title: Quinidine in the treatment of KCNT1-positive epilepsies.
abstract: We report 2 patients with drug-resistant epilepsy caused by KCNT1 mutations who were treated with quinidine. Both mutations manifested gain of function in vitro, showing increased current that was reduced by quinidine. One, who had epilepsy of infancy with migrating focal seizures, had 80% reduction in seizure frequency as recorded in seizure diaries, and partially validated by objective seizure evaluation on EEG. The other, who had a novel phenotype, with severe nocturnal focal and secondary generalized seizures starting in early childhood with developmental regression, did not improve. Although quinidine represents an encouraging opportunity for therapeutic benefits, our experience suggests caution in its application and supports the need to identify more targeted drugs for KCNT1 epilepsies.
authors.affiliation: Division of Pediatric Neurology, Department of Pediatrics and Department of Neurobiology, Duke University School of Medicine, Durham, NC.
authors.forename: Mohamad A
authors.initials: MA
authors.lastname: Mikati
authors.affiliation: Division of Medical Genetics, Department of Pediatrics, Duke University School of Medicine, Durham, NC.
authors.forename: Yong-Hui
authors.initials: YH
authors.lastname: Jiang
authors.affiliation: Division of Cardiology, Department of Pediatrics, Duke University School of Medicine, Durham, NC.
authors.forename: Michael
authors.initials: M
authors.lastname: Carboni
authors.affiliation: Division of Medical Genetics, Department of Pediatrics, Duke University School of Medicine, Durham, NC.
authors.forename: Vandana
authors.initials: V
authors.lastname: Shashi
authors.affiliation: Center for Human Genome Variation, Duke University School of Medicine, Durham, NC.
authors.forename: Slave
authors.initials: S
authors.lastname: Petrovski
authors.affiliation: Center for Human Genome Variation, Duke University School of Medicine, Durham, NC.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Spillmann
authors.affiliation: Florey Institute of Neuroscience and Mental Health, University of Melbourne, Melbourne, Victoria, Australia.
authors.forename: Carol J
authors.initials: CJ
authors.lastname: Milligan
authors.affiliation: Florey Institute of Neuroscience and Mental Health, University of Melbourne, Melbourne, Victoria, Australia.
authors.forename: Melody
authors.initials: M
authors.lastname: Li
authors.affiliation: Department of Neurology, Wake Forest University, Winston-Salem, NC.
authors.forename: Annette
authors.initials: A
authors.lastname: Grefe
authors.affiliation: Division of Medical Genetics, Department of Pediatrics, Duke University School of Medicine, Durham, NC.
authors.forename: Allyn
authors.initials: A
authors.lastname: McConkie
authors.affiliation: Epilepsy Research Centre, Department of Medicine, University of Melbourne, Melbourne, Victoria, Australia.
authors.forename: Samuel
authors.initials: S
authors.lastname: Berkovic
authors.affiliation: Epilepsy Research Centre, Department of Medicine, University of Melbourne, Melbourne, Victoria, Australia.
authors.forename: Ingrid
authors.initials: I
authors.lastname: Scheffer
authors.affiliation: Florey Institute of Neuroscience and Mental Health, University of Melbourne, Melbourne, Victoria, Australia.
authors.forename: Saul
authors.initials: S
authors.lastname: Mullen
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Duke University School of Medicine, Durham, NC.
authors.forename: Melanie
authors.initials: M
authors.lastname: Bonner
authors.affiliation: Epilepsy Research Centre, Department of Medicine, University of Melbourne, Melbourne, Victoria, Australia.
authors.forename: Steven
authors.initials: S
authors.lastname: Petrou
authors.affiliation: Center for Human Genome Variation, Duke University School of Medicine, Durham, NC.
authors.forename: David
authors.initials: D
authors.lastname: Goldstein
mesh_terms: D002648:Child; D002675:Child, Preschool; D000069279:Drug Resistant Epilepsy / Q000188:drug therapy* / Q000235:genetics; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D005260:Female; D006801:Humans; D008297:Male; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000235:genetics*; D015221:Potassium Channels / Q000235:genetics*; D000081033:Potassium Channels, Sodium-Activated; D011802:Quinidine / Q000008:administration & dosage / Q000494:pharmacology*
chemical_list: D004791:Enzyme Inhibitors; C585122:KCNT1 protein, human; D009419:Nerve Tissue Proteins; D015221:Potassium Channels; D000081033:Potassium Channels, Sodium-Activated; D011802:Quinidine