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Type: Journal article
Title: KCNT1 mutations in seizure disorders: the phenotypic spectrum and functional effects
Author: Lim, C.
Ricos, M.
Dibbens, L.
Heron, S.
Citation: Journal of Medical Genetics, 2016; 53(4):217-225
Publisher: BMJ Publishing Group
Issue Date: 2016
ISSN: 0022-2593
Statement of
Chiao Xin Lim, Michael G Ricos, Leanne M Dibbens, Sarah E Heron
Abstract: Mutations in the sodium-gated potassium channel subunit gene KCNT1 have recently emerged as a cause of several different epileptic disorders. This review describes the mutational and phenotypic spectrum associated with the gene and discusses the comorbidities found in patients, which include intellectual disability and psychiatric features. The gene may also be linked with cardiac disorders. KCNT1 missense mutations have been found in 39% of patients with the epileptic encephalopathy malignant migrating focal seizures of infancy (MMFSI), making it the most significant MMFSI disease-causing gene identified to date. Mutations in KCNT1 have also been described in eight unrelated cases of sporadic and familial autosomal-dominant nocturnal frontal lobe epilepsy (ADNFLE). These patients have a high frequency of associated intellectual disability and psychiatric features. Two mutations in KCNT1 have been associated with both ADNFLE and MMFSI, suggesting that the genotype-phenotype relationship for KCNT1 mutations is not straightforward. Mutations have also been described in several patients with infantile epileptic encephalopathies other than MMFSI. Notably, all mutations in KCNT1 described to date are missense mutations, and electrophysiological studies have shown that they result in increased potassium current. Together, these genetic and electrophysiological studies raise the possibility of delivering precision medicine by treating patients with KCNT1 mutations using drugs that alter the action of potassium channels to specifically target the biological effects of their disease-causing mutation. Such trials are now in progress. Better understanding of the mechanisms underlying KCNT1-related disease will produce further improvements in treatment of the associated severe seizure disorders.
Keywords: Epilepsy and seizures; KCNT1; mutation
Rights: Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to
DOI: 10.1136/jmedgenet-2015-103508
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