Molecular diagnostics in drug‐resistant focal epilepsy define new disease entities

Abstract

Structural brain lesions, including the broad range of malformations of cortical development (MCD) and glioneuronal tumors, are among the most common causes of drug‐resistant focal epilepsy. Epilepsy surgery can provide a curative treatment option in respective patients. The currently available pre‐surgical multi‐modal diagnostic armamentarium includes high‐ and ultra‐high resolution magnetic resonance imaging (MRI) and intracerebral EEG to identify a focal structural brain lesion as epilepsy underlying etiology. However, specificity and accuracy in diagnosing the type of lesion have proven to be limited. Moreover, the diagnostic process does not stop with the decision for surgery. The neuropathological diagnosis remains the gold standard for disease classification and patient stratification, but is particularly complex with high inter‐observer variability. Here, the identification of lesion‐specific mosaic variants together with epigenetic profiling of lesional brain tissue became new tools to more reliably identify disease entities. In this review, we will discuss how the paradigm shifts from histopathology toward an integrated diagnostic approach in cancer and the more recent development of the DNA methylation‐based brain tumor classifier have started to influence epilepsy diagnostics. Some examples will be highlighted showing how the diagnosis and our mechanistic understanding of difficult to classify structural brain lesions associated with focal epilepsy has improved with molecular genetic data being considered in decision making.

The ILAE consensus classification of focal cortical dysplasia: An update proposed by an ad hoc task force of the ILAE diagnostic methods commission

“…56 The dysregulation of the mTOR signaling pathway provides the rational mechanistic basis for a direct link between gene mutation and brain pathology involving dysmorphic neurons, balloon cells, oligodendrocytes, and astrocytes. 12,14,61 In contrast, a double hit with a germline and somatic lossof-function variant in repressors of the pathway (i.e., DEPDC5, NPRL2, NPRL3, TSC) is necessary for the expression of the brain lesion. Definite somatic second-hit events, either single nucleotide variants 19,60,62,63 or lossof-heterozygosity (LOH) 51,57 of the second allele leading to biallelic gene inactivation of DEPDC5 have now been reported, validating the two-hit model for mTORpathway repressor genes.…”

Developmental and epileptic encephalopathies after negative or inconclusive genetic testing: what is next?

“…Even in research, taking in account that individuals usually agree to share their whole data, access is usually a very limited process to ensure compliance. Strategies must be developed to capitalize on previous as well as future data and fully exploit the powerful collective data in order to assist the interpretation of genetic variation for patient care [76] . The balance between data sharing and maintaining confidentiality will ultimately impact our diagnostic capacity in the future.…”

Cutting-Edge Classification of Focal Cortical Dysplasia for Epilepsy Surgery

“…Separately, ongoing studies of FCD surgical specimens are revealing a growing number of both germline and somatic mutations that appear to be pathogenic. 2 Based on the latter it may be time to update the classification of FCDs. The novel study by Blümcke et al 3 is a significant step forward in the diagnosis and classification of patients with FCDs who may undergo surgical resection to treat epilepsy because it combines standard histological findings with immunohistology and genetic features.…”

“… 8 Moreover, many Type IIb (especially bottom-of-the sulcus frontal lobe) lesions are found to contain germline and/or somatic gain-of-function mutations in the mTOR pathway. 1 , 2 , 8 A newer entity called mild malformation of cortical development with oligodendroglial hyperplasia (MOGHE) is often also located in the frontal lobe and is frequently associated with somatic mutations in the SLC35A2 gene affecting the glycosylation pathway. In contrast, genetic mutations have not commonly been seen thus far in FCD Type I lesions, but recent unpublished data, reviewed by Blümcke and colleagues, 1 suggest that DNA methylation patterns could distinguish Type Ia from other FCD types.…”

“…Interestingly, both BCs and DNs carry aberrant DEPDC5 genes suggesting that the somatic mutation occurs early in a progenitor of both glia and neurons. 2 , 10 …”