Malformations of Cortical Development

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DESCRIPTION

  • Malformations of cortical development (MCDs) include a large group of heterogeneous disorders that occur due to disruption of the typical development of the cerebral cortex.
  • MCDs are associated with epilepsy, developmental delay, intellectual disability, and motor impairments.
  • Defining the specific malformation, and if possible, its genetic cause, has important prognostic and diagnostic value.
  • Classification schemes for MCDs are based on the stage of brain development first disrupted and imaging features.
  • Disorders of neurulation (neural tube closure, gestation days 21 to 26)
    • Disruptions to rostral neural tube closure may lead to encephalocele or anencephaly.
      • Anencephaly: Failure of rostral neural tube closure results in congenital absence of both cerebral hemispheres with preserved forebrain and upper brainstem.
      • Encephalocele: herniation of intracranial contents through a midline skull defect in the frontal or occipital regions
  • Disorders of prosencephalic development (gestation weeks 4 to 20)
    • The prosencephalon is the precursor to the cerebral hemispheres and deep nuclei.
      • Holoprosencephaly (HPE): three subtypes: alobar, semilobar, and lobar
      • Agenesis of the corpus callosum (ACC): Corpus callosum fails to develop, ranging from mild thinning to complete absence.
      • Septooptic dysplasia: hypoplasia of the optic nerve and pituitary plus midline abnormalities (ACC, absent septum pellucidum)
  • Disorders of neuronal-glial proliferation and apoptosis (peaks at 1 to 2 months gestation)
    • Microcephaly: orbitofrontal circumference (OFC, or head circumference) at or smaller than 2 SD below the patient’s age- and sex-related population mean; subclassified into primary microcephaly, which is noted at birth, and secondary or “acquired” microcephaly, which has onset after birth but typically within the first 2 years of life and is categorized as a disorder of abnormal postmigrational development
    • Megalencephaly: OFC >2 SD above the patient’s age- and sex-related population mean or brain weight >98th percentile for age
    • Focal cortical dysplasia (FCD) types IIa–b: localized disordered cortical lamination with morphologically abnormal cell types (IIa–dysmorphic neurons; IIb–dysmorphic neurons and balloon cells)
  • Disorders of cell migration (peaks at 5 months gestation)
    • Heterotopia: neuronal collections in the periventricular or subcortical white matter due to incomplete neuronal migration
    • Lissencephaly: a thick cerebral cortex with either no sulci or shallow sulci that gives the appearance of a smooth surface of the brain lacking gyral formation
    • Pachygyria: cortex containing a few coarse gyri and shallow sulci
    • Subcortical band heterotopia (double cortex): smooth circumferential band of subcortical gray matter just below the typical cortex, composed of incompletely migrated neurons
    • Cobblestone malformations (previously type II lissencephaly): protrusions of neurons over the brain surface into the subarachnoid space, giving the surface of the brain a cobblestone appearance; due to overmigration of neurons through gaps in the pial membrane
  • Disorders of abnormal postmigrational
    • Development/cortical organization
    • Polymicrogyria (PMG): cortex with excessive small gyri due to overfolding and lamination of the cortex; it may be focal, multifocal, bilateral, or generalized, and it may be subdivided based on location.
    • Schizencephaly: deep cleft lined with gray matter extending from the cortical surface to the ventricle; often PMG in or near cleft; subdivided into open-lip (cleft walls are separated) and closed-lip (cleft walls are in apposition); there may be bilateral or unilateral clefts.
    • Postmigrational microcephaly: See “Microcephaly” above.
    • FCD type Ia-c: localized abnormal cortical lamination with morphologically normal cells
    • FCD type III: Area of abnormal cortical lamination is adjacent to another principal lesion such as a vascular lesion.
    • Dysgyria: recently introduced term for a nonspecific malformation in which the cortex has an abnormal gyral pattern; it may be localized or generalized.

EPIDEMIOLOGY

  • The incidence varies depending on the specific malformation but is overall quite rare.
  • Estimated 40–50% of pediatric drug-resistant epilepsies treated surgically are due to an MCD.

