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

Autor:	Neuray C; UCL Queen Square Institute of Neurology, University College London, London, UK.; Department of Neurology, Christian Doppler Klinik, Paracelsus Medical University, Salzburg, Austria., Maroofian R; UCL Queen Square Institute of Neurology, University College London, London, UK., Scala M; UCL Queen Square Institute of Neurology, University College London, London, UK.; Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, University of Genoa, Genoa, Italy.; IRCCS Istituto Giannina Gaslini, Genoa, Italy., Sultan T; Department of Pediatric Neurology, Children's Hospital and Institute of Child Health, Lahore, Pakistan., Pai GS; Medical University of South Carolina, USA., Mojarrad M; Department of Medical Genetics, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.; Medical Genetics Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.; Genetic Center of Khorasan Razavi, Mashhad, Iran., Khashab HE; Department of Pediatrics, Children's Hospital, Ain Shams University, Cairo, Egypt.; Department of Pediatrics, Dr. Suliman Al Habib Medical Group, Riyadh, Saudi Arabia., deHoll L; Medical University of South Carolina, USA., Yue W; Structural Genomics Consortium, Nuffield Department of Clinical Medicine, University of Oxford, UK., Alsaif HS; Student Research Committee, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran., Zanetti MN; Department of Clinical and Experimental Epilepsy, University College London, London, UK., Bello O; Department of Clinical and Experimental Epilepsy, University College London, London, UK., Person R; GeneDx, Gaithersburg, MD, USA., Eslahi A; Department of Medical Genetics, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.; Student Research Committee, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran., Khazaei Z; Genetic Center of Khorasan Razavi, Mashhad, Iran., Feizabadi MH; Department of Medical Genetics, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran., Efthymiou S; UCL Queen Square Institute of Neurology, University College London, London, UK., El-Bassyouni HT; Clinical Genetics Department, National Research Centre, Cairo, Egypt., Soliman DR; Department of Pediatrics, Faculty of Medicine, Benha University, Benha, Egypt., Tekes S; Dicle University, School of Medicine, Department of Medical Genetics, Diyarbakir, Turkey., Ozer L; Yuksek Ihtisas University, School of Medicine, Department of Medical Genetics, Ankara, Turkey., Baltaci V; Mikrogen Genetic Diagnosis Center, Ankara, Turkey., Khan S; CENTOGENE AG, Rostock., Beetz C; CENTOGENE AG, Rostock., Amr KS; Molecular Genetics Department, National Research Centre, Cairo, Egypt., Salpietro V; UCL Queen Square Institute of Neurology, University College London, London, UK., Jamshidi Y; Molecular and Clinical Sciences Institute St George's, University of London, UK., Alkuraya FS; Department of Genetics, King Faisal Specialist Hospital and Research Center Riyadh, Saudi Arabia., Houlden H; UCL Queen Square Institute of Neurology, University College London, London, UK.
Jazyk:	angličtina
Zdroj:	Brain : a journal of neurology [Brain] 2020 Aug 01; Vol. 143 (8), pp. 2388-2397.
DOI:	10.1093/brain/awaa178
Abstrakt:	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. (© The Author(s) (2020). Published by Oxford University Press on behalf of the Guarantors of Brain.)
Databáze:	MEDLINE
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