Malformations of cerebral cortical development can be grouped and classified by the stages of cortical development(1). Attendees of the lecture will learn these stages of cortical development, the malformations associated with each stage and will receive an overview of the genetics, cell signaling pathways (2) and microstructural alterations(3) that lead to a malformed cerebral cortex.Central nervous system development initiates with primary neurulation when the neuro tube closes between the 3^rd and 4^th gestational weeks of embryonic development. The formation of the prosencephalon (telencephalon and the diencephalon) is completed in the 2^nd and 3^rd months of gestation. At the end of these processes of diverticulation and cleavage, the net result are two distinct cerebral hemispheres. At the cellular level, the key player in the formation of the cerebral cortex is the radial glial fiber. The radial glial fiber has a cell body, a foot process that extends down toward the ventricle and a process that projects out to the pial surface. Two types of proliferation occur: symmetric proliferation of the radial glial fiber and asymmetric division with formation of a new neuronal progenitor cell. In the 3^rd and 4^th months of gestation, the radial glial fibers give birth to precursor neurons in a process known as neuronal proliferation. The process by which excess neuronal progenitors are pruned occurs as a result of apoptosis (programmed cell death).After the cell bodies divide and precursor neurons are generated, the next (overlapping) phase of cortical development proceeds. This phase is called neuronal migration and it occurs from the 3^rd to the 5^th month of gestation. These precursor neurons follow the course of the radial glial fibers from the sub ventricular zone out to the periphery where the cerebral cortex is formed. The precursor neurons are initially deposited at the inner margin of the developing cortex and subsequently migrating precursor neurons are laid down in successive layers out to the pial surface until the six layer organization of the neocortex is achieved. The initial radial organization of the primitive cortex slowly transitions to a laminated, arborized cerebral cortex by the 5^th gestational month through a process known as post migrational organization.

1.A Decreased Proliferation with Microcephaly

*Osteodysplastic Primordial Dwarfism: Seckel Syndrome

--> Seckel syndrome 1, on chromosome 3 (3q22-q24)

--> Seckel syndrome 2, on chromosome 18 (18p11.31-q11)

--> Seckel syndrome 3, on chromosome 14 (14q21-q22)

*Osteodysplastic Primordial Dwarfism Type II

--> Autosomal recessive: Chromosome 21 (21q22)

--> Mutation in the PCNT gene, encoding pericentrin

--> Short stature and developmental delay

--> Brain aneurysms, dental & ocular abnormalities

1.B Increased Proliferation with Megalencephaly

*Macrocephaly-Capillary Malformation

--> Mutation in the mTOR pathway: The mammalian target of rapamycin.

--> mTOR pathway serves as a central regulator of cell metabolism, growth, proliferation & survival

--> Mutation of PIK3CA

*MPPH Syndrome

--> Megalencephaly-Polymicrogyria-Polydactyly-Hydrocephalus

--> mTOR pathway mutations of AKT3 & PIK3R2

1.C Abnormal Proliferation without Neoplasia

*Hemimegalencephaly

--> Associated with somatic mutations in PIK3CA, AKT3 in the mTOR pathway

*Type II Focal Cortical Dysplasia

--> mTOR pathway mutations including PTEN

*Tuberous Sclerosis

--> mTOR pathway mutations in TSC1 and TSC2

1.D Abnormal Proliferation with Neoplasia

*Dysembryoplastic Neuroepithelial Tumor

*Ganglioglioma

II.A Malformations with Neuroependymal Abnormalities

*Periventricular Nodular Heterotopia

--> Classical x-linked bilateral PNH: Mutations in filamin A (FLNA), Rarely seen with Ehlers-Danlos syndrome

--> Autosomal recessive PNH with microcephaly: Mutations in ARFGEF2 gene

--> Autosomal dominant with hydrocephalus

--> PNH due to 5p15 rearrangements

--> PNH with callosal dysgenesis and coloboma: Balanced translocation of 2p24 and 9q32

--> PNH due to reciprocal translocation: t(1;6)(p12;p12:2)

II.B Malformations Due to Generalized Abnormal Transmantle Migration

*Lissencephaly

--> Incomplete neuronal migration to the cerebral cortex

--> LIS1: Hemizygous deletion or mutation

--> XLIS or DCX: Lissencephaly in homozygous males, Subcortical band heterotopia in carrier females

--> Some cases are attributed to TUBA1A deficiency, which interferes with microtubule function and neuronal migration

*Pachygyria

*Laminar Heterotopia

II.C Malformations Presumably Due to Localized Abnormal Late Radial or Tangential Transmantle Migration

*Subcortical Heterotopia

*Transmantle Heterotopia

II.D Malformations Due to Abnormal Terminal Migration and Defects in Pial Limiting Membrane

Cobblestone Cortex

*Walker-Warburg Syndrome

--> Mutations in genes responsible for glycosylation of α-dystroglycan (POMT1, POMT2, ISPD, FKTN, FKRP, & LARGE)

--> Agyria

--> Cerebellar PMG with cysts

--> Hypoplastic cerebellar vermis and cerebellar hemispheres

--> Hypoplastic pons

--> Kinked brain stem

--> Unmyelinated white matter

III.A Malformations with Polymicrogyria (PMG) or Cortical Malformations Resembling PMG

*PMG (classic) with transmantle clefts (schizencephaly) or calcification

--> Abnormality of neuronal migration causing a gray matter lined cleft coursing from ventricular ependyma to pial surface

--> Location: 44% frontal, 30% frontoparietal, 19% occipital, bilateral in 35-50%

--> Described as open lip versus closed lip

--> Some cases related to intrauterine CMV exposure

--> Some have mutations in EMX2, SIX3, SHH, or COL4A1

*Polymicrogyria Syndromes

--> Bilateral frontal polymicrogyria

--> Bilateral frontoparietal polymicrogyria

--> Bilateral perisylvian polymicrogyria

--> Bilateral parasagittal parieto-occipital polymicrogyria

--> Bilateral generalized polymicrogyria

--> …

Syndromes with PMG

--> Aicardi syndrome

--> Fronto-parietal PMG, variable ACC and delayed myelination of anterior limb internal capsule with TUBB2B mutations at 6p25.2

III.B Cortical Dysgenesis Due to Inborn Errors of Metabolism

Non-ketotic Hyperglycinemia

Glutaric Aciduria Type II

Zellweger Syndrome

III.C Focal Cortical Dysplasia without Dysmorphic Neurons

FCD I

FCD III

III.D Postmigrational Microcephaly

*Angelman Syndrome

--> Chromosome 15: UBE3A gene

--> Delayed development, intellectual disability, severe speech impairment, ataxia, and epilepsy

--> Microcephaly and delayed myelination

Malformations of cortical development can occur as the result of an error in any of the stages of cortical development. The table presented is a framework of the types of malformations that result at each stage. This is not an exhaustive list. Many examples from this framework are presented in the lecture (indicated by *).