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

McTague, A. and Nair, U. and Malhotra, S. and Meyer, E. and Trump, N. and Gazina, E.V. and Papandreou, A. and Ngoh, A. and Ackermann, S. and Ambegaonkar, G. and Appleton, R. and Desurkar, A. and Eltze, C. and Kneen, R. and Kumar, A.V. and Lascelles, K. and Montgomery, T. and Ramesh, V. and Samanta, R. and Scott, R.H. and Tan, J. and Whitehouse, W. and Poduri, A. and Scheffer, I.E. and Chong, W.K. "Kling" and Cross, H.K. and Topf, Maya and Petrou, S. and Kurian, M.A. (2017) Clinical and molecular characterisation of KCNT1-related severe early onset epilepsy. Neurology 90 (1), ISSN 0028-3878.

Abstract

Objective: To characterise 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. Where possible, we performed homology modelling to predict putative effects of variants on protein structure and function. We undertook electrophysiological assessment of mutant KCNT1 channels in a Xenopus oocyte model system. Results: We identified pathogenic variants in KCNT1 in 12 patients, four of which are novel. Most variants occurred de novo. Ten had a clinical diagnosis of EIMFS and the other two presented with early onset severe nocturnal frontal lobe seizures. Three patients had a trial of quinidine with good clinical response in one. Computational modelling 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, though 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.

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