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

Abstract

We report detailed functional analyses and genotype-phenotype correlations in 433 individuals carrying disease-causing variants in SCN8A, encoding the voltage-gated Na+ channel NaV1.6. Five different clinical subgroups could be identified: 1) Benign familial infantile epilepsy (BFIE) (n=17, normal cognition, treatable seizures), 2) intermediate epilepsy (n=36, mild ID, partially pharmacoresponsive), 3) developmental and epileptic encephalopathy (DEE, n=191, severe ID, majority pharmacoresistant), 4) generalized epilepsy (n=21, mild to moderate ID, frequently with absence seizures), and 5) affected individuals without epilepsy (n=25, mild to moderate ID). Groups 1-3 presented with early-onset (median: four months) focal or multifocal seizures and epileptic discharges, whereas the onset of seizures in group 4 was later (median: 39 months) with generalized epileptic discharges. The epilepsy was not classifiable in 143 individuals. 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 165 individuals. All 133 individuals carrying GOF variants had either focal (76, groups 1-3), or unclassifiable epilepsy (37), whereas 32 with LOF variants had either generalized (14), no (11) or unclassifiable (5) epilepsy; only two 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 therapeutic treatment option in early onset SCN8A-related focal epilepsy.

Clinical Characteristics and Treatment Experience of Individuals with SCN8A Developmental and Epileptic Encephalopathy (SCN8A-DEE): Findings from an Online Caregiver Survey

“…4,7,15,24 Caregivers also reported a broad range of genetic variants in this study, many of which were among the more than 250 SCN8A mutations that have been previously characterized. 8 Repeat genetic mutations have been observed in about 25% of cases in previous studies 13 compared to 50% in this study, perhaps in part to the increasing number of SCN8A mutations that have been characterized over time. Despite the heterogeneity of the patient population in this study, most patients suffered from a high seizure burden and multiple neurologic and motor comorbidities.…”

“…SCN8A-DEE and SCN8A-related epilepsies are extremely rare, having been described in almost 400 published cases to date. 8 Existing characterizations of the heterogenous clinical presentation, progression, and prognosis of SCN8A-DEE and SCN8A-related epilepsies have been based on clinic samples with limited sample sizes. This is the first survey-based study of the experiences of caregivers of patients with SCN8A-related epilepsies.…”

“…For example, a recent study found that gain-of-function SCN8A mutations primarily caused focal epilepsy, suggesting that some of the generalized tonic/clonic seizures reported in this study could instead be classified as focal to bilateral tonic/clonic. 8 Second, this study included a relatively small number of caregiver respondents and patients, especially patients aged 18 years or older. However, the 116 caregiver responses included in this study represent a large proportion of the total cases of SCN8A-related epilepsy described to date.…”

“…[4][5][6] Subsequent studies have confirmed the critical role of SCN8A in the initiation and propagation of action potentials and neuronal activity in the brain, and almost 400 individuals with SCN8A-related epilepsy have been described in the literature or documented in registries. [1][2][3]5,[7][8][9][10] The majority of documented SCN8A mutations are de novo gain-of-function mutations that result in premature channel opening, impaired inactivation, or elevated persistent current. [1][2][3]5,7 Loss-of-function variants associated with a reduction of peak current have also been reported and are typically characterized by less severe phenotypes, including less severe developmental delay, cognitive impairment, movement disorder (e.g., myoclonus), and mild or no seizures.…”

In vitroeffects of S-Licarbazepine as a potential precision therapy onSCN8Avariants causing neuropsychiatric disorders

“…Subsequently, many pathogenic de novo SCN8A variants have been described in epileptic patients displaying phenotypes ranging from mild epilepsy (e.g. benign familial infantile seizures) to severe developmental and epileptic encephalopathies (DEEs, (Gardella & Moller, 2019; Gertler & Carvill, 2019; Johannesen et al, 2021) including non-epileptic symptoms such as intellectual disability (O’Brien & Meisler, 2013). To cover the full phenotypic and biophysical spectrum we chose two variants with biophysical and neuronal gain-of-function (GOF, M1760I, G1475R) and one with biophysical GOF but neuronal loss-of-function (LOF, A1622D), as outlined above (Fig.…”