Genetic and phenotypic heterogeneity suggest therapeutic implications in SCN2A-related disorders

Abstract

Mutations in SCN2A, a gene encoding the voltage-gated sodium channel Nav1.2, have been associated with a spectrum of epilepsies and neurodevelopmental disorders. Here, we report the phenotypes of 71 patients and review 130 previously reported patients. We found that (i) encephalopathies with infantile/childhood onset epilepsies (≥3 months of age) occur almost as often as those with an early infantile onset (<3 months), and are thus more frequent than previously reported; (ii) distinct phenotypes can be seen within the late onset group, including myoclonic-atonic epilepsy (two patients), Lennox-Gastaut not emerging from West syndrome (two patients), and focal epilepsies with an electrical status epilepticus during slow sleep-like EEG pattern (six patients); and (iii) West syndrome constitutes a common phenotype with a major recurring mutation (p.Arg853Gln: two new and four previously reported children). Other known phenotypes include Ohtahara syndrome, epilepsy of infancy with migrating focal seizures, and intellectual disability or autism without epilepsy. To assess the response to antiepileptic therapy, we retrospectively reviewed the treatment regimen and the course of the epilepsy in 66 patients for which well-documented medical information was available. We find that the use of sodium channel blockers was often associated with clinically relevant seizure reduction or seizure freedom in children with early infantile epilepsies (<3 months), whereas other antiepileptic drugs were less effective. In contrast, sodium channel blockers were rarely effective in epilepsies with later onset (≥3 months) and sometimes induced seizure worsening. Regarding the genetic findings, truncating mutations were exclusively seen in patients with late onset epilepsies and lack of response to sodium channel blockers. Functional characterization of four selected missense mutations using whole cell patch-clamping in tsA201 cells-together with data from the literature-suggest that mutations associated with early infantile epilepsy result in increased sodium channel activity with gain-of-function, characterized by slowing of fast inactivation, acceleration of its recovery or increased persistent sodium current. Further, a good response to sodium channel blockers clinically was found to be associated with a relatively small gain-of-function. In contrast, mutations in patients with late-onset forms and an insufficient response to sodium channel blockers were associated with loss-of-function effects, including a depolarizing shift of voltage-dependent activation or a hyperpolarizing shift of channel availability (steady-state inactivation). Our clinical and experimental data suggest a correlation between age at disease onset, response to sodium channel blockers and the functional properties of mutations in children with SCN2A-related epilepsy.

Genetic analysis of benign familial epilepsies in the first year of life in a Chinese cohort

“…This result was consistent with the rate that had been reported by other research groups [19,[21][22][23][24]. The identification of SCN2A mutations in 5 BFIE families in our cohort further proved that this gene is also involved in families with a delayed age of onset [25]. KCNQ2 was the only gene that could be related to these three benign familial epilepsies in our study.…”

Optimizing genomic medicine in epilepsy through a gene-customized approach to missense variant interpretation

“…6A). Among the subset of novel SCN2A missense variants in Wolff et al (2017) that qualified as having occurred de novo and restricting to severe epileptic encephalopathies, we observed a shift toward higher GPP scores (n = 24; median GPP score of 0.82) compared to the remaining novel missense variants (n = 28; median GPP score of 0.64; Mann-Whitney U test, P = 0.02). There was no significant difference between the GPP score distribution of the 52 novel variants and the SCN2A pathogenic qualified variants used to fit the SCN2A model (n = 62; median GPP score of 0.65; Mann-Whitney U test, P = 0.84).…”

“…After the conclusion of our analysis of SCN2A, a new paper with a large catalog of novel pathogenic-reported variants provided an ideal opportunity to validate our approach (Wolff et al 2017). This study reported 52 distinct SCN2A pathogenic missense changes not found among our case or control collections.…”

Two Distinct De novo Pathogenic Sequence Variants in the SCN2A Gene in Children with Early Infantile Epileptic Encephalopathy/Ohtahara Syndrome

“…Wolff et al defined two groups of patients with distinct seizure onset (before or after three months of age). These patients exhibit variable additional phenotypic features related to epilepsy, different impact of pathogenic variants in the SCN2A gene to encoded protein resulting in different response to treatment by Na+ channel blockers [43].…”

“…The Na+ channel blocker treatment may reduce the negative symptoms of EIEE/OS and improve the prognosis of significant proportion of affected children. Wolff et al (2017) reviewed a large cohort of 201 patients with SCN2A-related disorders including 71 patients not reported previously [43]. They reported six cases of recurrent p.Ala263Val variant.…”