Phenotypic spectrum of GABRA1

Katrine Marie Johannesen, Carla Marini, Siona Pfeffer, Rikke S. Møller, Thomas Dorn, Christina Niturad, E. Gardella, Yvonne Weber, Marianne Søndergård, Helle Hjalgrim, Marina Nikanorova, Felicitas Becker, Line H G Larsen, Hans Atli Dahl, Oliver Maier, Davide Mei, Saskia Biskup, Karl Martin Klein, Philipp S. Reif, Felix RosenowAbdallah F. Elias, Cindy Hudson, Katherine L. Helbig, Susanne Schubert-Bast, Maria R. Scordo, Dana Craiu, Tania Djémié, Dorota Hoffman-Zacharska, H. S. Caglayan, Ingo Helbig, Jose Serratosa, Pasquale Striano, Peter De Jonghe, Sarah Weckhuysen, Arvid Suls, Kai Muru, I. Talvik, T. Talvik, H. Muhle, Ingo Borggraefe, I. Rost, Renzo Guerrini, Holger Lerche, Johannes R. Lemke, Guido Rubboli, Snezana Maljevic

Research output: Contribution to journalArticle

Abstract

Objective: To delineate phenotypic heterogeneity, we describe the clinical features of a cohort of patients with GABRA1 gene mutations. Methods: Patients with GABRA1 mutations were ascertained through an international collaboration. Clinical, EEG, and genetic data were collected. Functional analysis of 4 selected mutations was performed using the Xenopus laevis oocyte expression system. Results: The study included 16 novel probands and 3 additional family members with a disease-causing mutation in the GABRA1 gene. The phenotypic spectrum varied from unspecified epilepsy (1), juvenile myoclonic epilepsy (2), photosensitive idiopathic generalized epilepsy (1), and generalized epilepsy with febrile seizures plus (1) to severe epileptic encephalopathies (11). In the epileptic encephalopathy group, the patients had seizures beginning between the first day of life and 15 months, with a mean of 7 months. Predominant seizure types in all patients were tonic-clonic in 9 participants (56%) and myoclonic seizures in 5 (31%). EEG showed a generalized photoparoxysmal response in 6 patients (37%). Four selected mutations studied functionally revealed a loss of function, without a clear genotype-phenotype correlation. Conclusions: GABRA1 mutations make a significant contribution to the genetic etiology of both benign and severe epilepsy syndromes. Myoclonic and tonic-clonic seizures with pathologic response to photic stimulation are common and shared features in both mild and severe phenotypes.

Original languageEnglish
Pages (from-to)1140-1151
Number of pages12
JournalNeurology
Volume87
Issue number11
DOIs
Publication statusPublished - Sep 13 2016

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Mutation
Seizures
Brain Diseases
Electroencephalography
Epilepsy
Juvenile Myoclonic Epilepsy
Photic Stimulation
Xenopus laevis
Genetic Association Studies
Genes
Oocytes
Phenotype

ASJC Scopus subject areas

  • Clinical Neurology

Cite this

Johannesen, K. M., Marini, C., Pfeffer, S., Møller, R. S., Dorn, T., Niturad, C., ... Maljevic, S. (2016). Phenotypic spectrum of GABRA1. Neurology, 87(11), 1140-1151. https://doi.org/10.1212/WNL.0000000000003087

Phenotypic spectrum of GABRA1. / Johannesen, Katrine Marie; Marini, Carla; Pfeffer, Siona; Møller, Rikke S.; Dorn, Thomas; Niturad, Christina; Gardella, E.; Weber, Yvonne; Søndergård, Marianne; Hjalgrim, Helle; Nikanorova, Marina; Becker, Felicitas; Larsen, Line H G; Dahl, Hans Atli; Maier, Oliver; Mei, Davide; Biskup, Saskia; Klein, Karl Martin; Reif, Philipp S.; Rosenow, Felix; Elias, Abdallah F.; Hudson, Cindy; Helbig, Katherine L.; Schubert-Bast, Susanne; Scordo, Maria R.; Craiu, Dana; Djémié, Tania; Hoffman-Zacharska, Dorota; Caglayan, H. S.; Helbig, Ingo; Serratosa, Jose; Striano, Pasquale; De Jonghe, Peter; Weckhuysen, Sarah; Suls, Arvid; Muru, Kai; Talvik, I.; Talvik, T.; Muhle, H.; Borggraefe, Ingo; Rost, I.; Guerrini, Renzo; Lerche, Holger; Lemke, Johannes R.; Rubboli, Guido; Maljevic, Snezana.

