Please use this identifier to cite or link to this item: http://ahro.austin.org.au/austinjspui/handle/1/18336
Title: Clinical and molecular characterization of KCNT1-related severe early-onset epilepsy.
Authors: McTague, Amy;Nair, Umesh;Malhotra, Sony;Meyer, Esther;Trump, Natalie;Gazina, Elena V;Papandreou, Apostolos;Ngoh, 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;Poduri, Annapurna;Scheffer, Ingrid E;Chong, W K Kling;Cross, J Helen;Topf, Maya;Petrou, Steven;Kurian, Manju A
Affiliation: Department of Medicine, Royal Melbourne Hospital, University of Melbourne, Australia
Department of Biochemistry, University of Cambridge, UK
Molecular Neurosciences, Developmental Neurosciences, UCL Great Ormond Street Institute of Child Health, London, UK
Department of Neurology, Great Ormond Street Hospital for Children, London, UK
Department of Neuroradiology, Great Ormond Street Hospital for Children, London, UK
The Florey Institute of Neuroscience and Mental Health, Melbourne, Australia
Department of Biological Sciences, Institute of Structural and Molecular Biology, Birkbeck College, University of London, London, UK
Regional Molecular Genetics Laboratory, North East Thames Regional Genetics Service, London, UK
Department of Clinical Genetics, Great Ormond Street Hospital, London, UK
Department of Paediatric Neurology, Red Cross War Memorial Children's Hospital, Cape Town, South Africa
Department of Paediatric Neurology, Addenbrooke's Hospital, Cambridge, UK
Roald Dahl EEG Unit, Department of Neurology, Alder Hey Children's Hospital, Liverpool, UK
Department of Neurology, Alder Hey Children's Hospital, Liverpool, UK
Department of Paediatric Neurology, Sheffield Children's Hospital, Sheffield, UK
Clinical Neurosciences , Developmental Neurosciences, UCL Great Ormond Street Institute of Child Health, London, UK
Institute of Infection and Global Health, University of Liverpool, Liverpool, UK
Department of Paediatric Neurology, Evelina Children's Hospital, Guys and St. Thomas' NHS Foundation Trust, London, UK
Department of Clinical Genetics, Northern Genetics Service, UK
Department of Pediatric Neurology, Great North Children's Hospital, Newcastle Upon TyneDepartment of Paediatric Neurology (R.S.), University Hospital Leicester Children's Hospital, UK
Department of Paediatric Neurology (J.T.), Royal Manchester Children's Hospital, UK
Department of Paediatric Neurology (W.W.), Nottingham University Hospitals NHS Trust, UK
Epilepsy Genetics Program, Department of Neurology, Boston Children's Hospital,Boston, MA
Department of Neurology, Harvard Medical School, Boston, MA
University of Melbourne, Royal Children's Hospital, Australia
Austin Health, The University of Melbourne, Heidelberg, Victoria, Australia
Issue Date: 2-Jan-2018
EDate: 2017-12-01
Citation: Neurology 2018; 90(1): e55-e66
Abstract: To characterize the phenotypic spectrum, molecular genetic findings, and functional consequences of pathogenic variants in early-onset KCNT1epilepsy. 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. 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. 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.
URI: http://ahro.austin.org.au/austinjspui/handle/1/18336
DOI: 10.1212/WNL.0000000000004762
ORCID: 0000-0002-2311-2174
PubMed URL: 29196579
Type: Journal Article
Appears in Collections:Journal articles

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