SCN8A variants typically result in a moderate-severe epileptic encephalopathy, and account for 1% of the childhood epileptic encephalopathies.(1) The median age of seizures onset is typically 5 months (range: postnatal day 1 to 18 months of age) with multiple seizure types. The majority of affected patients have mild to severe global developmental delay, abnormal tone, and abnormal movements may be present.(12) In our cohort of eight individuals from six families with SCN8A-related disorders, we observed an age of onset ranging from 3 months to 10 years with severe to no clinical seizures. Developmental outcomes varied from profound developmental delay with intellectual disability and behavioural abnormalities to normal development. Developmental delay and age of onset of seizures did not seem to have a correlation in our cohort.(13) The seizure semiology in SCN8A-related disorders is variable, including focal seizures, tonic-clonic seizures, epileptic spasms, clonic seizures, absence, and myoclonic seizures.(12, 14) Patients with SCN8A mutations also have a high incidence of Sudden Unexpected Death in Epilepsy (SUDEP).(15, 16) We noted a seizure course ranging from self-resolving focal seizures to Lennox-Gastaut syndrome (LGS) manifesting impaired awareness seizures, atypical absence seizures, generalized tonic-clonic seizures, epileptic spasms, and non-convulsive status epilepticus. The most common seizure type has been focal seizures as observed in the earlier reported patients.(17)
The three novel mutations are missense substitutions located on highly conserved transmembrane domains 1 and 2 of NaV1.6 (Fig. 1.). SCN8A gene variants causing substitution of amino acid residues in the highly conserved regions are often deleterious.(1) Three mutations (those of Patient 2(18, 19), Patient 3(20), and Patient 4(21)) were described previously. The clinical features of patient 2, and 3 were quite similar as the characterization of patients with each same mutation previously described. Patient 4’s mutation although published did not have phenotype information for comparison. Variants in Patient 5 and Patient 6 have been submitted to ClinVar (22) without any detailed phenotype descriptions. It is important to note that individual differences in clinical manifestations can occur even with the same genetic variation.
LoF variants include an early stop-gain, indel frameshift or splice-site disruption resulting in truncated protein and reduced or abolished NaV1.6 function.(23) Missense changes causing GoF is the most common pathogenic mechanism for neuronal hyperexcitability and seizures. LoF is associated with cognitive impairment, movement disorders, and autism with or without seizures.(24) The clinical manifestations of SCN8A encephalopathy are likely reliant on the degree of GoF or LoF.(25, 26) GoF phenotypes include mild to severe epileptic encephalopathy. There are a few reported cases of benign infantile seizures with mild gain of function too.(27) We identified two GoF and a LoF variant with experimental evidence and three variations with unknown functional consequences. The electrophysiological analyses performed on Patient 4, LoF SCN8A variant (p.Cys324Tyr), offer valuable insights into the pathogenesis of SCN8A-related disorders. By characterizing the functional consequences of this variant, we provide evidence supporting its role in altering neuronal excitability and ion channel function. This information could potentially inform the development of targeted therapeutic strategies aimed at modulating ion channel activity to alleviate symptoms and improve patient outcomes.
In terms of the KCNQ3 variant in Patient 4, this variant was found to be a conserved amino acid and all in-silico analyses suggest the variant has deleterious impact; however, the variant is novel and remains a variant of uncertain significance. Functional validation has not been performed. Pathogenic variations in KCNQ3 have been associated with benign familial neonatal and infantile seizures (OMIM 121201).(28, 29) Individuals are typically normal and grow out of their seizures, usually without any neurological sequalae in adulthood. More recently KCNQ3 mutations are identified in patients with neurodevelopmental disorders and abnormal EEG.(30) Furthermore, alterations in this gene have been reported to act as risk factors for complex diseases including other epilepsy types and autism spectrum disorder. Sands et al. delineated an electroclinical phenotype in 11 patients with 4 different heterozygous KCNQ3 GoF variants. Most of them did not have clinical seizures.(30) Patient 4 had EEG abnormalities with only possible clinical seizures which could plausibly be due to complex underlying molecular mechanisms involving KCNQ3 and SCN8A.
Many early onset neurological diseases are now known to have a molecular basis. A genetic diagnosis can have strong implications for prognosis and treatment of epilepsy.(31) Assessments of how often a genetic diagnosis has clinically actionable implications vary from 20–60%.(32, 33) These comparisons highlight the variability in clinical presentations, epilepsy diagnoses, and genetic diagnoses among the patients with SCN8A pathogenic variations.
Intellectual disability, epilepsy, behavioral abnormalities, and movement disorders belong to a complex set of conditions with both monogenic and multifactorial etiologies. Clinical overlap between heterogeneous phenotypes, pleiotropy, variable penetrance, and expressivity makes genetic testing a huge challenge in these families. We describe a cohort of SCN8A-related disorders in this research work. The results of this study contribute to expanding the clinical and genotypic spectrum of SCN8A-related disorders. By identifying three novel variants in SCN8A, we have enhanced our understanding of the genetic landscape associated with these disorders. The observed variability in clinical presentation further emphasizes the complex nature of SCN8A-related disorders and highlights the need for personalized approaches to diagnosis, treatment, and genetic counseling. The functional data for p.Cys324Tyr confirms causation in SCN8A-related disorders.