class 18: malformations of cortical development

what developmental processes, when disrupted, lead to malformations of cortical development?

disruptions in neuronal proliferation (neurogenesis), radial & tangential neuronal migration, and post-migrational organization during corticogenesis (gestational weeks 8 - 24)

which two genes are most commonly mutated in classical lissencephaly?

LIS1 and DCX

why does subcortical band heterotopia occur in heterozygous females with DCX mutations?

x-linked gene. because of random X-chromosome inactivation in heterozygous females, mosaic population of cells is created

• neurons in which wild-type DCX gene is active migrate normally to cortical plate, whereas neurons expressing mutant DCX gene are impaired in migration & arrest prematurely in white matter, forming subcortical band

how does a GPR56 mutation cause polymicrogyria?

mutation impairs RhoA activation, causing radial glial end feet to detach & pial basement membrane to fragment.

• result: migrating neurons over migrate past proper termination zone into subpial space, leading to cortical disorganization

structural feature of cobblestone lissencephaly

bumpy, pebbled, or rough cortical surface caused by pial basement membrane breaches that allow neurons to over migrate into subpial space

structural feature of type 1 lissencephaly

smooth cortical surface and cortical thickening resulting from impaired neuronal migration that fails to reach outer layers

what is major gene implicated in periventricular nodular heterotopia (PVNH)?

FLNA (x-linked gene encoding filamin-A)

how does loss of FLNA function impair neuronal migration?

neurons fail to initiate or sustain radial migration and remain stranded near ventricular wall as ectopic nodules

FCD type 1 histology

characterized by mild architectural dyslamination w/ cytologically normal cells

FCD type 2 histology

characterized by severe cortical disorganization / dyslamination w/ dysmorphic neurons, divided into type IIa (without balloon cells) and type IIb (with balloon cells)

what type of genetic alteration underlies focal cortical dysplasia type 2 (FCD 2)?

FDC 2 is caused by post-zygotic (somatic) activating muttaions in genes within mTOR pathway.

• these non-inherited somatic mutations lead to hyper activation of mTOR signaling, driving cellular overgrowth

mTOR pathway inhibitors

targeted rapalogs such as Everolimus that restore cell growth regulation and reduce seizure frequency in mTORpathy-related lesions

neuromodulation

advanced electrical stimulation options including vagus nerve stimulation, targeting anterior thalamic nucleus

stem cell=derived neural progenitor replacement

transplanting normal or iPSC-derived neural progenitors (or inhibitory interneurons) into dysplastic cortex to repair circuitry and suppress hyper excitability

optogenetic and chemogenetic modulation

targeted silencing of hyper excitable pyramidal neurons or activation of interneurons using light or DREADDs

advanced closed-loop microstimulation

experimental devices combining real-time detection of epileptiform discharges with microstimulation to abort seizures before they generalize