ETIOLOGY

  • Genetics of MCD: Some MCDs are associated with germline variants, including both single nucleotide changes in individual genes and copy number variants involving multiple genes. These are rare, inherited, and more often de novo (not detectable in parents). Postzygotic mutation leads to de novo somatic mosaic variants in conditions such as FCD and hemimegalencephaly (HME); these conditions require genetic testing of the abnormal brain tissue, which can be done if patients undergo epilepsy surgery.
  • Examples of genetic causes of MCD:
    • HPE: Chromosomal abnormalities include trisomy 13 and 18; majority of nonsyndromic HPE is caused by monogenic mutation in genes such as SHH, SIX3, TGIF, and ZIC2.
    • Microcephaly: $20 genes
  • Primary microcephaly: Most genes affect pathways involved in neurogenesis and cell replication and include ASPM, CDK5RAP2, CENPJ, CEP152, DYNC1H, KATNB1, KIF5C, MCPH1, NDE1, STIL, and WDR62.
  • Postmigrational microcephaly: CASK, CDKL5, FOXG1, MECP2, QARS, RAB18, RAB3GAP1, RAB3GAP2, SLC9A6, TCF4, UBE3A
    • (Hemi) megalencephaly genes: genes in the MTOR pathway, including AKT3, DEPDC5, HRAS, KRAS, MTOR, NF1, NSD1, PIK3CA, PIK3R2, PTEN, TSC2
    • FCD II: genes in the MTOR pathway, including AKT3 (1q duplication), CNTNAP2, DEPDC5, MTOR, PIK3CA, PTEN
    • FCD I and mild oligodendroglial hyperplasia in epilepsy (MOGHE): SLC35A2
    • Periventricular nodular heterotopia genes: ARGEF2, FLNA, MAP1B, NEDD4L.
    • Lissencephaly and subcortical band heterotopia genes: ACTB, ACTG1, ARX, TUBA1A, TUBB2B, DCX, DYNC1H1, KIF2A, LIS1 (PAFAH1B1), RELN, TUBG, VLDLR
  • Miller-Dieker syndrome due to LIS1: lissencephaly, microcephaly, facial dysmorphism
  • ARX: X-linked lissencephaly with abnormal genitalia (males)
  • DCX: X-linked lissencephaly (males) and X-linked subcortical band heterotopia (females)
    • Cobblestone malformation: may be seen in Walker-Warburg syndrome, Fukuyama congenital muscular dystrophy (FCMD), muscle-eye-brain (MEB) disease, or disorders of glycosylation
  • Walker-Warburg syndrome or MEB: FKRP, ISPD, LARGE, POMGNT1, POMT1, POMT2
  • FCMD: FKTN
  • Glycosylation disorders: LAMB1, LAMB2, LAMC3, SRD5A3
    • PMG genes: AKT3, CCND2, COL18A1, DYNC1H1, FH, GPR56, KIF5C, OCLN1, PEX, PIK3CA, PIK3R2, PXMP, PXR, TUBA1A, TUBAB, TUBB2B, TUBB3, TUBB5, WDR62
  • Some malformations are associated with neurocutaneous syndromes.
  • Tuberous sclerosis complex (TSC): a multiorgan mTORopathy due to pathogenic variants in TSC1 and TSC2; mTORopathy refers to clinical syndromes (typically that feature MCDs and epilepsy) caused by genetic mutations that lead to dysregulation of signalling in the mammalian target of rapamycin (mTOR) signaling cascade. CNS involvement includes cortical tubers (discrete areas of dysplastic cortex), subependymal nodules, and subependymal giant cell tumors (SEGA).
  • HME: hypomelanosis of Ito, linear sebaceous nevus syndrome, Klippel-Trenaunay-Weber syndrome
  • Infectious
    • Schizencephaly, microcephaly, anencephaly, and PMG associated with various prenatal infections including CMV, herpes, LCMV, rubella, toxoplasmosis, and Zika virus
  • Vascular (ischemia or hemorrhage)
    • Schizencephaly: often caused by MCA territory prenatal infarcts
    • Genetic risk for perinatal intracranial ischemia or hemorrhage: COL4A1, COL4A2
    • PMG: prenatal hypoxic-ischemic injury
  • Toxins/exposures
    • Valproate: neural tube defects
    • Phenytoin: microcephaly with craniofacial anomalies
    • Ethanol, radiation, mercury, retinoids: HPE
    • Hyperthermia: neural tube defects, including encephalocele, anencephaly
  • Metabolic syndromes

RISK FACTORS

  • Risk factors associated with schizencephaly include young maternal age, alcohol consumption, and lack of early prenatal care.
  • Maternal diabetes increases the risk of HPE and neural tube defects.

PATHOPHYSIOLOGY

  • Any disruption to the development of the CNS during the prenatal stage may lead to an MCD. These disruptions include genetic variants present in the germline or that occur in the postzygotic developing embryo, metabolic derangements, infections, and toxic exposures.
  • The timing of infections and toxic etiologies is key in determining the resultant malformation.
  • Genes implicated in MCD are involved at multiple stages of embryogenesis.

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