Expanding the phenotypic and genotypic spectrum of KCNT1-related epilepsies

Abstract

Abstract The KCNT1 gene encodes for a sodium-activated potassium channel involved in neuronal excitability. Since its initial description in 2012 in patients with Epilepsy of Infancy with Migrating Focal Seizures (EIMFS) and in Sleep-related Hypermotor Epilepsy (SHE), the associated phenotypic spectrum has broadened—encompassing other focal epilepsies and Developmental and Epileptic Encephalopathies (DEEs)—and has included extra-neurological features. We aimed to characterize the neurological outcomes, extra-neurological features, mortality and genotype-phenotype correlations expanding the follow-up of the reported cases with KCNT1 variants. A comprehensive literature review was performed to identify all reported cases of KCNT1 pathogenic or likely pathogenic variants. Corresponding authors were contacted to obtain updated clinical data, including current vital status, epilepsy progression, extra-neurological features, cognitive and psychiatric status. The entire dataset, including updated data from the literature, was combined for subsequent analyses. A total of 316 patients from 88 publications were included. Follow-up data were obtained for 60 patients (from 28 papers and 11 countries), increasing the median age at last assessment from 4.4 to 6.0 years. 181 patients had an EIMFS phenotype, 62 had SHE, and 59 had various DEEs. Five individuals were asymptomatic parents, six had other focal epilepsies, and three had other phenotypes. Extra-neurological features were predominantly observed in patients with EIMFS and DEE, notably systemic-to-pulmonary collateral arteries, other vascular or cardiac malformations and various respiratory, orthopaedic or gastrointestinal disorders. The main cause of death was pulmonary complications (haemorrhage or infection). Genotype–phenotype correlations revealed a trend for variants in the first regulator of conductance of potassium (RCK1) domain to associate with EIMFS/non-EIMFS DEE, while SHE-associated variants were predominantly located in the second regulator of conductance of potassium (RCK2) domain. Additionally, variants p.Arg474Cys may confer increased risk for vascular malformations, but the issue appears to be broader, and systematic screening of patients carrying pathogenic KCNT1 variants would allow us to better define this risk. This study offers a comprehensive understanding of the clinical spectrum and genotype-phenotype correlation in KCNT1-related disorders. This study has inherent biases related to the retrospective collection of already published data and underscores the need to develop multisource data methodologies and registries to reduce follow-up loss in real-world data collections based on health records.