Therapy-refractory epilepsies represent a clinically and etiologically heterogeneous group of disorders that often manifest in childhood and are associated with considerable morbidity. A significant portion of patients exhibit structural abnormalities of the central nervous system, particularly malformations of cortical development. Despite immense advancements in molecular genetic diagnostics, the underlying cause remains unresolved in many cases, resulting in predominantly empirical treatment approaches. 

Recent research has demonstrated that a relevant fraction of structural epilepsies is caused by somatic genetic alterations in brain tissue. As these variants are typically not detectable in peripheral blood, they frequently remain undiagnosed in conventional genetic testing.

This project aims to systematically investigate molecular genetic alterations in patients with therapy-refractory structural epilepsies, with particular emphasis on tissue-specific somatic variants. The central questions are:

1. Which somatic and human germline molecular genetic alterations can be identified in epileptogenic brain tissue and corresponding blood samples?
2. How do these genetic findings correlate with epilepsy phenotype, underlying structural brain abnormalities, and clinical course?
3. What is the relationship between identified molecular alterations and therapeutic outcomes, including antiepileptic drug treatment and epilepsy surgery?
4. Can clinically and molecularly defined subgroups be delineated to refine current etiological classifications and better characterize insufficiently understood entities?
5. Which pathophysiological and potentially therapeutically relevant signalling pathways can be derived from these findings?

This study is a retrospective, non-interventional analysis of patients with therapy-refractory structural epilepsies and epilepsy syndromes treated at the Heidelberg University clinic. The cohort includes patients for whom brain tissue samples from diagnostic or therapeutic procedures are available, alongside valid consent for scientific use of data and specimens. Data collection will be retrospective and will comprise demographic, clinical, molecular genetic (germline and, if available, tissue-specific somatic variants), therapeutic, and outcome parameters. Statistical analysis will be conducted primarily descriptively using R. The study is non-invasive, involves no additional study-related interventions, and data evaluation will be performed in a pseudonymized manner in accordance with the ethical guidelines of the Medical Faculty Heidelberg.