Clinical and molecular characterization of KCNT1-related severe early-onset epilepsy

McTague, Amy and Nair, Umesh and Malhotra, Sony and Meyer, Esther and Trump, Natalie and Gazina, Elena V. and Papandreou, Apostolos and Ngho, Adeline and Ackermann, Sally and Ambegaonkar, Gautam and Appleton, Richard and Desurkar, Archana and Eltze, Christin and Kneen, Rachel and Kumar, Ajith V. and Lascelles, Karine and Montgomery, Tara and Ramesh, Venkateswaran and Samanta, Rajib and Scott, Richard H. and Tan, Jeen and Whitehouse, William and Poduri, Annapurna and Scheffer, Ingrid E. and Chong, W.K. “Kling ” and Cross, J.Helen and Topf, Maya and Petrou, Steven and Kurian, Manju A. (2018) Clinical and molecular characterization of KCNT1-related severe early-onset epilepsy. Neurology, 90 . e1-e12. ISSN 1526-632X

[img]
Preview
PDF (Clinical and molecular characterization of KCNT1-related severe early-onset epilepsy) - Requires a PDF viewer such as GSview, Xpdf or Adobe Acrobat Reader
Available under Licence Creative Commons Attribution.
Download (1MB) | Preview

Abstract

Objective: To characterize the phenotypic spectrum, molecular genetic findings, and functional consequences of pathogenic variants in early-onset KCNT1 epilepsy.

Methods: We identified a cohort of 31 patients with epilepsy of infancy with migrating focal seizures (EIMFS) and screened for variants in KCNT1 using direct Sanger sequencing, a multiple-gene next-generation sequencing panel, and whole-exome sequencing. Additional patients with non-EIMFS early-onset epilepsy in whom we identified KCNT1 variants on local diagnostic multiple gene panel testing were also included. When possible, we performed homology modeling to predict the putative effects of variants on protein structure and function. We undertook electrophysiologic assessment of mutant KCNT1 channels in a xenopus oocyte model system.

Results: We identified pathogenic variants in KCNT1 in 12 patients, 4 of which are novel. Most variants occurred de novo. Ten patients had a clinical diagnosis of EIMFS, and the other 2 presented with early-onset severe nocturnal frontal lobe seizures. Three patients had a trial of quinidine with good clinical response in 1 patient. Computational modeling analysis implicates abnormal pore function (F346L) and impaired tetramer formation (F502V) as putative disease mechanisms. All evaluated KCNT1 variants resulted in marked gain of function with significantly increased channel amplitude and variable blockade by quinidine.

Conclusions: Gain-of-function KCNT1 pathogenic variants cause a spectrum of severe focal epilepsies with onset in early infancy. Currently, genotype-phenotype correlations are unclear, although clinical outcome is poor for the majority of cases. Further elucidation of disease mechanisms may facilitate the development of targeted treatments, much needed for this pharmacoresistant genetic epilepsy.

Item Type: Article
Schools/Departments: University of Nottingham, UK > Faculty of Medicine and Health Sciences > School of Medicine > Division of Child Health, Obstetrics and Gynaecology
University of Nottingham, UK > Faculty of Medicine and Health Sciences > School of Medicine
Identification Number: https://doi.org/10.1212/WNL.0000000000004762
Depositing User: Shreeve, Claire
Date Deposited: 05 Feb 2018 10:48
Last Modified: 05 Feb 2018 10:54
URI: http://eprints.nottingham.ac.uk/id/eprint/49506

Actions (Archive Staff Only)

Edit View Edit View