Bi-allelic GAD1 variants cause a neonatal onset syndromic developmental and epileptic encephalopathy

Brain. 2020 May 1;143(5):1447-1461. doi: 10.1093/brain/awaa085.

Nicolas Chatron ¹ ², Felicitas Becker ³ ⁴, Heba Morsy ⁵, Miriam Schmidts ⁶ ⁷ ⁸, Katia Hardies ⁹, Beyhan Tuysuz ¹⁰, Sandra Roselli ¹¹, Maryam Najafi ⁶ ⁷, Dilek Uludag Alkaya ¹⁰, Farah Ashrafzadeh ¹², Amira Nabil ⁵, Tarek Omar ¹³, Reza Maroofian ¹⁴, Ehsan Ghayoor Karimiani ¹⁴ ¹⁵, Haytham Hussien ¹³, Fernando Kok ¹⁶, Luiza Ramos ¹⁶, Nilay Gunes ¹⁰, Kaya Bilguvar ¹⁷, Audrey Labalme ¹, Eudeline Alix ¹, Damien Sanlaville ², Julitta de Bellescize ¹⁸, Anne-Lise Poulat ¹⁹, EuroEpinomics-RES consortium AR working group, Ali-Reza Moslemi ¹¹, Holger Lerche ⁴, Patrick May ²⁰, Gaetan Lesca ¹ ², Sarah Weckhuysen ⁹ ²¹, Homa Tajsharghi ²²

Affiliations

1 Genetics Department, Lyon University Hospital, Lyon, France.
2 Institut NeuroMyoGène CNRS UMR 5310 - INSERM U1217 Université de Lyon, Université Claude Bernard Lyon 1, Lyon, France.
3 Department of Neurology, University of Ulm, Ulm, Germany.
4 University of Tübingen, Department of Neurology and Epileptology, Hertie Institute for Clinical Brain Research, Tübingen, Germany.
5 Human Genetics Department, Medical Research Institute, Alexandria University, Alexandria, Egypt.
6 Genome Research Division, Human Genetics Department, Radboud University Medical Center Nijmegen, Nijmegen, The Netherlands.
7 Radboud Institute for Molecular Life Sciences, Geert Grooteplein Zuid 10, 6525KL Nijmegen, The Netherlands.
8 Center for Pediatrics and Adolescent Medicine, University Hospital Freiburg, Freiburg University Faculty of Medicine, Freiburg, Germany.
9 Neurogenetics Group, VIB-Center for Molecular Neurology, University of Antwerp, Antwerp, Belgium.
10 Department of Pediatric Genetics, Istanbul University-Cerrahpasa, Medical Faculty, Istanbul, Turkey.
11 Department of Pathology, University of Gothenburg, Sahlgrenska University Hospital, Sweden.
12 Department of Paediatric Neurology, Ghaem Medical Centre, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.
13 Pediatrics Department, Faculty of Medicine, Alexandria University, Alexandria, Egypt.
14 Genetics Research Centre, Molecular and Clinical Sciences Institute, St George's, University of London, Cranmer Terrace, London SW17 0RE, UK.
15 Innovative medical research center, Mashhad branch, Islamic Azad University, Mashhad, Iran.
16 Universidade de Sao Paulo Faculdade de Medicina, Sao Paulo, SP, Brazil.
17 Department of Genetics, Yale Center for Genome Analysis (YCGA), Yale University, School of Medicine, New Haven, Connecticut.
18 Department of Pediatric Clinical Epileptology, Sleep Disorders and Functional Neurology, ERN EpiCARE, University Hospitals of Lyon, Lyon, France.
19 Department of Pediatric Neurology, Lyon University Hospital, Lyon, France.
20 Luxemburg Centre for Systems Biomedicine, University of Luxembourg, Belvaux, Luxembourg.
21 Department of Neurology, University Hospital Antwerp, Antwerp, Belgium.
22 School of Health Sciences, Division Biomedicine, University of Skovde, Skovde, Sweden.

PMID: 32282878 DOI: 10.1093/brain/awaa085

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.

Keywords

GAD1; arthrogryposis; cleft palate; hypsarrhythmia; omphalocele; suppression-burst.

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