title: KCNT1 mutations in seizure disorders: the phenotypic spectrum and functional effects.
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.
authors.affiliation: Epilepsy Research Group, School of Pharmacy and Medical Sciences, Sansom Institute for Health Research and Centre for Cancer Biology, University of South Australia, Adelaide, South Australia, Australia.
authors.forename: Chiao Xin
authors.initials: CX
authors.lastname: Lim
authors.affiliation: Epilepsy Research Group, School of Pharmacy and Medical Sciences, Sansom Institute for Health Research and Centre for Cancer Biology, University of South Australia, Adelaide, South Australia, Australia.
authors.forename: Michael G
authors.initials: MG
authors.lastname: Ricos
authors.affiliation: Epilepsy Research Group, School of Pharmacy and Medical Sciences, Sansom Institute for Health Research and Centre for Cancer Biology, University of South Australia, Adelaide, South Australia, Australia.
authors.forename: Leanne M
authors.initials: LM
authors.lastname: Dibbens
authors.affiliation: Epilepsy Research Group, School of Pharmacy and Medical Sciences, Sansom Institute for Health Research and Centre for Cancer Biology, University of South Australia, Adelaide, South Australia, Australia.
authors.forename: Sarah E
authors.initials: SE
authors.lastname: Heron
mesh_terms: D004828:Epilepsies, Partial / Q000235:genetics* / Q000473:pathology; D004827:Epilepsy / Q000145:classification / Q000235:genetics* / Q000473:pathology; D006801:Humans; D008607:Intellectual Disability / Q000235:genetics* / Q000473:pathology; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000235:genetics*; D015221:Potassium Channels / Q000235:genetics*; D000081033:Potassium Channels, Sodium-Activated
chemical_list: C585122:KCNT1 protein, human; D009419:Nerve Tissue Proteins; D015221:Potassium Channels; D000081033:Potassium Channels, Sodium-Activated
keywords: ADNFLE; Epilepsy and seizures; KCNT1; MMFSI; Potassium channel