Focal cortical dysplasia

Focal cortical dysplasia (FCD) was first described as a distinct neuropathological entity in 1971 by Taylor and colleagues. FCD is thought to be an embryological migration disorder and is thus considered a non-progressive, unchangeable disease throughout life 1).

Focal cortical dysplasia is a malformation of cortical development, which is the most common cause of drug resistant epilepsy in the pediatric population 2).

Focal cortical dysplasia (FCD) is a localized cortical malformation and considerable morphological overlap exists between Focal cortical dysplasia type II B (FCD IIB) and neurological lesions associated with Tuberous sclerosis complex (TSC). Abnormal mTOR pathway secondary to somatic mTOR mutation and TSC gene mutation linked to PI3K/AKT/mTOR pathway have supported the hypothesis of common pathogenesis involved.

Emergence of dysmorphic neurons is the primary pathology in focal cortical dysplasia (FCD) associated pediatric intractable epilepsy; however, the etiologies related to the development and function of dysmorphic neurons are not fully understood.

Previous studies revealed that the expression of vascular endothelial growth factor-C (VEGF-C) and corresponding receptors VEGFR-2, VEGFR-3 was increased in the epileptic lesions of patients with tuberous sclerosis complex or mesial temporal lobe epilepsy.

Shen etal. showed that the expression of VEGF-C, VEGFR-2, and VEGFR-3 was increased at both mRNA and protein levels in patients with cortical lesions of type I, IIa, and IIb FCD. The immunoreactivity of VEGF-C, VEGFR-2 and VEGFR-3 was located in the micro-columnar neurons in FCD type I lesions, dysplastic neurons (DNs) in FCD type IIa lesions, balloon cells (BCs) and astrocytes in FCD type IIb lesions. Additionally, the amplitude of evoked-EPSCs (eEPSC) mediated by NMDA receptor, the ratio of NMDA receptor- and AMPA receptor-mediated eEPSC were increased in the dysmorphic neurons of FCD rats established by prenatal X-ray radiation. Furthermore, NMDA receptor mediated current in dysmorphic neurons was further potentiated by exogenous administration of VEGF-C, however, could be antagonized by ki8751, the blocker of VEGFR-2. These results suggest that VEGF-C system participate in the pathogenesis of cortical lesions in patients with FCD in association with modulating NMDA receptor-mediated currents 3).

Often caused by somatic variants of the mTOR pathway genes. In this study, we performed a genetic analysis of epileptogenic brain malformed lesions from 64 patients with focal cortical dysplasia, hemimegalencephy, brain tumors, or hippocampal sclerosis. Targeted sequencing, whole-exome sequencing, and single nucleotide polymorphism microarray detected four germline and 35 somatic variants, comprising three copy number variants and 36 single nucleotide variants and indels in 37 patients. One of the somatic variants in focal cortical dysplasia type IIB was an in-frame deletion in MTOR, in which only gain-of-function missense variants have been reported. In focal cortical dysplasia type I, somatic variants of MAP2K1 and PTPN11 involved in the RAS/MAPK pathway were detected. The in-frame deletions of MTOR and MAP2K1 in this study resulted in the activation of the mTOR pathway in transiently transfected cells. In addition, the PTPN11 missense variant tended to elongate activation of the mTOR or RAS/MAPK pathway, depending on culture conditions. We demonstrate that epileptogenic brain malformed lesions except for focal cortical dysplasia type II arose from somatic variants of diverse genes but were eventually linked to the mTOR pathway 4).

Kuroda N, Fujimoto A, Enoki H, Arai Y, Okanishi T. A case of focal cortical dysplasia type Ib atypically showing reversible intensity changes on magnetic resonance imaging which could be affected by epileptic discharge activity. Childs Nerv Syst. 2019 Feb 27. doi: 10.1007/s00381-019-04093-4. [Epub ahead of print] PubMed PMID: 30810857.
Kabat J, Król P. Focal cortical dysplasia - review. Pol J Radiol. 2012 Apr;77(2):35-43. PubMed PMID: 22844307; PubMed Central PMCID: PMC3403799.
Shen KF, Duan QT, Duan W, Xu SL, An N, Ke YY, Wang LT, Liu SY, Yang H, Zhang CQ. Vascular endothelial growth factor-C modulates cortical NMDA receptor activity in cortical lesions of young patients and rat model with focal cortical dysplasia. Brain Pathol. 2022 Mar 8:e13065. doi: 10.1111/bpa.13065. Epub ahead of print. PMID: 35259773.
Fujita A, Kato M, Sugano H, Iimura Y, Suzuki H, Tohyama J, Fukuda M, Ito Y, Baba S, Okanishi T, Enoki H, Fujimoto A, Yamamoto A, Kawamura K, Kato S, Honda R, Ono T, Shiraishi H, Egawa K, Shirai K, Yamamoto S, Hayakawa I, Kawawaki H, Saida K, Tsuchida N, Uchiyama Y, Hamanaka K, Miyatake S, Mizuguchi T, Nakashima M, Saitsu H, Miyake N, Kakita A, Matsumoto N. An integrated genetic analysis of epileptogenic brain malformed lesions. Acta Neuropathol Commun. 2023 Mar 2;11(1):33. doi: 10.1186/s40478-023-01532-x. PMID: 36864519.
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