Sleep related hyper motor epilepsy (SHE): a unique syndrome with heterogeneous genetic etiologies

Abstract Sleep-related hypermotor epilepsy (SHE), formerly known as Nocturnal Frontal Lobe Epilepsy is a focal epilepsy characterized by seizures with complex hyperkinetic automatisms and/or asymmetric tonic/dystonic posturing occurring mostly during sleep. SHE is a rare disease with an estimated minimum prevalence of 1.8/100,000 individuals and represent about 10% of drug-resistant surgical cases. This disorder, though uncommon, is of considerable interest to a broad spectrum of specialists, from child neurologists to neurosurgeons. Distinguishing this condition from non-epileptic paroxysmal behaviour occurring physiologically or pathologically during sleep is often difficult and sometimes impossible on clinical grounds alone, even for experienced epileptologists and sleep physicians. Recognized aetiologies of SHE are heterogeneous and include acquired injuries, genetic causes and structural anomalies such as focal cortical dysplasia. Multiple aetiologies (structural-genetic) are also possible. Non-specific clinical features distinguished different aetiologies even if SHE due to structural lesions usually manifests with early-onset drug-resistant seizures and showed a worse long-term prognosis. The causative genes for SHE are multiple and encode for proteins involved in different molecular pathways. The cholinergic system and the mTOR pathway are the most relevant. This review will provide an exhaustive overview of the genetic background of SHE.