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

Salvatore Mangano, Hala T. El-Bassyouni, Tipu Sultan, Salman Kirmani, Majid Mojarrad, Giangluigi Marseglia, Eleni Zamba Papanicolaou, Salvatore Savasta, Shahnaz Ibrahim, Jun Mine, Wolfgang Nachbauer, Richard Person, Stanislav Groppa, Leyla Ozer, Maria N. Zanetti, Simona Portaro, Oscar Bello, Michel D. Ferrari, Fuad Al-Mutairi, Stephanie EfthymiouHadil Kathom, Osama Atawneh, Reza Maroofian, Savvas Papacostas, Salvatore Mangano, Michail Vikelis, Doaa R. Soliman, Gabriella Di Rosa, Khalda S. Amr, Marianthi Breza, Gali Heimer, Hessa S. Alsaif, Blagovesta Marinova Karashova, Caroline Neuray, Atieh Eslahi, Yalda Jamshidi, Marcello Scala, Selina Banu, Benigno Monteagudo Sanchez, Issam Al-Khawaja, Mayte García-Silva, Shazia Maqbool, Nuzhat Noureen Rana, Hamed Sherifa, Giovanna Morello, Massimi Zollo, Alfons Macaya Ruiz, Zaynab Khazaei, Tipu Sultan, Suliman Khan, Pasquale Striano, Efthymios Dardiotis, Heba El Khashab, Wyatt Yue, Masoumeh H. Feizabadi, Leigh Deholl, Gurpur S. Pai, Volkan Baltaci, Giangluigi Marseglia, Jun Mine, Yves A. Dauvilliers, Hamed Sherifa, Larissa Arning, Daniela Avdjieva, Vincenzo Salpietro, Radka Tincheva, Eugenia Borgione, Fowzan S. Alkuraya, Belen Pérez-Dueñas, Mercedes Pineda-Marfa, Bru Cormand, Sylvia Boesch, Carmela Scuderi, Pasquale Striano, Henry Houlden, Yves A. Dauvilliers, Tanya Stojkovic, Christian Beetz, Pierangelo Veggiotti, Massimi Zollo, Barbara Garavaglia, Jatinder S. Goraya, Dagmar Timmann, Richard Boles, Alberto Verrotti, Michail Vikelis, George Koutsis, Selahattin Tekes

Risultato della ricerca: Articlepeer review

4 Citazioni (Scopus)

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.
Lingua originaleEnglish
pagine (da-a)2388-2397
Numero di pagine10
RivistaBRAIN (ONLINE)
Volume143
Stato di pubblicazionePublished - 2020

All Science Journal Classification (ASJC) codes

  • Clinical Neurology

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