Clinical and molecular characterization of KCNT1-related severe early-onset epilepsy
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 i...
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| Format: | Article |
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American Academy of Neurology
2018
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| Online Access: | https://eprints.nottingham.ac.uk/51288/ |
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| author | McTague, Amy Nair, Umesh Malhotra, Shalini Meyer, Esther Trump, Natalie Gazina, Elena V. Papandreou, Apostolos Ngho, Adeline Ackermann, Sally Ambegaonkar, Gautam Appleton, Richard Desurkar, Archana Eltze, Christin Kneen, Rachel Kumar, Ajith V. Lascelles, Karine Montgomery, Tara Ramesh, Venkateswaran Samanta, Rajib Scott, Richard H. Tan, Jeen Whitehouse, William P. Poduri, Annapurna Scheffer, Ingrid E. Chong, W.K. “Kling ” Cross, J.Helen Topf, M Petrou, S Kurian, Manju A. |
| author_facet | McTague, Amy Nair, Umesh Malhotra, Shalini Meyer, Esther Trump, Natalie Gazina, Elena V. Papandreou, Apostolos Ngho, Adeline Ackermann, Sally Ambegaonkar, Gautam Appleton, Richard Desurkar, Archana Eltze, Christin Kneen, Rachel Kumar, Ajith V. Lascelles, Karine Montgomery, Tara Ramesh, Venkateswaran Samanta, Rajib Scott, Richard H. Tan, Jeen Whitehouse, William P. Poduri, Annapurna Scheffer, Ingrid E. Chong, W.K. “Kling ” Cross, J.Helen Topf, M Petrou, S Kurian, Manju A. |
| author_sort | McTague, Amy |
| building | Nottingham Research Data Repository |
| collection | Online Access |
| description | 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. |
| first_indexed | 2025-11-14T20:20:08Z |
| format | Article |
| id | nottingham-51288 |
| institution | University of Nottingham Malaysia Campus |
| institution_category | Local University |
| last_indexed | 2025-11-14T20:20:08Z |
| publishDate | 2018 |
| publisher | American Academy of Neurology |
| recordtype | eprints |
| repository_type | Digital Repository |
| spelling | nottingham-512882020-05-04T19:25:25Z https://eprints.nottingham.ac.uk/51288/ Clinical and molecular characterization of KCNT1-related severe early-onset epilepsy McTague, Amy Nair, Umesh Malhotra, Shalini Meyer, Esther Trump, Natalie Gazina, Elena V. Papandreou, Apostolos Ngho, Adeline Ackermann, Sally Ambegaonkar, Gautam Appleton, Richard Desurkar, Archana Eltze, Christin Kneen, Rachel Kumar, Ajith V. Lascelles, Karine Montgomery, Tara Ramesh, Venkateswaran Samanta, Rajib Scott, Richard H. Tan, Jeen Whitehouse, William P. Poduri, Annapurna Scheffer, Ingrid E. Chong, W.K. “Kling ” Cross, J.Helen Topf, M Petrou, S Kurian, Manju A. 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. American Academy of Neurology 2018-01-02 Article PeerReviewed McTague, Amy, Nair, Umesh, Malhotra, Shalini, Meyer, Esther, Trump, Natalie, Gazina, Elena V., Papandreou, Apostolos, Ngho, Adeline, Ackermann, Sally, Ambegaonkar, Gautam, Appleton, Richard, Desurkar, Archana, Eltze, Christin, Kneen, Rachel, Kumar, Ajith V., Lascelles, Karine, Montgomery, Tara, Ramesh, Venkateswaran, Samanta, Rajib, Scott, Richard H., Tan, Jeen, Whitehouse, William P., Poduri, Annapurna, Scheffer, Ingrid E., Chong, W.K. “Kling ”, Cross, J.Helen, Topf, M, Petrou, S and Kurian, Manju A. (2018) Clinical and molecular characterization of KCNT1-related severe early-onset epilepsy. Neurology, 90 (1). 055. ISSN 1526-632X http://n.neurology.org/content/90/1/e55 doi:10.1212/WNL.0000000000004762 doi:10.1212/WNL.0000000000004762 |
| spellingShingle | McTague, Amy Nair, Umesh Malhotra, Shalini Meyer, Esther Trump, Natalie Gazina, Elena V. Papandreou, Apostolos Ngho, Adeline Ackermann, Sally Ambegaonkar, Gautam Appleton, Richard Desurkar, Archana Eltze, Christin Kneen, Rachel Kumar, Ajith V. Lascelles, Karine Montgomery, Tara Ramesh, Venkateswaran Samanta, Rajib Scott, Richard H. Tan, Jeen Whitehouse, William P. Poduri, Annapurna Scheffer, Ingrid E. Chong, W.K. “Kling ” Cross, J.Helen Topf, M Petrou, S Kurian, Manju A. Clinical and molecular characterization of KCNT1-related severe early-onset epilepsy |
| title | Clinical and molecular characterization of KCNT1-related severe early-onset epilepsy |
| title_full | Clinical and molecular characterization of KCNT1-related severe early-onset epilepsy |
| title_fullStr | Clinical and molecular characterization of KCNT1-related severe early-onset epilepsy |
| title_full_unstemmed | Clinical and molecular characterization of KCNT1-related severe early-onset epilepsy |
| title_short | Clinical and molecular characterization of KCNT1-related severe early-onset epilepsy |
| title_sort | clinical and molecular characterization of kcnt1-related severe early-onset epilepsy |
| url | https://eprints.nottingham.ac.uk/51288/ https://eprints.nottingham.ac.uk/51288/ https://eprints.nottingham.ac.uk/51288/ |