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Genes and Migraine
Kathy Gardner, MD Spring 1999 issue of ACHE
Posted Sept 1999

Many migraineurs have other family members who also suffer with migraine headache. Mom used to have migraine headaches with her menstrual cycle, grandmother once had "sick" headaches, and brother has "sinus" headaches which are less severe but sound strangely similar to migraine if you ask questions about symptoms and triggers.

For years scientists have argued whether disorders such as migraine that tend to run in families do so because of shared genes or the shared environment. People often assume that any disorder that occurs in several family members must be genetic. However, families tend to share similar diets, exposures and lifestyles, all of which might be involved in making someone susceptible to a specific disorder. A combination of genetic and environmental factors seems to be the best overall explanation for most common disorders, including migraine.

Nevertheless, the fact that you occasionally find large families with many members suffering from migraine suggest a stronger genetic basis for those particular families. As it turns out, a definite inheritance pattern has been found in a few families who suffer with a severe form of migraine called hemiplegic migraine.

Hemiplegic Migraine: The inherited or "familial" form of hemiplegic migraine is a rare disorder found in families where two or more people suffer migraine-type headache associated with a "stroke-like" aura of weakness on one side of the body. Other neurologic symptoms can also occur and might include visual loss, difficulty with speech, confusion and numbness. In these families, hemiplegic migraine has an autosomal dominant inheritance pattern, meaning that if either the mother or father has the gene and passes it on, that child will have hemiplegic migraine. So, on average, half of the children in these hemiplegic families will suffer from the disorder.

In one half of the hemiplegic migraine families that we have identified, the disorder is linked to a specific region on the 19th chromosone that includes a calcium channel gene found in the brain.

The brain and nervous system depend on a combination of electrical and chemical signals to do their work. A calcium channel is a type of a "gate" on the end of a cell that is operated electrically. When an electrical impulse of sufficient power (voltage) passes down a nerve cell, its calcium channel opens and releases chemical messengers that contact the neighboring cells and tell them how to respond. Serotonin and dopamine are a few of the many chemical messengers found in the brain.

These families with hempilegic migraine have mutations that cause a certain type of calcium channel to malfunction periodically. Some headache triggers may preclude altered electrical impulses that lead to temporary calcium channel malfunction, resulting in a series of biochemical changes that lead to a migraine attack.

Regular Migraine: Thus far, we don't really know whether the defective calcium channel gene found in these families with hemiplegic migraine genes will prove to have a direct or indirect role in the pathways that produce the much more common forms of migraine. The on-and-off, intermittent nature of the defect in the calcium channel gene and its dependence on electrical changes does make it a possible suspect for producing an episodic condition such as migraine. There are other "voltage-gated" signaling systems in the brain similar to the calcium channel, and these might also be involved in regular migraine. We know that the migraine pathway ultimately involves serotonin, dopamine and related chemicals in the brain, so many genes may be involved.

It's more difficult to clearly identify genes associated with regular migraine, given that environmental factors contribute significantly as well as genetic factors. In general, common disorders are more likely to have many contributing genetic influences, with different families showing distinct variations. Distinguishing one gene from among several contributing genes and from background environmental influences means that we need to study large numbers of patients and many small families to achieve reliable and significant data.

The Next Step: There are still more questions than answers regarding the genetics of migraine. Solving them will require imagination and the joint effort of researchers from many different fields. We also need the continued cooperation of migraine families and patients who have graciously participated in genetic and clinical studies. Though we have our first genetic clue, we now need to understand the consequences of the malfunctioning calcium channel. We will be particularly interested in seeing if there are secondary effects on serotonin and other brain chemicals that have been implicated in the production of a migraine attack.

As other genes are identified, we can construct a better picture of the biochemical pathways involved in migraine, beginning at the "starting point." With this knowledge, we will have the opportunity to develop a wider range of specific anti-migraine drugs that can block this pathway to stop the migraine.