Mutations in KCNT1 cause a spectrum of focal epilepsies

Rikke S. Møller, Sarah E. Heron, Line H G Larsen, Chiao Xin Lim, Michael G. Ricos, Marta A. Bayly, Marjan J A Van Kempen, Sylvia Klinkenberg, Ian Andrews, Kent Kelley, Gabriel M. Ronen, David Callen, Jacinta M. McMahon, Simone C. Yendle, Gemma L. Carvill, Heather C. Mefford, Rima Nabbout, Annapurna Poduri, Pasquale Striano, Maria G. BagliettoFederico Zara, Nicholas J. Smith, Clair Pridmore, Elena Gardella, Marina Nikanorova, Hans Atli Dahl, Pia Gellert, Ingrid E. Scheffer, Boudewijn Gunning, Bente Kragh-Olsen, Leanne M. Dibbens

Research output: Contribution to journalArticle

47 Citations (Scopus)

Abstract

Summary 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.

Original languageEnglish
Pages (from-to)e114-e120
JournalEpilepsia
Volume56
Issue number9
DOIs
Publication statusPublished - Sep 1 2015

Fingerprint

Partial Epilepsy
Mutation
Seizures
Frontal Lobe Epilepsy
Epilepsy
Penetrance
Phenotype
Potassium Channels
Brain Diseases
Sudden Death
Genes
Cardiac Arrhythmias
Sodium
Genotype

Keywords

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

ASJC Scopus subject areas

  • Clinical Neurology
  • Neurology

Cite this

Møller, R. S., Heron, S. E., Larsen, L. H. G., Lim, C. X., Ricos, M. G., Bayly, M. A., ... Dibbens, L. M. (2015). Mutations in KCNT1 cause a spectrum of focal epilepsies. Epilepsia, 56(9), e114-e120. https://doi.org/10.1111/epi.13071

Mutations in KCNT1 cause a spectrum of focal epilepsies. / Møller, Rikke S.; Heron, Sarah E.; Larsen, Line H G; Lim, Chiao Xin; Ricos, Michael G.; Bayly, Marta A.; Van Kempen, Marjan J A; Klinkenberg, Sylvia; Andrews, Ian; Kelley, Kent; Ronen, Gabriel M.; Callen, David; McMahon, Jacinta M.; Yendle, Simone C.; Carvill, Gemma L.; Mefford, Heather C.; Nabbout, Rima; Poduri, Annapurna; Striano, Pasquale; Baglietto, Maria G.; Zara, Federico; Smith, Nicholas J.; Pridmore, Clair; Gardella, Elena; Nikanorova, Marina; Dahl, Hans Atli; Gellert, Pia; Scheffer, Ingrid E.; Gunning, Boudewijn; Kragh-Olsen, Bente; Dibbens, Leanne M.

In: Epilepsia, Vol. 56, No. 9, 01.09.2015, p. e114-e120.

Research output: Contribution to journalArticle

Møller, RS, Heron, SE, Larsen, LHG, Lim, CX, Ricos, MG, Bayly, MA, Van Kempen, MJA, Klinkenberg, S, Andrews, I, Kelley, K, Ronen, GM, Callen, D, McMahon, JM, Yendle, SC, Carvill, GL, Mefford, HC, Nabbout, R, Poduri, A, Striano, P, Baglietto, MG, Zara, F, Smith, NJ, Pridmore, C, Gardella, E, Nikanorova, M, Dahl, HA, Gellert, P, Scheffer, IE, Gunning, B, Kragh-Olsen, B & Dibbens, LM 2015, 'Mutations in KCNT1 cause a spectrum of focal epilepsies', Epilepsia, vol. 56, no. 9, pp. e114-e120. https://doi.org/10.1111/epi.13071
Møller RS, Heron SE, Larsen LHG, Lim CX, Ricos MG, Bayly MA et al. Mutations in KCNT1 cause a spectrum of focal epilepsies. Epilepsia. 2015 Sep 1;56(9):e114-e120. https://doi.org/10.1111/epi.13071
Møller, Rikke S. ; Heron, Sarah E. ; Larsen, Line H G ; Lim, Chiao Xin ; Ricos, Michael G. ; Bayly, Marta A. ; Van Kempen, Marjan J A ; Klinkenberg, Sylvia ; Andrews, Ian ; Kelley, Kent ; Ronen, Gabriel M. ; Callen, David ; McMahon, Jacinta M. ; Yendle, Simone C. ; Carvill, Gemma L. ; Mefford, Heather C. ; Nabbout, Rima ; Poduri, Annapurna ; Striano, Pasquale ; Baglietto, Maria G. ; Zara, Federico ; Smith, Nicholas J. ; Pridmore, Clair ; Gardella, Elena ; Nikanorova, Marina ; Dahl, Hans Atli ; Gellert, Pia ; Scheffer, Ingrid E. ; Gunning, Boudewijn ; Kragh-Olsen, Bente ; Dibbens, Leanne M. / Mutations in KCNT1 cause a spectrum of focal epilepsies. In: Epilepsia. 2015 ; Vol. 56, No. 9. pp. e114-e120.
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AU - Møller, Rikke S.

AU - Heron, Sarah E.

AU - Larsen, Line H G

AU - Lim, Chiao Xin

AU - Ricos, Michael G.

AU - Bayly, Marta A.

AU - Van Kempen, Marjan J A

AU - Klinkenberg, Sylvia

AU - Andrews, Ian

AU - Kelley, Kent

AU - Ronen, Gabriel M.

AU - Callen, David

AU - McMahon, Jacinta M.

AU - Yendle, Simone C.

AU - Carvill, Gemma L.

AU - Mefford, Heather C.

AU - Nabbout, Rima

AU - Poduri, Annapurna

AU - Striano, Pasquale

AU - Baglietto, Maria G.

AU - Zara, Federico

AU - Smith, Nicholas J.

AU - Pridmore, Clair

AU - Gardella, Elena

AU - Nikanorova, Marina

AU - Dahl, Hans Atli

AU - Gellert, Pia

AU - Scheffer, Ingrid E.

AU - Gunning, Boudewijn

AU - Kragh-Olsen, Bente

AU - Dibbens, Leanne M.

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N2 - Summary 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.

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KW - Autosomal dominant nocturnal frontal lobe epilepsy

KW - Cardiac arrhythmia

KW - Epileptic encephalopathy

KW - KCNT1

KW - Sudden unexpected death in epilepsy

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