Malformations of Cortical Development and Epilepsy

Abstract

Malformations of cortical development (MCDs) are an important cause of epilepsy and an extremely interesting group of disorders from the perspective of brain development and its perturbations. Many new MCDs have been described in recent years as a result of improvements in imaging, genetic testing, and understanding of the effects of mutations on the ability of their protein products to correctly function within the molecular pathways by which the brain functions. In this review, most of the major MCDs are reviewed from a clinical, embryological, and genetic perspective. The most recent literature regarding clinical diagnosis, mechanisms of development, and future paths of research are discussed.

GRIN2Bencephalopathy: novel findings on phenotype, variant clustering, functional consequences and treatment aspects

“…This has also been referred to as tubulinopathy-related dysgyria. 29 Whereas tubulinopathies are classified as disorders of neuronal migration leading to cortical dysgenesis, 30 PMG is considered to be due to postmigrational disruption of cortical development with fusion of cortical laminae. 31 Knockdown of Grin2b in rat has been shown to disturb proper neuronal migration 32 and glutamate has been implemented in its regulation.…”

Malformations of cortical development

“…40 Disorders of MT formation/function result in multiple brain abnormalities, including microcephaly (impaired mitosis); lissencephaly, pachygyria, band heterotopia, and other types of cortical dysgenesis (impaired neuronal migration); anomalies of white matter tracts and cranial nerves (impaired axonal pathfinding); and malformations of the mid-and hindbrain (impairment of both neuronal migration and axonal pathfinding). 4 Highly associated with heterozygous missense mutations of tubulin and MAP genes, these malformations have a range of characteristic features on both physical (A,B), the most common appearance is blurring of the gray/white matter boundary (white arrows), seen here in the the left superior frontal gyrus. In FCD type IIb (C,D), abnormal "funnel"-shaped T2 hyperintensity (the transmantle sign, arrows in C) is seen within the left parietal lobe extending radially to the left lateral ventricle.…”

“…4 Highly associated with heterozygous missense mutations of tubulin and MAP genes, these malformations have a range of characteristic features on both physical examination and on imaging studies (best seen on structural MRI). Patients with tubulin mutations ( TUBA1A , TUBB2B , TUBB3 , and TUBG ) typically have a) microcephaly (impaired mitosis) (see Figure 1), b) varying degrees of cerebral cortical dysgenesis due to both undermigration (impaired neuronal migration along radial glia) and overmigration into the subarachnoid space secondary to defects in attachment of the radial glia to the glial/pial limiting membrane similar to cobblestone malformations 41 , c) absent or dysmorphic corpus callosum and other white matter pathways/cranial nerves (impaired axonal navigation, including cranial neuropathies) 42 , d) basal ganglia abnormalities (included fused striatum due to impaired formation of the anterior limb of the internal capsule), e) cortical ‘dysgyria’ (sometimes mistakenly called polymicrogyria; probably impaired neuronal migration and axonal navigation), and f) asymmetric brainstem and small cerebellar vermis (probably a combined defect of neuronal migration and axonal navigation) 11-13 (Table and Figure 4).…”

“…57 On MRI, Reelin pathway disorders result in a gradient of disorders ranging from a simplified gyral pattern with slight cortical thickening to frank lissencephaly with substantial thickening, an anterior to posterior gradient of gyration, and a variably small, smooth cerebellum with disproportionate vermian involvement (Table). 4 …”

“…57 On MRI, Reelin pathway disorders result in a gradient of disorders ranging from a simplified gyral pattern with slight cortical thickening to frank lissencephaly with substantial cortical thickening, an anterior to posterior gradient of gyration, and a variably small, smooth cerebellum with disproportionate vermian involvement (Table). 4 Gray Matter Heterotopia Neuronal accumulations in abnormal locations, commonly called heterotopia, vary widely in location and size; phenotypes vary from periventricular nodular heterotopia (PNH), which are thought to result from loss of radial glial cell attachment to disrupted neuroependyma, 58 to subcortical heterotopia (many types, causes not established) 59 to subpial heterotopia, which may be part of a continuum with cobblestone cortex, and likely result from loss of radial glial attachment to a disrupted glial limitans. 60 Disruption of the neuroepithelium (neuroependyma), likely attributed to membrane "gaps" and impaired adhesion of neural progenitors and radial glial cells to the neuroependyma, leads to impaired neuronal migration from the ventricular zone.…”