Cortical Dysplasia, Genetic Abnormalities and Neurocutaneous Syndromes

Abstract

Cortical dysplasia (CD) represents a common neuropathologic substrate of pediatric epilepsy, one frequently encountered in surgical resection specimens from infants and children with intractable seizure disorders, including infantile spasms. Severe CD shows similarities to structural features noted in tubers from individuals with tuberous sclerosis (TSC). The latter disorder, one with neurocutaneous and visceral manifestations, results from mutations in one of two recently cloned genes, TSC1 or TSC2, which encode (respectively) the proteins hamartin and tuberin. There is circumstantial evidence that both proteins may influence cell growth and differentiation, specifically that they may represent growth suppressors. Neither protein has a defined role in brain development. We discuss and illustrate neuropathologic features of both CD and TSC, and discuss the patterns and time course of hamartin/tuberin expression in normal brain, CD and TSC. Other recently cloned genes associated with cortical malformations encompassed by the term CD are briefly described.

Hamartin expression and interaction with tuberin in tumor cell lines and primary cultures

“…Cerebral arteriolar media, comprised of smooth muscle cells, exhibits variable hamartin immunoreactivity. No expression is observed in astrocyte or oligodendroglia cell populations, although cortical tubers of TSC patients, which contain cells with both neuronal and astrocytic characteristics, are variably immunoreactive for both hamartin and tuberin (Johnson et al, 1999; Vinters et al, 1999). Within viscera, hamartin is expressed in many tissues, with particularly high expression found in heart, kidney, bronchial epithelia and macrophages, pancreas, and regions of the adrenal cortex.…”

“…Western analysis has shown that primary fetal mouse astrocyte cultures express hamartin as well (Gutmann et al, 2000). In humans, hamartin is expressed in neuronal populations as early as gestational age 20 weeks, but is consistently absent from astrocytes, an expression pattern maintained into adulthood (Johnson et al, 1999; Plank et al, 1999; Vinters et al, 1999). A potentially important finding in the brain of a fetus with TSC was sub‐pial radial glia that were either absent or not expressing vimentin and GFAP in regions of cerebral cortex exhibiting cytoarchitectural abnormalities consistent with a cortical tuber, suggesting a possible explanation for abnormal neuronal migration in TSC (Park et al, 1997).…”

Hamartin and Tuberin Expression in Human Tissues

“…We have previously reported that hamartin and tuberin are expressed in similar neuronal populations within the human CNS as early as 20 weeks of gestation (17,20). This study was performed in order to compare the expression of the TSC gene products tuberin and hamartin in other human tissues at various prenatal and postnatal ages.…”

TACC3-TSC2 maintains nuclear envelope structure and controls cell division

“…84 These observations may be linked to the putative neuronal migration defect in TSC disease. 85,86 Interestingly, Tsc1 and Tsc2 have recently been shown to regulate axon formation and growth through the key polarity protein SAD kinase, 87 which also regulates cell cycle checkpoints. 88 The question of whether SAD integrates TACC3 with TSC1/TSC2 in neuronal and/or epithelial differentiation, in addition to regulating CHFR function, may appear as a fundamental issue in the study of TSC pathology.…”