Publication
Title
Bi-allelic GAD1 variants cause a neonatal onset syndromic developmental and epileptic encephalopathy
Author
Institution/Organisation
EuroEpinomics-RES Consortium AR Wo
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 c-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.
Language
English
Source (journal)
Brain. - London
Publication
London : 2020
ISSN
0006-8950
DOI
10.1093/BRAIN/AWAA085
Volume/pages
143 :5 (2020) , p. 1447-1461
ISI
000541777000026
Pubmed ID
32282878
Full text (Publisher's DOI)
Full text (open access)
UAntwerpen
Faculty/Department
Research group
Project info
Allele-specific silencing of mutant KCNQ2 as a targeted treatment for KCNQ2 encephalopathy: an in vitro proof of concept study.
Publication type
Subject
Affiliation
Publications with a UAntwerp address
External links
Web of Science
Record
Identifier
Creation 20.08.2020
Last edited 03.12.2024
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