SYNGAP1 encephalopathy: A distinctive generalized developmental and epileptic encephalopathy

Danique R.M. Vlaskamp, Benjamin J. Shaw, Rosemary Burgess, Davide Mei, Martino Montomoli, Han Xie, Candace T. Myers, Mark F. Bennett, Wenshu XiangWei, Danielle Williams, Saskia M. Maas, Alice S. Brooks, Grazia M.S. Mancini, Ingrid M.B.H. van de Laar, Johanna M. van Hagen, Tyson L. Ware, Richard I. Webster, Stephen Malone, Samuel F. Berkovic, Renate M. KalninsFederico Sicca, G. Christoph Korenke, Conny M.A. van Ravenswaaij-Arts, Michael S. Hildebrand, Heather C. Mefford, Yuwu Jiang, Renzo Guerrini, Ingrid E. Scheffer

Research output: Contribution to journalArticle

5 Citations (Scopus)

Abstract

OBJECTIVE: To delineate the epileptology, a key part of the SYNGAP1 phenotypic spectrum, in a large patient cohort. METHODS: Patients were recruited via investigators' practices or social media. We included patients with (likely) pathogenic SYNGAP1 variants or chromosome 6p21.32 microdeletions incorporating SYNGAP1. We analyzed patients' phenotypes using a standardized epilepsy questionnaire, medical records, EEG, MRI, and seizure videos. RESULTS: We included 57 patients (53% male, median age 8 years) with SYNGAP1 mutations (n = 53) or microdeletions (n = 4). Of the 57 patients, 56 had epilepsy: generalized in 55, with focal seizures in 7 and infantile spasms in 1. Median seizure onset age was 2 years. A novel type of drop attack was identified comprising eyelid myoclonia evolving to a myoclonic-atonic (n = 5) or atonic (n = 8) seizure. Seizure types included eyelid myoclonia with absences (65%), myoclonic seizures (34%), atypical (20%) and typical (18%) absences, and atonic seizures (14%), triggered by eating in 25%. Developmental delay preceded seizure onset in 54 of 56 (96%) patients for whom early developmental history was available. Developmental plateauing or regression occurred with seizures in 56 in the context of a developmental and epileptic encephalopathy (DEE). Fifty-five of 57 patients had intellectual disability, which was moderate to severe in 50. Other common features included behavioral problems (73%); high pain threshold (72%); eating problems, including oral aversion (68%); hypotonia (67%); sleeping problems (62%); autism spectrum disorder (54%); and ataxia or gait abnormalities (51%). CONCLUSIONS: SYNGAP1 mutations cause a generalized DEE with a distinctive syndrome combining epilepsy with eyelid myoclonia with absences and myoclonic-atonic seizures, as well as a predilection to seizures triggered by eating.

Original languageEnglish
Pages (from-to)e96-e107
JournalNeurology
Volume92
Issue number2
DOIs
Publication statusPublished - Dec 20 2018

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Brain Diseases
Seizures
Eyelids
Absence Epilepsy
Eating
Epilepsy
Gait Ataxia
Social Media
Infantile Spasms
Generalized Epilepsy
Mutation
Muscle Hypotonia
Pain Threshold
Syncope
Age of Onset
Intellectual Disability
Medical Records
Electroencephalography
Chromosomes
Research Personnel

ASJC Scopus subject areas

  • Clinical Neurology

Cite this

Vlaskamp, D. R. M., Shaw, B. J., Burgess, R., Mei, D., Montomoli, M., Xie, H., ... Scheffer, I. E. (2018). SYNGAP1 encephalopathy: A distinctive generalized developmental and epileptic encephalopathy. Neurology, 92(2), e96-e107. https://doi.org/10.1212/WNL.0000000000006729

SYNGAP1 encephalopathy : A distinctive generalized developmental and epileptic encephalopathy. / Vlaskamp, Danique R.M.; Shaw, Benjamin J.; Burgess, Rosemary; Mei, Davide; Montomoli, Martino; Xie, Han; Myers, Candace T.; Bennett, Mark F.; XiangWei, Wenshu; Williams, Danielle; Maas, Saskia M.; Brooks, Alice S.; Mancini, Grazia M.S.; van de Laar, Ingrid M.B.H.; van Hagen, Johanna M.; Ware, Tyson L.; Webster, Richard I.; Malone, Stephen; Berkovic, Samuel F.; Kalnins, Renate M.; Sicca, Federico; Korenke, G. Christoph; van Ravenswaaij-Arts, Conny M.A.; Hildebrand, Michael S.; Mefford, Heather C.; Jiang, Yuwu; Guerrini, Renzo; Scheffer, Ingrid E.

In: Neurology, Vol. 92, No. 2, 20.12.2018, p. e96-e107.

