Causes of Narcolepsy

Causes of Narcolepsy
Taylor Smith a Certified Medical Assistant talks about
what the potential causes of Narcolepsy might be.
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Narcolepsy is a neurological sleep disorder that causes uncontrollable sleep and wakefulness cycles [1]. Symptoms of narcolepsy are increased levels of sleepiness in the daytime, sleep paralysis and cataplexy. This disorder affects around 0.02% of the population, men and women are affected equally and symptoms usually appear around young adulthood or adolescence [1]. The exact cause of narcolepsy is not known however, a factor that causes predisposition to this disorder is deficiency in hypocretin or Orexin A and –B and their receptors OX1 and OX2 produced by Human Leukocyte Antigen (HLA) complex variations[2]. These excitatory neuropeptides produced in the lateral hypothalamus are important in regulating wakefulness and appetite. In 2009, the cause of this deficiency was discovered to an autoimmune process that caused progressive degeneration of these neuropeptides in the brain. This neurowiki will provide more insight into the causes of narcolepsy[2].

1.1 HLA complex in Chromosome 6

Orexin A
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NMR of Orexin A. Image source:

The most important area in which variations increase the risk of narcolepsy is the Human Leukocyte Antigen (HLA) Complex in chromosome 6. The HLA complex genes encode for the major histocompatibility complex (MHC) in humans. The variations lead to an autoimmune response to certain neurons which produce protein in the brain. These neuropeptides are called hypocretin or orexin, and individuals with narcolepsy have reduced numbers of these in their brains[2].

1.1a Neurobiology of Orexin system

Orexin Projections in the Brain
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Orexin projections from hypothalamus to the brain. Image

Cells which contain hypocretin are found within the lateral hypothalamus and project to the cortex, the thalamus, the basal forebrain, limbic structures, and most of the brainstem and spinal cord[3]. This neurotransmitter regulates appetite, arousal, and sleep patterns. These strongly conserved orexins have excitatory effects; they increase intracellular Ca2+ concentration and also project to all monoaminergic cell groups. The hypocretins come from a protein precursor called prepro-hypocretin, which is cleaved enzymatically into two peptides called orexin A and B (hypocretin 1 and 2). Orexin A is composed of 33 amino acids, and orexin B is composed of 28 amino acids. Furthermore, hypocretin has 2 G-protein coupled receptors in the hypothalamus called HCRTR1 and HCRTR2 (OX1 and OX2) [3].

1.1b Experimental Evidence of Orexin Deficiency

Experiments have shown that canine narcolepsy was the result of mutations in the HCRTR2 gene. Orexin knockout mice have also shown symptoms that are similar to narcolepsy in humans. In these mice, the ones which do not have the full hypocretin peptides or both their receptors (OX1 and OX2) had harsher symptoms compared to the mice without only one of the receptors[4]. Using mutation screening experiments of a severe case of narcolepsy-cataplexy patient who started having symptoms at six months of age showed a single mutation in the HCRT. This mutation affected peptide trafficking and processing. In situ hybridization of that patient’s perifornical area of the hypothalamus and radioimmunoassays showed a loss of orexins which was global, but there was no inflammation of gliosis seen[5]. Furthermore, CSF samples were measured in control and narcolepsy patients, control CSF samples all had measureable hypocretin-1 levels, but 90% of the narcolepsy patients had undetectable levels of hypocretin-1[6]. The lateral hypothalamus of narcolepsy patients does not show endogenous opiate dynorphin and NARP –a protein associated with glutamate signalling, both of which are produced by hypocretin neurons[7].

1.2 Autoimmune hypothesis

Prevalence rates of Narcoplexy
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Genome-wide association studies for narcoleptics with cataplexy,
narcoleptics without cataplexy and the general population made up of healthy Americans.
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1.2a HLA-DQB1*0602 genotype

Narcolepsy is associated with four alleles which are DQB1*0602, DRB5*0101, DRB1*1501, and DQA1*0102[8]. DRB1 and DQB1 genes in narcolepsy patients that have been sequenced showed no mutation, this suggests that they cause susceptibility to the onset of this disease but their function is not faulty. As a result, genes which are non-HLA like tumour necrosis factor alpha, catechol-O-metyltransferase, monoamine oxidase- A, and TNFR2 are involved in the propensity to acquire narcolepsy. But the specific HLA with which narcolepsy is most associated with is the DQB1*0602[4]. This was confirmed by a study on Japanese patients which showed a 100% association between the HLA-DR2 haplotype and narcolepsy. The HLA DQB1*0602 was found in 90% of patients with narcolepsy. A carrier of this gene has an approximately 200 fold increase in the risk of getting narcolepsy[8].

