KCNT1 encodes a sodium-activated potassium channel highly expressed in the brain, regulating hyperpolarization following repetitive firing. Mutations in KCNT1 were originally implicated in autosomal-dominant nocturnal frontal lobe epilepsy and epilepsy of infancy with migrating focal seizures. It is now known that there is variability in phenotypic expression and incomplete penetrance. We describe 2 patients with KCNT1-related epilepsy, one with epilepsy of infancy with migrating focal seizures and one with multifocal epilepsy. As most patients with KCNT1 variants have treatment-resistant epilepsy, drugs that specifically target the KCNT1 channel have been of great interest. Quinidine, a broad-spectrum potassium channel blocker, has shown promise; however, clinical trial results have been variable. Our patient with epilepsy of infancy with migrating focal seizures did not respond to a trial of quinidine at 6 weeks of age—one of the earliest reported quinidine trials in the literature for KCNT1-related epilepsy. This indicates that timing of treatment and response may not be related. Both patients responded to high-dose phenobarbital. The patient with epilepsy of infancy with migrating focal seizures also had a significant reduction in seizures with potassium bromide (KBr). Our data suggest that alternative therapies to quinidine should be considered as a therapeutic option for patients with KCNT1-related epilepsy. Although improved seizure control led to parent-reported improvements in neurodevelopment, it is unknown if phenobarbital and KBr impact the overall developmental trajectory of patients with KCNT1-related epilepsy. Further multicenter longitudinal studies are required.
YuanASantiCMWeiA, et al.The sodium-activated potassium channel is encoded by a member of the Slo gene family. Neuron. 2003;37(5):765–773.
2.
BhattacharjeeAKaczmarekLK.For K+ channels, Na+ is the new Ca2+. Trends Neurosci. 2005;28(8):422–428.
3.
HeronSESmithKRBahloM, et al.Missense mutations in the sodium-gated potassium channel gene KCNT1 cause severe autosomal dominant nocturnal frontal lobe epilepsy. Nat Genet. 2012;44(11):1188–1190.
4.
BarciaGFlemingMRDeligniereA, et al.De novo gain-of-function KCNT1 channel mutations cause malignant migrating partial seizures of infancy. Nat Genet. 2012;44(11):1255–1259.
5.
MollerRSHeronSELarsenLH, et al.Mutations in KCNT1 cause a spectrum of focal epilepsies. Epilepsia. 2015;56(9):e114–e120.
6.
MartinHCKimGEPagnamentaAT, et al.Clinical whole-genome sequencing in severe early-onset epilepsy reveals new genes and improves molecular diagnosis. Hum Mole Genet. 2014;23(12):3200–3211.
7.
OhbaCKatoMTakahashiN, et al.De novo KCNT1 mutations in early-onset epileptic encephalopathy. Epilepsia. 2015;56(9):e121–e128.
8.
JuangJMLuTPLaiLC, et al.Disease-targeted sequencing of ion channel genes identifies de novo mutations in patients with non-familial Brugada syndrome. Sci Rep. 2014;4:6733.
9.
MilliganCJLiMGazinaEV, et al.KCNT1 gain of function in 2 epilepsy phenotypes is reversed by quinidine. Ann Neurol. 2014;75(4):581–590.
10.
MikatiMAJiangYHCarboniM, et al.Quinidine in the treatment of KCNT1-positive epilepsies. Ann Neurol. 2015;78(6):995–999.
11.
KimGEKronengoldJBarciaG, et al.Human slack potassium channel mutations increase positive cooperativity between individual channels. Cell Rep. 2014;9(5):1661–1672.
12.
YangBGribkoffVKPanJ, et al.Pharmacological activation and inhibition of Slack (Slo2.2) channels. Neuropharmacology. 2006;51(4):896–906.
13.
BeardenDStrongAEhnotJDiGiovineMDlugosDGoldbergEM. Targeted treatment of migrating partial seizures of infancy with quinidine. Ann Neurol. 2014;76(3):457–461.
14.
ChongPFNakamuraRSaitsuHMatsumotoNKiraR. Ineffective quinidine therapy in early onset epileptic encephalopathy with KCNT1 mutation. Ann Neurol. 2016; 79(3):502–503.
15.
AbdelnourEGallentineWMcDonaldMSachdevMJiangYHMikatiMA. Does age affect response to quinidine in patients with KCNT1 mutations? Report of three new cases and review of the literature. Seizure. 2018;55:1–3.
16.
MadaanPJauhariPGuptaAChakrabartyBGulatiS. A quinidine non responsive novel KCNT1 mutation in an Indian infant with epilepsy of infancy with migrating focal seizures. Brain Dev. 2018;40(3):229–232.
17.
DilenaRDiFrancescoJCSoldovieriMV, et al.Early treatment with quinidine in 2 patients with epilepsy of infancy with migrating focal seizures (EIMFS) due to gain-of-function KCNT1 mutations: functional studies, clinical responses, and critical issues for personalized therapy. Neurotherapeutics. 2018;15(4):1112–1126.
18.
McTagueANairUMalhotraS, et al.Clinical and molecular characterization of KCNT1-related severe early-onset epilepsy. Neurology. 2018;90(1):e55–e66.
19.
