Genotype-phenotype correlations in focal malformations of cortical development: a pathway to integrated pathological diagnosis in epilepsy surgery

Abstract

Malformations of cortical development (MCD) comprise a broad spectrum of developmental brain abnormalities. Patients presenting with MCDs often suffer from drug-resistant focal epilepsy, and some become candidates for epilepsy surgery. Their likelihood of achieving freedom from seizures, however, remains uncertain, and depends in a major part on the underlying pathology. Tissue samples obtained in epilepsy surgery form the basis of definite histopathological diagnosis; however, new molecular genetic methods have not yet been implemented in diagnostic processes for MCD cases. Furthermore, it has not been completely understood how the underlying pathology affects patients' outcomes after epilepsy surgery. We performed a systematic literature review of studies describing both histopathological and molecular genetic findings in MCD, along with studies on epilepsy surgery outcomes. We aimed to correlate the genetic causes with the underlying morphological abnormalities in focal cortical malformations and to stress the importance of the underlying biology for patient management and counseling. From the summarized findings of multiple authors, it is obvious that MCD may have a diverse genetic background despite a similar or even identical histopathological picture. Even though most of their molecular genetic findings converge on various levels of the PI3K/AKT/mTOR pathway, the exact mechanisms underlying MCD formation have not yet been completely described or indeed how this pathway generates a diverse range of histological abnormalities. Based on our findings, we therefore propose that all patients diagnosed and operated for drug-resistant epilepsy should have an integrated molecular and pathological diagnosis similar to the current practice in brain tumor diagnostic processes that might lead to more accurate diagnosis and effective stratification of patients undergoing epilepsy surgery.

Keywords: mTOR; epilepsy surgery; malformations of cortical development; neuropathology; somatic variant.

Figure 1

Overview of the proposed diagnostic work‐up for patients with MCD.

Figure 2

Overview of the proposed approach toward incorporating molecular genetic methods in clinical and research practice. Brain by Simon Stratford from the Noun Project. Gene by Nithinan Tatah from the Noun Project. Human body by H Alberto Gongora from the Noun Project.

Figure 3

Summary of the genes involved in formation of FCD type IIa, type IIb and type I. The bottom photomicrograph shows FCD type Ia, but the genes described are involved in the formation of the respective types of FCD type I (for details see Tables 1 and 2). The schematic picture of the brain refers to somatic variants and the schematic picture of the human body refers to germline variants. Brain by Simon Stratford from the Noun Project. Human body by H Alberto Gongora from the Noun Project.