LONDON ¿ The cause of narcolepsy, a disabling illness which causes sufferers to suddenly fall asleep, may be related to abnormalities of the monoamine neurotransmitter system in the brain, a small study in the U.K. has suggested.

Researchers at King¿s Neuroscience, based at King¿s College School of Medicine and Dentistry, and at the Institute of Psychiatry, both in London, have found that one particular variant of a marker within the gene encoding monoamine oxidase B was twice as common in people with narcolepsy than in controls. The results of their study are summarized in a letter to the Lancet¿s Feb. 20 edition, titled ¿Analysis of the monoamine oxidase genes and the Norrie disease gene locus in narcolepsy.¿

About 20,000 people in the U.K. have narcolepsy. The symptoms are daytime sleepiness, and the tendency to suffer cataplexy, a sudden loss of muscle tone, similar to that normally experienced in rapid eye movement (REM) sleep. The cataplexy is usually triggered by emotions such as laughter and surprise, so that laughter, for example, can cause the person to collapse.

Many cases of narcolepsy go undiagnosed, with the person being labeled lazy, tired, depressed or bored. The onset is usually at adolescence, although it can begin at any age, and it continues for the rest of the person¿s life. In severe cases, the disease can be extremely disabling.

Since there are no visible abnormalities of the brain of narcolepsy sufferers on scans or at postmortem, the condition is assumed to be due to a biochemical disturbance of REM sleep.

In 1985, David Parkes, professor of clinical neurology at King¿s, and colleagues, as well as a group of Japanese researchers, made the discovery that about 98 percent of people with narcolepsy have one particular variant of the human leukocyte antigen (HLA) gene, called DR2. This was not the whole story, however, as it turned out that only 1 in 500 people in the U.K. who were HLA DR2 positive have narcolepsy.

One Allele Twice As Common In Narcoleptics

So, the search was on for other genetic factors that could be responsible for the disease, particularly as it was known that narcolepsy could be inherited, often through the female line. But studies of twins also suggested that environmental factors could play a role: There are some pairs of monozygous twins where only one has the disease.

Parkes and his colleagues set out to look for other genetic factors responsible for narcolepsy. They began their search with the chemicals involved in the control of sleep and waking, some of which are believed to be monoamine oxidases.

The genes coding for monoamine oxidase A and monoamine oxidase B were already known to be close to that for a condition called Norrie¿s disease, an X-linked recessive disorder causing congenital blindness. Furthermore, there had been reports of abnormal REM sleep patterns in people with Norrie¿s disease, some of whom also suffered from cataplexy.

Parkes¿ group therefore studied markers in this area of the X chromosome to see whether there was any particular association with narcolepsy. Their scrutiny failed to find any rearrangements or deletions of the Norrie¿s disease gene. However, they found that one allele, 181 base pairs long, of a variable microsatellite marker, present in the region of the monoamine oxidase B gene, was twice as common in narcoleptics than in controls.

Ian Craig, head of molecular genetics at the Social Genetic and Developmental Psychiatry Research Centre at the Institute of Psychiatry in London, told BioWorld International: ¿This is a step forward, a clue to open up further studies. It is unlikely to be the marker itself which is the cause of the narcolepsy, but it is probably going to be linked very closely to some version of the monoamine oxidase gene which is causing some kind of effect. It could be the monoamine oxidase A gene or the B gene because they are both very close to each other.¿

Reducing Monoamine Oxidase The Key?

Assuming that the study can be replicated, he said, future studies should examine the genes involved in the metabolism of monoamines in people with sleep disorders.

Parkes added: ¿This study, if it can be repeated, suggests that monoamine oxidase A and B inhibitors may improve narcolepsy. It may be that monoamine oxidase activity is excessive in these patients and that damping it down is what improves the situation. So, the question is whether you can develop more selective monoamine oxidase A and B inhibitors.¿ Monoamine oxidase A inhibitors are currently used to treat depression; an example of a monoamine oxidase B inhibitor is selegiline, which has been used in attempts to prevent Parkinson¿s disease.

The letter to the Lancet says, ¿No major variation in allele pattern was detected between the 20 HLA DR2 positive and 8 DR2 negative narcoleptics.¿ (Very few DR2 negative patients were available for study.) This leaves, said Parkes, an enormous gap, because ¿one hoped one would find a clear link in the DR2 negative cases with the monoamine oxidase system, different to the ones that do have the DR2 antigen. We did not find that link so the cause of HLA DR2 negative narcolepsy at a genetic level still remains totally uncertain.¿ n