Epilepsy in rare diseases: clinical, electroencephalographic and neuroimaging findings in a retrospective observational study

Abstract

Background: Epilepsy comprises a heterogeneous group of disorders with multiple etiologies, including structural and genetic causes. Advances in molecular diagnostics have expanded the identification of pathogenic variants associated with epilepsy, particularly in patients with early-onset seizures and neurodevelopmental disorders, features commonly observed in rare genetic conditions. Accordingly, rare disease clinics represent an important setting for the recognition of syndromic and genetically determined epilepsies. Objective: To characterize the clinical, electroencephalographic, neuroimaging, and etiological profile of patients with epilepsy followed at a medical genetics outpatient clinic. Methods: A retrospective observational study was conducted through the review of medical records of patients with epilepsy followed at a rare diseases outpatient clinic between 2023 and 2026. Demographic data, age at symptom onset, associated neurological manifestations, electroencephalographic (EEG) findings, neuroimaging results, genetic testing, and etiological diagnoses were collected. Descriptive statistical analysis was performed to characterize the clinical and investigational profile of the study population. Results: Twenty-five patients with epilepsy followed at a rare diseases outpatient clinic were analyzed, 16 (69.6%) had generalized and 5 (21.7%) had focal epilepsy. In 8 patients (33.3%), epilepsy was a symptom of a genetic disorder; in 8 (33.3%), it was due to a structural cause; in 2 (8.3%), it was classified as an epileptic syndrome; and in 6 (25%), the etiology was undefined. Pharmacoresistance was observed in 6 patients (24%), 1.89±1.41 (mean±SD) antiepileptic drugs. Genetic etiologies were identified in 17 (71%), including monogenic disorders such as tuberous sclerosis and Dravet syndrome, as well as chromosomal syndromes including Wolf–Hirschhorn, Williams, and Edwards syndromes. Neuroimaging was available in 17 (71%) patients, with structural abnormalities identified in 59% (n=15), most commonly corpus callosum malformations. Electroencephalography (EEG) was performed in 16 (64%) patients, with 69% demonstrating epileptiform discharges or encephalopathic abnormalities. Genetic testing was performed in 7 (29%). Developmental delay or intellectual disability was present in 17 patients (71%), representing the most frequent associated neurological phenotype. Conclusion: The predominance of genetic and chromosomal etiologies observed in this population is consistent with findings reported in the literature, highlighting the strong association between epilepsy and rare neurogenetic disorders. The high frequency of developmental delay and syndromic features reinforces the importance of careful phenotypic assessment and early referral for genetic evaluation in patients with epilepsy and associated neurodevelopmental abnormalities. The relatively low rate of genetic testing also highlights the need to expand access to molecular diagnostics in patients with suspected rare genetic disorders.