Genotype-phenotype correlations in SCN8A-related disorders reveal prognostic and therapeutic implications

Abstract

We report detailed functional analyses and genotype-phenotype correlations in 392 individuals carrying disease-causing variants in SCN8A, encoding the voltage-gated Na+ channel NaV1.6, with the aim of describing clinical phenotypes related to functional effects. Six different clinical subgroups could be identified: 1) Benign familial infantile epilepsy (BFIE) (n = 15, normal cognition, treatable seizures), 2) intermediate epilepsy (n = 33, mild ID, partially pharmaco-responsive), 3) developmental and epileptic encephalopathy (DEE, n = 177, severe ID, majority pharmaco-resistant), 4) generalized epilepsy (n = 20, mild to moderate ID, frequently with absence seizures), 5) unclassifiable epilepsy (n = 127), and 6) neurodevelopmental disorder without epilepsy (n = 20, mild to moderate ID). Groups 1–3 presented with focal or multifocal seizures (median age of onset: four months) and focal epileptiform discharges, whereas the onset of seizures in group 4 was later (median: 42 months) with generalized epileptiform discharges. We performed functional studies expressing missense variants in ND7/23 neuroblastoma cells and primary neuronal cultures using recombinant tetrodotoxin-insensitive human NaV1.6 channels and whole-cell patch-clamping. Two variants causing DEE showed a strong gain-of-function (GOF, hyperpolarising shift of steady-state activation, strongly increased neuronal firing rate), and one variant causing BFIE or intermediate epilepsy showed a mild GOF (defective fast inactivation, less increased firing). In contrast, all three variants causing generalized epilepsy induced a loss-of-function (LOF, reduced current amplitudes, depolarising shift of steady-state activation, reduced neuronal firing). Including previous studies, functional effects were known for 170 individuals. All 136 individuals carrying a functionally tested GOF variant had either focal (97, groups 1–3), or unclassifiable epilepsy (39), whereas 34 with a LOF variant had either generalized (14), no (11) or unclassifiable (6) epilepsy; only three had DEE. Computational modeling in the GOF group revealed a significant correlation between the severity of the electrophysiological and clinical phenotypes. GOF variant carriers responded significantly better to sodium channel blockers (SCBs) than to other anti-seizure medications, and the same applied for all individuals of groups 1–3. In conclusion, our data reveal clear genotype-phenotype correlations between age at seizure onset, type of epilepsy and gain- or loss-of-function effects of SCN8A variants. Generalized epilepsy with absence seizures is the main epilepsy phenotype of LOF variant carriers and the extent of the electrophysiological dysfunction of the GOF variants is a main determinant of the severity of the clinical phenotype in focal epilepsies. Our pharmacological data indicate that SCBs present a treatment option in SCN8A-related focal epilepsy with onset in the first year of life.

Pathogenic in-Frame Variants in SCN8A: Expanding the Genetic Landscape of SCN8A-Associated Disease

“…Johannesen et al also recently reported two “likely pathogenic” in-frame SCN8A variants in a large cohort of Danish patients with SCN8A mutations ( Johannesen et al, 2021 ). The maternally inherited p.I888_V892delinsM variant was identified in one patient with moderate intellectual disability without epilepsy ( Johannesen et al, 2021 ).…”

“…Johannesen et al also recently reported two "likely pathogenic" in-frame SCN8A variants in a large cohort of Danish patients with SCN8A mutations (Johannesen et al, 2021). The maternally inherited p.I888_V892delinsM variant was identified in one patient with moderate intellectual disability without epilepsy (Johannesen et al, 2021). Another patient had a maternally inherited variant (E1774_A1777del) and presented with several types of seizures, including febrile, myoclonic, and atonic seizures, but normal intellect (Johannesen et al, 2021).…”

“…The maternally inherited p.I888_V892delinsM variant was identified in one patient with moderate intellectual disability without epilepsy ( Johannesen et al, 2021 ). Another patient had a maternally inherited variant (E1774_A1777del) and presented with several types of seizures, including febrile, myoclonic, and atonic seizures, but normal intellect ( Johannesen et al, 2021 ). It is unclear whether the mothers of these patients displayed similar clinical features.…”

Genome-wide meta-analysis of over 29,000 people with epilepsy reveals 26 loci and subtype-specific genetic architecture

“…Na v 1.6 (encoded by SCN8A) is targeted by commonly used sodium channel blocking drugs that have been found to be the most efficacious ASMs for people with monogenic SCN8A- related epilepsies that are often due to channel gain-of-function. 48 Additional drugs targeting Na v 1.6 include safinamide and quinidine. RYR2 encodes a ryanodine receptor, is an established cardiac disorder gene, has recently been implicated in epilepsy 49,50 and is targeted by caffeine as well simvastatin, atorvastatin and carvedilol.…”

Neonatal Seizures: An Overview of Genetic Causes and Treatment Options

“…EEG generally shows a diffuse background with slow activities and focal epileptiform discharges, mainly in the posterior regions [48]. However, disease-causing variants of SCN8A have been recently related to rare cases of BFNE, increasing the number of genes associated with a wide range of epilepsy phenotypes [49,50].…”