Annual Meeting Abstracts: View

  • (Abst. 3.337|C.07), 2015
  • KCNQ2 p.Arg198Gln, a gain-of-function variant presenting recurrently as West syndrome without preceding neonatal seizures
  • Authors: John Millichap, Francesco Miceli, Baouyen Tran, Cynthia Keator, Nishtha Joshi, Maria Virginia Soldovieri, Edward C. Cooper, Maurizio Taglialatela
  • Content:

    Rationale: Variants in KCNQ2 and, less frequently, KCNQ3, lead to a spectrum of early onset epilepsy, including self-limiting forms transmitted in an autosomal dominant pattern and severe forms with persistent seizures and global developmental impairment that usually emerge de novo. Whereas most cases present in the first week of life with recurrent seizures, a minority present later in infancy. Recently, whole exome sequencing of 149 patients diagnosed with infantile spasm revealed one with the KCNQ2 Arg144Gln variant, later shown by heterologous cell expression and patch recording to give gain-of-function1,2. We encountered three unrelated West Syndrome patients sharing the KCNQ2 variant, Arg198Gln. To analyze this uncommon presentation, we compared the case histories and performed functional experiments.Methods: Under an approved IRB protocol and with informed parental consent, patients with histories of epilepsy and positive KCNQ2 testing were entered into a case registry/database. All Arg198Gln cases enrolled are included here. Plasmid DNA for mammalian KCNQ2 expression was mutated to Arg198Gln in vitro, transfected into Chinese hamster ovary cells, and the resulting currents were studied using whole cell patch clamp electrophysiology.Results: Three infants with West syndrome were enrolled. All infants were born after term gestation and discharged home from the nursery without seizures or concern of encephalopathy. Onset of infantile spasms in clusters with hypsarhythmia occurred at ages 1 month, 4 months, and 5 months old. At last follow up, all infants had developmental delay. In each patient, a KCNQ2 Arg198Gln variant was identified by multigene next-generation sequencing. The patients were unrelated, and negative parental testing confirmed each case occurred de novo. KCNQ2 Arg198Gln subunits, when expressed as homomeric channels, exhibited an approximately 2-fold increase in maximal current density and a robust leftward shift in activation voltage-dependence of about 30 mV. When expressed with wild-type KCNQ2 and KCNQ3, current density was equal to control, but activation was shifted approximately 10 mV to hyperpolarized potentials. These results indicate that a gain-of-function mechanism is associated to this variant, as previously seen with several other variants located within the KCNQ2 and KCNQ3 voltage-sensor domains2.Conclusions: These results suggest that KCNQ2 Arg198Gln variant is pathogenic for West Syndrome emerging without prior neonatal seizures, representing a novel KCNQ2 phenotype. At the molecular level, the variant causes gain-of-function when expressed in heterologous cells. Such gain-of-function is an atypical functional profile, but has been seen in previous cases with neonatal onset epileptic encephalopathy. More work is needed to better understand the mechanisms accounting for this phenotypic heterogeneity. 1Allen, Nature (2013) 501:217. 2Miceli, JNeurosci (2015) 35:3782 Support: AES/EF Research Infrastructure Grant, The Jack Pribaz Foundation, NIH NS49119, Telethon Foundation, Univ. of Molise