Abstracts

Germline RORB Variants and Absence Seizures: A Neurobiological Continuum?

Abstract number : 2.325
Submission category : 12. Genetics / 12A. Human Studies
Year : 2022
Submission ID : 2204465
Source : www.aesnet.org
Presentation date : 12/4/2022 12:00:00 PM
Published date : Nov 22, 2022, 05:25 AM

Authors :
gaetan Lesca, MD, PhD – Hospices Civils de Lyon; Rami Abou Jamra, MD – Institute of Human Genetics – University Hospitals of Leipzig; Margaret Au, MD – Division of Clinical Genetics and Dysmorphology – Cedars-Sinai Medical Center, Los Angeles; Tobias Bartolomaeus, MD – Institute of Human Genetics – University Hospitals of Leipzig; Roseline Caumes, MD – Department of Pediatric Neurology – University Hospitals of Lille; Julien Courchet, PhD – CNRS, INSERM, UMR5261, U1315 – Univ Lyon, Univ Lyon 1, Institut NeuroMyoGène, Lyon; Renzo Guerrini, MD, PhD – Department of Pediatric Neurology, Neurogenetics and Neurobiology Unit and Laboratories – Children's Hospital A. Meyer-University of Florence; Ingo Helbig, MD, PhD – Department of Pediatric Neurology – Children’s Hospital of Philadelphia; Arnaud Isapof, MD – Department of Pediatric Neurology – University Hospitals of Armand Trousseau; Floor Jansen, MD – Department of Pediatric Neurology – Brain Center UMC Utrecht; Klaas Koop, MD – Department of Pediatric Neurology – Brain Center UMC Utrecht; Sebastien Kury, PhD – Department of Genetics – University Hospitals of Nantes; Jill Anne Mokry, MD – Department of Molecular and Human Genetics – Baylor College of Medicine, Houston; Sonja Neuser, MD – Institute of Human Genetics, – University Hospitals of Leipzig; Konrad Platzner, MD, PhD – Institute of Human Genetics – University Hospitals of Leipzig; Thomas Smol, MD, PhD – Department of Medical Genetics – University Hospitals of Lille; Sigrid Tinschert, MD – Institute of Human Genetics – University Hospitals of Leipzig; Nathalie Villeneuve, MD – Department of Pediatric Neurology – University Hospitals of Marseille; Pia Zacher, MD – Institute of Human Genetics – University Hospitals of Leipzig; Dana Craiu, MD – Pediatric Neurology Clinic – Al Obregia Hospital, Bucharest; Lucia Gerstl, MD – Department of Pediatric Neurology – Ludwig-Maximilians-University of Munich; Chad Haldeman-Englert, MD – Mission Fullerton, Asheville; Manuela Pendziwiat, MD – Department of Neurology – UKSH, Campus Kiel; Deepa Rajan, MD – Department of Pediatric Neurology – Children's Hospital of Pittsburgh; Silvia Vieker, MD – Epido, Schwerpunktpraxis Epileptologie, Dortmund; Alexis Arzimanoglou, MD, PhD – Department of Pediatric epileptology – Hospices Civils de Lyon; Elisabetta Cesaroni, MD – 5Department of Pediatric Neurology – Ospedali Riuniti, Ancona; Nicolas Chatron, MD, Ph – Department of Mdical Genetics – Hospices Civils de Lyon; Vishnu Cuddapah, MD – Department of Medical Genetics – Children’s Hospital of Philadelphia; Julitta de Bellescize, MD – Department of Pediatric epileptology – Hospices Civils de Lyon; Joel Fluss, MD – Department of Pediatric Neurology – University of Geneva; Zeynep Gokce-Samar, MD – Department of Pediatric epileptology – Hospices Civils de Lyon; Anne-Marie Guerrot, MD – Department of Medical Genetics – University Hospitals of Rouen; katherine helbig, MS-GC – Department of Pediatric Neurology – Children’s Hospital of Philadelphia; Pascal Joset, MD, PhD – Institute of Human Genetics – University of Zürich; Christian Korff, MD, PhD – Department of Pediatric Neurology – University Hospital of Geneva, Geneva; Martin Krenn, MD, PhD – Department of Neurology – Medical University of Vienna; Manju Kurian, MD, PhD – University College London; Francois Lecoquierre, MD – Department of Medical Genetics – University Hospital of Rouen; Carla Marini, MD – 5Department of Pediatric Neurology – Ospedali Riuniti, Ancona; Blanca Mercedes Alvarez, MD – Department of Pediatric Neurology – University Hospitals of Montpellier; Adeline Ngoh, MD – University College London; Tiziana Pisano, MD – Department of Pediatric Neurology, Neurogenetics and Neurobiology Unit and Laboratories – Children's Hospital A. Meyer-University of Florence; Georgia Ramantani, MD, PhD – Department of Pediatric Neurology – University Children’s Hospital, Zürich; Anna Ruiz, MD – Department of Pediatric Neurology – Barcelona Children's Hospital; Damien Sanlaville, MD, PhD – Department of Medical Genetics – Hospices Civils de Lyon; Katharina Steindl, MD – Department of Pediatric Neurology – University Children’s Hospital, Zürich; Herve Testard, MD – Department of Pediatrics – Hospital of Alpes Léman, Annemasse; Annalisa Vetro, PhD – Department of Pediatric Neurology, Neurogenetics and Neurobiology Unit and Laboratories – Children's Hospital A. Meyer-University of Florence

Rationale: RORB, a gene recently involved in neurodevelopmental disorders with epilepsy, is expressed in thalamocortical networks which can generate typical absence seizures.  In this study, we aimed at better defining the epileptic phenotype associated with RORBpathogenic variants.

Methods: Through an international collaboration, we analyzed seizure characteristics, EEG data and genotypes of a cohort of patients included on the basis of RORB variant without clinical selection. Functional consequences of selected variants was evaluated upon expression in mouse cortical neurons and quantification of changes in axonal morphology._x000D_
Results: A total of 35 patients carrying RORB variants were included, 33 unreported and 2 patients with revised data (17 male, median age, 10 years (range 2.5 – 23 y). Seizures were present in 31/35 (89%) with a median age at onset of 3 years (range 4 mo–12y). Intellectual disability (ID) was present in 29/34, being mild in 14, moderate in 12, and severe in 2. Twenty-nine of the 31 patients (94%) were diagnosed having generalized seizures of whom 25 had absence seizures (AS), only two presented atypical absences. A generalized spike-wave (GSW) ictal pattern was observed in 21/23 (91%) with an “absence-signature” at 2.5-3.5 Hz documented in 16/23 (70%). In half of the patients (16/31, 52%), AS (n=9 of whom 3 with early onset), or MA (n=4) or EMA (n=3) occurred as the only seizure type. Four patients had a combination of AS of childhood or early-onset or EMA and generalized tonic-clonic seizures (GTCS) and one patient showed the peculiar association of photosensitive occipital seizures with absences and GTCS. A total of 7 (23%) patients had developmental and epileptic encephalopathy (DEE). Compared to wild-type RORB which increased axon length, none of the tested variants (2 nonsense and three missense variants) had a positive effect on axon growth._x000D_
Conclusions: The RORB related absence seizure spectrum harbors the typical “absence signature at 3-Hz” in line with the anatomical expression of RORB. Lack of obvious genotype phenotype correlation may be due to the fact that all variant types lead to haplo-insufficiency, as suggested by the identical morphological consequences observed on the axon length in cultured neurons._x000D_
Funding: None
Genetics