Research output: Contribution to journalArticle

Vlaskamp, DRM, Shaw, BJ, Burgess, R, Mei, D, Montomoli, M, Xie, H, Myers, CT, Bennett, MF, XiangWei, W, Williams, D, Maas, SM, Brooks, AS, Mancini, GMS, van de Laar, IMBH, van Hagen, JM, Ware, TL, Webster, RI, Malone, S, Berkovic, SF, Kalnins, RM, Sicca, F, Korenke, GC, van Ravenswaaij-Arts, CMA, Hildebrand, MS, Mefford, HC, Jiang, Y, Guerrini, R & Scheffer, IE 2018, 'SYNGAP1 encephalopathy: A distinctive generalized developmental and epileptic encephalopathy', Neurology, vol. 92, no. 2, pp. e96-e107. https://doi.org/10.1212/WNL.0000000000006729
Vlaskamp DRM, Shaw BJ, Burgess R, Mei D, Montomoli M, Xie H et al. SYNGAP1 encephalopathy: A distinctive generalized developmental and epileptic encephalopathy. Neurology. 2018 Dec 20;92(2):e96-e107. https://doi.org/10.1212/WNL.0000000000006729
Vlaskamp, Danique R.M. ; Shaw, Benjamin J. ; Burgess, Rosemary ; Mei, Davide ; Montomoli, Martino ; Xie, Han ; Myers, Candace T. ; Bennett, Mark F. ; XiangWei, Wenshu ; Williams, Danielle ; Maas, Saskia M. ; Brooks, Alice S. ; Mancini, Grazia M.S. ; van de Laar, Ingrid M.B.H. ; van Hagen, Johanna M. ; Ware, Tyson L. ; Webster, Richard I. ; Malone, Stephen ; Berkovic, Samuel F. ; Kalnins, Renate M. ; Sicca, Federico ; Korenke, G. Christoph ; van Ravenswaaij-Arts, Conny M.A. ; Hildebrand, Michael S. ; Mefford, Heather C. ; Jiang, Yuwu ; Guerrini, Renzo ; Scheffer, Ingrid E. / SYNGAP1 encephalopathy : A distinctive generalized developmental and epileptic encephalopathy. In: Neurology. 2018 ; Vol. 92, No. 2. pp. e96-e107.
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abstract = "OBJECTIVE: To delineate the epileptology, a key part of the SYNGAP1 phenotypic spectrum, in a large patient cohort. METHODS: Patients were recruited via investigators' practices or social media. We included patients with (likely) pathogenic SYNGAP1 variants or chromosome 6p21.32 microdeletions incorporating SYNGAP1. We analyzed patients' phenotypes using a standardized epilepsy questionnaire, medical records, EEG, MRI, and seizure videos. RESULTS: We included 57 patients (53{\%} male, median age 8 years) with SYNGAP1 mutations (n = 53) or microdeletions (n = 4). Of the 57 patients, 56 had epilepsy: generalized in 55, with focal seizures in 7 and infantile spasms in 1. Median seizure onset age was 2 years. A novel type of drop attack was identified comprising eyelid myoclonia evolving to a myoclonic-atonic (n = 5) or atonic (n = 8) seizure. Seizure types included eyelid myoclonia with absences (65{\%}), myoclonic seizures (34{\%}), atypical (20{\%}) and typical (18{\%}) absences, and atonic seizures (14{\%}), triggered by eating in 25{\%}. Developmental delay preceded seizure onset in 54 of 56 (96{\%}) patients for whom early developmental history was available. Developmental plateauing or regression occurred with seizures in 56 in the context of a developmental and epileptic encephalopathy (DEE). Fifty-five of 57 patients had intellectual disability, which was moderate to severe in 50. Other common features included behavioral problems (73{\%}); high pain threshold (72{\%}); eating problems, including oral aversion (68{\%}); hypotonia (67{\%}); sleeping problems (62{\%}); autism spectrum disorder (54{\%}); and ataxia or gait abnormalities (51{\%}). CONCLUSIONS: SYNGAP1 mutations cause a generalized DEE with a distinctive syndrome combining epilepsy with eyelid myoclonia with absences and myoclonic-atonic seizures, as well as a predilection to seizures triggered by eating.",
author = "Vlaskamp, {Danique R.M.} and Shaw, {Benjamin J.} and Rosemary Burgess and Davide Mei and Martino Montomoli and Han Xie and Myers, {Candace T.} and Bennett, {Mark F.} and Wenshu XiangWei and Danielle Williams and Maas, {Saskia M.} and Brooks, {Alice S.} and Mancini, {Grazia M.S.} and {van de Laar}, {Ingrid M.B.H.} and {van Hagen}, {Johanna M.} and Ware, {Tyson L.} and Webster, {Richard I.} and Stephen Malone and Berkovic, {Samuel F.} and Kalnins, {Renate M.} and Federico Sicca and Korenke, {G. Christoph} and {van Ravenswaaij-Arts}, {Conny M.A.} and Hildebrand, {Michael S.} and Mefford, {Heather C.} and Yuwu Jiang and Renzo Guerrini and Scheffer, {Ingrid E.}",
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T1 - SYNGAP1 encephalopathy

T2 - A distinctive generalized developmental and epileptic encephalopathy

AU - Vlaskamp, Danique R.M.

