Focal cortical dysplasia type II: review of neuropathological manifestations and pathogenetic mechanisms

Abstract

Focal cortical dysplasia (FCD) is an important cause of intractable epilepsy, with FCD type II (FCD II) being the most common subtype. FCD II is characterized by cortical dyslamination accompanied by dysmorphic neurons (DNs). Identifying the molecular alterations and targetable biomarkers is pivotal for developing therapies. Here, we provide a detailed description of the neuropathological manifestations of FCD II, including morphological alterations and immunophenotypic profiles, indicating that abnormal cells exhibit a diverse spectrum of mixed differentiation states. Furthermore, we summarize current research on the pathogenetic mechanisms, indicating that gene mutations, epigenetic alterations, cortical developmental protein disturbances, inflammatory processes, and extrinsic damages may lead to abnormal neuronal proliferation and migration, thereby contributing to the emergence and progression of FCD II. These findings not only enhance our understanding of the pathogenesis of FCD II but also offer new directions for clinical diagnosis and treatment. Future research should further explore the interactions among these factors and employ multidisciplinary approaches to advance our understanding of FCD II.

Keywords: Abnormal differentiation; Epigenetic alterations; Focal cortical dysplasia; Gene mutations.

Fig. 1

The schematic depicts the architectural and cellular abnormalities in FCD II. In FCD II, lamination is virtually absent, except for an expanded layer I. Dysmorphic pyramidal neurons and cytomegalic interneurons are dispersed throughout layers II to VI, frequently extending into the white matter. In FCD IIb, BCs are predominantly observed in the upper layers and within the white matter

Fig. 2

The pathogenic mechanisms in FCD II. Gene mutations, epigenetic alterations, cortical developmental protein disturbances, inflammatory processes, and extrinsic damages may contribute to the emergence and progression of FCD II

Fig. 3

The mTOR pathway and its regulators. mTOR is a protein kinase present in the cell in two complexes: mTORC1 and mTORC2. mTORC1 is related to cell size and proliferation, whereas mTORC2 influences cytoskeleton dynamics. Activation of the PI3K-Akt pathway leads to the inactivation of the TSC1/TSC2 complex, resulting in the indirect activation of mTORC1. PTEN inhibits the PI3K-Akt pathway. Furthermore, PI3K signaling also activates mTORC2. The GATOR1 complex, composed of DEP domain-containing protein 5 (DEPDC5), nitrogen permease regulator-like 2 (Nprl2), and nitrogen permease regulator-like 3 (Nprl3), inhibits mTORC1 signaling by repressing Ras-related GTP-binding protein A/B (RagA/B). Rapamycin binds to FK506-binding protein 12 (FKBP12) and inhibits mTORC1. Red diamonds indicate the proteins whose corresponding genes are mutated in FCD II

Fig. 4

Two hypothesized pathogenetic mechanisms underlying the presence of pS6-positive DNs in FCD II include: (1) activation of the upstream mTOR pathway, and (2) involvement of inflammatory processes