, Volume 15, Issue 4, pp 1112–1126 | Cite as

Early Treatment with Quinidine in 2 Patients with Epilepsy of Infancy with Migrating Focal Seizures (EIMFS) Due to Gain-of-Function KCNT1 Mutations: Functional Studies, Clinical Responses, and Critical Issues for Personalized Therapy

  • Robertino Dilena
  • Jacopo C. DiFrancesco
  • Maria Virginia Soldovieri
  • Antonella Giacobbe
  • Paolo Ambrosino
  • Ilaria Mosca
  • Maria Albina Galli
  • Sophie Guez
  • Monica Fumagalli
  • Francesco Miceli
  • Dario Cattaneo
  • Francesca Darra
  • Elena Gennaro
  • Federico Zara
  • Pasquale Striano
  • Barbara Castellotti
  • Cinzia Gellera
  • Costanza Varesio
  • Pierangelo Veggiotti
  • Maurizio TaglialatelaEmail author
Original Article


Epilepsy of infancy with migrating focal seizures (EIMFS) is a rare early-onset developmental epileptic encephalopathy resistant to anti-epileptic drugs. The most common cause for EIMFS is a gain-of-function mutation in the KCNT1 potassium channel gene, and treatment with the KCNT1 blocker quinidine has been suggested as a rational approach for seizure control in EIMFS patients. However, variable results on the clinical efficacy of quinidine have been reported. In the present study, we provide a detailed description of the clinical, genetic, in vitro, and in vivo electrophysiological profile and pharmacological responses to quinidine of 2 EIMFS unrelated patients with a heterozygous de novo KCNT1 mutation: c.2849G>A (p.R950Q) in patient 1 and c.2677G>A (p.E893K) in patient 2. When expressed heterologously in CHO cells, KCNT1 channels carrying each variant showed gain-of-function effects, and were more effectively blocked by quinidine when compared to wild-type KCNT1 channels. On the basis of these in vitro results, add-on quinidine treatment was started at 3 and 16 months of age in patients 1 and 2, respectively. The results obtained reveal that quinidine significantly reduced seizure burden (by about 90%) and improved quality of life in both patients, but failed to normalize developmental milestones, which persisted as severely delayed. Based on the present experience, early quinidine intervention associated with heart monitoring and control of blood levels is among the critical factors for therapy effectiveness in EIMFS patients with KCNT1 gain-of-function mutations. Multicenter studies are needed to establish a consensus protocol for patient recruitment, quinidine treatment modalities, and outcome evaluation, to optimize clinical efficacy and reduce risks as well as variability associated to quinidine use in such severe developmental encephalopathy.

Key Words:

KCNT1 Developmental encephalopathy Epilepsy of infancy with migrating focal seizures (EIMFS) Quinidine Therapeutic drug monitoring (TDM) 



The present work was supported by the Telethon Foundation (grant number GGP15113) to MT, the Italian Ministry of Health Ricerca Finalizzata Giovani Ricercatori 2010 (Project GR-2010-2304834 to JCD) and Ricerca Finalizzata Giovani Ricercatori 2016 (Project GR-2016-2363337 to JCD and MVS), and the Italian Ministry for University and Research (Project Scientific Independence of Researchers 2014 RBSI1444EM) and the University of Naples “Federico II” and Compagnia di San Paolo in the frame of Program STAR “Sostegno Territoriale alle Attività di Ricerca” (project number 6-CSP-UNINA-120) to FM.

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Supplementary material

13311_2018_657_MOESM1_ESM.pdf (1.2 mb)
ESM 1 (PDF 1197 kb)
13311_2018_657_MOESM2_ESM.docx (17 kb)
Supplementary Figure 1 (DOCX 17 kb)
13311_2018_657_MOESM3_ESM.docx (17 kb)
Supplementary Table 1 (DOCX 17 kb)


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Copyright information

© The American Society for Experimental NeuroTherapeutics, Inc. 2018

Authors and Affiliations

  • Robertino Dilena
    • 1
  • Jacopo C. DiFrancesco
    • 2
    • 3
  • Maria Virginia Soldovieri
    • 4
  • Antonella Giacobbe
    • 1
  • Paolo Ambrosino
    • 4
  • Ilaria Mosca
    • 4
  • Maria Albina Galli
    • 1
  • Sophie Guez
    • 1
  • Monica Fumagalli
    • 1
  • Francesco Miceli
    • 5
  • Dario Cattaneo
    • 6
  • Francesca Darra
    • 7
  • Elena Gennaro
    • 8
  • Federico Zara
    • 8
  • Pasquale Striano
    • 9
  • Barbara Castellotti
    • 10
  • Cinzia Gellera
    • 10
  • Costanza Varesio
    • 11
  • Pierangelo Veggiotti
    • 12
  • Maurizio Taglialatela
    • 4
    • 5
    • 13
    Email author
  1. 1.Pediatric Epileptology and Neurophysiology (RD), Infantile Neuropsichiatry (AG), Cardiology (MAG), High Intensity Pediatric Care (SG), Neonatology (MF)Fondazione IRCCS Ca’ Granda Ospedale Maggiore PoliclinicoMilanItaly
  2. 2.Clinical Neurophysiology and Epilepsy CenterFondazione IRCCS Istituto Neurologico Carlo BestaMilanItaly
  3. 3.Department of Neurology, San Gerardo Hospital, School of Medicine and Surgery, Milan Center for Neuroscience (NeuroMi)University of Milano-BicoccaMonzaItaly
  4. 4.Department of Medicine and Health ScienceUniversity of MoliseCampobassoItaly
  5. 5.Division of Pharmacology, Department of NeuroscienceUniversity of Naples “Federico II”NaplesItaly
  6. 6.Unit of Clinical PharmacologyASST Fatebenefratelli SaccoMilanItaly
  7. 7.Department of Surgical, Odontostomatological, and Maternal-Infantile SciencesUniversity of VeronaVeronaItaly
  8. 8.Laboratory of GeneticsE.O. Ospedali GallieraGenoaItaly
  9. 9.Pediatric Neurology and Muscular Diseases Unit, Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child HealthUniversity of Genoa, “G. Gaslini” InstituteGenoaItaly
  10. 10.Unit of Genetics of Neurodegenerative and Metabolic DiseasesFondazione IRCCS Istituto Neurologico Carlo BestaMilanItaly
  11. 11.Department of Child Neurology and Psychiatry“C. Mondino” National Neurological InstitutePaviaItaly
  12. 12.Department of Biomedical and Clinical Sciences, Children’s Hospital Vittore BuzziUniversity of Milan, and Pediatric NeurologyMilanItaly
  13. 13.Department of NeuroscienceUniversity of Naples “Federico II”NaplesItaly

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