FukuokaMKukiIKawawakiH, et al.Quinidine therapy for West syndrome with KCNTI mutation: a case report. Brain Dev. 2017;39(1):80–83.
20.
NumisALNairUDattaAN, et al.Lack of response to quinidine in KCNT1-related neonatal epilepsy. Epilepsia. 2018;59(10):1889–1898.
21.
MeierkordHGrunigFGutschmidtU, et al.Sodium bromide: effects on different patterns of epileptiform activity, extracellular pH changes and GABAergic inhibition. Naunyn Schmiedebergs Arch Pharmacol. 2000;361(1):25–32.
22.
ShimadaSHiranoYItoS, et al.A novel KCNT1 mutation in a Japanese patient with epilepsy of infancy with migrating focal seizures. Hum Genome Var. 2014;1:14027.
23.
LeeHDeignanJLDorraniN, et al.Clinical exome sequencing for genetic identification of rare Mendelian disorders. JAMA. 2014;312(18):1880–1887.
24.
Arai-IchinoiNUematsuMSatoR, et al.Genetic heterogeneity in 26 infants with a hypomyelinating leukodystrophy. Hum Genet. 2016;135(1):89–98.
25.
VanderverASimonsCSchmidtJL, et al.Identification of a novel de novo p.Phe932Ile KCNT1 mutation in a patient with leukoencephalopathy and severe epilepsy. Pediatr Neurol. 2014;50(1):112–114.
26.
GertlerTBeardenDBhattacharjeeACarvillG. KCNT1-related epilepsy. In: AdamMPArdingerHHPagonRA, et al, eds. GeneReviews((R)). Seattle, WA: Washington University; 1993.
27.
KawasakiYKukiIEharaE, et al.Three cases of KCNT1 mutations: malignant migrating partial seizures in infancy with massive systemic to pulmonary collateral arteries. J Pediatr. 2017;191:270–274.
28.
IshiiAShiodaMOkumuraA, et al.A recurrent KCNT1 mutation in two sporadic cases with malignant migrating partial seizures in infancy. Gene. 2013;531(2):467–471.
29.
CoppolaGPlouinPChironCRobainODulacO. Migrating partial seizures in infancy: a malignant disorder with developmental arrest. Epilepsia. 1995;36(10):1017–1024.
30.
CoppolaGVeggiottiPDel GiudiceEM, et al.Mutational scanning of potassium, sodium and chloride ion channels in malignant migrating partial seizures in infancy. Brain Dev. 2006;28(2):76–79.
31.
De FilippoMRRizzoFMarcheseG, et al.Lack of pathogenic mutations in six patients with MMPSI. Epilepsy Res. 2014;108(2):340–344.
32.
KorinthenbergRBurkartPWoelfleCMoentingJSErnstJP. Pharmacology, efficacy, and tolerability of potassium bromide in childhood epilepsy. J Child Neurol. 2007;22(4):414–418.
33.
OkudaKYasuharaAKameiAArakiAKitamuraNKobayashiY. Successful control with bromide of two patients with malignant migrating partial seizures in infancy. Brain Dev. 2000;22(1):56–59.
34.
CoppolaGOpertoFFAuricchioGD’AmicoAFortunatoDPascottoA. Temporal lobe dual pathology in malignant migrating partial seizures in infancy. Epileptic Disord. 2007;9(2):145–148.
35.
DjuricMKravljanacRKovacevicGMarticJ. The efficacy of bromides, stiripentol and levetiracetam in two patients with malignant migrating partial seizures in infancy. Epileptic Disord. 2011;13(1):22–26.
36.
FasuloLSaucedoSCaceresLSolisSCaraballoR. Migrating focal seizures during infancy: a case report and pathologic study. Pediatr Neurol. 2012;46(3):182–184.
37.
NabatameSSaitoYSakumaH, et al.Bromoderma in a patient with migrating partial seizures in infancy. Epilepsy Res. 2010;91(2-3):283–288.
38.
CaraballoRHFontanaEDarraF, et al.Migrating focal seizures in infancy: analysis of the electroclinical patterns in 17 patients. J Child Neurol. 2008;23(5):497–506.
39.
UnverOIncecikFDundarHKomurMUnverAOkuyazC. Potassium bromide for treatment of malignant migrating partial seizures in infancy. Pediatr Neurol. 2013;49(5):355–357.
40.
MoriTImaiKOboshiT, et al.Usefulness of ketogenic diet in a girl with migrating partial seizures in infancy. Brain Dev. 2016;38(6):601–604.
41.
AurlienDLerenTPTaubollEGjerstadL. New SCN5A mutation in a SUDEP victim with idiopathic epilepsy. Seizure. 2009;18(2):158–160.
42.
HindochaNNashefLElmslieF, et al.Two cases of sudden unexpected death in epilepsy in a GEFS+ family with an SCN1A mutation. Epilepsia. 2008;49(2):360–365.
43.
LimCXRicosMGDibbensLMHeronSE. KCNT1 mutations in seizure disorders: the phenotypic spectrum and functional effects. J Med Genet. 2016;53(4):217–225.
44.
NumisALAngrimanMSullivanJE, et al.KCNQ2 encephalopathy: delineation of the electroclinical phenotype and treatment response. Neurology. 2014;82(4):368–370.
