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Bi-allelic GAD1 variants cause a neonatal onset syndromic developmental and epileptic encephalopathy.

Chatron, N; Becker, F; Morsy, H; Schmidts, M; Hardies, K; Tuysuz, B; Roselli, S; Najafi, M; Alkaya, DU; Ashrafzadeh, F; et al. Chatron, N; Becker, F; Morsy, H; Schmidts, M; Hardies, K; Tuysuz, B; Roselli, S; Najafi, M; Alkaya, DU; Ashrafzadeh, F; Nabil, A; Omar, T; Maroofian, R; Karimiani, EG; Hussien, H; Kok, F; Ramos, L; Gunes, N; Bilguvar, K; Labalme, A; Alix, E; Sanlaville, D; de Bellescize, J; Poulat, A-L; EuroEpinomics-RES consortium AR working group; Moslemi, A-R; Lerche, H; May, P; Lesca, G; Weckhuysen, S; Tajsharghi, H (2020) Bi-allelic GAD1 variants cause a neonatal onset syndromic developmental and epileptic encephalopathy. Brain, 143 (5). pp. 1447-1461. ISSN 1460-2156 https://doi.org/10.1093/brain/awaa085
SGUL Authors: Maroofian, Reza

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Abstract

Developmental and epileptic encephalopathies are a heterogeneous group of early-onset epilepsy syndromes dramatically impairing neurodevelopment. Modern genomic technologies have revealed a number of monogenic origins and opened the door to therapeutic hopes. Here we describe a new syndromic developmental and epileptic encephalopathy caused by bi-allelic loss-of-function variants in GAD1, as presented by 11 patients from six independent consanguineous families. Seizure onset occurred in the first 2 months of life in all patients. All 10 patients, from whom early disease history was available, presented with seizure onset in the first month of life, mainly consisting of epileptic spasms or myoclonic seizures. Early EEG showed suppression-burst or pattern of burst attenuation or hypsarrhythmia if only recorded in the post-neonatal period. Eight patients had joint contractures and/or pes equinovarus. Seven patients presented a cleft palate and two also had an omphalocele, reproducing the phenotype of the knockout Gad1-/- mouse model. Four patients died before 4 years of age. GAD1 encodes the glutamate decarboxylase enzyme GAD67, a critical actor of the γ-aminobutyric acid (GABA) metabolism as it catalyses the decarboxylation of glutamic acid to form GABA. Our findings evoke a novel syndrome related to GAD67 deficiency, characterized by the unique association of developmental and epileptic encephalopathies, cleft palate, joint contractures and/or omphalocele.

Item Type: Article
Additional Information: © The Author(s) (2020). Published by Oxford University Press on behalf of the Guarantors of Brain. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.
Keywords: GAD1, arthrogryposis, cleft palate, hypsarrhythmia, omphalocele, suppression-burst, Neurology & Neurosurgery, 11 Medical and Health Sciences, 17 Psychology and Cognitive Sciences
SGUL Research Institute / Research Centre: Academic Structure > Molecular and Clinical Sciences Research Institute (MCS)
Journal or Publication Title: Brain
ISSN: 1460-2156
Language: eng
Dates:
DateEvent
May 2020Published
13 April 2020Published Online
5 March 2020Accepted
Projects:
Project IDFunderFunder ID
608473Seventh Framework Programmehttp://dx.doi.org/10.13039/501100004963
FFB180053University of AntwerpUNSPECIFIED
1861419NUniversity of AntwerpUNSPECIFIED
716344European Research Councilhttp://dx.doi.org/10.13039/501100000781
UM1HG006504National Institutes of Healthhttp://dx.doi.org/10.13039/100000002
U24 HG008956National Institutes of Healthhttp://dx.doi.org/10.13039/100000002
PubMed ID: 32282878
Go to PubMed abstract
URI: http://openaccess.sgul.ac.uk/id/eprint/111879
Publisher's version: https://doi.org/10.1093/brain/awaa085

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