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

(2017) BRAIN. 140(5). p.1316-1336
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Abstract
Mutations in SCN2A, a gene encoding the voltage-gated sodium channel Na(v)1.2, 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 (53 months of age) occur almost as often as those with an early infantile onset (53 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 (53 months), whereas other antiepileptic drugs were less effective. In contrast, sodium channel blockers were rarely effective in epilepsies with later onset (53 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, treatment response, sodium channel blockers, NEONATAL-INFANTILE SEIZURES, DE-NOVO MUTATIONS, AUTISM SPECTRUM DISORDER, MIGRATING FOCAL SEIZURES, ONSET EPISODIC ATAXIA, SODIUM-CHANNEL, SCN2A MUTATION, EPILEPTIC ENCEPHALOPATHY, INTELLECTUAL DISABILITY, MISSENSE MUTATION

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Citation

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MLA
Wolff, Markus et al. “Genetic and Phenotypic Heterogeneity Suggest Therapeutic Implications in SCN2A-related Disorders.” BRAIN 140.5 (2017): 1316–1336. Print.
APA
Wolff, M., Johannesen, K. M., Hedrich, U. B., Masnada, S., Rubboli, G., Gardella, E., Lesca, G., et al. (2017). Genetic and phenotypic heterogeneity suggest therapeutic implications in SCN2A-related disorders. BRAIN, 140(5), 1316–1336.
Chicago author-date
Wolff, Markus, Katrine M Johannesen, Ulrike BS Hedrich, Silvia Masnada, Guido Rubboli, Elena Gardella, Gaetan Lesca, et al. 2017. “Genetic and Phenotypic Heterogeneity Suggest Therapeutic Implications in SCN2A-related Disorders.” Brain 140 (5): 1316–1336.
Chicago author-date (all authors)
Wolff, Markus, Katrine M Johannesen, Ulrike BS Hedrich, Silvia Masnada, Guido Rubboli, Elena Gardella, Gaetan Lesca, Dorothée Ville, Mathieu Milh, Laurent Villard, Alexandra Afenjar, Sandra Chantot-Bastaraud, Cyril Mignot, Caroline Lardennois, Caroline Nava, Niklas Schwarz, Marion Gérard, Laurence Perrin, Diane Doummar, Stéphane Auvin, Maria J Miranda, Maja Hempel, Eva Brilstra, Nine Knoers, Nienke Verbeek, Marjan van Kempen, Kees P Braun, Grazia Mancini, Saskia Biskup, Konstanze Hörtnagel, Miriam Döcker, Thomas Bast, Tobias Loddenkemper, Lily Wong-Kisiel, Friedrich M Baumeister, Walid Fazeli, Pasquale Striano, Robertino Dilena, Elena Fontana, Federico Zara, Gerhard Kurlemann, Joerg Klepper, Jess G Thoene, Daniel H Arndt, Nicolas Deconinck, Thomas Schmitt-Mechelke, Oliver Maier, Hiltrud Muhle, Beverly Wical, Claudio Finetti, Reinhard Brückner, Joachim Pietz, Günther Golla, Dinesh Jillella, Karen M Linnet, Perrine Charles, Ute Moog, Eve Õiglane-Shlik, John F Mantovani, Kristen Park, Marie Deprez, Damien Lederer, Sandrine Mary, Emmanuel Scalais, Laila Selim, Rudy Van Coster, Lieven Lagae, Marina Nikanorova, Helle Hjalgrim, G Christoph Korenke, Marina Trivisano, Nicola Specchio, Berten Ceulemans, Thomas Dorn, Katherine L Helbig, Katia Hardies, Hannah Stamberger, Peter de Jonghe, Sarah Weckhuysen, Johannes R Lemke, Ingeborg Krägeloh-Mann, Ingo Helbig, Gerhard Kluger, Holger Lerche, and Rikke S Møller. 2017. “Genetic and Phenotypic Heterogeneity Suggest Therapeutic Implications in SCN2A-related Disorders.” Brain 140 (5): 1316–1336.
Vancouver
1.
