Molecular and clinical spectrum of epilepsy-dyskinesia syndromes: a cross-sectional study of 609 patients

Epilepsy-dyskinesia syndromes (EDS) are a complex group of neurogenetic disorders characterized by the co-occurrence of epilepsy and movement disorders. Despite their increasing clinical recognition, the molecular and clinical spectrum of EDS remains poorly understood. While numerous genetic aetiologies have been implicated, systematic characterization across diverse populations is lacking. This study aimed to delineate the molecular and clinical landscape of EDS in a large, multinational cohort, focusing on movement disorder phenomenologies, genotype-phenotype correlations, and treatment responses. We conducted a multicentre, cross-sectional study involving 609 patients with childhood-onset movement disorders associated with pathogenic variants in 105 predefined genes. Clinical data were collected from over 30 centres across 25 countries using a standardized survey, capturing movement disorder phenomenologies, seizure types, developmental trajectories, motor function and treatment outcomes. We classified EDS-associated genes into biologically meaningful groups by performing unsupervised clustering, which integrated protein-protein interactions and functional data. Genotype-phenotype correlations were assessed using a one-versus-remainder approach to quantify differential enrichment of clinical manifestations and treatment responses. Pathogenic variants were identified in 74 of the 105 predefined genes, with 12 genes accounting for two-thirds of cases. The most frequently reported genes were MECP2, ATP1A3, and GNAO1. Data-driven gene cluster analysis identified 12 functional groups, mapping EDS to relevant biological pathways and informing genotype-phenotype analyses. Dystonia (34.2%), stereotypies (24.6%) and ataxia (16.2%) were the most prevalent movement disorders, with gene- and pathway-specific movement disorder signatures extending beyond previously known associations. Notably, most patients exhibited mixed movement disorders, highlighting the phenotypic complexity of EDS. Epilepsy was diagnosed in only 66.8% of cases, suggesting that some EDS primarily manifest as movement disorders. Developmental trajectories varied by genetic aetiology. Pharmacological responses demonstrated gene- and pathway-specific treatment effects, confirming established therapeutic associations (e.g. PRRT2 variants responding to carbamazepine) and identifying previously unrecognized effects, such as exacerbation of motor symptoms with levodopa/carbidopa in GNAO1 and MECP2 variants. This study provides a detailed characterization of EDS, identifying distinct genetic, phenotypic and therapeutic patterns. The findings underscore the need for early recognition of movement disorders within epilepsy cohorts, offer immediate insights to improve anticipatory guidance and clinical management of EDS, and advocate for personalized treatment strategies. By laying the groundwork for longitudinal studies to refine genotype-phenotype correlations and establish a natural history, this work paves the way for interventional clinical trials and precision medicine approaches.

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Journal
Brain
Published
2025-08-08
DOI
https://doi.org/10.1093/brain/awaf297
Citations
5
Primary Topic
Genetics and Neurodevelopmental Disorders
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article
Field-Weighted Citation Impact
9.09
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article

Molecular and clinical spectrum of epilepsy-dyskinesia syndromes: a cross-sectional study of 609 patients

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5 citations
Brain
Genetics and Neurodevelopmental Disorders
9.09
article

Molecular and clinical spectrum of epilepsy-dyskinesia syndromes: a cross-sectional study of 609 patients

Carolina Gorodetsky, Kathryn Yang, Roser Pons, Emanuele Bartolini, Poonam Bhatia, Jitendra Kumar Sahu, Alissa M. D’Gama, Manju A. Kurian, Carolina Arias, Wei‐Sheng Lin, David Crosiers, Davide Caputo, Mina Zamani, Hendrik Schmidt, Amy Tam, Deepak Gill, Anne Koy, Emmanuel Flamand Roze, Alia H. Mansour, Sanjay Bhate, Loreto Ríos‐Pohl, Núria López Ariztegui, Darius Ebrahimi‐Fakhari, Alexander Maximilian Münchau, Michael C. Kruer, Lindsey M. Vogt, Zainab Zaman, Tobias Loddenkemper, Julian E. Alecu, Nardo Nardocci, Alonso Zea Vera, Wafa Bani Uraba, Russell C. Dale, Wei Kang Lim, Mary Iype, Chahnez Triki, Luca Soliani, María Stamelou, J. Jofre, Soaham Desai, Juan Darío Ortigoza‐Escobar, Hugo Morales‐Briceño, Marios Kaliakatsos, Katerina Bernardi, Hannah Jones, Ján Necpál, Jane Hassell, Robert Robinson, Laura Tochen, Tamara Pringsheim, Asif Doja, Vicente Quiroz, Claudia Castiglioni, Phillip L. Pearl, Gholamreza Shariati, Patricia Dumke da Silva Möller, J.R. Pérez Sánchez, Shekeeb S. Mohammad, Avaneesh Kunta, Luca Schierbaum, Ainara Salazar‐Villacorta, Tian Xiaojuan, Andre Felipe Pinto Duarte, Junkang Rong, Changhong Ding, Esra Demir, Umar Zubair, Dario Resch, Kavitha Kothur, Emilio Fernández‐Álvarez, Sruthi Kola, Bernardita Suárez, Lifang Dai, Leonie Becker, Nicole Battaglia, Pardis Nourbakhsh, Noah Wyman, Alexander Eggers-Lisboa, Magdalena Gonzalez-Ubilla, Chinmay Chaudhari, Habibah P Agianda
article en
5 citations

