Orexin (hypocretin) deficiency in type 1 narcolepsy
Core concept
- Orexin (hypocretin) A and B from ~70,000 neurons in the lateral/posterior hypothalamus
- Single precursor prepro-orexin; receptors OX1R and OX2R
- Project to the monoaminergic and cholinergic arousal nuclei - LC (NA), raphe (5-HT), TMN (histamine), VTA (DA)
- Orexin stabilises the flip-flop switch between wake and sleep - it does not generate wakefulness, it prevents state transitions
- Type 1 narcolepsy = loss of >85-90% of orexin neurons
- -> unstable boundaries -> REM phenomena intrude into wake (cataplexy, hypnagogic hallucinations, sleep paralysis) and wake intrudes into sleep (fragmented nocturnal sleep)
- Autoimmune, not degenerative in the usual sense
- *HLA-DQB106:02 in >98%** (present in ~20-25% of the population -> high sensitivity, poor specificity)
- CD4/CD8 T cells reactive to prepro-orexin; TCR alpha polymorphism
- Pandemrix H1N1 vaccine and 2009 H1N1 infection triggered incident cases - molecular mimicry
3 more sections, plus exam facts
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