Morphogenesis timing of genetically programmed brain malformations in relation to epilepsy

Cerebral malformations are best understood as abnormal tissue morphogenesis in the context of disorders of ontogenesis. In neuroembryology, the timing of onset and duration of abnormal genetic expression and neurodevelopmental processes are primordial and must always be assessed, regardless whether the dysgenesis is primarily genetic in origin or acquired in utero due to ischemia, fetal infarcts that interrupt cellular migration or exposure to teratogenic drugs or neurotoxins. Defective timing interferes with the synchrony between different developmental processes, such as synaptogenesis in relation to other aspects of neuronal maturation. Timing may be delay or arrest development at an immature stage or may be precocious but asynchronous with other developmental features. Focal cortical dysplasia (FCD) types 1 and 3 may be arrested maturation of the radial microcolumnar neocortical architecture that is normal in the first half of gestation, without the expected transition to a horizontal or tangential laminar cortical architecture in the second half. Lack of lamination in either the vertical or horizontal planes may be due to defective extracellular adhesion molecules that cause detachment of migratory neuroblasts from their radial glial guide fibers, to enable recently arriving neuroblasts to bypass those already in place within the cortical plate for the programmed inside-out neuronal arrangement. FCD type 2 has a different pathogenesis. The megalocytic and dysmorphic neurons may result from somatic mutations of some, but not all, neuronal precursors in the periventricular region. FCD2 and hemimegalencephaly (HME) may have the same pathogenesis, the principal difference being timing of onset within the 33 mitotic cycles of the periventricular neuroepithelium to exponentially produce the total neuronal population of the cerebral cortex: if the mutation occurs during the late mitotic cycles, FCD2 results as a small dysgenesis; if the mutation occurs in the early mitotic cycles, the distribution of abnormal neurons is more extensive and HME may result. Why some cerebral malformations are more epileptogenic than others, despite similar histological features, remains enigmatic but probably involves differences in synaptic circuitry among individual cases.