title: Infantile spasms and encephalopathy without preceding neonatal seizures caused by KCNQ2 R198Q, a gain-of-function variant.
abstract: Variants in KCNQ2 encoding for Kv7.2 neuronal K+channel subunits lead to a spectrum of neonatal-onset epilepsies, ranging from self-limiting forms to severe epileptic encephalopathy. Most KCNQ2 pathogenic variants cause loss-of-function, whereas few increase channel activity (gain-of-function). We herein provide evidence for a new phenotypic and functional profile in KCNQ2-related epilepsy: infantile spasms without prior neonatal seizures associated with a gain-of-function gene variant. With use of an international registry, we identified four unrelated patients with the same de novo heterozygous KCNQ2 c.593G>A, p.Arg198Gln (R198Q) variant. All were born at term and discharged home without seizures or concern of encephalopathy, but developed infantile spasms with hypsarrhythmia (or modified hypsarrhythmia) between the ages of 4 and 6 months. At last follow-up (ages 3-11 years), all patients were seizure-free and had severe developmental delay. In vitro experiments showed that Kv7.2 R198Q subunits shifted current activation gating to hyperpolarized potentials, indicative of gain-of-function; in neurons, Kv7.2 and Kv7.2 R198Q subunits similarly populated the axon initial segment, suggesting that gating changes rather than altered subcellular distribution contribute to disease molecular pathogenesis. We conclude that KCNQ2 R198Q is a model for a new subclass of KCNQ2 variants causing infantile spasms and encephalopathy, without preceding neonatal seizures. A PowerPoint slide summarizing this article is available for download in the Supporting Information section here.
authors.affiliation: Epilepsy Center and Division of Neurology, Departments of Pediatrics and Neurology, Ann & Robert H. Lurie Children's Hospital of Chicago, Northwestern University Feinberg School of Medicine, Chicago, Illinois, U.S.A.
authors.forename: John J
authors.identifier: 0000-0002-0798-0131
authors.initials: JJ
authors.lastname: Millichap
authors.affiliation: Department of Neuroscience, University of Naples "Federico II", Naples, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Miceli
authors.affiliation: Department of Medicine and Health Science, University of Molise, Campobasso, Italy.
authors.forename: Michela
authors.initials: M
authors.lastname: De Maria
authors.affiliation: Jane and John Justin Neurosciences Center, Cook Children's Hospital, Fort Worth, Texas, U.S.A.
authors.forename: Cynthia
authors.initials: C
authors.lastname: Keator
authors.affiliation: Departments of Neurology, Neuroscience, Molecular, and Human Genetics, Baylor College of Medicine, Houston, Texas, U.S.A.
authors.forename: Nishtha
authors.initials: N
authors.lastname: Joshi
authors.affiliation: Departments of Neurology, Neuroscience, Molecular, and Human Genetics, Baylor College of Medicine, Houston, Texas, U.S.A.
authors.forename: Baouyen
authors.initials: B
authors.lastname: Tran
authors.affiliation: Department of Medicine and Health Science, University of Molise, Campobasso, Italy.
authors.forename: Maria Virginia
authors.initials: MV
authors.lastname: Soldovieri
authors.affiliation: Department of Medicine and Health Science, University of Molise, Campobasso, Italy.
authors.forename: Paolo
authors.initials: P
authors.lastname: Ambrosino
authors.affiliation: Division of Neurology, Department of Pediatrics, Duke University School of Medicine, Durham, North Carolina, U.S.A.
authors.forename: Vandana
authors.initials: V
authors.lastname: Shashi
authors.affiliation: Division of Neurology, Department of Pediatrics, Duke University School of Medicine, Durham, North Carolina, U.S.A.
authors.forename: Mohamad A
authors.initials: MA
authors.lastname: Mikati
authors.affiliation: Departments of Neurology, Neuroscience, Molecular, and Human Genetics, Baylor College of Medicine, Houston, Texas, U.S.A.
authors.forename: Edward C
authors.initials: EC
authors.lastname: Cooper
authors.affiliation: Department of Neuroscience, University of Naples "Federico II", Naples, Italy.|Department of Medicine and Health Science, University of Molise, Campobasso, Italy.
authors.forename: Maurizio
authors.initials: M
authors.lastname: Taglialatela
mesh_terms: D000818:Animals; D001120:Arginine / Q000235:genetics; D001927:Brain Diseases / Q000235:genetics*; D016466:CHO Cells; D002478:Cells, Cultured; D002648:Child; D002675:Child, Preschool; D003412:Cricetulus; D005973:Glutamine / Q000235:genetics; D006624:Hippocampus / Q000166:cytology; D006801:Humans; D007223:Infant; D051658:KCNQ2 Potassium Channel / Q000235:genetics*; D008137:Longitudinal Studies; D008564:Membrane Potentials / Q000235:genetics; D008958:Models, Molecular; D009154:Mutation / Q000235:genetics*; D009474:Neurons / Q000502:physiology; D051381:Rats; D013036:Spasms, Infantile / Q000235:genetics*; D014162:Transfection
chemical_list: D051658:KCNQ2 Potassium Channel; D005973:Glutamine; D001120:Arginine
keywords: Epileptic encephalopathy; Gene variants; Genotype-phenotype; KCNQ2; Potassium channels; axon initial segment; retigabine