Review Outlines Latest Updates, Unmet Needs in Type 1 Narcolepsy Research

Type 1 narcolepsy (NT1) is a severe neurological disorder characterized by the loss of hypocretin/orexin neurons, which is linked with associated symptoms of chronic sleepiness cataplexy, a key diagnostic marker for NT1 that is not found in type 2 narcolepsy (NT2).

Similar to other hypersomnolence disorders, NT1 shares the component of severe sleepiness during the day. However, as a review authored by Hanna M. Ollila, PhD, and published in the journal Sleep notes, these related disorders are not shown to be associated with cataplexy, warranting further investigation into the genetic factors contributing to NT1.

“This perspective will synthesize the genetic associations in hypersomnolence disorders focusing on NT1, compare findings with population-level symptoms of sleepiness and long sleep duration, challenge separating normal sleep regulation from clinical sleep disorders, and finally examine potential functional mechanisms that lead to disease,” expanded Ollila.

Researchers note that genetic studies have focused mainly on NT1, with research pointing to an autoimmune distinction rather than psychiatric origin. Notably, a variant of the human leukocyte antigen (HLA), known as DQB1*06:02, is associated with a nearly 20-fold increased risk of NT1, making it the most impactful risk factor for the condition.

The discovery of the HLA variant in association with NT1 has sparked newfound possibility of immunity. Moreover, these genetic associations have sparked research into T-cell receptor change usage, which can assist in identifying additional regulatory regions in NT1.

While promising in this specific area, the lack of genetic mechanisms uncovered for related hypersomnolence disorders, such as NT2 and idiopathic hypersomnia, limits the widespread understanding of this field. Additionally, as studies have yet to prove causality for hypocretin cell destruction through autoimmune mechanisms, these efforts require further research.

“Genetic studies are now needed to explore causal effects across different hypersomnolence disorders and validate the role of previously suggested environmental triggers and differences in these diseases,” said Ollila.

Ollila highlighted the potential of genetics in delineating the overlapping mechanisms of NT1, NT2, and other hypersomnolence disorders, but cited the need for clear phenotypic characterization and to examine shared and unique disease risk factors.

To do this, Ollila signaled the need to collect a sufficient sample size to study all hypersomnia disorders, perform deeper phenotyping, and include atypical cases in genetic studies to reveal the underlying disease mechanisms in these disorders. “These mechanisms will serve as starting point for validating disease mechanisms in hypersomnolence disorders, and for understanding novel, yet unexplored disease mechanisms across hypersomnolence disorders,” concluded Ollila.

Reference

Ollila HM. Narcolepsy type 1: what have we learned from genetics? Sleep. Published online May 22, 2020. doi:10.1093/sleep/zsaa099