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

Markus Wolff , Katrine M. Johannesen , Ulrike B. S. Hedrich , Silvia Masnada , Guido Rubboli , Elena Gardella , Gaetan Lesca (1) , Dorothée Ville (1) , Mathieu Milh (2) , Laurent Villard (1) , Alexandra Afenjar (3, 4) , Sandra Chantot-Bastaraud (4) , Cyril Mignot (5) , Caroline Lardennois , Caroline Nava (6) , Niklas Schwarz , Marion Gérard (7) , Laurence Perrin (8) , Diane Doummar (3) , Stéphane Auvin (9) , Maria J. Miranda , Maja Hempel (10) , Eva Brilstra , Nine Knoers (11) , Nienke Verbeek , Marjan van Kempen , Kees P. Braun , Grazia Mancini , Saskia Biskup (12) , Konstanze Hörtnagel (12) , Miriam Döcker , Thomas Bast (13) , Tobias Loddenkemper , Lily Wong-Kisiel , Friedrich M. Baumeister , Walid Fazeli , Pasquale Striano (14) , Robertino Dilena , Elena Fontana (15) , Federico Zara (14) , Gerhard Kurlemann , Joerg Klepper , Jess G. Thoene , Daniel H. Arndt , Nicola Deconinck , Thomas Schmitt-Mechelke , Oliver Maier , Hiltrud Muhle , Beverly Wical , Claudio Finetti , Reinhard Brückner , Joachim Pietz , Günther Golla , Dinesh Jillella , Karen M. Linnet (16) , Perrine Charles , Ute Moog (17) , Eve Õiglane-Shlik , John F. Mantovani , Kristen Park , Marie Deprez , Damien Lederer (18) , Sandrine Mary , Emmanuel Scalais , Laila Selim , Rudy C van Coster (19) , Lieven Lagae (20) , Marina Nikanorova , Helle Hjalgrim (21) , G. Christoph Korenke , Marina Trivisano , Nicola Specchio , Berten Ceulemans , Thomas Dorn , Katherine L. Helbig (22) , Katia Hardies (23) , Hannah Stamberger , Peter de Jonghe (24) , Sarah Weckhuysen (25) , Johannes R. Lemke , Ingeborg Krägeloh-Mann (26) , Ingo Helbig (27) , Gerhard Kluger (28) , Holger Lerche , Rikke S Møller

1 GMGF - Génétique Médicale et Génomique Fonctionnelle
2 Epilepsie et ischémie cérébrale
3 CHU Trousseau [APHP]
4 UF de Génétique chromosomique [CHU Trousseau]
5 CHU Pitié-Salpêtrière [AP-HP]
6 Service de Génétique Cytogénétique et Embryologie [CHU Pitié-Salpêtrière]
7 Unité fonctionnelle de génétique clinique
8 Département de génétique [Robert Debré]
9 PPAV - "Personal Protection Against Vectors" working group
10 Institute of Human Genetics
11 University Medical Center [Utrecht]
12 CeGaT GmbH
13 Epilepsy Center Kork
14 Pediatric Neurology and Neuromuscular Diseases Unit
15 F. Hoffmann-La Roche [Basel]
16 Perinatal Epidemiology Research Unit, Department of Pediatrics
17 Human Genetics Institute
18 I.P.G. - Institut de Pathologie et Génétique [Gosselies]
19 Department of Pediatrics
20 Department of Pediatric Neurology
21 Medical Genetics Laboratory
22 University of Calgary
23 VIB11 - Department of Molecular and Developmental Genetics
24 UZA - Antwerp University Hospital [Edegem]
25 ICM - Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute
26 Department of Paediatric Neurology and Developmental Medicine
27 CHOP - Children’s Hospital of Philadelphia
28 Epilepsy Center for Children and Adolescents

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.

Keywords: SCN2A; epilepsy; epilepsy genetics; sodium channel blockers; treatment response

Domains: Life Sciences [q-bio]; Genetics; Human genetics; Life Sciences [q-bio]; Neurons and Cognition [q-bio.NC]; Neurobiology

Markus Wolff, Katrine M. Johannesen, Ulrike B. S. Hedrich, Silvia Masnada, Guido Rubboli, et al.. Genetic and phenotypic heterogeneity suggest therapeutic implications in SCN2A-related disorders. Brain - A Journal of Neurology , 2017, 140 (5), pp.1316-1336. ⟨10.1093/brain/awx054⟩. ⟨hal-01668653⟩