Asleep on the job

Most of us have fallen asleep in a lecture - the lights go down, the power-points start to flicker past, the voice-over drones and . . .  zzzzzz.  I found it was fatal to eat half of a free sandwich offered to encourage attendance at lunchtime Departmental Seminars - only a quarter and I had a chance of staying awake beyond slide 5/80.   But falling asleep at inopportune moments is only one of the symptoms of nacrolepsy. Distressing as nacrolepsy  is for narcoleptics and their families, its diversity of symptoms opens a fascinating window in how our bodies work in normal circumstances and how every player in the sub-sub-microscopic genetic and biochemical landscape has to multi-task.  We only have 23,000 protein-coding genes to play with after all: about 10% more than Caenorhabditis elegans and that worm is only 1mm or 1000 cells in size.

Perhaps the least expected co-symptom of nacrolepsy is

• cataplexy - a sudden muscle weakness often under conditions of emotional stress: anger and fear, but also laughter - cataplectics really do tend to go Ha Ha Bonk

Other symptoms are sleep-related:

• nightmare-quality hypnagogic (falling asleep) and hypnopompic (coming awake) hallucinations.  
• sleep paralysis - inability to move and/or speak when falling asleep (how scary is that?)
• a real quick drop into REM (dreaming) sleep.

Then again perhaps cataplexy falls into the same bin because one of the 'symptoms' of normal sleep is loss of muscle-tone.  And the hypnagogic hallucinations could be seen as part of the instant REM sleep - we usually have 60-90 minutes of relaxation before the dream-scape starts in our head. Clearly something or somethings are regulating a lot of quite disparate effects to control normal sleep. And I think we should all be grateful that we forget most of the dreams we have. Seemingly, it's because nighttime sleep is so bitty that the body needs to catch up during the day.

And at an epidemiological rate of 1:2000 it's not uncommon!  That's a little more common than, say, cystic fibrosis (1:2500) and about the same prevalence as Parkinson's and MS; all of which get a much bigger press than narcolepsy.  But a lot of this lies hidden as sufferers and their families cope - I know quite well three people with MS and three other people with Parkinson's but I don't know anyone with narcolepsy despite the fact that there are at least 2000 in Ireland.

Narcolepsy has a clear genetic component, or it wouldn't have an OMIM number, that's for the gene NRCLP1. But it's more complex than that because there are other OMIM entries for NRCLP2, NRCLP3, NRCLP4, NRCLP5, NRCLP6 and NRCLP7.  Seven different genes at different places in the human genome have all been shown to be associated with the condition.  So you can see why scientists get petulant when the press reports that Dr Mephistopheles has found The gene for homosexuality, schizophrenia, gout or any other traits with complex causation (or etiology αἰτιολογία as we like to call it to bamboozle outsiders).

At a molecular level, nacroleptics almost always have greatly reduced levels of a neuropeptide HCTR/hypocretin/orexin (all synonyms) in the brain and the cerebro-spinal fluid.  Orexin is made by the gene NRCLP1, so that's a direct connexion - banjaxed NRCLP1 means no orexin which is known to be the main mediator of sleep and arousal, but orexin also has roles in feeding behaviour, fluid balance, and hormonal regulation.  So far, so not so simple: to switch on the gene that makes orexin must involve a cascade of other genes (probably NRCLP2-7) and if you banjax any of those then you're going to have lower levels of orexin.  This all makes it complex and difficult to a) work out what causes narcolepsy b) how to cure, avoid or treat it.  One factor that seems to predispose is what variants you carry among the HLA Major HistoCompatibility (MHC) genes.  Notably pretty much ALL European narcoleptics have variant DRB5*0101-DRB1*1501-DQA1*0102-DQB1*0602 (known to its friends as DQ0602) but so do 15% of the normal population so this immune variant is necessary but not sufficient. Specific HLA variants are known to be associated with predisposition to a number of different diseases and it turns out that the same DQ0602 that does for you with narcolepsy also protects you from diabetes. There is a suggestion that narcolepsy - which often kicks in during adolescence - starts because an autoimmune reaction specifically attacks the orexin producing neurons in the brain.  That's like rheumatoid arthritis where the capsule of the joints is attacked by the body's own immune system.  But it's more like Guillain–Barré syndrome where the immune system attacks the nerves. That is triggered by exposure to Campylobacter jejuni and common cause of chicken-driven food poisoning.

If this is ringing bells, you might like to contact the narcolepsy support group at
http://www.sleepy-heads.org/; me I'm just glad I don't doze off in the normal oufeller way too often.

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