Focal Cortical Dysplasia Type II: Somatic Mutations, Molecular Mechanisms, and Integrative Multi-Omics Framework.

BACKGROUND

Focal cortical dysplasia Type II (FCD II) is a major cause of drug-resistant epilepsy in children. Somatic mosaic variants affecting the PI3K-AKT-mTOR pathway are implicated in a substantial proportion of cases. The links between genotype, cellular pathology, epileptogenic networks, and clinical outcome remain incompletely defined.

METHODS

This review synthesizes evidence on somatic mTOR-pathway variants, lesion development, pathological cell populations, circuit mechanisms, single-cell and spatial multi-omics approaches in FCD II.

RESULTS

The developmental timing, lineage distribution, and local expansion of somatic variants influence lesion extent and phenotypic heterogeneity. Dysmorphic neurons may contribute to epileptogenicity through altered intrinsic excitability and synaptic function, whereas balloon cells may predominantly affect local circuits through secretory and microenvironmental mechanisms. mTOR hyperactivation may also alter interneuron development, subtype specification, and synaptic connectivity, thereby disrupting excitation-inhibition balance. Single-cell and spatial approaches, including RNA velocity, pseudotime analysis, chromatin-age inference, and somatic genotyping, provide tools to resolve pathological cell states and lineage trajectories.

CONCLUSIONS

FCD II should be considered a mosaic developmental disorder involving both cell-autonomous and non-cell-autonomous mechanisms. Integrating somatic variant detection with cellular, spatial, electrophysiological, and surgical outcomes from matched patient tissue may enable biologically meaningful stratification and support the development of novel therapies.