09 Jun New Research Sheds Light on the Causes of Narcolepsy
Study Supports a Causal Role in Narcolepsy for a Common Genetic Variant
Results show a remarkable genetic association of almost 100%
American Academy of Sleep Medicine
A new study conducted across Europe found an extraordinary association between narcolepsy and a specific gene variant related to the immune system. The modified genome-wide association study involved 1,261 people with narcolepsy, representing nearly 90% of European patients suffering from narcolepsy with cataplexy who have complete diagnostic work-up and DNA available. They were matched with 1,422 controls. High-resolution genotyping identified genetic variants including those in the human leukocyte antigen (HLA) system, which contains genes related to immune system function. Analysis was performed by logistic regression.
Results show that participants with the HLA allele DQB1*06:02 were 251 times more likely to have narcolepsy with cataplexy than participants without the gene variant. DQB1*06:02 had a remarkably high negative predictive value of 99.32 percent, which means that nearly 100 percent of narcolepsy with cataplexy patients are DQB1*06:02 positive. Four other DQB1 alleles provided protection against narcolepsy, strongly supporting a causal role for DQB1 in narcolepsy.
“For the first time we have tested the HLA association all over Europe,” said principal investigator and lead author Mehdi Tafti, professor in the Center for Integrative Genomics at the University of Lausanne and Lausanne Hospital in Switzerland. “This almost 100 percent association with HLA is somehow unique to narcolepsy and suggests a causal implication.”
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Orexin Neurons Suppress Narcolepsy via 2 Distinct Efferent Pathways
The Journal of Clinical Investigation
The loss of orexin neurons in humans is associated with the sleep disorder narcolepsy, which is characterized by excessive daytime sleepiness and cataplexy. Mice lacking orexin peptides, orexin neurons, or orexin receptors recapitulate human narcolepsy phenotypes, further highlighting a critical role for orexin signaling in the maintenance of wakefulness. Despite the known role of orexin neurons in narcolepsy, the precise neural mechanisms downstream of these neurons remain unknown. We found that targeted restoration of orexin receptor expression in the dorsal raphe (DR) and in the locus coeruleus (LC) of mice lacking orexin receptors inhibited cataplexy-like episodes and pathological fragmentation of wakefulness (i.e., sleepiness), respectively. The suppression of cataplexy-like episodes correlated with the number of serotonergic neurons restored with orexin receptor expression in the DR, while the consolidation of fragmented wakefulness correlated with the number of noradrenergic neurons restored in the LC. Furthermore, pharmacogenetic activation of these neurons using designer receptor exclusively activated by designer drug (DREADD) technology ameliorated narcolepsy in mice lacking orexin neurons. These results suggest that DR serotonergic and LC noradrenergic neurons play differential roles in orexin neuron–dependent regulation of sleep/wakefulness and highlight a pharmacogenetic approach for the amelioration of narcolepsy.
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