Bi-allelic GAD1 variants cause a neonatal onset syndromic developmental and epileptic encephalopathy
| Autor: | Eudeline Alix, Anne-Lise Poulat, Nilay Güneş, Yvonne G. Weber, Maryam Najafi, José M. Serratosa, Ehsan Ghayoor Karimiani, Kaya Bilguvar, Tarek Omar, Katia Hardies, Dana Craiu, Hande Caglayan, Stéphanie Baulac, Fernando Kok, Reza Maroofian, Gaetan Lesca, Heba Morsy, Damien Sanlaville, Carla Marini, Renzo Guerrini, Nina Barišić, Luiza Ramos, Sarah von Spiczak, Miriam Schmidts, Patrick May, Karl Martin Klein, Beyhan Tüysüz, Audrey Labalme, Sarah Weckhuysen, Dilek Uludağ Alkaya, Julitta de Bellescize, Felix Rosenow, Farah Ashrafzadeh, Rudi Balling, Homa Tajsharghi, Amira Nabil, Katalin Sterbova, Felicitas Becker, Nicolas Chatron, Ali-Reza Moslemi, Holger Lerche, Hiltrud Muhle, Ingo Helbig, Haytham Hussien, Sandra Roselli |
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| Přispěvatelé: | EuroEpinomics-RES Consortium AR Wo, İÜC, Cerrahpaşa Tıp Fakültesi, Dahili Tıp Bilimleri Bölümü |
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Pediatrics medicine.medical_specialty suppression-burst hypsarrhythmia Glutamate decarboxylase Neonatal onset arthrogryposis 03 medical and health sciences Epilepsy All institutes and research themes of the Radboud University Medical Center 0302 clinical medicine Medicine Medicinsk genetik cleft palate Arthrogryposis omphalocele Omphalocele GAD1 business.industry Neurosciences Original Articles medicine.disease Hypsarrhythmia 3. Good health Epileptic spasms Renal disorders Radboud Institute for Molecular Life Sciences [Radboudumc 11] 030104 developmental biology Epilepsy syndromes Human medicine Neurology (clinical) medicine.symptom business Medical Genetics Neurovetenskaper 030217 neurology & neurosurgery |
| Zdroj: | Brain Brain, 143, pp. 1447-1461 Brain, 143, 1447-1461 |
| ISSN: | 1460-2156 0006-8950 |
| DOI: | 10.1093/brain/awaa085 |
| Popis: | Chatron et al. describe a novel syndrome caused by bi-allelic loss-of-function mutations in GAD1, the gene encoding the GABA synthetic enzyme GAD67. The syndrome is characterized by the unique association of developmental and epileptic encephalopathy, cleft palate, joint contractures and/or omphalocele. 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. |
| Databáze: | OpenAIRE |
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