What is the genetic basis of narcolepsy (hypersomnia disorder of central origin)?

From the Guidelines

Narcolepsy, particularly type 1, has a strong genetic basis associated with the degeneration of hypothalamic neurons that produce orexin, and is linked to the HLA-DQB1*06:02 gene variant, although the exact genetic mechanism in the context of Prader-Willi Syndrome (PWS) may differ. The study published in the Journal of Clinical Sleep Medicine in 2022 1 highlights that while patients with PWS have lower levels of orexin in the cerebrospinal fluid, the levels are not as low as those found in patients with narcolepsy type 1, suggesting a different underlying mechanism. Key points to consider include:

• The genetic basis of narcolepsy involves an autoimmune destruction of hypocretin (orexin)-producing neurons in the hypothalamus, which is strongly associated with the HLA-DQB1*06:02 gene variant.
• In the context of PWS, the genetic basis of narcolepsy may not involve the same level of degeneration of orexin-producing neurons as in typical narcolepsy type 1, as indicated by higher orexin levels in the cerebrospinal fluid of PWS patients compared to narcolepsy type 1 patients 1.
• The presence of the HLA-DQB1*06:02 gene variant is a significant risk factor for narcolepsy, but it is not the sole cause, and environmental triggers such as infections or head trauma may also play a role.
• Family studies have shown that first-degree relatives of narcolepsy patients have a higher risk of developing the condition, indicating a genetic component to the disease.
• Genetic testing for narcolepsy is not routinely recommended, as clinical evaluation and sleep studies provide more definitive diagnostic information, according to the study 1.

The exact genetic mechanism underlying narcolepsy in PWS may involve a generalized 24-hour state of hypoarousal, rather than a direct destruction of orexin-producing neurons, as suggested by the study 1. In clinical practice, the diagnosis of narcolepsy should be based on a combination of clinical evaluation, sleep studies, and measurement of hypocretin levels in cerebrospinal fluid, rather than genetic testing alone.

From the Research

Genetic Basis of Narcolepsy

The genetic basis of narcolepsy is complex and involves multiple genetic variants. Key findings include:

• Narcolepsy is strongly associated with the HLA-DQB1*06:02 allele, with almost all patients with narcolepsy type 1 (NT1) carrying this allele 2, 3, 4, 5, 6
• Genome-wide association studies have identified polymorphisms in T-cell receptor loci and other genomic variations associated with NT1 2, 3
• Rare variants associated with NT1 have also been identified by DNA genome sequencing 3
• The HLA-DQA1*0102 allele is also associated with narcolepsy, particularly in Chinese patients 5
• Specific amino acids, such as serine182 and threonine185, located on the epitope of the DQβ1 chain receptor, may contribute to the susceptibility to narcolepsy 4

Genetic Variants and Narcolepsy Symptoms

Different genetic variants have been associated with specific symptoms of narcolepsy, including:

• HLA-DQB10602-positive patients have significant differences in orexin-A levels, presence or absence of cataplexy, and sleep parameters compared to HLA-DQB10602-negative patients 5
• HLA-DQA10102-positive patients have significant differences in disease course, presence or absence of sudden onset, and sleep parameters compared to HLA-DQA10102-negative patients 5
• Homozygous individuals with HLA-DQB10602/DQA10102 have a shorter mean REM latency in the MSLT and greater genetic susceptibility to narcolepsy 5

Autoimmune Etiology

Narcolepsy is believed to be an autoimmune disorder, with an autoimmune process probable 2, 3, 6

• The exact mechanisms of the autoimmune process are not fully understood, but it is thought to involve the loss of signaling by hypocretin-producing neurons 2
• Environmental factors may trigger the autoimmune response, leading to the development of narcolepsy 3, 6