Early-infantile onset epilepsy and developmental delay caused by bi-allelic GAD1 variants
Caroline Neuray, Reza Maroofian, Marcello Scala, Tipu Sultan, G. Shashidhar Pai, Majid Mojarrad, Heba El Khashab, Leigh deHoll, Wyatt W. Yue, Hessa S. Alsaif, M. Natalia Zanetti, Oscar D. Bello, Richard Person, Atieh Eslahi, Zaynab Khazaei, Masoumeh Heidari Feizabadi, Stéphanie Efthymiou, SYNaPS Study Group, Stanislav Groppa, Blagovesta Marinova Karashova, Wolfgang Nachbauer, Sylvia Boesch, Larissa Arning, Dagmar Timmann, Bru Cormand, Belén 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 Verrottı, Gian Luigi Marseglia, Salvatore Savasta, Mayte García-Silva, Alfons Macaya Ruiz, Barbara Garavaglia, Eugenia Borgione, Simona Portaro, Benigno Monteagudo Sanchez, Richard G. Boles, Savvas Papacostas, Michail Vikelis, Eleni Zamba Papanicolaou, Efthymios Dardiotis, Shazia Maqbool, Shahnaz Ibrahim, Salman Kirmani, Nuzhat Rana, Osama Atawneh, George Koutsis, Marianthi Breza, Salvatore Mangano, Carmela Scuderi, Eugenia Borgione, Giovanna Morello, Tanya Stojkovic, Massimi Zollo, Gali Heimer, Yves Dauvilliers, Pasquale Striano, Issam Al-Khawaja, Fuad Al-Mutairi, Sherifa A. Hamed, Hala T. El‐Bassyouni, Doaa Soliman, Selahattin Tekeş, Leyla Özer, Volkan Baltacı, Suliman Khan, Christian Beetz, Khalda Amr, Vincenzo Salpietro, Yalda Jamshidi, Fowzan S. Alkuraya, Henry Houlden
Abstract
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.