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

01. Mai, 2017

Wolff M1, Johannesen KM2,3, Hedrich UBS4, Masnada S5, Rubboli G2,6, Gardella E2,3, Lesca G7,8,9, Ville D10, Milh M11,12, Villard L12, Afenjar A13, Chantot-Bastaraud S13, Mignot C14, Lardennois C15, Nava C16,17, Schwarz N4, Gérard M18, Perrin L19, Doummar D20, Auvin S21,22, Miranda MJ23, Hempel M24, Brilstra E25, Knoers N25, Verbeek N25, van Kempen M25, Braun KP26, Mancini G27, Biskup S28, Hörtnagel K28, Döcker M28, Bast T29, Loddenkemper T30, Wong-Kisiel L31, Baumeister FM32, Fazeli W33, Striano P34, Dilena R35, Fontana E36, Zara F37, Kurlemann G38, Klepper J39, Thoene JG40, Arndt DH41, Deconinck N42, Schmitt-Mechelke T43, Maier O44, Muhle H45, Wical B46, Finetti C47, Brückner R48, Pietz J49, Golla G50, Jillella D51, Linnet KM52, Charles P53, Moog U54, Õiglane-Shlik E55, Mantovani JF56, Park K57, Deprez M58, Lederer D58, Mary S58, Scalais E59, Selim L60, Van Coster R61, Lagae L62, Nikanorova M2, Hjalgrim H2,3, Korenke GC63, Trivisano M64, Specchio N64, Ceulemans B65, Dorn T66, Helbig KL67, Hardies K68,69, Stamberger H68,69,70, de Jonghe P68,69,70, Weckhuysen S68,69,70, Lemke JR71, Krägeloh-Mann I1, Helbig I45,72, Kluger G73,74, Lerche H4, Møller RS2,3.


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.