It is time to move on

Tom Jacques and Barbora Benova published a timely review on genotype‐phenotype correlations in malformations of cortical development (MCD). MCD lesions are increasingly recognized by high and ultra‐high power MRI in patients with focal and drug‐resistant epilepsy 1, and many of these patients are excellent candidates for surgical treatment 5. Increasing availability of surgical human brain tissue specimens obtained from anatomically and functionally well‐characterized areas fostered neuropathology analysis to better classify the etiology and pathogenesis of human MCD. Hence, the overly large spectrum of morphological variants make any current histopathology‐based disease classification system difficult to apply 2, 3, 6, 7. It requires long experience with many surgical specimens, which is difficult to accomplish by most centers across the globe. International histopathology agreement studies support the notion of difficult‐to‐classify and ‐agree histopathology patterns in focal epilepsies 3, 9, 10. The authors of this current feature article promote the strategy, therefore, to integrate genetic analysis with histopathology patterns to reach a more reliable diagnosis and consensus classification system. They performed a systematic literature review of articles published between 2000 and 2017 which described studies with both, histopathology and genetic findings in MCD lesions. Seven genes harboring somatic brain mutations were identified in Focal Cortical Dysplasia (FCD) and germline mutations were detected in cortical tubers and FCD in eight genes, with three genes being identified in both conditions, that is TSC1, TSC2 and DEPDC5. The authors concluded that the PI3K/AKT/mTOR pathway is a major target of genetic alterations identified so far in MCD, although the exact pathogenesis by which the known gene mutation translates into a structural brain lesion or epileptogenic brain network remains to be further clarified 12, 17. Similar to the successful implementation of molecular‐genetic testing in human brain tumors, the authors propose a pipeline integrating histopathology with gene testing in human brain specimens obtained from epilepsy surgery to better understand the diverse genetic backgrounds and their correlation with phenotype.

In 2016, the implementation of the 4th revised edition of the WHO classification system of tumors of the nervous system achieved a successful translation of genetics and histopathology into an integrated genotype‐phenotype diagnostic scheme 20. Notwithstanding, this applies foremost to gliomas and embryonal brain tumors whereas less frequent tumor entities still await this transition, including those low‐grade glioneuronal epilepsy‐associated tumors often encountered in epilepsy surgery 3. It will take, therefore, concerted efforts from the entire community TO MOVE ON. Today, we already face a significant gap in the implementation of research data into clinical diagnostics for many epilepsy‐associated brain lesions, including MCD.

A major challenge in the genetic analysis of MCD is the broad phenotypic variability which derives from the complex neurodevelopmental programming of the human neocortex, the different time points of the acquired genetic or environmental impact and its targeted cell population, which will dissolve into an otherwise normal brain scaffolding 4, 12. In contrast to brain tumor specimens, however, in which clonal proliferation of cell progenies help to increase the detection rate in small tissue samples, maldevelopmental tissues often encounter small populations of affected neurons and/or glial cells amalgamated into the large population of apparently normal neurons, glia, vascular endothelia, blood leucocytes or mesenchymal cells from meninges and vessels. Intracerebral EEG recordings prior to surgical resection is often applied and causes brain inflammation and proliferation of reactive astrocytes, which adds further to the dilution of the target cell population in any somatic mutation analysis.

The International League against Epilepsy (ILAE) has recognized this challenge 21 and a Task Force was launched to update the successful and broadly used consensus classification of FCD 7. Indeed, FCD represents the vast majority of MCD in epilepsy surgery series representing roughly 75% of all cases 5. FCD type II shares intriguing histopathology features similar to those observed in hemimegalencephaly (HME) and cortical tubers (TSC) and up to now pathogenic somatic variants have been identified in roughly 25% of FCD cases. It is indeed the mTOR pathway being affected and same genes play a role in HME and TSC. It has already been proposed that HME, TSC and FCDII should be grouped together as mTORopathy rather than single etiological disease conditions 11, 12. The ILAE approach is to introduce those genetic variants reliably confirmed in multicenter studies into an integrated genotype‐phenotype classification system 21. Hence, difficulties to classify somatic gene variants in human brain tissue are also multifold, as reviewed recently 22. Nevertheless, there must be international consensus how to approach the issue of DNA extraction from Formalin‐fixed Paraffin‐embedded (FFPE) or fresh frozen tissue, of comparisons with blood DNA and the implementation of a validation strategy for any newly detected gene variant.

TIME WILL MOVE ON and the arena of focal epilepsies with its broad spectrum of brain lesions, including malformations, brain tumors and hippocampal sclerosis is increasingly approached with advanced molecular genetic testing protocols. The recently introduced methodology of DNA methylation analysis may offer another successful path to address this issue 8. Hence, epilepsies per se tend to change the methylation signature as shown in many human epilepsy tissues and animal models 13, 14, 15, 16. Similar to the challenging dilution of a target cell population in epilepsy tissues, it remains to be shown if FFPE material is reliable to achieve such measures or if we need to further develop low‐input protocols or enrich specific cell populations for such studies. Since technology has gained so much momentum for innovation, and economic interest spreads into the field of epilepsies, mainly because currently know mTOR pathway genes are targetable for personalized medicine 18, 19, we are hopeful to see such avenues and pipelines coming into action soon, as suggested by Jacques and Benova.