Genetic and phenotypic heterogeneity suggest therapeutic implications in SCN2A-related disorders - Aix-Marseille Université Access content directly
Journal Articles Brain - A Journal of Neurology Year : 2017

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, 3) , Sandra Chantot-Bastaraud (3) , Cyril Mignot (4) , Caroline Lardennois , Caroline Nava (4) , Niklas Schwarz , Marion Gérard (5) , Laurence Perrin (6) , Diane Doummar (3) , Stéphane Auvin (7) , Maria J. Miranda , Maja Hempel (8) , Eva Brilstra , Nine Knoers (9) , Nienke Verbeek , Marjan van Kempen , Kees P. Braun , Grazia Mancini , Saskia Biskup (10) , Konstanze Hörtnagel (10) , Miriam Döcker , Thomas Bast (11) , Tobias Loddenkemper , Lily Wong-Kisiel , Friedrich M. Baumeister , Walid Fazeli , Pasquale Striano (12) , Robertino Dilena , Elena Fontana (13) , Federico Zara (12) , 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 (14) , Perrine Charles , Ute Moog (15) , Eve Õiglane-Shlik , John F. Mantovani , Kristen Park , Marie Deprez , Damien Lederer (16) , Sandrine Mary , Emmanuel Scalais , Laila Selim , Rudy C van Coster (17) , Lieven Lagae (18) , Marina Nikanorova , Helle Hjalgrim (19) , G. Christoph Korenke , Marina Trivisano , Nicola Specchio , Berten Ceulemans , Thomas Dorn , Katherine L. Helbig (20) , Katia Hardies (21) , Hannah Stamberger , Peter de Jonghe (22) , Sarah Weckhuysen (23) , Johannes R. Lemke , Ingeborg Krägeloh-Mann (24) , Ingo Helbig (25) , Gerhard Kluger (26) , Holger Lerche , Rikke S Møller
Markus Wolff
  • Function : Author
Katrine M. Johannesen
  • Function : Author
Ulrike B. S. Hedrich
  • Function : Author
Silvia Masnada
  • Function : Author
Guido Rubboli
  • Function : Author
Elena Gardella
Alexandra Afenjar
  • Function : Author
  • PersonId : 902592
Sandra Chantot-Bastaraud
Caroline Lardennois
  • Function : Author
Caroline Nava
Niklas Schwarz
  • Function : Author
Diane Doummar
  • Function : Author
  • PersonId : 953196
Maria J. Miranda
  • Function : Author
Maja Hempel
  • Function : Author
  • PersonId : 895562
Eva Brilstra
  • Function : Author
Nine Knoers
  • Function : Author
  • PersonId : 906800
Nienke Verbeek
  • Function : Author
Marjan van Kempen
  • Function : Author
Kees P. Braun
  • Function : Author
Grazia Mancini
  • Function : Author
Saskia Biskup
  • Function : Author
Konstanze Hörtnagel
  • Function : Author
Miriam Döcker
  • Function : Author
Thomas Bast
  • Function : Author
Tobias Loddenkemper
  • Function : Author
Lily Wong-Kisiel
  • Function : Author
Friedrich M. Baumeister
  • Function : Author
Walid Fazeli
  • Function : Author
Robertino Dilena
  • Function : Author
Gerhard Kurlemann
  • Function : Author
Joerg Klepper
  • Function : Author
Jess G. Thoene
  • Function : Author
Daniel H. Arndt
  • Function : Author
Nicola Deconinck
  • Function : Author
Thomas Schmitt-Mechelke
  • Function : Author
Oliver Maier
  • Function : Author
Hiltrud Muhle
  • Function : Author
Beverly Wical
  • Function : Author
Claudio Finetti
  • Function : Author
Reinhard Brückner
  • Function : Author
Joachim Pietz
  • Function : Author
Günther Golla
  • Function : Author
Dinesh Jillella
  • Function : Author
Perrine Charles
  • Function : Author
Ute Moog
  • Function : Author
  • PersonId : 887755
Eve Õiglane-Shlik
  • Function : Author
John F. Mantovani
  • Function : Author
Kristen Park
  • Function : Author
Marie Deprez
  • Function : Author
Sandrine Mary
  • Function : Author
Emmanuel Scalais
  • Function : Author
Laila Selim
  • Function : Author
Marina Nikanorova
  • Function : Author
G. Christoph Korenke
  • Function : Author
Marina Trivisano
  • Function : Author
Nicola Specchio
  • Function : Author
Berten Ceulemans
  • Function : Author
Thomas Dorn
  • Function : Author
Hannah Stamberger
  • Function : Author
Johannes R. Lemke
  • Function : Author
Gerhard Kluger
  • Function : Author
  • PersonId : 908466
Holger Lerche
  • Function : Author
Rikke S Møller
  • Function : Author

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.
Fichier principal
Vignette du fichier
awx054_biffé.pdf (825.06 Ko) Télécharger le fichier
Origin : Files produced by the author(s)
Loading...

Dates and versions

hal-01668653 , version 1 (23-03-2018)

Identifiers

Cite

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⟩
1021 View
289 Download

Altmetric

Share

Gmail Facebook X LinkedIn More