Neonatal‐onset developmental and epileptic encephalopathy: High genetic yield and long‐term outcomes in a multicenter southern European cohort
Júlia Sala‐Coromina, Anna Marcé‐Grau, Gianluca D'Onofrio, Antonella Riva, Roser Pons, Elisabeta Kollia E, Miquel Raspall‐Chaure, Eduardo López‐Laso, Javier López‐Pisón, Edgard Verdura, Agatha Schlüter, Dolors Casellas‐Vidal, Maria Camós‐Carreras, Michele Iacomino, Alberto Spalice, Pasquale Parisi, Alejandro Martínez de la Ossa‐Vela, Mónica Vicente‐Rasoamalala, Aurora Pujol, Vincenzo Salpietro, Pasquale Striano, Alfons MacayaAbstract
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.