KCNT1-related epilepsies and epileptic encephalopathies: phenotypic and mutational spectrum

Abstract

Variants in KCNT1, encoding a sodium-gated potassium channel (subfamily T member 1), have been associated with a spectrum of epilepsies and neurodevelopmental disorders. These range from familial autosomal dominant or sporadic sleep-related hypermotor epilepsy ((AD)SHE) to epilepsy of infancy with migrating focal seizures (EIMFS) and include developmental and epileptic encephalopathies (DEE). This study aims to provide a comprehensive overview of the phenotypic and genotypic spectrum of KCNT1 mutation-related epileptic disorders in 248 individuals, including 66 unpreviously published and 182 published cases, the largest cohort reported so far. Four phenotypic groups emerged from our analysis: i) EIMFS (152 individuals, 33 previously unpublished); ii) DEE other than EIMFS (non-EIMFS DEE) (37 individuals, 17 unpublished); iii) (AD)SHE (53 patients, 14 unpublished); iv) other phenotypes (6 individuals, 2 unpublished). In our cohort of 66 new cases, the most common phenotypic features were: a) in EIMFS, heterogeneity of seizure types, including epileptic spasms, epilepsy improvement over time, no epilepsy-related deaths; b) in non-EIMFS DEE, possible onset with West syndrome, occurrence of atypical absences, possible evolution to DEE with SHE features; one case of sudden unexplained death in epilepsy (SUDEP); c) in (AD)SHE, we observed a high prevalence of drug-resistance, although seizure frequency improved with age in some individuals, appearance of cognitive regression after seizure onset in all patients, no reported severe psychiatric disorders, although behavioural/psychiatric comorbidities were reported in about 50% of the patients, SUDEP in one individual; d) other phenotypes in individuals with mutation of KCNT1 included temporal lobe epilepsy, and epilepsy with tonic-clonic seizures and cognitive regression. Genotypic analysis of the whole cohort of 248 individuals showed only missense mutations and one inframe deletion in KCNT1. Although the KCNT1 mutations in affected individuals were seen to be distributed among the different domains of the KCNT1 protein, genotype-phenotype considerations showed many of the (AD)SHE-associated mutations to be clustered around the RCK2 domain in the C-terminus, distal to the NADP domain. Mutations associated with EIMFS/non-EIMFS DEE did not show a particular pattern of distribution in the KCNT1 protein. Recurrent KCNT1 mutations were seen to be associated with both severe and less severe phenotypes. Our study further defines and broadens the phenotypic and genotypic spectrums of KCNT1-related epileptic conditions and emphasizes the increasingly important role of this gene in the pathogenesis of early onset DEEs as well as in focal epilepsies, namely (AD)SHE.

Incidence of Aicardi-Goutières syndrome and KCNT1-related epilepsy in Denmark

“…The limitation of delayed genetic confirmation appears to be more prominent for KCNT1 -related epilepsies. A recent publication by Bonardi et al [ 14 ], summarizing 248 cases of KCNT1 -related epilepsy, reported lower ages of seizure onset than the ages at diagnosis of KCNT1 patients reported in our study. The calculated incidence is therefore likely an overestimate that includes prevalent cases which were incident before the discovery of the KCNT1 gene but only genetically confirmed during the study period, as well as familial ADSHE cases that were diagnosed after one member (i.e., the proband) was diagnosed ( Section 4.4 ).…”

“…The calculated incidence is therefore likely an overestimate that includes prevalent cases which were incident before the discovery of the KCNT1 gene but only genetically confirmed during the study period, as well as familial ADSHE cases that were diagnosed after one member (i.e., the proband) was diagnosed ( Section 4.4 ). Notably, the phenotypes included in the Bonardi et al study [ 14 ] largely consisted of EIMFS, which tend to be sporadic and not familial, while in our study ADSHE was the most common phenotype. Compared with EIMFS, ADSHE cases tend to be less severe in the prognosis and are associated with longer survival.…”

“…Compared with EIMFS, ADSHE cases tend to be less severe in the prognosis and are associated with longer survival. Since there may be a stronger tradition to perform genetic testing for pediatric epileptic patients, this also explains the age discrepancy between the very predominantly young pediatric cases in Bonardi et al [ 14 ] in contrast to the adult and older pediatric cases in our study. The average annual incidence estimated in the population aged 18–50 years is likely biased as it included prevalent cases; in addition, the upper age limit of the population at risk was set at 50 years of age empirically based on the data since they fulfilled the common definition of incident cases as newly diagnosed cases despite that the diagnoses were delayed due to unavailability of genetic testing before 2012.…”

“…Pathogenic variants in potassium sodium-activated channel subfamily T member 1 ( KCNT1 ) have been associated with a wide spectrum of epilepsies. The most common phenotypes are epilepsy of infancy with migrating focal seizure (EIMFS) with onset before 6 months of age [ 11 ], other DEEs (non-EIMFS) with onset before 12 months of age, and familial autosomal dominant or sporadic sleep-related hypermotor epilepsy (ADSHE) with onset after 12 months of age [ [12] , [13] , [14] ]. The diagnosis of KCNT1 -related epilepsy is established based on the clinical symptoms and the identification of a heterozygous pathogenic variant.…”

A novel de novo heterozygous variant of the KCNQ2 gene: Contribution to early‑onset epileptic encephalopathy in a female infant

“…With the development of high-throughput sequencing technology, opportunities have been provided to investigate the underlying molecular-genetic basis of epilepsy. More than 100 genes have been identified to be related to EOEE, such as cdc42 guanine nucleotide exchange factor 9 [arHGeF9; online Mendelian inheritance in Man (oMiM) #300607], cyclin-dependent kinase-like 5 (cdKl5; oMiM #300203), potassium sodium-activated channel subfamily T member 1 (KcnT1; oMiM #614959), sodium voltage-gated channel α subunit 8 (Scn8a; oMiM #614558), solute carrier family 2 member 1 (Slc2a1; oMiM #614847) syntaxin-binding protein 1 (STXBP1; oMiM #602926), polynucleotide kinase 3'-phosphatase (PnKP; oMiM #605610) and potassium voltage-gated channel subfamily Q member 2 (KcnQ2; oMiM #602235) (4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14). among these, KcnQ2 is the causative gene for 7-10% of cases of eoee (15)(16)(17).…”