Neuroimaging and genetic characteristics of malformation of cortical development due to mTOR pathway dysregulation: clues for the epileptogenic lesions and indications for epilepsy surgery.

Hyperactivation of the mechanistic target of rapamycin complex 1 (mTORC1) due to mutations in genes along the PI3K-mTOR pathway and the GATOR1 complex causes a spectrum of neurodevelopmental disorders (termed mTORopathies) associated with malformation of cortical development and intractable epilepsy. Despite these gene variants’ converging impact on mTORC1 activity, emerging findings suggest that these variants contribute to epilepsy through both mTORC1-dependent and -independent mechanisms. Here, we review the literature on in utero electroporation-based animal models of mTORopathies, which recapitulate the brain mosaic pattern of mTORC1 hyperactivity, and compare the effects of distinct PI3K-mTOR pathway and GATOR1 complex gene variants on cortical development and epilepsy. We report the outcomes on cortical pyramidal neuronal placement, morphology, and electrophysiological phenotypes, and discuss some of the converging and diverging mechanisms responsible for these alterations and their contribution to epileptogenesis. We also discuss potential therapeutic strategies for epilepsy, beyond mTORC1 inhibition with rapamycin or everolimus, that could offer personalized medicine based on the gene variant.

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Compound heterozygous variants in LAMC3 in association with posterior periventricular nodular heterotopia

BMC Medical Genomics ◽

10.1186/s12920-021-00911-4 ◽

2021 ◽

Vol 14 (1) ◽

Author(s):

Carla De Angelis ◽

Alicia B. Byrne ◽

Rebecca Morrow ◽

Jinghua Feng ◽

Thuong Ha ◽

...

Keyword(s):

Cortical Development ◽

Occipital Cortex ◽

Compound Heterozygous ◽

Valuable Insight ◽

Periventricular Nodular Heterotopia ◽

Case Presentation ◽

Malformation Of Cortical Development ◽

Nodular Heterotopia ◽

Compound Heterozygous Variants ◽

Insight Into

Abstract Background Periventricular nodular heterotopia (PNH) is a malformation of cortical development characterized by nodules of abnormally migrated neurons. The cause of posteriorly placed PNH is not well characterised and we present a case that provides insights into the cause of posterior PNH. Case presentation We report a fetus with extensive posterior PNH in association with biallelic variants in LAMC3. LAMC3 mutations have previously been shown to cause polymicrogyria and pachygyria in the occipital cortex, but not PNH. The occipital location of PNH in our case and the proposed function of LAMC3 in cortical development suggest that the identified LAMC3 variants may be causal of PNH in this fetus. Conclusion We hypothesise that this finding extends the cortical phenotype associated with LAMC3 and provides valuable insight into genetic cause of posterior PNH.

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

Brain Pathology ◽

10.1111/bpa.12686 ◽

2019 ◽

Vol 29 (4) ◽

pp. 473-484 ◽

Cited By ~ 4

Author(s):

Barbora Benova ◽

Thomas S. Jacques

Keyword(s):

Epilepsy Surgery ◽

Cortical Development ◽

Pathological Diagnosis ◽

Malformations Of Cortical Development

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A case of mild malformation of cortical development with oligodendroglial hyperplasia and epilepsy (MOGHE)

Diagnostic radiology and radiotherapy ◽

10.22328/2079-5343-2021-12-3-93-100 ◽

2021 ◽

Vol 12 (3) ◽

pp. 93-100

Author(s):

V. S. Khalilov ◽

A. N. Kislyakov ◽

T. V. Basalay ◽

A. V. Levov ◽

A. A. Kholin

Keyword(s):

White Matter ◽

Frontal Lobe ◽

Focal Cortical Dysplasia ◽

Epileptiform Activity ◽

Cortical Development ◽

Dynamic Mri ◽

Subtotal Resection ◽

Pharmacoresistant Epilepsy ◽

Malformation Of Cortical Development ◽

The Right

Recently, in the scientist community of specialists dealing with structural epilepsy, it has been noticed an increasing interest in a special form of cortical development disorder not to be included in the ILAE Classification of the epilepsies the 2017 revision. It is so-called mild malformation of cortical development with oligodendroglial hyperplasia and epilepsy (MOGHE). There are a number of publications devoted to the neuroimaging features of MOGHE, which are possible to distinguish from other epileptogenic substrates in comparisons with clinical/anamnestic data and dynamic observation. Our paper describes the case of a patient under 6 years suffering from pharmacoresistant epilepsy with histologically confirmed MOGHE, and having undergone the procedure of epileptic surgery. MRI showed an increased intensity of the T2/FLAIR signal from the white matter in combination with signs of laminar hyperintensivity, regional sulcation disturbance, smoothness of gray-white matter demarcation in the right frontal lobe. A signal intensification from the white matter with the formation similarity of the «transmantl» sign and further pronounced smoothness of the gray-white matter demarcation was observed on dynamic MRI. These changes were estimated as focal cortical dysplasia. Pre-surgical examination revealed a correlation of epileptiform activity with MRI changes. The subtotal resection of the right frontal lobe and the morphological conclusion established the presence of MOGHE was performed.

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