The epilepsy phenotypic spectrum associated with a recurrent CUX2 variant

Nicolas Chatron, Rikke S. Møller, Neena L. Champaigne, Amy L. Schneider, Alma Kuechler, Audrey Labalme, Thomas Simonet, Lauren Baggett, Claire Bardel, Erik Jan Kamsteeg, Rolph Pfundt, Corrado Romano, Johan Aronsson, Antonino Alberti, Mirella Vinci, Maria J. Miranda, Amy Lacroix, Dragan Marjanovic, Vincent des Portes, Patrick EderyDagmar Wieczorek, Elena Gardella, Ingrid E. Scheffer, Heather Mefford, Damien Sanlaville, Gemma L. Carvill, Gaetan Lesca

Research output: Contribution to journalArticle

Abstract

Objective: Cut homeodomain transcription factor CUX2 plays an important role in dendrite branching, spine development, and synapse formation in layer II to III neurons of the cerebral cortex. We identify a recurrent de novo CUX2 p.Glu590Lys as a novel genetic cause for developmental and epileptic encephalopathy (DEE). Methods: The de novo p.Glu590Lys variant was identified by whole-exome sequencing (n = 5) or targeted gene panel (n = 4). We performed electroclinical and imaging phenotyping on all patients. Results: The cohort comprised 7 males and 2 females. Mean age at study was 13 years (0.5–21.0). Median age at seizure onset was 6 months (2 months to 9 years). Seizure types at onset were myoclonic, atypical absence with myoclonic components, and focal seizures. Epileptiform activity on electroencephalogram was seen in 8 cases: generalized polyspike-wave (6) or multifocal discharges (2). Seizures were drug resistant in 7 or controlled with valproate (2). Six patients had a DEE: myoclonic DEE (3), Lennox-Gastaut syndrome (2), and West syndrome (1). Two had a static encephalopathy and genetic generalized epilepsy, including absence epilepsy in 1. One infant had multifocal epilepsy. Eight had severe cognitive impairment, with autistic features in 6. The p.Glu590Lys variant affects a highly conserved glutamine residue in the CUT domain predicted to interfere with CUX2 binding to DNA targets during neuronal development. Interpretation: Patients with CUX2 p.Glu590Lys display a distinctive phenotypic spectrum, which is predominantly generalized epilepsy, with infantile-onset myoclonic DEE at the severe end and generalized epilepsy with severe static developmental encephalopathy at the milder end of the spectrum. Ann Neurol 2018;83:926–934.

Original languageEnglish
Pages (from-to)926-934
Number of pages9
JournalAnnals of Neurology
Volume83
Issue number5
DOIs
Publication statusPublished - May 1 2018

ASJC Scopus subject areas

  • Neurology
  • Clinical Neurology

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    Chatron, N., Møller, R. S., Champaigne, N. L., Schneider, A. L., Kuechler, A., Labalme, A., Simonet, T., Baggett, L., Bardel, C., Kamsteeg, E. J., Pfundt, R., Romano, C., Aronsson, J., Alberti, A., Vinci, M., Miranda, M. J., Lacroix, A., Marjanovic, D., des Portes, V., ... Lesca, G. (2018). The epilepsy phenotypic spectrum associated with a recurrent CUX2 variant. Annals of Neurology, 83(5), 926-934. https://doi.org/10.1002/ana.25222