1.2b TCRα locus

Many patients start exhibiting symptoms of narcolepsy after infections. During immune responses the TCR protein which is on T cells is important in recognizing the antigen that is on the antigen presenting cells (APCs). Specific variations in the J region of the TCRα locus were shown to cause an increased risk of narcolepsy. In the TCRα locus, polymorphisms have been shown to change the immune response after an infection or strep throat. This can suggest that the immune response to the antigen associated with these conditions causes the immune system to attack the orexin neurons[1][8]. Further evidence for this can be seen in section 3.2.

2.1 Neurobiology of Cataplexy

Cataplexy is a symptom of narcolepsy and is triggered by strong, powerful emotions such as laughing or terror. It is characterized by sudden muscle weakness and loss of muscle tone with full consciousness[9].

2.1a Histaminergic neurons of TMN

Pathways in Atonia
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During cataplexy and normal states the Atonia pathways function differently.
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The tuberomammillary nucleus (TMN) is important in sleep and arousal, it contains histamine neurons which are depolarized by orexin-A and orexin-B causing increased firing rate. Since orexin neuropeptides are what innervate the only source of histamine which is the tubermammillary nucleus (TMN) neurons in the posterior hypothalamus, this connection was further analyzed. By examining patients and mice models with narcolepsy, it was seen that narcoleptic patients possessed 94% more histaminergic TMN neurons, furthermore in patients with greater orexin loss (greater than 90%) there was higher histamine neurons than the patients with less than 75% orexin loss. This increased histamine seems to contribute to the preserved consciousness state of cataplexy in narcolepsy and it might be a response from the body to compensate for the orexin loss[10].

2.1b REM sleep –alpha motor neuron depolarization

In narcolepsy, REM sleep occurs at unusual times. REM sleep atonia is when the skeletal muscles are paralyzed using the descending reticulospinal pathway and this can be seen in cataplexy. This paralysis happens due to gutamatergic neurons in the sublaterodorsal nucleus (SLD) that activate GABAergic neurons in the medial medulla and spinal cord which inhibit the motor neurons. During times in which the patient is awake, these pathways are regulated by serotonin and norepinephrine. In a control human, GABAergic neurons like serotonin which are in the adjacent lateral pontine tegmentum and the ventrolateral periaqueductal gray (VIPAG /LPT) control these atonia-pathways and make sure they are not activated. Positive emotions are said to turn on the atonia pathway, by activating the limbic system and inhibiting serotonin and norepinephrine. In cataplexy there is reduced noreadrenergic and serotonergic neuron activity which allow for atonia. In general the orexin peptides suppress atonia, but narcolepsy patients have lower orexin so likelihood of atonia would increase[11].

3.1 Genetic and Familial studies

Familial narcolepsy is seen in 10% of the cases. 1-2% of the first-degree relatives of narcoleptics will have an onset of narcolepsy, compared to 0.02-0.18% of prevelance in the general population. This finding suggests that some predisposition genetic factors are involved. Twin studies show 25-31% concordance; therefore the development of narcolepsy is also a result of environmental factors which interact with genetic variations[4].

3.2 Link to Infections

Environmental factors play a big role in the onset of Narcolepsy. There have been increased rates of narcolepsy onset in children who have been exposed to the influenza A H1N1, Streptococcus pyogenes and some H1N1 vaccines[6].

3.2a Correlation to seasonal patterns of upper airway infections

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Narcolepsy susceptibility has a correlation with upper airway infections such as Streptococcus pyogenes and Influenza A. In China, the months of winter show an increase in the cases of narcolepsy. Individuals with streptococcal infections have 5 times more chance of getting narcolepsy, and 65% of narcoleptic patients have the streptococcus antibodies versus the 26% of controls of the same age. This association could be due to the activation of an immune response by molecular mimicry and bystander activation which cause loss of hypocretin neurons. Further correlation between influenza A and narcolepsy onset was seen after the 2009 H1N1 pandemic. Following that pandemic 95% of the patients who had been diagnosed with narcolepsy did not receive the H1N1 vaccination, which implies that the influenza A infection increases narcolepsy susceptibility[4][2].

3.2b Pandemrix Vaccination in Scandinavia

Pandemrix was developed as a response to the 2009 H1N1 influenza pandemic, this AS03 (squalene, alpha-tocopherol) H1N1 vaccine contributed to the increase in narcolepsy amongst children and young adults. Eight months after the vaccination there was a 12.7 fold increase in narcoleptic patients compared to individuals of the same age who did not get vaccinated was reported by researchers in Finland. There was also an increased narcolepsy onset in individuals aged 5-19 after the AS03-adjuvanted vaccine in Sweden, Ireland, and UK. Therefore, these observations suggest that the adjuvant contained in this vaccine produced a strong immune response[12].

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