"Not tonight dear. I have a migraine."

This intimacy alibi is most often invoked by women; less by men. Specifically, three times as many human females as males suffer from migrainous headaches. Some 24 million Americans between the ages of 10 and 40 - and 15 percent of Western populations - report starting to have bouts of the throbbing, unilateral symptoms of the disorder, which may last from four hours to three days, and recur several times a week. After age 50, the symptoms frequently decline. Migraine genetics has lately become a hot research topic, aimed at identifying susceptibility genes, and helping develop new diagnostic and therapeutic strategies.

Half of all migraines - 50 percent - are thought to be inherited. "We now know that part of the migraine's mechanism," observed neurologist/geneticist Anne Ducros, "is of genetic origin, but how does all this work nobody knows."

Ducros is an assistant professor of neurology at the Headache Emergency Department of Lariboisière Hospital in Paris. "I see patients every day in the emergency unit," she observed. "Every kind of headache. People in Paris with migraine can come here 24/7."

Ducros is senior author of a paper in the September 2002 The Lancet titled "The genetics of migraine."

"It describes a sort of overview of knowledge about the genetics of migraine," she told BioWorld Today. "I think the main finding is that there are indeed migraine genes, but the consequences of their mutations are still not understood."

Fittingly, the very word "migraine" comes from the French "hemi-crane" meaning half-cranium. One of migraine's hallmarks is that in half of its patients the headache afflicts the head unilaterally - right half or left half at a time. Migraines come in two main variants, with or without prior auras, plus a rare familial hemiplegic migraine - FHM.

Auras are the coming shadowy events that migraines cast before.

"The aura," Ducros explained, "is presented by the transient neurological phenomenon that takes place before the headache. People who have a complete aura - with visual, sensory, aphasic and motor signs - the closer they get to visual aural symptoms. For example, a patient is reading, and then in front of his eyes he sees in the middle of the visual field, a flickering spot or scotoma that grows into a sort of line. Then he sometimes doesn't see anything on one part of the visual field."

Migraine Varieties, With, Without Auras

"This occurs in both eyes," Ducros recounted. "And these growing flickering spots may last for 50 minutes or 20 minutes. After that," she continued, "he begins to feel a sort of tingling or numbness of his fingers, for example in the right arm. And this sensation is going up the entire arm, then the face, in the tongue, then goes back. And sometimes, people who have motor symptoms lose their strength in the arm or face or even in all the upper half of the body. After that he cannot speak, is stuttering, or searching for words. This may go on for one or two hours. Then everything is OK again until the migrainous headache proper takes over. The most frequent aura is visual."

Ducros reviewed the main migraine variants: "For the diagnosis of FHM we need a family with at least two affected people having an aura marked by a motor deficit. FHM is of 100 percent genetic origin. Sporadic familial migraine means an isolated case in a family you don't know. Some of these cases can be of genetic origin and others not. For the moment it's not possible to determine how many people with sporadic hemiplegic migraine have a mutation in a gene because all the genes responsible are not known. Also, not all migraine sufferers seek medical assistance, so they remain anonymous.

"For the other varieties - migraine with aura, including visual aura - no specific gene has been identified yet. The only thing we now know is that there are several chromosomal loci. One is on chromosome 4, another on chromosome 19 and, perhaps with less certainty, on chromosome 1 and on chromosome X. For migraine without aura, things are not very clear."

She added: "I think that a lot of people can have one attack in their life, so it's a sort of abnormal but quite typical response to a neuronal aggression. In man, triggers for migraine can be various aggression factors - stress, alcohol drinking, excess of sleep." Ducros pointed out, "The model for the migrainous aura is spreading depression." This is not a mood disorder but a decrease of activity evoked by local stimulation of the brain's cerebral cortex, which spreads slowly over the whole cortex.

"Dilated blood vessels in the brain are a sort of secondary phenomenon within the migraine attack," Ducros pointed out. "So in migraine with aura, during the aura there is spreading depression. That means that this phenomenon is a sort of dysfunction of the neurons. And it's associated with vasoconstriction in the brain's blood vessels."

Why Female Of Species Outnumbers Male

Among other key mechanisms under study by migraine researchers are mutations in the neuronal genes that encode ion channels, which may cause the headache attacks. Another distinct factor is the female hormone estrogen. "For migraine without aura," Ducros said, "there is an important link in women with the menstrual cycle. A lot of them get migraine during menstruation, because of the lowering of estrogen in the blood and brain. So in women having pure' menstrual migraine - suffering attacks only during menstrual periods - then the working treatment is to give them estrogen during seven days at the end of their cycle to prevent the migraine attack.

"It's very rare to have pure menstrual migraine," Ducros went on. "In those who have these attacks, they occur between 48 hours before the start of menstruation to 48 hours after. To prevent that, for those who are taking contraceptive pills, we give them estrogen during the seven days of stopping the pill.

"Of course," Ducros noted, "estrogen plays a role in the frequency of migraine in women - three times that of men. Then there is another hypothesis," she concluded, "that this genetic factor is localized on the female-only X chromosome."