NeuroTherapeutics, Inc. 2019

Authors and Affiliations

  • Mark P. Fitzgerald
    • 1
    Email author
  • 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
    • 1
  • Dennis Dlugos
    • 1
  • Rikke S. Møller
    • 2
    • 23
  • David Bearden
    • 22
  1. 1.Division of Neurology, Departments of Neurology and PediatricsThe Children’s Hospital of Philadelphia and the Perelman School of Medicine at the University of PennsylvaniaPhiladelphiaUSA
  2. 2.Danish Epilepsy CentreDianalund,Denmark
  3. 3.Minnesota Epilepsy GroupSaint PaulUSA
  4. 4.Division of Neurology, Department of PediatricsAnn and Robert H. Lurie Children’s Hospital of ChicagoChicagoUSA
  5. 5.Stichting Epilepsie Instellingen NederlandZwolleNetherlands
  6. 6.Division of Child Neurology and Inherited Metabolic Diseases, Department of General Paediatrics, Centre for Paediatrics and Adolescent MedicineUniversity Hospital HeidelbergHeidelbergGermany
  7. 7.Department of GeneticsUniversity Medical Center UtrechtUtrechtThe Netherlands
  8. 8.Neurogenetics group, Center for Molecular Neurology, Vlaams Instituut voor Biotechnologie, and Institute Born BungeUniversity of AntwerpAntwerpBelgium
  9. 9.Department of NeurologyAntwerp University HospitalAntwerpBelgium
  10. 10.Department of Paediatric Neurology, Antwerp University HospitalUniversity of AntwerpAntwerpBelgium
  11. 11.Neurogenetics Research GroupVrije Universiteit Brussel (VUB), Universitair Ziekenhuis Brussel (UZ Brussel)BrusselsBelgium
  12. 12.Genetics department, Hospices Civils de Lyon, and Institut National de la Santé et de la Recherche Médicale U1028, Centre national de la recherche scientifique Unité Mixte de Recherche 5292, Lyon Neuroscience Research Center, GENDEV TeamClaude Bernard Lyon 1 UniversityBronFrance
  13. 13.Department of Functional Neurology and Epileptology, Hospices Civils de Lyon and Centre national de la recherche scientifique, Unité Mixte de Recherche 5292, Lyon Neuroscience Research Center, Auditory Cognition and Psychoacoustics TeamLyonFrance
  14. 14.Department of Human GeneticsRadboud University Medical CenterNijmegenThe Netherlands
  15. 15.Centre of Pediatric ResearchHospital for Children and AdolescentsLeipzigGermany
  16. 16.Sorbonne Université, UPMC Univ Paris 06, Unité Mixte de Recherche S 1127ParisFrance
  17. 17.Institut National de la Santé et de la Recherche Médicale, U1127ParisFrance
  18. 18.Centre national de la recherche scientifique, Unité Mixte de Recherche 7225ParisFrance
  19. 19.Institut du Cerveau et de la Moelle épinière (ICM)Hôpital Pitié-SalpêtrièreParisFrance
  20. 20.Department of Genetics, Assistance Publique des Hôpitaux de Paris (AP-HP)Hôpital Pitié-SalpêtrièreParisFrance
  21. 21.University of CopenhagenCopenhagenDenmark
  22. 22.Division of Child Neurology, Department of NeurologyUniversity of Rochester School of MedicineRochesterUSA
  23. 23.Institute for Regional Health ResearchUniversity of Southern DenmarkOdenseDenmark

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