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Overview Edit

Narcolepsy is an a CNS disorder that is characterized by the inability of the body to regulate sleep-wake cycles, leading to increased and often sudden bouts of sleep during the day and premature entry into REM sleep, often directly after falling asleep.[1]

Disease CharacteristicsEdit

Hypocretin

Human hypocretin protein structure pdb ref

Narcolepsy is caused by an inability to regulate the chemical hypocretin (also known as orexin), a peptide neurotransmitter that has been discovered to be involved in the sleep-wake cycle and general wakefulness. Low levels of, or poor response to, hypocretin can be attributed to various factors. The most notable of these is the autoimmune destruction of hypocretin containing cells, which is thought to be the main cause of genetically inherited predisposition to narcolepsy.[2] This disorder can also be accompanied by sudden muscle weakness called cataplexy in respon se to emotional stimuli, hallucinations, sleep paralysis, mental clouding, memory issues, depression, and exhaustion.[1] Narcolepsy can be diagnosed through having a patient fill out a questionnaire regarding their sleep susceptibility during specific tasks, as well as tests monitoring a patient utilizing electrical readings from the brain and muscles during the sleep process. Treatment is generally carried out through scheduled naps, stimulant drugs to ward off the onset of daytime sleep, and drugs that help treat cataplexy if it is present in an individual's specific case of narcolepsy.[3]

Genetic Basis of Narcolepsy in Relation to John Burke's 23andMe data Edit

Narcolepsy stats

Manhattan plot from Faraco et al. showing association between specific genes and narcolepsy, specifically the TNFSF4 and TRCA genes. A higher -Log 10(P) Value corresponds to higher association[4]

Narcolepsy in people of European ancestry can be attributed to three specific SNP markers having a high association with the observed phenotype: rs1154155, rs7553711, and rs2305795. Depending on what the actual nucleotide change in the SNP is, and individual can have an a varying increase in susceptibility, normal susceptibility, or a reduced susceptibility to narcolepsy compared to the general public.[5] The rs1154155 SNP has been identified to be a change in the J region of the T-cell receptor alpha protein consistent with narcolepsy in a SNP selective chip assay carried out with samples from a total of 1,886 patients that met the criteria of cataplexic narcolepsy characterized by reduced hypocretin and 7,898 control samples. All of the samples involved in the study were from individuals of european origin. These proteins are involved in immune response and recognizing molecules for immune response, and a mutation here (T>G) has been implicated in the autoimmune recognition and response to hypocretin containing cells. The same study found a connection to the T>C SNP rs7553711 associated with Tumor Necrosis Factor superfamily member 4 (TNFSF4), which was the SNP in the study found to have the strongest relation to narcolepsy. The proteins expressed by the TNFSF4 gene have been found to increase T-cell proliferation and survival and ability to resist suppression that may lead the autoimmune response that targets hypocretin.[4] Another study utilizing a RT-PCR based 5' genotyping assay to determine narcolepsy markers in a variety of ethnic backgrounds including European, Asian, and African. The SNP in question, rs2305795, is a G>A mutation in the 3' untranslated region of the P2RY11 gene which encodes for a version of the purinergic receptor subtype 2Y11 that has a reduced function in comparison to the wild type version. There is not much known about how this receptor and mutations in it can have an effect on narcolepsy, however it is speculated that it holds an important role in increasing immune responses in the brain that target Hypocretin containing dendritic cells when their responses are modulated by this SNP.[6]

In terms of John Burke, his rs1154155 and rs2305795 SNPs show typical odds for narcolepsy in relation to the population of European ancestry, having TT and AG genotypes respectively. In terms of rs7553711, there is a slightly higher chance of developing narcolepsy with genotype CT. This is not as high of a chance as is possible, however, because the genotype is not the heterozygous CC version.

SourcesEdit

  1. 1.0 1.1 What is Narcolepsy? NIH Public Health Information (2010)
  2. M. Hungs and E. Mignot. (2001) Hypocretin/orexin, sleep and narcolepsy. BioEssays 23:397-408 [1]
  3. Narcolepsy University of Maryland Medical Center (2013)
  4. 4.0 4.1 J. Faraco et al. (Feb 2013) ImmunoChip Study Implicates Antigen Presentation to T Cells in Narcolepsy. PLoS Genet. 9(2): e1003270. PubMed
  5. Narcolepsy Overview 23andME Health and Traits info.
  6. B. Kornum et al. (July 2011) Common variants in P2RY11 are associated with narcolepsy. Nat Genet. 43(1):66-71 PubMed