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

doi:10.1002/ana.v83.5

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

Institut for Klinisk Medicin

4 Citationer (Scopus)

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.

Originalsprog	Engelsk
Tidsskrift	Annals of Neurology
Vol/bind	83
Udgave nummer	5
Sider (fra-til)	926-934
Antal sider	9
ISSN	0364-5134
DOI	https://doi.org/10.1002/ana.v83.5
Status	Udgivet - maj 2018

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10.1002/ana.v83.5

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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., 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.v83.5

Chatron, N, Møller, RS, Champaigne, NL, Schneider, AL, Kuechler, A, Labalme, A, Simonet, T, Baggett, L, Bardel, C, Kamsteeg, E, Pfundt, R, Romano, C, Aronsson, J, Alberti, A, Vinci, M, Miranda, MJ, Lacroix, A, Marjanovic, D, Des Portes, V, Edery, P, Wieczorek, D, Gardella, E, Scheffer, IE, Mefford, H, Sanlaville, D, Carvill, GL & Lesca, G 2018, 'The epilepsy phenotypic spectrum associated with a recurrent CUX2 variant', Annals of Neurology, bind 83, nr. 5, s. 926-934. https://doi.org/10.1002/ana.v83.5

@article{32da51fde5774304bcb6f5e2059f2268,

title = "The epilepsy phenotypic spectrum associated with a recurrent CUX2 variant",

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.",

author = "Nicolas Chatron and M{\o}ller, {Rikke S.} and Champaigne, {Neena L.} and Schneider, {Amy L.} and Alma Kuechler and Audrey Labalme and Thomas Simonet and Lauren Baggett and Claire Bardel and Erik-jan Kamsteeg and Rolph Pfundt and Corrado Romano and Johan Aronsson and Antonino Alberti and Mirella Vinci and Miranda, {Maria J.} and Amy Lacroix and Dragan Marjanovic and {Des Portes}, Vincent and Patrick Edery and Dagmar Wieczorek and Elena Gardella and Scheffer, {Ingrid E.} and Heather Mefford and Damien Sanlaville and Carvill, {Gemma L.} and Gaetan Lesca",

year = "2018",

month = may,

doi = "10.1002/ana.v83.5",

language = "English",

volume = "83",

pages = "926--934",

journal = "Annals of Neurology",

issn = "0364-5134",

publisher = "JohnWiley & Sons, Inc.",

number = "5",

}

TY - JOUR

T1 - The epilepsy phenotypic spectrum associated with a recurrent CUX2 variant

AU - Chatron, Nicolas

AU - Møller, Rikke S.

AU - Champaigne, Neena L.

AU - Schneider, Amy L.

AU - Kuechler, Alma

AU - Labalme, Audrey

AU - Simonet, Thomas

AU - Baggett, Lauren

AU - Bardel, Claire

AU - Kamsteeg, Erik-jan

AU - Pfundt, Rolph

AU - Romano, Corrado

AU - Aronsson, Johan

AU - Alberti, Antonino

AU - Vinci, Mirella

AU - Miranda, Maria J.

AU - Lacroix, Amy

AU - Marjanovic, Dragan

AU - Des Portes, Vincent

AU - Edery, Patrick

AU - Wieczorek, Dagmar

AU - Gardella, Elena

AU - Scheffer, Ingrid E.

AU - Mefford, Heather

AU - Sanlaville, Damien

AU - Carvill, Gemma L.

AU - Lesca, Gaetan

PY - 2018/5

Y1 - 2018/5

N2 - 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.

AB - 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.

U2 - 10.1002/ana.v83.5

DO - 10.1002/ana.v83.5

M3 - Journal article

SN - 0364-5134

VL - 83

SP - 926

EP - 934

JO - Annals of Neurology

JF - Annals of Neurology

IS - 5

ER -

The epilepsy phenotypic spectrum associated with a recurrent CUX2 variant

Abstract

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