Читать книгу Canine and Feline Epilepsy - Luisa De Risio - Страница 39

The major developmental disorders noted in humans giving rise to epilepsy are disorders of neuronal migration that may have genetic or intrauterine causes (Engelborghs et al., 2000). Abnormal patterns of neuronal migration lead to various forms of agyria or pachygyria whereas lesser degrees of failure of neuronal migration induce neuronal heterotopia in the subcortical white matter. Experimental data suggest that cortical malformations can both form epileptogenic foci and alter brain development such that diffuse hyperexcitability of the cortical network occurs (Chevassusau-Louis et al., 1999). Other studies revealed increases in postsynaptic glutamate receptors and decreases in GABAA receptors in micro-gyric cortex, which could promote epileptogenesis (Jacobs et al., 1999).

Periventricular heterotopia is a human X-linked dominant disorder of cerebral cortical development. Mutations in the filamin 1 gene prevent migration of cerebral cortical neurons causing periventricular heterotopia (Fox et al., 1998). Affected females present with epilepsy whereas affected males die embryonically.

Lissencephaly is a brain malformation characterized by a paucity of gyral formation and a thickening of the cerebral cortex. It is presumed to occur secondary to incomplete migration of immature neurons to the cortical plate during fetal development (Saito et al., 2002). Lissencephaly is considered to be the most severe type of neuronal migration disorder compatible with survival. In humans, it is presumed to result from an arrest of neuronal migration at approximately 3 to 4 months (Dobyns et al., 1993). Once they exit the cell cycle in the periventricular proliferative zone, immature neurons must migrate to the cortical plate along radial glial fibres (Rakic, 1988). The six layers of the cerebral cortex are formed in an ‘inside out’ pattern, with early migrating neurons forming the deep layer and later migrating neurons passing their migratory predecessors to form the superficial layers. Interruption at any stage of the process of neuronal migration may result in the arrest of neurons in an intermediate position between the periventricular zone and the cortex (Saito et al., 2002). Such an interruption may be due to a genetic lack of appropriate molecular cues, or secondary to non-genetic influences such as in utero infection or ischaemia. Secondary influences are a more common mechanism for the related cortical malformation, polymicrogyria.

In humans, mutations of two genes, LIS1 (located on 17p13.3) and DCX (located on Xq22.3), have been found to account for the majority of cases (Pilz et al., 1998). Both of these genes have been shown to have roles in neuronal migration by their interactions with the neuron microtubule network (Gleeson et al., 1999a; Sapir et al., 1999). X-linked lissencephaly and double cortex syndrome is a disorder of neuronal migration documented in humans. Double cortex or subcortical band heterotopias often occur in females whereas more severe lissencephaly is found in affected males. A causal mutation in a gene called doublecortin has been identified (Gleeson et al., 1998). It was suggested that doublecortin acts as an intracellular signalling molecule critical for the migration of developing neurons (Allen and Walsh, 1999; Gleeson et al., 1999b). Lissencephaly has been documented in Lhasa apsos with histopathology indicating the condition to be very similar to that seen in people (Greene et al., 1976; Saito et al., 2002). This condition has also been documented in a mixed breed dog and together with either cerebellar hypoplasia in two wire-haired fox terriers and three Irish setters, with cyclopia in one German shepherd-mixed breed dog, or with microencephaly in the Korat breed of cat (Saito et al., 2002; Lee et al., 2011).

Although these disorders are relatively rare, studying the underlying pathophysio-logical mechanisms may shed light on the pathophysiology of more common epileptic syndromes.