Brain malformations, epilepsy, and infantile spasms.
The models of cortical dysplasia discussed earlier--the Lis1 knockout, the MAM-induced cobblestone LIS, the spontaneous tish mutant, and focal freeze injury-induced PMG--illustrate several important insights into epileptogenesis in malformed brain. First, the appearance of epilepsy varies according to the pathogenesis of the dysplasia and may well depend more on the intrinsic properties of the neurons in these models rather than on the disturbed position of the cells. This is supported by models such as the reeler mouse, in which the dysfunctional extracellular matrix molecule leads to a form of lissencephaly in mouse and human, but there is a far less impressive association with seizures than for LIS1 mutations. However, Lis1 and Dex mutations that appear to affect the cytoskeleton and perhaps intracellular protein trafficking are frequently associated with infantile spasms and epilepsy. Second, the possible mechanisms of epileptogenesis in these models include (a) a loss of subsets of neurons, (b) altered neurotransmitter release, (c) differences in neurotransmitter receptor levels and changes in receptor subunit composition, (d) altered neurite density and/or synaptogenesis, (e) changed membrane properties (e.g., altered voltage-gated channels), (f) altered cell morphology (neuronal differentiation), and (g) effects on cytoskeletal function. Finally, it is important to note that the "generator" of excitability in affected brain may be within the heterotopia or in the normotopic cortex. As additional genetic models come to light and the ability to distinguish their clinical counterparts improves, more individually tailored therapies, including standards for surgical interventions, will surely evolve.
Ross
M Elizabeth
ME
Department of Neurology and Neuroscience, Weill Medical College of Cornell University, New York, New York 10021, USA.
D043203:1-Alkyl-2-acetylglycerophosphocholine Esterase; D000818:Animals; D001921:Brain / Q000002:abnormalities*; D002886:Chromosomes, Human, Pair 17; D000013:Congenital Abnormalities / Q000235:genetics; D000089622:Doublecortin Domain Proteins; D004827:Epilepsy / Q000209:etiology*; D008040:Genetic Linkage; D006801:Humans; D007223:Infant; D008869:Microtubule-Associated Proteins / Q000235:genetics; D009479:Neuropeptides / Q000235:genetics; D013036:Spasms, Infantile / Q000209:etiology*
D000089622:Doublecortin Domain Proteins; D008869:Microtubule-Associated Proteins; D009479:Neuropeptides; D043203:1-Alkyl-2-acetylglycerophosphocholine Esterase; C084102:PAFAH1B1 protein, human; C513190:Pafah1b1 protein, mouse