Genetics of Narcolepsy and Other Sleep Disorders

Mignot, Emmanuel

doi:10.1086/515487

Cited by 44 publications

(20 citation statements)

References 159 publications

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“…26 A difference in the occurrence of familial cases, however, may reflect either founder effects or the influence of local environmental factors. 27 It seems possible that the onset of the disease is recognized earlier in families with hereditary RLS because of the increased awareness of RLS symptoms. This could be one reason for the significantly younger age of onset in hereditary RLS.…”

Section: Discussionmentioning

confidence: 99%

Clinical Characteristics and Frequency of the Hereditary Restless Legs Syndrome in a Population of 300 Patients

Winkelmann

Wetter

Collado-Seidel

et al. 2000

Sleep

319

152

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Section: Discussionmentioning

confidence: 99%

Clinical Characteristics and Frequency of the Hereditary Restless Legs Syndrome in a Population of 300 Patients

Winkelmann

Wetter

Collado-Seidel

et al. 2000

Sleep

319

152

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“…A genetic association of narcolepsy with HLA-DR2 and HLA-DQ1 in the major histocompatibility (MHC) region was described more than 25 years ago [37]. Mignot et al discovered that HLA DQA1*01:02 and DQB1*06:02 are the primary candidate susceptibility genes for narcolepsy in the HLA class II region and reported that complex HLA-DR and -DQ interactions contribute to the genetic predisposition to human narcolepsy [38,39]. Additional studies established that more than 85% of patients diagnosed with narcolepsy with cataplexy have HLA DQB1*06:02, often in combination with HLA DR2 (DRB1*1501), while only half of patients displaying atypical, mild, or narcolepsy without cataplexy have HLA DQB1*06:02 [40].…”

Section: Introductionmentioning

confidence: 99%

Genetic association, seasonal infections and autoimmune basis of narcolepsy

Singh¹,

Mahlios²,

Mignot³

2013

Journal of Autoimmunity

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In recent years, a growing number of potential autoimmune disorders affecting neurons in the central nervous system have been identified, including narcolepsy. Narcolepsy is a lifelong sleep disorder characterized by excessive daytime sleepiness with irresistible sleep attacks, cataplexy (sudden bilateral loss of muscle tone), hypnagogic hallucinations, and abnormalities of Rapid Eye Movement sleep. Narcolepsy is generally a sporadic disorder and is caused by the loss of hypocretin (orexin)-producing neurons in the hypothalamus region of the brain. Studies have established that more than 90% of patients have a genetic association with HLA DQB1*06:02. Genome-wide association analysis shows a strong association between narcolepsy and polymorphisms in the TCRα locus and weaker associations within TNFSF4 (also called OX40L), Cathepsin H and the P2RY11-DNMT1 (purinergic receptor subtype P2Y11 to DNMT1, a DNA methytransferase) loci, suggesting an autoimmune basis. Mutations in DNMT1 have also been reported to cause narcolepsy in association with a complex neurological syndrome, suggesting the importance of DNA methylation in the pathology. More recently, narcolepsy was identified in association with seasonal streptococcus, H1N1 infections and following AS03-adjuvanted pH1N1 influenza vaccination in Northern Europe. Potential immunological pathways responsible for the loss of hypocretin producing neurons in these cases may be molecular mimicry or bystander activation. Specific autoantibodies or T cells cross-reactive with hypocretin neurons have not yet been identified, however, thus narcolepsy does not meet Witebsky’s criteria for an autoimmune disease. As the brain is not an easily accessible organ, mechanisms of disease initiation and progression remain a challenge to researchers.

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“…Only 1–2% of first degree relatives share narcolepsy diagnoses, which represents a 10–40× increased risk factor compared to the general population (Mignot, 1998). Monozygotic twins that have narcolepsy with cataplexy are only 25–30% concordant for the disorder (Mignot, 1997). While this evidence supports a role for environmental factors to contribute to narcolepsy onset, genetic predisposition is clearly important.…”

Section: Overview Of Narcolepsymentioning

confidence: 99%

Challenges in the development of therapeutics for narcolepsy

Black

Yamanaka

Kilduff

2017

Progress in Neurobiology

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Narcolepsy is a neurological disorder that afflicts 1 in 2000 individuals and is characterized by excessive daytime sleepiness and cataplexy—a sudden loss of muscle tone triggered by positive emotions. Features of narcolepsy include dysregulation of arousal state boundaries as well as autonomic and metabolic disturbances. Disruption of neurotransmission through the hypocretin/orexin (Hcrt) system, usually by degeneration of the HCRT-producing neurons in the posterior hypothalamus, results in narcolepsy. The cause of Hcrt neurodegeneration is unknown but thought to be related to autoimmune processes. Current treatments for narcolepsy are symptomatic, including wake-promoting therapeutics that increase presynaptic dopamine release and anticataplectic agents that activate monoaminergic neurotransmission. Sodium oxybate is the only medication approved by the US Food and Drug Administration that alleviates both sleep/wake disturbances and cataplexy. Development of therapeutics for narcolepsy has been challenged by historical misunderstanding of the disease, its many disparate symptoms and, until recently, its unknown etiology. Animal models have been essential to elucidating the neuropathology underlying narcolepsy. These models have also aided understanding the neurobiology of the Hcrt system, mechanisms of cataplexy, and the pharmacology of narcolepsy medications. Transgenic rodent models will be critical in the development of novel therapeutics for the treatment of narcolepsy, particularly efforts directed to overcome challenges in the development of hypocretin replacement therapy.

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Genetics of Narcolepsy and Other Sleep Disorders

Cited by 44 publications

References 159 publications

Clinical Characteristics and Frequency of the Hereditary Restless Legs Syndrome in a Population of 300 Patients

Clinical Characteristics and Frequency of the Hereditary Restless Legs Syndrome in a Population of 300 Patients

Genetic association, seasonal infections and autoimmune basis of narcolepsy

Challenges in the development of therapeutics for narcolepsy

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