Genetic Aspects Of Narcolepsy

A genetic component to narcolepsy was suggested by Westphal's (1877) initial report, in which both the patient and his mother were afflicted with the condition. Recent studies have, though, indicated that narcolepsy-cataplexy is only rarely a familial disorder. Only 1 to 2% of first-degree narcolepsy relatives ever develop the disorder;29 it is interesting to note however, that this 1 to 2% increase in risk represents a 20 to 40-fold increased risk over the prevalence in the general population (0.02-0.18%), suggesting genetic effects or shared environmental factors, as this increase in risk is too low for simple Mendelian inheritance. However, single families without HLA-DQB1*0602 and a high familial transmission have been also been reported, suggesting genetic heterogeneity.29 Therefore, narcolepsy must be considered a complex, multigenic disorder that is in part, environmentally determined.

Only 25 to 31% of monozygotic twins are concordant for narcolepsy.29 In one case, low and high CSF hypocretin-1 levels were reported in monozygotic twins with and without narcolepsy, respectively.30 Symptomatic concordance in monozygotic twins has been reported in the face of HLA-DQB1*0602 positivity with normal hypocretin levels31 or in the context of HLA negativity.29 This suggests that some non-HLA, non-hypocretin-mediated cases of narcolepsy may have a yet undetermined genetic basis. As discordant twins can develop narcolepsy later in life in association with environmental triggers such as emotional stress or chronic sleep deprivation,32 additional, non-genetic factors are likely to be associated with the onset of the disease.

A familial tendency for narcolepsy has also been suggested by animal studies. Narcolepsy was first reported in canines in 197312 and, like humans, most canine cases are sporadic. However, in 1976, a genetic form of canine narcolepsy was discovered in Dobermans and Labradors,33 from which a colony of narcoleptic canines was established. Extensive neurophysiologic and neuro-pharmacological studies were conducted using this canine model, demonstrating clinical similarities with the human disorder;14 affected dogs display emotionally-triggered cataplexy often elicited by food or by play, fragmented sleep, and a short sleep latency. In Doberman Pinschers, Labrador Retrievers and in a family of Dachshunds, narcolepsy is transmitted as a single autosomal recessive trait with high penetrance. In 1999, the gene causing this familial form of canine narcolepsy in the former two breeds was localized within an 800-kb region of canine chromosome 12 and positionally cloned;34 this was followed two years later by the identification of a single novel point mutation in the Hcrtr2 gene in a narcoleptic Dachshund multiplex family (E54K).35 Hypocretin gene mutations have not been detected in the sporadic form of canine narcolepsy, but these dogs do have an absence of the hypocretin peptide in the CSF and the brain36 as in human narcoleptics, suggesting a

Narcolepsy Chromosome

Figure 1 HLA DR and HLA DQ alleles most typically observed in narcoleptic patients. Modified from . The genes located on the short arm of chromosome 6 encode heterodimeric HLA proteins. The HLA DQB1 and DQA1 genes located 85kb centromeric to the gene DRB1, on chromosome 6p21. Initial serological typing of the 80' revealed the DR2, DR5, and DQ1 subtypes. These HLA antigens have been further split into two allelic subtypes, DR15 and DR16 on the one hand, and DQ5 and DQ6 on the other hand, and with the use of highresolution serological typing, all narcoleptic patients are positive for DR15 and DQ6. Subsequent highresolution DNA sequencing or oligotyping have identified molecular subtypes of DR15 and DQ6: Caucasians and Asians are DRB1*1501, DQA1*0102-DQB1*0602, while Blacks are more often DRB1*1503, DQA1*0102-DQB1*0602. In addition, some African Americans are negative for DR2 but generally carry the DR11 subtype DRB1*1101.