Abstract

Epilepsy-dyskinesia syndromes (EDS) are a complex group of neurogenetic disorders characterized by the co-occurrence of epilepsy and movement disorders. Despite their increasing clinical recognition, the molecular and clinical spectrum of EDS remains poorly understood. While numerous genetic aetiologies have been implicated, systematic characterization across diverse populations is lacking. This study aimed to delineate the molecular and clinical landscape of EDS in a large, multinational cohort, focusing on movement disorder phenomenologies, genotype-phenotype correlations, and treatment responses. We conducted a multicentre, cross-sectional study involving 609 patients with childhood-onset movement disorders associated with pathogenic variants in 105 predefined genes. Clinical data were collected from over 30 centres across 25 countries using a standardized survey, capturing movement disorder phenomenologies, seizure types, developmental trajectories, motor function and treatment outcomes. We classified EDS-associated genes into biologically meaningful groups by performing unsupervised clustering, which integrated protein-protein interactions and functional data. Genotype-phenotype correlations were assessed using a one-versus-remainder approach to quantify differential enrichment of clinical manifestations and treatment responses. Pathogenic variants were identified in 74 of the 105 predefined genes, with 12 genes accounting for two-thirds of cases. The most frequently reported genes were MECP2, ATP1A3, and GNAO1. Data-driven gene cluster analysis identified 12 functional groups, mapping EDS to relevant biological pathways and informing genotype-phenotype analyses. Dystonia (34.2%), stereotypies (24.6%) and ataxia (16.2%) were the most prevalent movement disorders, with gene- and pathway-specific movement disorder signatures extending beyond previously known associations. Notably, most patients exhibited mixed movement disorders, highlighting the phenotypic complexity of EDS. Epilepsy was diagnosed in only 66.8% of cases, suggesting that some EDS primarily manifest as movement disorders. Developmental trajectories varied by genetic aetiology. Pharmacological responses demonstrated gene- and pathway-specific treatment effects, confirming established therapeutic associations (e.g. PRRT2 variants responding to carbamazepine) and identifying previously unrecognized effects, such as exacerbation of motor symptoms with levodopa/carbidopa in GNAO1 and MECP2 variants. This study provides a detailed characterization of EDS, identifying distinct genetic, phenotypic and therapeutic patterns. The findings underscore the need for early recognition of movement disorders within epilepsy cohorts, offer immediate insights to improve anticipatory guidance and clinical management of EDS, and advocate for personalized treatment strategies. By laying the groundwork for longitudinal studies to refine genotype-phenotype correlations and establish a natural history, this work paves the way for interventional clinical trials and precision medicine approaches.

BrainVol. 149(2)
Ain Shams University (EG), Boston Children's Hospital (US), Hospital Sant Joan de Déu Barcelona (ES), Barrow Neurological Institute (US), Children's Hospital of Philadelphia (US), Children's National (US), Harvard University (US), Ankara University (TR), University of Auckland (NZ), University of Calgary (CA), Capital Medical University (CN), Children's Hospital of Eastern Ontario (CA), Great Ormond Street Hospital (GB), Hospital for Sick Children (CA), ProMedica Toledo Hospital (US), Children's Hospital at Westmead (AU), Taipei Veterans General Hospital (TW), Hospital General Universitario Gregorio Marañón (ES), University of Malaya (MY), Sorbonne Université (FR), Clínica Las Condes (CL), Railway Repair and Engineering Works (Slovakia) (SK), Technická univerzita vo Zvolene (SK), Antwerp University Hospital (BE), Shree Krishna Hospital (IN), Hopital Universitaire Hedi Chaker (TN), Azienda USL di Bologna (IT), Pramukhswami Medical College (IN), Children's Hospital Agia Sophia (GR), Pitié-Salpêtrière Hospital (FR), Hygeia Hospital (GR), Istituto delle Scienze Neurologiche di Bologna (IT), Instituto Nacional de Rehabilitación (MX), Fondazione Stella Maris (IT), Kerala Institute of Medical Sciences (IN), Sree Gokulam Medical College and Research Foundation (IN), Yashoda Hospital (IN), Clínica MEDS (Chile) (CL), Hospital Universitário de Brasília (BR), Beijing Children’s Hospital (CN), Sultan Qaboos University Hospital (OM), University Hospital Cologne (DE), Complejo Hospitalario Universitario de Toledo (ES), Fondazione IRCCS Istituto Neurologico Carlo Besta (IT), University College London (GB), Post Graduate Institute of Medical Education and Research (IN), HealthPartners (US), University of Lübeck (DE)
Openalex Percentile: Top 2%
Genetics and Neurodevelopmental Disorders
9.09
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