STOWE, VT—“You obviously cannot do genetics unless you are able to diagnose specific or relatively specific entities,” said Jes Olesen, MD, a renowned clinician and researcher who knows a thing or two about headache classification. Among his many accomplishments, Dr. Olesen contributed significantly to both the first and second editions of the International Classification of Headache Disorders (ICHD.Currently, Dr. Olesen is a Professor of Neurology at the University of Copenhagen and Chief of the Danish Headache Center, Department of Neurology, at Glostrup University Hospital, Denmark. At the Headache Cooperative of New England’s 20th Annual Headache Symposium, Dr. Olesen offered a brief history of genetic research in migraine.
“We have a line of research that starts with classification and moves on to epidemiology, and from there to genetic epidemiology, and from there on to genetics. So looking at migraine, having the classification, the question comes up: Are the genetics the same in these different kinds of migraine?”
Back in 1988, when the first edition of the ICHD was created, headaches were classified purely on the basis of clinical information—nothing else, just the clinical picture. Familial hemiplegic migraine was distinguished from migraine with aura, and migraine with aura was noted as different than migraine without aura, and so on. “We never said they were completely different diseases, but they are very clearly distinct subforms of migraine,” Dr. Olesen said.
Familial Hemiplegic Migraine—An In-Road to Understanding Common Migraine?
Three different genes—CACNA1A, ATP1A2, and SCN1A—have been implicated in familial hemiplegic migraine, and mutations in those genes cause, respectively, FHM1, FHM2, and FHM3. But the question is, how relevant are these genes to migraine with aura and migraine without aura? Extensive studies have not been able to find mutations in any of these three genes in patients with migraine with aura or migraine without aura. “So from a genetic point of view, it looks as if, unfortunately, the in-road to migraine genetics is not via the familial hemiplegic migraine discoveries. Because it doesn’t look like these genes are involved in the common types of migraine,” Dr. Olesen said.
Although the genetic abnormalities in familial hemiplegic migraine and more common types of migraines do not appear to be the same, Dr. Olesen and colleagues speculated that perhaps other genetic abnormalities might work on the same pathophysiologic pathway. “This is fully possible and may be true,” he said. “We have worked a lot with nitroglycerin and calcitonin gene-related peptide (CGRP), and we have shown that the common types of migraine are very sensitive to these two molecules, so there is obviously something about that biochemical pathway that is different. Migraine patients are hypersensitive to nitric oxide and to CGRP.” This finding led the researchers to ask whether patients with familial hemiplegic migraine were also sensitive to nitric oxide and CGRP. “Our hypothesis was that they would have the same hypersensitivity,” Dr. Olesen said. But the patients with familial hemiplegic migraine that Dr. Olesen and colleagues studied were not hypersensitive to nitric oxide. The researchers therefore concluded that there are different pathophysiologic pathways when it comes to the handling of nitric oxide in familial hemiplegic migraine and in migraine without aura. CGRP provocation studies showed no significant difference between the FHM patients and controls. “But we do see a difference when we look at migraine without aura patients and migraine with aura patients,” Dr. Olesen noted. “Those kinds of patients—and this last study is not published yet—we’ve done it now in migraine with typical aura, and sure enough they are also hypersensitive to CGRP and to nitroglycerin, just like the migraine without aura patients are.” So the researchers concluded that familial hemiplegic migraine also differs from more common migraine with regard to CGRP sensitivity.
This latest finding, Dr. Olesen said, is very important in trying to understand the mechanisms of migraine. “Early on we thought that an understanding of familial hemiplegic migraine would lead to an understanding of migraine with and migraine without aura. Now it looks like this is questionable.”
Dr. Olesen and colleagues have also identified a large number of patients with familial hemiplegic migraine who do not have any of the three known genes mutated. “They have been mostly smaller families, and their penetrance is not 100%, so it’s quite uncertain how they inherited it.”
In those patients, the researchers did not see a hypersensitivity to nitric oxide or CGRP. But when the researchers subdivided them into those patients who also had attacks of typical migraine with aura or without aura and those who had purely hemiplegic attacks, they saw that the subgroup who also had migraine with or without aura were hypersensitive, but the ones with the pure hemiplegic attacks were not hypersensitive.