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Early-infantile onset epilepsy and developmental delay caused by bi-allelic GAD1 variants

Authors :
Neuray, C.
Maroofian, R.
Scala, M.
Sultan, T.
Pai, G. S.
Mojarrad, M.
Khashab, H. E.
Deholl, L.
Yue, W.
Alsaif, H. S.
Zanetti, M. N.
Bello, O.
Person, R.
Eslahi, A.
Khazaei, Z.
Feizabadi, M. H.
Efthymiou, S.
El-Bassyouni, H. T.
Soliman, D. R.
Tekes, S.
Ozer, L.
Baltaci, V.
Khan, S.
Beetz, C.
Amr, K. S.
Salpietro, V.
Jamshidi, Y.
Alkuraya, F. S.
Houlden, H.
Groppa, S.
Karashova, B. M.
Nachbauer, W.
Boesch, S.
Arning, L.
Timmann, D.
Cormand, B.
Perez-Duenas, B.
Synaps, Group
Di Rosa, G.
Aguennouz, M.
Goraya, J. S.
Mine, J.
Avdjieva, D.
Kathom, H.
Tincheva, R.
Banu, S.
Pineda-Marfa, M.
Veggiotti, P.
Ferrari, M. D.
Verrotti, A.
Marseglia, G.
Savasta, S.
Garcia-Silva, M.
Ruiz, A. M.
Garavaglia, B.
Borgione, E.
Portaro, S.
Sanchez, B. M.
Boles, R.
Papacostas, S.
Vikelis, M.
Papanicolaou, E. Z.
Dardiotis, E.
Maqbool, S.
Ibrahim, S.
Kirmani, S.
Rana, N. N.
Atawneh, O.
Koutsis, G.
Breza, M.
Mangano, S.
Scuderi, C.
Morello, G.
Stojkovic, T.
Zollo, M.
Heimer, G.
Dauvilliers, Y. A.
Striano, P.
Al-Khawaja, I.
Al-Mutairi, F.
Sherifa, H.
Neuray C.
Maroofian R.
Scala M.
Sultan T.
Pai G.S.
Mojarrad M.
Khashab H.E.
deHoll L.
Yue W.
Alsaif H.S.
Zanetti M.N.
Bello O.
Person R.
Eslahi A.
Khazaei Z.
Feizabadi M.H.
Efthymiou S.
El-Bassyouni H.T.
Soliman D.R.
Tekes S.
Ozer L.
Baltaci V.
Khan S.
Beetz C.
Amr K.S.
Salpietro V.
Jamshidi Y.
Alkuraya F.S.
Houlden H.
Mangano S.
Dicle Üniversitesi, Tıp Fakültesi, Temel Tıp Bilimleri Bölümü, Tıbbi Biyoloji Ana Bilim Dalı
Tekeş, Selahattin
University College of London [London] (UCL)
Paracelsus Medizinische Privatuniversität = Paracelsus Medical University (PMU)
University of Genoa (UNIGE)
IRCCS Istituto Giannina Gaslini [Genoa, Italy]
Children's Hospital [Lahore]
Institute of Child Health [Lahore]
Medical University of South Carolina [Charleston] (MUSC)
Mashhad University of Medical Sciences
Ain Shams University (ASU)
University of Oxford [Oxford]
GeneDx [Gaithersburg, MD, USA]
Khorasan Razavi Agricultural and Natural Resources Research and Education Center
National Research Centre [Cairo, Egypt]
Benha University (BU)
Dicle University
CENTOGENE AG
University of London [London]
King Faisal Specialist Hospital [Riyadh, Saudi Arabia] (Research Centre)
SYNaPS Study Group: Stanislav Groppa, Blagovesta Marinova Karashova, Wolfgang Nachbauer, Sylvia Boesch, Larissa Arning, Dagmar Timmann, Bru Cormand, Belen Pérez-Dueñas, Gabriella Di Rosa, Jatinder S Goraya, Tipu Sultan, Jun Mine, Daniela Avdjieva, Hadil Kathom, Radka Tincheva, Selina Banu, Mercedes Pineda-Marfa, Pierangelo Veggiotti, Michel D Ferrari, Alberto Verrotti, Giangluigi Marseglia, Salvatore Savasta, Mayte García-Silva, Alfons Macaya Ruiz, Barbara Garavaglia, Eugenia Borgione, Simona Portaro, Benigno Monteagudo Sanchez, Richard Boles, Savvas Papacostas, Michail Vikelis, Eleni Zamba Papanicolaou, Efthymios Dardiotis, Shazia Maqbool, Shahnaz Ibrahim, Salman Kirmani, Nuzhat Noureen Rana, Osama Atawneh, George Koutsis, Marianthi Breza, Salvatore Mangano, Carmela Scuderi, Eugenia Borgione, Giovanna Morello, Tanya Stojkovic, Massimi Zollo, Gali Heimer, Yves A Dauvilliers, Pasquale Striano, Issam Al-Khawaja, Fuad Al-Mutairi, Hamed Sherifa
Source :
Dipòsit Digital de la UB, Universidad de Barcelona, Brain, CONICET Digital (CONICET), Consejo Nacional de Investigaciones Científicas y Técnicas, instacron:CONICET, Brain-A Journal of Neurology, Brain-A Journal of Neurology, Oxford University Press (OUP), 2020, 143 (8), pp.2388-2397. ⟨10.1093/brain/awaa178⟩, Publons
Publication Year :
2020
Publisher :
NLM (Medline), 2020.

Abstract

Mice lacking GAD1 show neonatal mortality, but the human phenotype associated with GAD1 disruption is poorly characterized. Neuray et al. describe six patients with biallelic GAD1 mutations, presenting with early-infantile onset epilepsy, neurodevelopmental delay, muscle weakness and non-CNS manifestations.<br />Gamma-aminobutyric acid (GABA) and glutamate are the most abundant amino acid neurotransmitters in the brain. GABA, an inhibitory neurotransmitter, is synthesized by glutamic acid decarboxylase (GAD). Its predominant isoform GAD67, contributes up to ∼90% of base-level GABA in the CNS, and is encoded by the GAD1 gene. Disruption of GAD1 results in an imbalance of inhibitory and excitatory neurotransmitters, and as Gad1−/− mice die neonatally of severe cleft palate, it has not been possible to determine any potential neurological dysfunction. Furthermore, little is known about the consequence of GAD1 disruption in humans. Here we present six affected individuals from six unrelated families, carrying bi-allelic GAD1 variants, presenting with developmental and epileptic encephalopathy, characterized by early-infantile onset epilepsy and hypotonia with additional variable non-CNS manifestations such as skeletal abnormalities, dysmorphic features and cleft palate. Our findings highlight an important role for GAD1 in seizure induction, neuronal and extraneuronal development, and introduce GAD1 as a new gene associated with developmental and epileptic encephalopathy.

Details

Language :
English
ISSN :
14602156 and 00068950
Database :
OpenAIRE
Journal :
Dipòsit Digital de la UB, Universidad de Barcelona, Brain, CONICET Digital (CONICET), Consejo Nacional de Investigaciones Científicas y Técnicas, instacron:CONICET, Brain-A Journal of Neurology, Brain-A Journal of Neurology, Oxford University Press (OUP), 2020, 143 (8), pp.2388-2397. ⟨10.1093/brain/awaa178⟩, Publons
Accession number :
edsair.doi.dedup.....55108cc53157474a74f1616404044b9d