Figure 1 HLA DR and HLA DQ alleles most typically observed in narcoleptic patients. Modified from . The genes located on the short arm of chromosome 6 encode heterodimeric HLA proteins. The HLA DQB1 and DQA1 genes located 85kb centromeric to the gene DRB1, on chromosome 6p21. Initial serological typing of the 80' revealed the DR2, DR5, and DQ1 subtypes. These HLA antigens have been further split into two allelic subtypes, DR15 and DR16 on the one hand, and DQ5 and DQ6 on the other hand, and with the use of highresolution serological typing, all narcoleptic patients are positive for DR15 and DQ6. Subsequent highresolution DNA sequencing or oligotyping have identified molecular subtypes of DR15 and DQ6: Caucasians and Asians are DRB1*1501, DQA1*0102-DQB1*0602, while Blacks are more often DRB1*1503, DQA1*0102-DQB1*0602. In addition, some African Americans are negative for DR2 but generally carry the DR11 subtype DRB1*1101.

similar pathogenesis. It is of interest to note however, that sporadic canines do not share a single dog leukocyte antigen DLA-DQ allele.38,39

After the discovery of the Hcrtr2 gene mutation in dogs, several studies in human narcoleptics looked for similar mutations in the genes for Hcrt and its receptors (Hcrtr1 and Hcrtr2). Peyron and colleagues21 screened 74 patients with narcolepsy, using familial cases and otherwise "unusual" cases of narcolepsy-cataplexy with the expectation that mutations would be more readily detected, but no hypocretin receptor mutations specific to narcolepsy were found. Furthermore, while frequent Hcrtr1 and Hcrtr2 polymorphisms were identified, they were also not associated with the disorder;40 other corroborating studies have since been published.39,41 However, in one atypical case of narcolepsy (cataplexy presenting at the age of 6 months), a heterozygous mutation within the secretory signal sequence of the prepro-hypocretin (peptide precursor) gene was observed.21. Functional studies indicated that this mutation impaired trafficking and processing of the peptide, leading to intracellular accumulation, and presumably to cell death.21

Honda, Juji, and colleagues42 in Japan were the first to report that 100% of narcoleptics with cataplexy were positive for HLA-DR2 (Figure 1), a tight association subsequently confirmed in Europe and North America.25 About 25% of the normal Caucasian and Japanese population is positive for HLA-DR2 versus 90 to 100% of individuals with narcolepsy-cataplexy. Further studies have indicated that the association extends to the HLA-DQ region, most specifically in the context of the DR15, DQ6 (DR2, DQ1- Dw2) haplotype.43 Interestingly, however, there is a lower DR2 association in African American patients.44 Sequencing of HLA DRB1, DQA1 and DQB1 genes later indicated that all Caucasian and Japanese narcoleptic subjects have the same alleles, now called DRB1*1501, DQA1*0102 and DQB1*0602.45 In African American subjects, however, a primary association with DQA1*0102 and DQB1*0602 was observed,15,46,47 explaining the lower HLA-DR2 association. DQB1*0602, an allele found in only 12%, 25% and 38% of the control Japanese, Caucasian and African American populations respectively, but in 90% of those with narcolepsy-cataplexy, is now considered the primary HLA susceptibility gene. The allele is found in only 40% of cases with narcolepsy without cataplexy,48 suggesting more heterogeneity.

Even in cases with cataplexy, the HLA association observed in narcolepsy is complex and not simply the result of a dominant effect of DQB 1*0602. HLA-DQB1*0602 homozygosity doubles or quadruples the risk for developing narcolepsy.49 Additionally, the relative risk for narcolepsy varies in heterozygous subjects according to the allele associated with DQB1*0602.18,50 These alleles convey either an increased or decreased risk for developing narcolepsy; for example, a higher risk has been observed in heterozygotes co-expressing DQB1*0301, while those carrying either DQB1*0601 or DQB1*0501 have a lower risk.18 Additional small effects are suspected for various DRB1 and DQA1 alleles but have not been yet fully characterized.