AU - Shaw, Benjamin J.

AU - Burgess, Rosemary

AU - Mei, Davide

AU - Montomoli, Martino

AU - Xie, Han

AU - Myers, Candace T.

AU - Bennett, Mark F.

AU - XiangWei, Wenshu

AU - Williams, Danielle

AU - Maas, Saskia M.

AU - Brooks, Alice S.

AU - Mancini, Grazia M.S.

AU - van de Laar, Ingrid M.B.H.

AU - van Hagen, Johanna M.

AU - Ware, Tyson L.

AU - Webster, Richard I.

AU - Malone, Stephen

AU - Berkovic, Samuel F.

AU - Kalnins, Renate M.

AU - Sicca, Federico

AU - Korenke, G. Christoph

AU - van Ravenswaaij-Arts, Conny M.A.

AU - Hildebrand, Michael S.

AU - Mefford, Heather C.

AU - Jiang, Yuwu

AU - Guerrini, Renzo

AU - Scheffer, Ingrid E.

PY - 2018/12/20

Y1 - 2018/12/20

N2 - OBJECTIVE: To delineate the epileptology, a key part of the SYNGAP1 phenotypic spectrum, in a large patient cohort. METHODS: Patients were recruited via investigators' practices or social media. We included patients with (likely) pathogenic SYNGAP1 variants or chromosome 6p21.32 microdeletions incorporating SYNGAP1. We analyzed patients' phenotypes using a standardized epilepsy questionnaire, medical records, EEG, MRI, and seizure videos. RESULTS: We included 57 patients (53% male, median age 8 years) with SYNGAP1 mutations (n = 53) or microdeletions (n = 4). Of the 57 patients, 56 had epilepsy: generalized in 55, with focal seizures in 7 and infantile spasms in 1. Median seizure onset age was 2 years. A novel type of drop attack was identified comprising eyelid myoclonia evolving to a myoclonic-atonic (n = 5) or atonic (n = 8) seizure. Seizure types included eyelid myoclonia with absences (65%), myoclonic seizures (34%), atypical (20%) and typical (18%) absences, and atonic seizures (14%), triggered by eating in 25%. Developmental delay preceded seizure onset in 54 of 56 (96%) patients for whom early developmental history was available. Developmental plateauing or regression occurred with seizures in 56 in the context of a developmental and epileptic encephalopathy (DEE). Fifty-five of 57 patients had intellectual disability, which was moderate to severe in 50. Other common features included behavioral problems (73%); high pain threshold (72%); eating problems, including oral aversion (68%); hypotonia (67%); sleeping problems (62%); autism spectrum disorder (54%); and ataxia or gait abnormalities (51%). CONCLUSIONS: SYNGAP1 mutations cause a generalized DEE with a distinctive syndrome combining epilepsy with eyelid myoclonia with absences and myoclonic-atonic seizures, as well as a predilection to seizures triggered by eating.

AB - OBJECTIVE: To delineate the epileptology, a key part of the SYNGAP1 phenotypic spectrum, in a large patient cohort. METHODS: Patients were recruited via investigators' practices or social media. We included patients with (likely) pathogenic SYNGAP1 variants or chromosome 6p21.32 microdeletions incorporating SYNGAP1. We analyzed patients' phenotypes using a standardized epilepsy questionnaire, medical records, EEG, MRI, and seizure videos. RESULTS: We included 57 patients (53% male, median age 8 years) with SYNGAP1 mutations (n = 53) or microdeletions (n = 4). Of the 57 patients, 56 had epilepsy: generalized in 55, with focal seizures in 7 and infantile spasms in 1. Median seizure onset age was 2 years. A novel type of drop attack was identified comprising eyelid myoclonia evolving to a myoclonic-atonic (n = 5) or atonic (n = 8) seizure. Seizure types included eyelid myoclonia with absences (65%), myoclonic seizures (34%), atypical (20%) and typical (18%) absences, and atonic seizures (14%), triggered by eating in 25%. Developmental delay preceded seizure onset in 54 of 56 (96%) patients for whom early developmental history was available. Developmental plateauing or regression occurred with seizures in 56 in the context of a developmental and epileptic encephalopathy (DEE). Fifty-five of 57 patients had intellectual disability, which was moderate to severe in 50. Other common features included behavioral problems (73%); high pain threshold (72%); eating problems, including oral aversion (68%); hypotonia (67%); sleeping problems (62%); autism spectrum disorder (54%); and ataxia or gait abnormalities (51%). CONCLUSIONS: SYNGAP1 mutations cause a generalized DEE with a distinctive syndrome combining epilepsy with eyelid myoclonia with absences and myoclonic-atonic seizures, as well as a predilection to seizures triggered by eating.

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