Review: Mechanistic target of rapamycin (mTOR) pathway, focal cortical dysplasia and epilepsy

Abstract

E. Marsan, S. Baulac (2018) Neuropathology and Applied Neurobiology 44, 6-17 Mechanistic target of rapamycin (mTOR) pathway, focal cortical dysplasia and epilepsy Over the last decade, there has been increasing evidence that hyperactivation of the mechanistic target of rapamycin (mTOR) pathway is a hallmark of malformations of cortical development such as focal cortical dysplasia (FCD) or hemimegalencephaly. The mTOR pathway governs protein and lipid synthesis, cell growth and proliferation as well as metabolism and autophagy. The molecular genetic aetiology of mTOR hyperactivation has only been recently clarified. This article will review the current and still evolving genetic advances in the elucidation of the molecular basis of FCD. Activating somatic mutations in the MTOR gene are to date the most frequent mutations found in FCD brain specimens.

Genomic DNA methylation distinguishes subtypes of human focal cortical dysplasia

“…Furthermore, in silico pathogenicity prediction results were inconclusive, segregation studies were not possible in the families, and none of the control cases exhibited seizures at any point before death/ sampling. Activation of mTOR signaling has been postulated in FCD II, 37 but analysis of mRNA profiling data for our panel of mTOR pathway-related genes did not identify changes in gene expression. However, we found seven genes (FOXO6, GNAQ, PHLPP1, PDPK1, TSC2, DEPDC5, and CNTNAP2) to be differentially methylated either in their promoter region or gene body (Table 1, Figure S4).…”

Somatic Depdc5 deletion recapitulates electroclinical features of human focal cortical dysplasia type IIA

“…A plausible emerging hypothesis is that DEPDC5 germline LoF mutation together with a second biallelic somatic hit in DEPDC5 itself lead to the development of FCD, known as “two-hit” mechanism initially described in cancer and tuberous sclerosis[9]. This biallelic inactivation hypothesis is also supported by a recent report of a DEPDC5 somatic nonsense variant in the resected brain tissue from an individual with FCD IIA and a familial history of focal epilepsy due to a germline mutation in DEPDC5 [9]. Pathologically, both cell autonomous and cell non-autonomous mTOR hyperactivation were observed in our model, in line with the clinical observation that FCD histologic and electrographic abnormality occur beyond the MRI margin[17].…”

“…8 Germline or somatic DEPDC5 mutations are increasingly recognized as the common cause of familial or sporadic FEs including monogenic entities such as familial focal epilepsy with variable foci, autosomal dominant nocturnal frontal lobe epilepsy, and familial temporal lobe epilepsy. 9 In addition to its role in magnetic resonance imaging (MRI)-negative FEs, DEPDC5 has also been associated with epileptogenic structural brain malformations, from FCD to large cortical malformations, such as hemimegalencephaly. 8 DEPDC5 is part of a complex named GAP activity toward RAGs complex 1 (GATOR1), together with the proteins NPRL2 and NPRL3.…”

2017 WONOEP appraisal: Studying epilepsy as a network disease using systems biology approaches

“…Moreover, new bioinformatic tools and databases such as ClinVar 5 have been developed to connect researchers who have identified similar rare variants in their patients to compare clinical phenotypes. For example, mutations in mTOR-pathway genes have been associated with pediatric brain tumors, brain malformations, intractable epilepsy, autism, learning disability, and mental retardation, 9 but not all carriers of these mutations manifest all of these phenotypes to the same degree. 6 The sequencing of novel variants is a highly advanced field.…”

“…Clinical phenotypes associated with single mutations vary widely to expose a spectrum of outcomes. For example, mutations in mTOR-pathway genes have been associated with pediatric brain tumors, brain malformations, intractable epilepsy, autism, learning disability, and mental retardation, 9 but not all carriers of these mutations manifest all of these phenotypes to the same degree. 10,11 Variants in ion channels 12 and γ-aminobutyric acid receptors 13 are also pleiotropic and arise in complex profiles in the epilepsy and general populations.…”