Mutations in KCNT1 cause a spectrum of focal epilepsies

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.

Figure 1

(A) Pedigrees of families 1 and 2 with KCNT1 mutations. Diagonal lines indicate deceased individuals. (B) Diagram of the KCNT1 protein showing the protein structure and the locations of the mutations identified in this and previous studies.^-, The KCNT1 protein consists of a small amino-terminal domain, a transmembrane domain containing six transmembrane segments with the pore-loop between segments 5 and 6 and a large intracellular carboxy-terminal domain containing tandem RCK domains and an NAD⁺ binding domain. Mutations seen in this study are indicated by stars and those seen in other studies are indicated by dots. ADNFLE mutations are marked in red, MMFSI mutations in blue, the leukoencephalopathy mutation in yellow, the mutation seen in the multifocal epilepsy patient in blue-green, and mutations seen in both ADNFLE and MMFSI patients in green. The homozygous mutation seen in Ohtahara syndrome is marked in orange and the mutation seen in Brugada syndrome is marked in dark gray. Mutations observed in multiple families/patients are indicated by the numbers in bold type. Epilepsia © ILAE