Neonatal-onset developmental and epileptic encephalopathy: High genetic yield and long-term outcomes in a multicenter southern European cohort.
23 affiliations
- 1Department of Pediatric Neurology, University Hospital Vall d'Hebron (HUVH), Vall d'Hebron University Hospital Research Institute (IIS IR-HUVH), Barcelona, Spain.
- 2Therapeutics and Innovations in Neuropediatrics and Other Paediatric Rare Diseases, Vall d'Hebron Institute of Research (VHIR), Instituto de Investigación Sanitaria Hospital Universitari Vall d'Hebron (IIS IR-HUVH), Barcelona, Spain.
- 3Department of Pediatrics, Universitat Autònoma de Barcelona, Barcelona, Spain.
- 4Department of Neurosciences Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health (DiNOGMI), University of Genoa, Genoa, Italy.
- 5Unit of Pediatric Neurophysiology, Necker Enfants Malades Hospital, AP-HP, Paris, France.
- 6Agia Sofia Hospital, First Department of Pediatrics, Special Unit of Pediatric Neurology, National and Kapodistrian Universtiy of Athens, Athens, Greece.
- 7Pediatric Neurology Unit, Department of Pediatrics, University Hospital Reina Sofía and Maimónides Institute for Biomedical Research of Córdoba (IMIBIC), Córdoba, Spain.
- 8Centre for Biomedical Network Research on Rare Diseases (CIBERER) Associated Clinical Group, Instituto de Salud Carlos III, Madrid, Spain.
- 9Department of Pediatric Neurology and Metabolism, Miguel Servet University Hospital, Zaragoza, Spain.
- 10Molecular Biology CORE, Hospital Clínic de Barcelona, Barcelona, Spain.
- 11Division of Molecular Genetics, Biochemistry and Molecular Genetics Department, Hospital Clínic de Barcelona, Barcelona, Spain.
- 12Neurometabolic Diseases Laboratory, Bellvitge Biomedical Research Institute (IDIBELL), Hospital Duran i Reynals, L'Hospitalet de Llobregat, Spain.
- 13Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), ISCIII, Madrid, Spain.
- 14Department of Pediatrics, Hospital Universitari Doctor Josep Trueta, Girona, Spain.
- 15Neurodevelopmental Group (Girona Biomedical Research Institute) - IDIBGI, Institute of Health Assistance (IAS), Parc Hospitalari Martí i Julià, Girona, Spain.
- 16Medical Genetics Unit, IRCCS Istituto Giannina Gaslini, Genoa, Italy.
- 17Umberto I University Hospital, Sapienza University of Rome, Rome, Italy.
- 18Sant'Andrea University Hospital, Sapienza University of Rome, Rome, Italy.
- 19Department of Clinical Neurophysiology, Pediatric and Neonatal EEG Unit, University Hospital Vall d'Hebron (HUVH), Vall d'Hebron University Hospital Research Institute (IIS IR-HUVH), Barcelona, Spain.
- 20Catalan Institution of Research and Advanced Studies (ICREA), Barcelona, Catalonia, Spain.
- 21European Brain Research Institute "Rita Levi-Montalcini", Rome, Italy.
- 22Department of Biotechnology and Applied Sciences, University of L'Aquila, L'Aquila, Italy.
- 23Full Member of ERN EpiCARE, IRCCS Istituto Giannina Gaslini, Genova, Italy.
Abstract
Objective
To determine the genetic diagnostic yield, characterize the clinical and genetic landscape, and evaluate long-term epilepsy, neurodevelopmental, and survival outcomes in a strictly defined cohort of neonatal-onset developmental and epileptic encephalopathy (DEE).Methods
Retrospective multicenter observational study across tertiary epilepsy centers in Italy, Greece, and Spain. Sixty-two full-term neonates fulfilling ILAE 2022 criteria for DEE with seizure onset within the first 30 days of life and a minimum follow-up of 18 months were included. All patients underwent next-generation sequencing-based genetic testing. Genetic findings, clinical characteristics, and long-term outcomes were systematically analyzed.Results
A molecular diagnosis was established in 82.2% of patients (51/62), identifying variants across 29 genes grouped, for descriptive purposes, into four broad categories according to principal biological role. First-line whole-exome sequencing achieved higher diagnostic yield than targeted gene panels (88.9% vs. 41.2%), although this comparison was influenced by differences in testing era and strategy. KCNQ2 variants were the most frequent genetic cause (29.4%), and several treatable metabolic disorders were identified. After a mean follow-up of 11.9 years, 64.5% of patients had drug-resistant epilepsy and mortality reached 17.7%. Seizure freedom was achieved in a subset of patients, particularly those with KCNQ2-related DEE. Nevertheless, severe-to-profound intellectual disability affected 71.7% of evaluable patients and persisted even among those who became seizure-free, suggesting that neurodevelopmental outcomes are influenced by factors beyond seizure burden, including the underlying genetic disorder and other disease-related factors. However, the marked variability observed precludes any causal inference from these data.Significance
This large European cohort demonstrates a high genetic diagnostic yield in neonatal-onset DEE, supporting first-line whole-exome sequencing as the preferred first-tier genetic test. The persistence of severe neurodevelopmental impairment despite seizure control highlights the need for precision therapies targeting disease mechanisms in addition to seizure management.Plain language summary
We studied 62 newborns who developed severe epilepsy caused by genetic changes, following them for up to 25 years. We found a genetic cause in over 80% of cases, and genetic testing that reads the entire genetic code was far more effective than tests that only look at specific genes. Although seizures improved in some children over time, nearly all had lasting intellectual disability regardless of seizure control. This suggests that the underlying genetic condition may contribute substantially to brain development in addition to the effects of seizures, although our study cannot determine the relative contribution of each factor.