Wolff M, Johannesen KM, Hedrich UB, Masnada S, Rubboli G, Gardella E, et al. Genetic and phenotypic heterogeneity suggest therapeutic implications in SCN2A-related disorders. BRAIN. 2017;140(5):1316–36.
IEEE
[1]
M. Wolff et al., “Genetic and phenotypic heterogeneity suggest therapeutic implications in SCN2A-related disorders,” BRAIN, vol. 140, no. 5, pp. 1316–1336, 2017.
@article{8525063,
  abstract     = {Mutations in SCN2A, a gene encoding the voltage-gated sodium channel Na(v)1.2, 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 (53 months of age) occur almost as often as those with an early infantile onset (53 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 (53 months), whereas other antiepileptic drugs were less effective. In contrast, sodium channel blockers were rarely effective in epilepsies with later onset (53 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.},
  author       = {Wolff, Markus and Johannesen, Katrine M and Hedrich, Ulrike BS and Masnada, Silvia and Rubboli, Guido and Gardella, Elena and Lesca, Gaetan and Ville, Dorothée and Milh, Mathieu and Villard, Laurent and Afenjar, Alexandra and Chantot-Bastaraud, Sandra and Mignot, Cyril and Lardennois, Caroline and Nava, Caroline and Schwarz, Niklas and Gérard, Marion and Perrin, Laurence and Doummar, Diane and Auvin, Stéphane and Miranda, Maria J and Hempel, Maja and Brilstra, Eva and Knoers, Nine and Verbeek, Nienke and van Kempen, Marjan and Braun, Kees P and Mancini, Grazia and Biskup, Saskia and Hörtnagel, Konstanze and Döcker, Miriam and Bast, Thomas and Loddenkemper, Tobias and Wong-Kisiel, Lily and Baumeister, Friedrich M and Fazeli, Walid and Striano, Pasquale and Dilena, Robertino and Fontana, Elena and Zara, Federico and Kurlemann, Gerhard and Klepper, Joerg and Thoene, Jess G and Arndt, Daniel H and Deconinck, Nicolas and Schmitt-Mechelke, Thomas and Maier, Oliver and Muhle, Hiltrud and Wical, Beverly and Finetti, Claudio and Brückner, Reinhard and Pietz, Joachim and Golla, Günther and Jillella, Dinesh and Linnet, Karen M and Charles, Perrine and Moog, Ute and Õiglane-Shlik, Eve and Mantovani, John F and Park, Kristen and Deprez, Marie and Lederer, Damien and Mary, Sandrine and Scalais, Emmanuel and Selim, Laila and Van Coster, Rudy and Lagae, Lieven and Nikanorova, Marina and Hjalgrim, Helle and Korenke, G Christoph and Trivisano, Marina and Specchio, Nicola and Ceulemans, Berten and Dorn, Thomas and Helbig, Katherine L and Hardies, Katia and Stamberger, Hannah and de Jonghe, Peter and Weckhuysen, Sarah and Lemke, Johannes R and Krägeloh-Mann, Ingeborg and Helbig, Ingo and Kluger, Gerhard and Lerche, Holger and Møller, Rikke S},
  issn         = {0006-8950},
  journal      = {BRAIN},
  keywords     = {SCN2A,epilepsy,epilepsy genetics,treatment response,sodium channel blockers,NEONATAL-INFANTILE SEIZURES,DE-NOVO MUTATIONS,AUTISM SPECTRUM DISORDER,MIGRATING FOCAL SEIZURES,ONSET EPISODIC ATAXIA,SODIUM-CHANNEL,SCN2A MUTATION,EPILEPTIC ENCEPHALOPATHY,INTELLECTUAL DISABILITY,MISSENSE MUTATION},
  language     = {eng},
  number       = {5},
  pages        = {1316--1336},
  title        = {Genetic and phenotypic heterogeneity suggest therapeutic implications in SCN2A-related disorders},
  url          = {http://dx.doi.org/10.1093/brain/awx054},
  volume       = {140},
  year         = {2017},
}

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