The finding that approximately 25% of familial narcoleptic cases are negative for DQB1*060225,51 points towards the existence of highly penetrant non-HLA narcolepsy genes. Systematic genome screening in extended narcoleptic families has revealed a significant link in 4q13-q21 (lod score of 3.09) in 8 small multigenerational families of narcoleptics. Furthermore, reported associations between narcolepsy and monoamine oxidase-A (MAO-A),52 catechol-O-methyl transferase (COMT)53 and tumor necrosis factor-alpha (TNF-alpha)54 polymorphisms suggest that other susceptibility genes may be found, in addition to or independently of, the HLA and/or hypocretin system. COMT is a key enzyme in dopaminergic and noradrenergic transmission, and while no association has been found between genotype or allele frequency in narcoleptics, a sexual dimorphism and a strong effect of COMT genotype on disease phenotype has been reported. Female narcoleptics with high COMT activity fall asleep twice as fast on the MSLT as women with low COMT activity, while the opposite is true in narcoleptic men. The COMT genotype also strongly affects the presence of sleep paralysis and the number of REM sleep onsets during the MSLT. TNF-alpha is also interesting in that its intravenous or intracerebral administration produces sleepiness,55 and it is an HLA class III gene which is physically located within the susceptibility region of the HLA class II on chromosome 6 in humans. While initial studies failed to find any mutations or polymorphisms in the TNF-alpha gene or its promoter, the analysis of single-nucleotide polymorphisms (SNPs) in DRB 1*1501 positive Japanese narcoleptics has revealed an association between the disorder and the rare chromosomal recombinant TNF-alpha gene (TNF alpha(-857T)), independent of DRB 1*1501.54 Furthermore, a single-nucleotide polymorphism in the TNF receptor 2 gene (TNFR2-196R)56 has also been associated with narcolepsy, suggesting that the genetic impairment in the TNF-alpha pathway may interfere directly with the phenotype of narcolepsy, and that an inflammatory mechanism may play a role in the development of the disorder.39 This inflammatory mechanism may be in part, related to environmental factors.

A severe physiological stress, divorce, bereavement, change in the sleep-wakefulness cycle, accident (including head trauma), illness or pregnancy, often precedes the appearance of the symptoms of narcolepsy (sleepiness and/or cataplexy) by a few weeks or months.25 Patients with narcolepsy are also more likely to be born in March and less frequently in September, suggesting perinatal environmental effects.57 However, because of its very tight HLA allele association, it is likely that it is ultimately an autoimmune-based degeneration of hypocretin neurons that leads to the narcolepsy phenotype in humans. The association of autoimmune diseases with various MHC proteins, particularly HLA class II antigens, is well established;39 examples include diseases such as Rheumatoid Arthritis (DR4), Diabetes Mellitus type I (IDDM) (DR3, DR4, DQB 1*0302, DQB 1*0201, DQB1*0602), and Multiple Sclerosis (DRB1*1501, DQB 1*0602). In these autoimmune disorders, susceptibility HLA proteins from particular alleles are believed to bind peptide motifs derived from processed foreign antigen, leading to the HLA presentation of self-antigens and a sustained immune response causing tissue and cell destruction.39 The interaction of particular HLA proteins with processed autoantigens then determines whether tolerance or autoimmunity occurs. Because HLA-DQB 1*0602 confers disease susceptibility while the very similar DQB1*0601 is protective, very minor variations in the peptide binding pockets of these molecules determine the disease occurrence, but how these minor changes damage hypocretin neurons in the hypothalamus is unclear.39 Indeed, studies of narcoleptic brains do suggest a degeneration of hypocretin neurons, as evidenced by the absence of prepro-orexin mRNA and orexin immunoreactivity from the lateral hypothalamic area of human brains.21,22 However, hypocretin neurons may also express other neurotransmitters, and the pathophysiology of narcolepsy may be affected by the additional loss of these as yet unknown factors.

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Responses

  • cassidy
    What chromosome is narcolepsy located on?
    6 years ago

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