Narcolepsy presents one of the tightest associations with a specific HLA an
tigen (DQB1*0602) but there is strong evidence that non-HLA genes also conf
er susceptibility. Recent observations have implicated the hypocretin/orexi
n system in narcolepsy in both humans and animals. In addition, the implica
tion of monoaminergic systems in the pathophysiology of narcolepsy is well
established and a significant association between the monoamine oxydase-A (
MAO-A) gene and human narcolepsy has recently provided a possible genetic l
ink. We investigated polymorphisms of MAO-A and catechol-O-methyltransferas
e (COMT) in 97 Caucasians with well-defined narcolepsy-cataplexy and sought
for genotypic effects on disease symptoms. No evidence of association betw
een genotype or allele frequencies of both MAO-A or COMB gene and narcoleps
y was found. However, a sexual dimorphism and a strong effect of COMB genot
ype on disease severity were found. Women narcoleptics with high COMB activ
ity fell asleep twice as fast as those with low COMB activity during the mu
ltiple sleep latency test (MSLT) while the opposite was true for men. COMB
genotype also strongly affected the presence of sleep paralysis and the num
ber of REM sleep onsets during the MSLT. In agreement with well-documented
pharmacological results in canine narcolepsy, this study reports the first
genetic evidence for the critical involvement of the dopaminergic and/or no
radrenergic systems in human narcolepsy.