Adult phenotypes of genetic developmental and epileptic encephalopathies.

Abstract

Developmental and epileptic encephalopathies constitute a group of severe epilepsies, with seizure onset typically occurring in infancy or childhood, and diverse clinical manifestations, including neurodevelopmental deficits and multimorbidities. Many have genetic aetiologies, identified in up to 50% of individuals. Whilst classically considered paediatric disorders, most are compatible with survival into adulthood, but their adult phenotypes remain inadequately understood. This cross-sectional study presents detailed phenotypes of 129 adults (age range 17-71 years), with genetic developmental and epileptic encephalopathies involving causal variants in 42 genes. We describe diverse disease aspects, and we sought genetic insights from the age-related trends of expression of the genes involved. Most developmental and epileptic encephalopathies (69.7%) are epileptic encephalopathies in adulthood, with the presence of epileptic encephalopathy correlating with worse cognitive phenotypes (P = 0.0007). However, phenotypic variability was observed, ranging from those with epileptic encephalopathy to seizure-free individuals with normal EEG or intermediate clinical and EEG phenotypes. This variability was found across individual genes and age-related gene expression trends, suggesting that other influential factors are likely at play. Mobility, feeding and communication impairments were common, with significant dependence on others for activities of daily living. Neurological and psychiatric comorbidities were most prevalent, along with additional systemic comorbidities observed, particularly musculoskeletal, cardiac and gastrointestinal conditions, highlighting the need for comprehensive and multisystemic monitoring. Despite an average diagnostic delay of 25.2 years, aetiology-based therapeutic interventions were feasible for 54.8% of the cohort, underscoring the critical need for genome-wide genetic testing for adults with these phenotypes. Optimizing seizure control remains necessary, but it may not be sufficient to ensure good outcomes, which may differ significantly from childhood metrics, like cognitive function and independence in daily living. Therapies addressing additional aspects beyond seizures are necessary for improving overall outcomes. Understanding the intricate relationship between molecular pathways and the age-related trends of gene expression is crucial for development of appropriate gene-specific therapies and timely intervention. Whilst prospective data are also needed to define these complexities, such studies of necessity take years to acquire: insights from adults can inform care strategies for both paediatric and adult populations now.