Background and purpose: Although the orexin system has an established role in narcolepsy, the mechanism of orexin deficiency in human cases is unknown. The strong association with human leukocyte antigen (HLA) DQB1*0602 suggests an autoimmune basis, but supporting evidence is lacking. Although data indicate that HLA status is not the sole genetic factor, only a single case of a functional orexin system mutation has been discovered, in a study with a selection bias designed to increase yield. In this study, we examined the prepro-orexin gene for mutations in a cohort of unrelated patients with narcolepsy from a national UK referral centre.
Patients and methods: Subjects with a diagnosis of narcolepsy were recruited from a patient database. DNA samples were obtained using buccal smear kits. The prepro-orexin gene was amplified using polymerase chain reactions and screened for polymorphisms and mutations.
Results: Eighty-one patients were recruited, of whom 69 provided DNA samples. A previously described intronic single nucleotide polymorphism, of unlikely significance, was identified in one subject who had typical clinical and electrophysiological features of narcolepsy. It was located 16 base pairs downstream from exon 1. No other mutations were found.
Conclusion: This result supports existing evidence which indicates that mutations of the prepro-orexin gene are rare and that the genetic contribution to the aetiology of human narcolepsy is likely to be complex.