Autosomal dominant nocturnal frontal lobe epilepsy (
ADNFLE) is a
focal epilepsy with attacks typically arising in the frontal lobe during non-rapid eye movement (NREM) sleep. It is characterized by clusters of complex and stereotyped hypermotor
seizures, frequently accompanied by sudden arousals. Cognitive and psychiatric symptoms may be also observed. Approximately 12% of the
ADNFLE families carry mutations on genes coding for subunits of the heteromeric neuronal
nicotinic receptors (nAChRs). This is consistent with the widespread expression of these receptors, particularly the α4β2(*) subtype, in the neocortex and thalamus. However, understanding how mutant nAChRs lead to partial frontal
epilepsy is far from being straightforward because of the complexity of the
cholinergic regulation in both developing and mature brains. The relation with the sleep-waking cycle must be also explained. We discuss some possible pathogenetic mechanisms in the light of recent advances about the nAChR role in prefrontal regions as well as the studies carried out in murine models of
ADNFLE. Functional evidence points to alterations in prefrontal
GABA release, and the synaptic unbalance probably arises during the cortical circuit maturation. Although most of the available functional evidence concerns mutations on nAChR subunit genes, other genes have been recently implicated in the disease, such as KCNT1 (coding for a Na(+)-dependent K(+) channel), DEPD5 (Disheveled, Egl-10 and
Pleckstrin Domain-containing
protein 5), and CRH (
Corticotropin-Releasing Hormone). Overall, the uncertainties about both the etiology and the pathogenesis of
ADNFLE point to the current gaps in our knowledge the regulation of neuronal networks in the cerebral cortex.