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BibTeX
@article{salacoromina2026neonatalonset,
title = {{Neonatal-onset developmental and epileptic encephalopathy: High genetic yield and long-term outcomes in a multicenter southern European cohort.}},
author = {Júlia Sala-Coromina and Anna Marcé-Grau and Gianluca D'Onofrio and Antonella Riva and Roser Pons and Elisabeta Kollia E and Miquel Raspall-Chaure and Eduardo López-Laso and Javier López-Pisón and Edgard Verdura and Agatha Schlüter and Dolors Casellas-Vidal and Maria Camós-Carreras and Michele Iacomino and Alberto Spalice and Pasquale Parisi and Alejandro Martínez de la Ossa-Vela and Mónica Vicente-Rasoamalala and Aurora Pujol and Vincenzo Salpietro and Pasquale Striano and Alfons Macaya},
journal = {Epilepsia open},
year = {2026},
month = oct,
doi = {10.1002/epi4.70375},
url = {https://europepmc.org/article/MED/42949433},
note = {CC BY-NC-ND},
}
RIS
TY - JOUR
TI - Neonatal-onset developmental and epileptic encephalopathy: High genetic yield and long-term outcomes in a multicenter southern European cohort.
AU - Júlia Sala-Coromina
AU - Anna Marcé-Grau
AU - Gianluca D'Onofrio
AU - Antonella Riva
AU - Roser Pons
AU - Elisabeta Kollia E
AU - Miquel Raspall-Chaure
AU - Eduardo López-Laso
AU - Javier López-Pisón
AU - Edgard Verdura
AU - Agatha Schlüter
AU - Dolors Casellas-Vidal
AU - Maria Camós-Carreras
AU - Michele Iacomino
AU - Alberto Spalice
AU - Pasquale Parisi
AU - Alejandro Martínez de la Ossa-Vela
AU - Mónica Vicente-Rasoamalala
AU - Aurora Pujol
AU - Vincenzo Salpietro
AU - Pasquale Striano
AU - Alfons Macaya
PY - 2026
DA - 2026/10/28
JO - Epilepsia open
DO - 10.1002/epi4.70375
UR - https://europepmc.org/article/MED/42949433
AB - Objective To determine the genetic diagnostic yield, characterize the clinical and genetic landscape, and evaluate long-term epilepsy, neurodevelopmental, and survival outcomes in a strictly defined cohort of neonatal-onset developmental and epileptic encephalopathy (DEE).Methods Retrospective multicenter observational study across tertiary epilepsy centers in Italy, Greece, and Spain. Sixty-two full-term neonates fulfilling ILAE 2022 criteria for DEE with seizure onset within the first 30 days of life and a minimum follow-up of 18 months were included. All patients underwent next-generation sequencing-based genetic testing. Genetic findings, clinical characteristics, and long-term outcomes were systematically analyzed.Results A molecular diagnosis was established in 82.2% of patients (51/62), identifying variants across 29 genes grouped, for descriptive purposes, into four broad categories according to principal biological role. First-line whole-exome sequencing achieved higher diagnostic yield than targeted gene panels (88.9% vs. 41.2%), although this comparison was influenced by differences in testing era and strategy. KCNQ2 variants were the most frequent genetic cause (29.4%), and several treatable metabolic disorders were identified. After a mean follow-up of 11.9 years, 64.5% of patients had drug-resistant epilepsy and mortality reached 17.7%. Seizure freedom was achieved in a subset of patients, particularly those with KCNQ2-related DEE. Nevertheless, severe-to-profound intellectual disability affected 71.7% of evaluable patients and persisted even among those who became seizure-free, suggesting that neurodevelopmental outcomes are influenced by factors beyond seizure burden, including the underlying genetic disorder and other disease-related factors. However, the marked variability observed precludes any causal inference from these data.Significance This large European cohort demonstrates a high genetic diagnostic yield in neonatal-onset DEE, supporting first-line whole-exome sequencing as the preferred first-tier genetic test. The persistence of severe neurodevelopmental impairment despite seizure control highlights the need for precision therapies targeting disease mechanisms in addition to seizure management.Plain language summary We studied 62 newborns who developed severe epilepsy caused by genetic changes, following them for up to 25 years. We found a genetic cause in over 80% of cases, and genetic testing that reads the entire genetic code was far more effective than tests that only look at specific genes. Although seizures improved in some children over time, nearly all had lasting intellectual disability regardless of seizure control. This suggests that the underlying genetic condition may contribute substantially to brain development in addition to the effects of seizures, although our study cannot determine the relative contribution of each factor.
SN - 2470-9239
ER -