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The epilepsy phenotypic spectrum associated with a recurrent CUX2 variant

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  • 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 Edery
  • Dagmar Wieczorek
  • Elena Gardella
  • Ingrid E Scheffer
  • Heather Mefford
  • Damien Sanlaville
  • Gemma L Carvill
  • Gaetan Lesca
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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.

OriginalsprogEngelsk
TidsskriftAnnals of Neurology
Vol/bind83
Udgave nummer5
Sider (fra-til)926-934
Antal sider9
ISSN0364-5134
DOI
StatusUdgivet - maj 2018

ID: 56219569