In: Neurology, Vol. 87, No. 11, 13.09.2016, p. 1140-1151.

Research output: Contribution to journalArticle

Johannesen, KM, Marini, C, Pfeffer, S, Møller, RS, Dorn, T, Niturad, C, Gardella, E, Weber, Y, Søndergård, M, Hjalgrim, H, Nikanorova, M, Becker, F, Larsen, LHG, Dahl, HA, Maier, O, Mei, D, Biskup, S, Klein, KM, Reif, PS, Rosenow, F, Elias, AF, Hudson, C, Helbig, KL, Schubert-Bast, S, Scordo, MR, Craiu, D, Djémié, T, Hoffman-Zacharska, D, Caglayan, HS, Helbig, I, Serratosa, J, Striano, P, De Jonghe, P, Weckhuysen, S, Suls, A, Muru, K, Talvik, I, Talvik, T, Muhle, H, Borggraefe, I, Rost, I, Guerrini, R, Lerche, H, Lemke, JR, Rubboli, G & Maljevic, S 2016, 'Phenotypic spectrum of GABRA1', Neurology, vol. 87, no. 11, pp. 1140-1151. https://doi.org/10.1212/WNL.0000000000003087
Johannesen KM, Marini C, Pfeffer S, Møller RS, Dorn T, Niturad C et al. Phenotypic spectrum of GABRA1. Neurology. 2016 Sep 13;87(11):1140-1151. https://doi.org/10.1212/WNL.0000000000003087
Johannesen, Katrine Marie ; Marini, Carla ; Pfeffer, Siona ; Møller, Rikke S. ; Dorn, Thomas ; Niturad, Christina ; Gardella, E. ; Weber, Yvonne ; Søndergård, Marianne ; Hjalgrim, Helle ; Nikanorova, Marina ; Becker, Felicitas ; Larsen, Line H G ; Dahl, Hans Atli ; Maier, Oliver ; Mei, Davide ; Biskup, Saskia ; Klein, Karl Martin ; Reif, Philipp S. ; Rosenow, Felix ; Elias, Abdallah F. ; Hudson, Cindy ; Helbig, Katherine L. ; Schubert-Bast, Susanne ; Scordo, Maria R. ; Craiu, Dana ; Djémié, Tania ; Hoffman-Zacharska, Dorota ; Caglayan, H. S. ; Helbig, Ingo ; Serratosa, Jose ; Striano, Pasquale ; De Jonghe, Peter ; Weckhuysen, Sarah ; Suls, Arvid ; Muru, Kai ; Talvik, I. ; Talvik, T. ; Muhle, H. ; Borggraefe, Ingo ; Rost, I. ; Guerrini, Renzo ; Lerche, Holger ; Lemke, Johannes R. ; Rubboli, Guido ; Maljevic, Snezana. / Phenotypic spectrum of GABRA1. In: Neurology. 2016 ; Vol. 87, No. 11. pp. 1140-1151.
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abstract = "Objective: To delineate phenotypic heterogeneity, we describe the clinical features of a cohort of patients with GABRA1 gene mutations. Methods: Patients with GABRA1 mutations were ascertained through an international collaboration. Clinical, EEG, and genetic data were collected. Functional analysis of 4 selected mutations was performed using the Xenopus laevis oocyte expression system. Results: The study included 16 novel probands and 3 additional family members with a disease-causing mutation in the GABRA1 gene. The phenotypic spectrum varied from unspecified epilepsy (1), juvenile myoclonic epilepsy (2), photosensitive idiopathic generalized epilepsy (1), and generalized epilepsy with febrile seizures plus (1) to severe epileptic encephalopathies (11). In the epileptic encephalopathy group, the patients had seizures beginning between the first day of life and 15 months, with a mean of 7 months. Predominant seizure types in all patients were tonic-clonic in 9 participants (56{\%}) and myoclonic seizures in 5 (31{\%}). EEG showed a generalized photoparoxysmal response in 6 patients (37{\%}). Four selected mutations studied functionally revealed a loss of function, without a clear genotype-phenotype correlation. Conclusions: GABRA1 mutations make a significant contribution to the genetic etiology of both benign and severe epilepsy syndromes. Myoclonic and tonic-clonic seizures with pathologic response to photic stimulation are common and shared features in both mild and severe phenotypes.",
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T1 - Phenotypic spectrum of GABRA1

AU - Johannesen, Katrine Marie

AU - Marini, Carla

AU - Pfeffer, Siona

AU - Møller, Rikke S.

