A 30-year-old man has sudden episodes of bilateral leg weakness triggered by laughter, startling, or strong emotion, followed by irresistible sleep attacks. He sometimes hallucinates vivid images when falling asleep. Which neurotransmitter system deficit is central to the pathophysiology of this condition?
- A Serotonergic deficit in raphe nuclei
- B Dopaminergic deficit in the mesolimbic pathway
- C Noradrenergic excess in the locus coeruleus
- D Hypocretin (orexin) deficiency due to autoimmune destruction of lateral hypothalamic neurons ✓
Explanation
Narcolepsy type 1 (narcolepsy with cataplexy) is caused by near-complete loss of hypocretin (orexin)-producing neurons in the lateral hypothalamus, likely through HLA-linked (DQB1*0602) autoimmune destruction. Hypocretin normally promotes wakefulness and stabilises REM sleep. Its loss leads to inappropriate intrusion of REM sleep elements into wakefulness: cataplexy (emotionally triggered muscle atonia — loss of REM sleep muscle inhibition), hypnagogic hallucinations (dreaming at sleep onset), sleep paralysis, and excessive daytime sleepiness. CSF hypocretin-1 <110 pg/mL is diagnostic.
Reference: Kaplan & Sadock's Synopsis of Psychiatry, 11th ed.
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