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. 2020 Jan 26;5(1):97-106.
doi: 10.1002/epi4.12377. eCollection 2020 Mar.

mTOR pathway somatic variants and the molecular pathogenesis of hemimegalencephaly

Camila A B Garcia  1 , Simone C S Carvalho  2 , Xiaoxu Yang  3 , Laurel L Ball  3 , Renee D George  3 , Kiely N James  3 , Valentina Stanley  3 , Martin W Breuss  3 , Ursula Thomé  4 , Marcelo V Santos  1 , Fabiano P Saggioro  5 , Luciano Neder Serafini  5 , Wilson A Silva Jr  2   6 , Joseph G Gleeson  3 , Hélio R Machado  1
Affiliations

mTOR pathway somatic variants and the molecular pathogenesis of hemimegalencephaly

Camila A B Garcia et al. Epilepsia Open. .

Abstract

Objectives: Recently, defects in the protein kinase mTOR (mammalian target of rapamycin) and its associated pathway have been correlated with hemimegalencephaly (HME). mTOR acts as a central regulator of important physiological cellular functions such as growth and proliferation, metabolism, autophagy, death, and survival. This study was aimed at identifying specific variants in mTOR signaling pathway genes in patients diagnosed with HME.

Methods: Using amplicon and whole exome sequencing (WES) of resected brain and paired blood samples from five HME patients, we were able to identify pathogenic mosaic variants in the mTOR pathway genes MTOR, PIK3CA, and DEPDC5.

Results: These results strengthen the hypothesis that somatic variants in PI3K-Akt-mTOR pathway genes contribute to HME. We also describe one patient presenting with a pathogenic variant on DEPDC5 gene, which reinforces the role of DEPDC5 on cortical structural changes due to mTORC1 hyperactivation. These findings also provide insights into when in brain development these variants occurred. An early developmental variant is expected to affect a larger number of cells and to result in a larger malformation, whereas the same variant occurring later in development would cause a minor malformation.

Significance: In the future, numerous somatic variants in known or new genes will undoubtedly be revealed in resected brain samples, making it possible to draw correlations between genotypes and phenotypes and allow for a genetic clinical diagnosis that may help to predict a given patient's outcome.

Keywords: epilepsy; hemimegalencephaly; mTOR.

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Conflict of interest statement

We thank the support provided by the Research Support Foundation (FAEPA) of the University Hospital of Ribeirão Preto Medical School and the Center of Genomic Medicine, University Hospital, Ribeirão Preto Medical School (CMG/HCFMRP) for patient recruitment and sample preparation. This work was supported by grants from the Howard Hughes Medical Institute (to JGG), and Camila B. Garcia was recipient of a scholarship from the National Support Program for the Health Care of Persons with Disabilities (PRONAS/PCD) and Coordination of Improvement of Higher Education Personnel‐Brazil (CAPES). The authors confirm that they have read the journal's position on issues involved in ethical publication and affirm that this report is consistent with those guidelines.

Figures

Figure 1
Figure 1
A, INTERICTAL: Left frontal spikes (arrow). B, ICTAL EEG: Left frontal (arrow). ICTAL SEMIOLOGY: right head version with bilateral asymmetric tonic posture
Figure 2
Figure 2
Somatic‐positive HME cases exhibit MRI and histopathological findings. A, Tissue shows the presence of balloon cells by coloration hematoxylin and eosin and pre‐op FLAIR MRI left and right cerebral cerebellar volume increase, with lateral ventricular dilatation and periventricular hypersignal areas. B, Tissue shows cytomegalic and dysmorphic neurons, with accumulation of Nissel's substance at the periphery coloration hematoxylin/eosin, and pre‐op FLAIR MRI shows right hemisphere enlargement, cortical thickening, lateral ventricular dilatation, and periventricular hypersignal areas. C, Astrogliosis immunostained to GFAP and pre‐op T2 MRI shows evidence of signal change and morphology throughout the left hemisphere. D, Tissue shows the presence of heterotopic neurons in the white matter neocortex transition, immunostained to NeuN, and (E) tissues show neurofilaments accumulating in the body of dysplastic neurons immunostained for NeuN, and pre‐op FLAIR MRI shows increased right brain hemisphere volume and lateral ventricular dilatation. F, Tissue shows disorganization of the cortical layers IV, V, VI with neuronal loss by immunostaining for NeuN, and pre‐op FLAIR MRI shows increased left cerebral hemisphere volume, cortical thickening, lateral ventricular dilatation, and periventricular hypersignal areas
Figure 3
Figure 3
Schematic representation of the mTOR pathway annotated with pathogenic mutations identified in this study
See this image and copyright information in PMC

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