Genotype–phenotype correlations in Polish patients with SCN8A-related epilepsy: A multicentre observational study.

• This paper summarizes the clinical and genetic findings in the Polish multicenter pediatric group of patients with SCN8A mutations. • The results are discussed and compared in relation to the literature, with special attention paid to genotype-phenotype correlations, neurological symptoms, defects and epilepsy and its treatment. • In this study, we assessed 17 patients with diverse phenotypical spectra harbouring 11 novel mutations in the SCN8A gene. The neurological disorders included alterations in muscular tone accompanied by typical features of SCN8A-related encephalopathies, namely developmental delay and a wide range of seizures. The onset of seizures in children with DEE and EOEE occurs within the first months of life. Voltage-gated sodium channels are involved in the initial depolarisation of neurones. As such, they play important roles in neurotransmission. Variants in the genes encoding these channels may lead to altered functionality and neurodevelopmental disorders. Pathogenic variants of SCN8A , which encodes the voltage-gated Na+ channel Nav1.6, have been associated with various encephalopathies characterised by developmental delay and epileptic seizures. Herein, we discuss the genotype-phenotype associations in a group of 17 novel Polish patients with SCN8A mutations, further expanding the molecular and phenotypic spectrum of SCN8A -related diseases. The participants were recruited from five clinical centres in Poland. Pathogenic and likely pathogenic SCN8A variants were identified using a next-generation sequencing (NGS) panel and exome sequencing, respectively. Magnetic resonance imaging (MRI) and electroencephalography (EEG) recordings were performed to obtain relevant clinical data on brain malformations and epileptic seizures. Three phenotypes were observed in the study group: developmental and epileptic encephalopathy, early onset epileptic encephalopathy, and neurodevelopmental disorders without epilepsy. Patients in the first two phenotypic subgroups presented with epileptic seizures within the first few months of life. Their semiology evolved with age, comprising mostly tonic, clonic, and tonic-clonic seizures, with eyelid myoclonia, myoclonic seizures, and epileptic spasms. The most prevalent neurological feature was developmental delay. Alterations in muscle tone were more frequent than in previous reports. Seventeen patients with 11 novel mutations in SCN8A had alterations in muscular tone accompanied by typical features of SCN8A-related encephalopathies (i.e., developmental delay and a wide range of seizures). [ABSTRACT FROM AUTHOR]