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Epilepsia. 2015 Sep;56(9):e114-20. doi: 10.1111/epi.13071. Epub 2015 Jun 30.

Mutations in KCNT1 cause a spectrum of focal epilepsies.

Author information

1
Danish Epilepsy Center, Dianalund, Denmark.
2
Institute for Regional Health Services, University of Southern Denmark, Odense, Denmark.
3
Epilepsy Research Program, School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, South Australia, Australia.
4
Sansom Institute for Health Research, University of South Australia, Adelaide, South Australia, Australia.
5
Amplexa Genetics, Odense, Denmark.
6
Department of Medical Genetics, University Medical Centre Utrecht, Utrecht, The Netherlands.
7
Department of Neurology, Maastricht University Medical Center, Maastricht, The Netherlands.
8
Neurology Service, Sydney Children's Hospital, Randwick, New South Wales, Australia.
9
School of Women's and Children's Health, University of New South Wales, Kensington, New South Wales, Australia.
10
NorthShore University HealthSystem, Evanston, Illinois, U.S.A.
11
Department of Pediatrics, McMaster University, Hamilton, Ontario, Canada.
12
Department of Medicine, Austin Health, The University of Melbourne, Heidelberg, Victoria, Australia.
13
Division of Genetic Medicine, Department of Pediatrics, University of Washington, Seattle, Washington, U.S.A.
14
Department of Pediatric Neurology, Reference Center for Rare Epilepsies, Hospital Necker-Enfants Malades, Paris, France.
15
Epilepsy Genetics Program, Division of Epilepsy and Clinical Neurophysiology, Department of Neurology, Boston Children's Hospital, Boston, Massachusetts, U.S.A.
16
Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, G. Gaslini Institute, University of Genoa, Genova, Italy.
17
Laboratory of Neurogenetics, Department of Neurosciences, G. Gaslini Institute, Genova, Italy.
18
Department of Neurology, Women's and Children's Health Network, Adelaide, South Australia, Australia.
19
School of Paediatrics and Reproductive Health, University of Adelaide, Adelaide, South Australia, Australia.
20
Florey Institute for Neuroscience and Mental Health, The University of Melbourne, Parkville, Victoria, Australia.
21
Department of Paediatrics, Royal Children's Hospital, The University of Melbourne, Melbourne, Victoria, Australia.
22
SEIN - Epilepsy Institutes in the Netherlands Foundation, Zwolle, The Netherlands.
23
Department of Pediatrics, Aarhus University Hospital, Aarhus, Denmark.

Abstract

Autosomal dominant mutations in the sodium-gated potassium channel subunit gene KCNT1 have been associated with two distinct seizure syndromes, nocturnal frontal lobe epilepsy (NFLE) and malignant migrating focal seizures of infancy (MMFSI). To further explore the phenotypic spectrum associated with KCNT1, we examined individuals affected with focal epilepsy or an epileptic encephalopathy for mutations in the gene. We identified KCNT1 mutations in 12 previously unreported patients with focal epilepsy, multifocal epilepsy, cardiac arrhythmia, and in a family with sudden unexpected death in epilepsy (SUDEP), in addition to patients with NFLE and MMFSI. In contrast to the 100% penetrance so far reported for KCNT1 mutations, we observed incomplete penetrance. It is notable that we report that the one KCNT1 mutation, p.Arg398Gln, can lead to either of the two distinct phenotypes, ADNFLE or MMFSI, even within the same family. This indicates that genotype-phenotype relationships for KCNT1 mutations are not straightforward. We demonstrate that KCNT1 mutations are highly pleiotropic and are associated with phenotypes other than ADNFLE and MMFSI. KCNT1 mutations are now associated with Ohtahara syndrome, MMFSI, and nocturnal focal epilepsy. They may also be associated with multifocal epilepsy and cardiac disturbances.

KEYWORDS:

Autosomal dominant nocturnal frontal lobe epilepsy; Cardiac arrhythmia; Epileptic encephalopathy; KCNT1; Sudden unexpected death in epilepsy

PMID:
26122718
PMCID:
PMC5915334
DOI:
10.1111/epi.13071
[Indexed for MEDLINE]
Free PMC Article

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