Narcolepsy

Narcolepsy most commonly begins during childhood, adolescence, or early adulthood, although symptoms may develop at any age. The hallmark symptoms include:

• Excessive daytime sleepiness
• Sudden sleep attacks
• Cataplexy (sudden muscle weakness triggered by emotions)
• Sleep paralysis
• Vivid hallucinations during sleep onset or awakening
• Fragmented nighttime sleep
• Cognitive difficulties, including problems with attention and concentration

Two major forms of narcolepsy are currently recognised:

Narcolepsy Type 1

• Excessive daytime sleepiness
• Cataplexy and/or low cerebrospinal fluid hypocretin (orexin) levels

Narcolepsy Type 2

• Excessive daytime sleepiness without cataplexy
• Normal or undetermined hypocretin levels

Symptoms typically persist throughout life, although their severity may fluctuate over time and often improves with appropriate treatment.

Narcolepsy affects approximately 1 in 2,000 individuals in North America and Europe, although the condition is believed to be significantly underdiagnosed. Many patients experience symptoms for years before receiving a correct diagnosis.

The prevalence of HLA-DQB106:02 is substantially higher than the prevalence of narcolepsy itself. A considerable proportion of the general population carries the allele, while the vast majority of patients with narcolepsy type 1 are HLA-DQB106:02 positive. This highlights the strong association between the genetic marker and disease susceptibility while demonstrating its limited predictive value as a stand-alone test.

The exact cause of narcolepsy is not yet fully understood. Current evidence suggests that disease development results from a complex interaction between:

• Genetic susceptibility
• Immune system dysregulation
• Environmental influences
• Loss of hypocretin (orexin)-producing neurons in the hypothalamus

In narcolepsy type 1, the disorder is strongly associated with a deficiency of hypocretin (also known as orexin), a neurotransmitter that plays a critical role in maintaining wakefulness and stabilising the sleep–wake cycle. Most patients with narcolepsy type 1 have a substantial loss of hypocretin-producing neurons.

The strong association with HLA-DQB1*06:02 supports the hypothesis that autoimmune mechanisms contribute to disease development. However, no single genetic factor fully explains narcolepsy, and additional genetic and environmental influences are believed to be involved.

HLA-DQB1*06:02 is an inherited genetic variant located within the HLA region on chromosome 6. Although the allele strongly increases susceptibility to narcolepsy, most carriers never develop the disorder.

Family studies have demonstrated an increased risk of narcolepsy among first-degree relatives of affected individuals, suggesting a significant genetic contribution. Nevertheless, environmental and immunological factors are also required for disease development.

A negative HLA-DQB1*06:02 result makes narcolepsy type 1 considerably less likely, but it does not completely exclude the diagnosis.

HLA-DQB1*06:02 testing can be a useful component of the diagnostic evaluation in patients with suspected narcolepsy.

Testing may be particularly helpful in individuals with:

• Excessive daytime sleepiness
• Suspected cataplexy
• Sleep paralysis
• Hypnagogic or hypnopompic hallucinations
• Unexplained hypersomnia
• Atypical sleep disorder presentations

When interpreted together with clinical findings and sleep laboratory studies, including polysomnography and the Multiple Sleep Latency Test (MSLT), a positive HLA-DQB1*06:02 result can increase diagnostic confidence.

However, HLA-DQB106:02 testing should not be used as a general population screening tool. Because many healthy individuals carry the allele, a positive result alone is not diagnostic. Conversely, the absence of HLA-DQB106:02 has a high negative predictive value, particularly in patients suspected of having narcolepsy type 1.

Consequently, HLA testing is most valuable when performed as part of a comprehensive clinical and sleep medicine evaluation.

• MedlinePlus Genetics. Narcolepsy [Internet]. Bethesda (MD): National Library of Medicine. Available from:
• National Institute of Neurological Disorders and Stroke. Narcolepsy [Internet]. Bethesda (MD): National Institute of Neurological Disorders and Stroke. Available from:
• National Heart, Lung, and Blood Institute. Narcolepsy [Internet]. Bethesda (MD): National Heart, Lung, and Blood Institute. Available from:
• MedlinePlus Genetics. HLA-DQB1 gene [Internet]. Bethesda (MD): National Library of Medicine. Available from:
• Chabas D, Taheri S, Renier C, Mignot E. The genetics of narcolepsy. Annu Rev Genomics Hum Genet. 2003;4:459-83. doi:10.1146/annurev.genom.4.070802.110432. PMID:.