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

Overview of attention for article published in Brain: A Journal of Neurology, April 2017
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  • In the top 5% of all research outputs scored by Altmetric
  • High Attention Score compared to outputs of the same age (94th percentile)
  • High Attention Score compared to outputs of the same age and source (90th percentile)

Mentioned by

news
4 news outlets
twitter
25 tweeters
facebook
1 Facebook page

Citations

dimensions_citation
188 Dimensions

Readers on

mendeley
207 Mendeley
citeulike
1 CiteULike
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Title
Genetic and phenotypic heterogeneity suggest therapeutic implications in SCN2A-related disorders
Published in
Brain: A Journal of Neurology, April 2017
DOI 10.1093/brain/awx054
Pubmed ID
Authors

Markus Wolff, Katrine M. Johannesen, Ulrike B. S. 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, Rikke S Møller

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.

Twitter Demographics

The data shown below were collected from the profiles of 25 tweeters who shared this research output. Click here to find out more about how the information was compiled.

Mendeley readers

The data shown below were compiled from readership statistics for 207 Mendeley readers of this research output. Click here to see the associated Mendeley record.

Geographical breakdown

Country Count As %
Germany 1 <1%
Luxembourg 1 <1%
Unknown 205 99%

Demographic breakdown

Readers by professional status Count As %
Researcher 44 21%
Student > Master 28 14%
Student > Ph. D. Student 25 12%
Professor 14 7%
Other 13 6%
Other 46 22%
Unknown 37 18%
Readers by discipline Count As %
Medicine and Dentistry 63 30%
Neuroscience 42 20%
Biochemistry, Genetics and Molecular Biology 17 8%
Agricultural and Biological Sciences 15 7%
Psychology 9 4%
Other 13 6%
Unknown 48 23%

Attention Score in Context

This research output has an Altmetric Attention Score of 44. This is our high-level measure of the quality and quantity of online attention that it has received. This Attention Score, as well as the ranking and number of research outputs shown below, was calculated when the research output was last mentioned on 03 June 2018.
All research outputs
#471,024
of 15,220,640 outputs
Outputs from Brain: A Journal of Neurology
#472
of 5,567 outputs
Outputs of similar age
#15,698
of 266,167 outputs
Outputs of similar age from Brain: A Journal of Neurology
#7
of 73 outputs
Altmetric has tracked 15,220,640 research outputs across all sources so far. Compared to these this one has done particularly well and is in the 96th percentile: it's in the top 5% of all research outputs ever tracked by Altmetric.
So far Altmetric has tracked 5,567 research outputs from this source. They typically receive a lot more attention than average, with a mean Attention Score of 18.7. This one has done particularly well, scoring higher than 91% of its peers.
Older research outputs will score higher simply because they've had more time to accumulate mentions. To account for age we can compare this Altmetric Attention Score to the 266,167 tracked outputs that were published within six weeks on either side of this one in any source. This one has done particularly well, scoring higher than 94% of its contemporaries.
We're also able to compare this research output to 73 others from the same source and published within six weeks on either side of this one. This one has done particularly well, scoring higher than 90% of its contemporaries.