Bi-allelic GAD1 variants cause a neonatal onset syndromic developmental and epileptic encephalopathy
Nicolas Chatron, Felicitas Becker, Heba Morsy, Miriam Schmidts, Katia Hardies, Beyhan Tüysüz, Sandra Roselli, Maryam Najafi, Dilek Uludağ Alkaya, Farah Ashrafzadeh, Amira Nabil, Tarek Omar, Reza Maroofian, Ehsan Ghayoor Karimiani, Haytham Hussien, Fernando Kok, Luiza Ramos, Nilay Güneş, Kaya Bilgüvar, Audrey Labalme, Eudéline Alix, Damien Sanlaville, Julitta de Bellescize, Anne‐Lise Poulat, Ingo Helbig, Sarah von Spiczak, Stéphanie Baulac, Nina Barišić, Rudi Balling, Hande Çağlayan, Dana Craiu, Renzo Guerrini, Karl Martin Klein, Carla Marini, Hiltrud Muhle, Felix Rosenow, José M. Serratosa, Katalin Štěrbová, Yvonne Weber, Ali‐Reza Moslemi, Holger Lerche, Patrick May, Gaëtan Lesca, Sarah Weckhuysen, Homa Tajsharghi
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.