Mutations of the orexin system, a regulator of sleep arousal, are not a common cause of ADNFLE

Gain-of-function mutations in genes coding for subunits of the neuronal nicotinic acetylcholine receptor have been identified in 15% of families with autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE),¹ and in the promoter of the corticotropin-releasing hormone (CRH) gene.¹ In remaining families, the responsible genes are unknown. Patients with ADNFLE typically present many seizures per night involving intense motor agitation (frenetic movements of the trunk and limbs or sequence of various dystonic postures) lasting less than 1 minute. There are no clinical differences between families with and without identified mutations.

The seizures seem to occur at the time of arousal from nonrapid eye movement (non-REM) sleep stage 2.² Clinical and EEG observations and the identification by in vivo nuclear imaging in patients with ADNFLE carrying nicotinic receptor mutations of an increased nicotinic receptor density in the brainstem, suggesting a hyperactivity of the brainstem-thalamic cholinergic ascending arousal pathway, led to ADNFLE being considered as an arousal disorder.³

In parallel to the cholinergic system, the orexin/hypocretin system is also involved in inducing arousal from sleep. Orexin neurons, like cholinergic neurons, discharge …