Early-infantile onset epilepsy and developmental delay caused by bi-allelic GAD1 variants-Reference-Cited by-同舟云学术

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

Published:2020-07-23 Issue:8 Volume:143 Page:2388-2397
ISSN:0006-8950
Container-title:Brain
language:en
Short-container-title:

Author:

Neuray Caroline¹²^ORCID,Maroofian Reza¹,Scala Marcello¹³⁴,Sultan Tipu⁵,Pai Gurpur S⁶,Mojarrad Majid⁷⁸⁹,Khashab Heba El¹⁰¹¹,deHoll Leigh⁶,Yue Wyatt¹²,Alsaif Hessa S¹³,Zanetti Maria N¹⁴,Bello Oscar¹⁴,Person Richard¹⁵,Eslahi Atieh⁷¹³,Khazaei Zaynab⁹,Feizabadi Masoumeh H⁷^ORCID,Efthymiou Stephanie¹,Groppa Stanislav,Karashova Blagovesta Marinova,Nachbauer Wolfgang,Boesch Sylvia,Arning Larissa,Timmann Dagmar,Cormand Bru,Pérez-Dueñas Belen,Di Rosa Gabriella,Goraya Jatinder S,Sultan Tipu,Mine Jun,Avdjieva Daniela,Kathom Hadil,Tincheva Radka,Banu Selina,Pineda-Marfa Mercedes,Veggiotti Pierangelo,Ferrari Michel D,Verrotti Alberto,Marseglia Giangluigi,Savasta Salvatore,García-Silva Mayte,Macaya Ruiz Alfons,Garavaglia Barbara,Borgione Eugenia,Portaro Simona,Sanchez Benigno Monteagudo,Boles Richard,Papacostas Savvas,Vikelis Michail,Papanicolaou Eleni Zamba,Dardiotis Efthymios,Maqbool Shazia,Ibrahim Shahnaz,Kirmani Salman,Rana Nuzhat Noureen,Atawneh Osama,Koutsis George,Breza Marianthi,Mangano Salvatore,Scuderi Carmela,Borgione Eugenia,Morello Giovanna,Stojkovic Tanya,Zollo Massimi,Heimer Gali,Dauvilliers Yves A,Striano Pasquale,Al-Khawaja Issam,Al-Mutairi Fuad,Sherifa Hamed,El-Bassyouni Hala T¹⁶^ORCID,Soliman Doaa R¹⁷,Tekes Selahattin¹⁸,Ozer Leyla¹⁹,Baltaci Volkan²⁰,Khan Suliman²¹,Beetz Christian²¹,Amr Khalda S²²,Salpietro Vincenzo¹,Jamshidi Yalda²³^ORCID,Alkuraya Fowzan S²⁴,Houlden Henry¹^ORCID,

Affiliation:

1. UCL Queen Square Institute of Neurology, University College London, London, UK

2. Department of Neurology, Christian Doppler Klinik, Paracelsus Medical University, Salzburg, Austria

3. Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, University of Genoa, Genoa, Italy

4. IRCCS Istituto Giannina Gaslini, Genoa, Italy

5. Department of Pediatric Neurology, Children’s Hospital and Institute of Child Health, Lahore, Pakistan

6. Medical University of South Carolina, USA

7. Department of Medical Genetics, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran

8. Medical Genetics Research Center, Mashhad University of Medical Sciences, Mashhad, Iran

9. Genetic Center of Khorasan Razavi, Mashhad, Iran

10. Department of Pediatrics, Children’s Hospital, Ain Shams University, Cairo, Egypt

11. Department of Pediatrics, Dr. Suliman Al Habib Medical Group, Riyadh, Saudi Arabia

12. Structural Genomics Consortium, Nuffield Department of Clinical Medicine, University of Oxford, UK

13. Student Research Committee, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran

14. Department of Clinical and Experimental Epilepsy, University College London, London, UK

15. GeneDx, Gaithersburg, MD, USA

16. Clinical Genetics Department, National Research Centre, Cairo, Egypt

17. Department of Pediatrics, Faculty of Medicine, Benha University, Benha, Egypt

18. Dicle University, School of Medicine, Department of Medical Genetics, Diyarbakir, Turkey

19. Yuksek Ihtisas University, School of Medicine, Department of Medical Genetics, Ankara, Turkey

20. Mikrogen Genetic Diagnosis Center, Ankara, Turkey

21. CENTOGENE AG, Rostock

22. Molecular Genetics Department, National Research Centre, Cairo, Egypt

23. Molecular and Clinical Sciences Institute St George’s, University of London, UK

24. Department of Genetics, King Faisal Specialist Hospital and Research Center Riyadh, Saudi Arabia

Abstract

Abstract 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.

Funder

MRC

The National Institute for Health Research University College London Hospitals Biomedical Research Centre, Rosetree Trust

Brain Research UK

Sparks GOSH Charity

Muscular Dystrophy UK

Muscular Dystrophy Association

Wellcome Trust

University College London

National Institute for Health Research University College London Hospitals Biomedical Research Centre

Publisher

Oxford University Press (OUP)