AU - Dorn, Thomas

AU - Niturad, Christina

AU - Gardella, E.

AU - Weber, Yvonne

AU - Søndergård, Marianne

AU - Hjalgrim, Helle

AU - Nikanorova, Marina

AU - Becker, Felicitas

AU - Larsen, Line H G

AU - Dahl, Hans Atli

AU - Maier, Oliver

AU - Mei, Davide

AU - Biskup, Saskia

AU - Klein, Karl Martin

AU - Reif, Philipp S.

AU - Rosenow, Felix

AU - Elias, Abdallah F.

AU - Hudson, Cindy

AU - Helbig, Katherine L.

AU - Schubert-Bast, Susanne

AU - Scordo, Maria R.

AU - Craiu, Dana

AU - Djémié, Tania

AU - Hoffman-Zacharska, Dorota

AU - Caglayan, H. S.

AU - Helbig, Ingo

AU - Serratosa, Jose

AU - Striano, Pasquale

AU - De Jonghe, Peter

AU - Weckhuysen, Sarah

AU - Suls, Arvid

AU - Muru, Kai

AU - Talvik, I.

AU - Talvik, T.

AU - Muhle, H.

AU - Borggraefe, Ingo

AU - Rost, I.

AU - Guerrini, Renzo

AU - Lerche, Holger

AU - Lemke, Johannes R.

AU - Rubboli, Guido

AU - Maljevic, Snezana

PY - 2016/9/13

Y1 - 2016/9/13

N2 - Objective: To delineate phenotypic heterogeneity, we describe the clinical features of a cohort of patients with GABRA1 gene mutations. Methods: Patients with GABRA1 mutations were ascertained through an international collaboration. Clinical, EEG, and genetic data were collected. Functional analysis of 4 selected mutations was performed using the Xenopus laevis oocyte expression system. Results: The study included 16 novel probands and 3 additional family members with a disease-causing mutation in the GABRA1 gene. The phenotypic spectrum varied from unspecified epilepsy (1), juvenile myoclonic epilepsy (2), photosensitive idiopathic generalized epilepsy (1), and generalized epilepsy with febrile seizures plus (1) to severe epileptic encephalopathies (11). In the epileptic encephalopathy group, the patients had seizures beginning between the first day of life and 15 months, with a mean of 7 months. Predominant seizure types in all patients were tonic-clonic in 9 participants (56%) and myoclonic seizures in 5 (31%). EEG showed a generalized photoparoxysmal response in 6 patients (37%). Four selected mutations studied functionally revealed a loss of function, without a clear genotype-phenotype correlation. Conclusions: GABRA1 mutations make a significant contribution to the genetic etiology of both benign and severe epilepsy syndromes. Myoclonic and tonic-clonic seizures with pathologic response to photic stimulation are common and shared features in both mild and severe phenotypes.

AB - Objective: To delineate phenotypic heterogeneity, we describe the clinical features of a cohort of patients with GABRA1 gene mutations. Methods: Patients with GABRA1 mutations were ascertained through an international collaboration. Clinical, EEG, and genetic data were collected. Functional analysis of 4 selected mutations was performed using the Xenopus laevis oocyte expression system. Results: The study included 16 novel probands and 3 additional family members with a disease-causing mutation in the GABRA1 gene. The phenotypic spectrum varied from unspecified epilepsy (1), juvenile myoclonic epilepsy (2), photosensitive idiopathic generalized epilepsy (1), and generalized epilepsy with febrile seizures plus (1) to severe epileptic encephalopathies (11). In the epileptic encephalopathy group, the patients had seizures beginning between the first day of life and 15 months, with a mean of 7 months. Predominant seizure types in all patients were tonic-clonic in 9 participants (56%) and myoclonic seizures in 5 (31%). EEG showed a generalized photoparoxysmal response in 6 patients (37%). Four selected mutations studied functionally revealed a loss of function, without a clear genotype-phenotype correlation. Conclusions: GABRA1 mutations make a significant contribution to the genetic etiology of both benign and severe epilepsy syndromes. Myoclonic and tonic-clonic seizures with pathologic response to photic stimulation are common and shared features in both mild and severe phenotypes.

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