The role of the nicotinic acetylcholine receptors in sleep-related epilepsy.
The role of neuronal acetylcholine receptors (nAChRs) in epilepsy has been clearly established by the finding of mutations in a subset of genes coding for subunits of the nAChRs in a form of sleep-related epilepsy with familial occurrence in about 30% of probands and dominant inheritance, named autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE). Sporadic and familial forms have similar clinical and EEG features. Seizures begin in middle childhood as clusters of sleep-related attacks with prominent motor activity, and sustained dystonic posturing. In addition to nocturnal seizures, psychosis or schizophrenia, behavioral disorders, memory deficits and mental retardation were described in some individuals. Although over hundred families are on record, only a minority of them have been linked to mutations in the genes coding for the alpha4, alpha2 and beta2 (CHRNA4, CHRNA2, and CHRNB2) subunits of the nAChRs, indicating that ADNFLE is genetically heterogeneous despite a relatively homogeneous clinical picture. Functional characterization of some mutations suggests that gain of the receptor function might be the basis for epileptogenesis. In vitro and in vivo studies have shown high density of nAChRs in the thalamus, over activated brainstem ascending cholinergic pathway and enhanced GABAergic function, reinforcing the hypothesis that cortico-subcortical networks, regulating arousal from sleep, play a central role in seizure precipitation in ADNFLE.
Marini
Carla
C
Epilepsy, Neurophysiology and Neurogenetics Unit, Department of Child Neurology and Psychiatry, IRCCS Stella Maris Foundation, Pisa, Italy. carla.marini@inpe.unipi.it
Guerrini
Renzo
R
D000818:Animals; D004569:Electroencephalography; D017034:Epilepsy, Frontal Lobe / Q000209:etiology* / Q000235:genetics; D005838:Genotype; D006801:Humans; D009154:Mutation; D010641:Phenotype; D011978:Receptors, Nicotinic / Q000235:genetics / Q000502:physiology*; D012890:Sleep
D011978:Receptors, Nicotinic