Physicians discuss the role of heredity and genetic mutations in patients with chronic migraine, who predominantly report a family history of the disease.
Stephen Silberstein, MD; David Dodick, MD; and Peter Goadsby, MBBS
PUBLISHED December 12, 2018
Stephen Silberstein, MD: Hello, and thank you for joining us. Migraine is a neurological disease that is associated with extensive disability and a poor quality of life. Successful treatment often requires a multifaceted approach. We’re consistently looking for new, safe, and effective therapies. At this Neurology Live™ Peer Exchange® discussion, I am joined by a panel of my colleagues, all experts in the field of headache medicine. Together we’re going to discuss the use of new and exciting therapeutic options; we’ll review the latest clinical trials, and provide you with a perspective on how they can best be used in your clinical practice.
I’m Dr. Stephen Silberstein, professor of neurology at Thomas Jefferson University and director of the Jefferson Headache Center.
It is my great pleasure to announce our distinguished panel. They include Dr. David Dodick, professor of neurology at Mayo Clinic College of Medicine in Scottsdale, Arizona; Dr. Peter Goadsby, director of the NIHR-Wellcome Trust, King’s College Research Facility, King’s College Hospital, and professor of neurology at the University of California in San Francisco; Dr. Stewart Tepper, professor of neurology at the Geisel School of Medicine, and director of the Dartmouth-Hitchcock Medical Center;
And we’ll also be joined by Dr. Jessica Ailani, director of the MedStar Georgetown Headache Center, and associate professor of neurology at Georgetown University.
Thank you for joining us and let’s begin.
The first segment that we’re going to be talking about today is the biology of migraine. What do we really know about it? The first topic I’d like to cover is, what role do genetics play? What are the diseases that are associated with migraine? Is this something that you’re stuck with because of your bad ancestors? David, tell us about this.
David Dodick, MD: Well, Steve, as you know, when we’re in clinical practice most of the patients that we see will report a family history of migraine. Even in those who don’t report a family history, if you dig deep enough you’ll find that there are people in the family who suffered from sick headaches or who complained of headaches but didn’t necessarily receive a formal diagnosis of migraine. In fact, about 80% of the people we see have a family history of migraine.
Migraine, like diabetes and asthma, is a rather complex polygenetic disorder in most people; by that I mean there are multiple genes that increase the risk of developing or expressing migraine. In fact, there are probably over 40 genes now that have been demonstrated in large genome-wide association studies to possibly increase the risk of migraine.
Recently it’s been shown that the more variations an individual inherits—something called the polygenetic risk score—the more likely it is that they’re going to express migraine as a disease, express a severe form of the disease, and the more likely it is that they’re going to express it at an earlier age. The more variations in those genes and the more genes that they’ve acquired or inherited, the more likely they are to express severe forms of the disease.
There is a subtype of migraine called familial hemiplegic migraine. It’s an autosomal dominant monogenetic disorder. About 70% of people are hemiplegic; on familial hemiplegic migraines we can do genetic tests. There are 3 definite genes that have been identified with multiple mutations that are responsible for at least 70% of the patients that we see with familial hemiplegic migraine. The other 30% have different genes that are involved—we just haven’t discovered them yet.
So in general, migraine is definitely a genetic disorder; it’s an inherited disorder; it’s polygenetic in most forms of migraine. But in 1 subtype it is truly a monogenetic autosomal-dominant disease with single mutations that are involved in transmitting the disease.
Stephen Silberstein, MD: Do my other colleagues have any comments?
Peter Goadsby, MBBS: It’s extraordinary how much progress we have made in the narrow area with hemiplegic migraine and the fact that the channel behavior—the FHM1 familial hemiplegic migraine type 1 gene—is a channelopathy: the PQ voltage-gated calcium channel. And then, if you contrast that with the G. West findings, the point is a variety of targets. It’s going to be a long time before genetic testing hits the primetime for diagnosis or indeed for therapeutic selection, which is challenging and disappointing at the same time.
David Dodick, MD: I agree with Peter. When I see patients with familial hemiplegic migraine and tell them there’s genetic testing available, and that we can do the gene testing, they say, “Well, what are the implications of that? What are you going to do?” Unfortunately, right now, as you say, it doesn’t guide our therapy in one direction. Someday undoubtedly it will—hopefully that’ll happen during our careers, but right now that’s very true. What these genes do point to is some consistency in what the gene products are responsible for doing, like glutamatergic transmission. We often hear that migraine is a hyperexcitable disorder in the brain. A lot of these genetic variations encode, and the end result is an increased release or decreased uptake of glutamate at the synapse. We need to understand how that could be related. And then there are some genes that are responsible for vascular homeostasis, which is interesting because we know that people with migraine with aura are at an increased risk for ischemic stroke. And so perhaps there are genetic factors that influence some of the complications that some of these patients experience.
Stephen Silberstein, MD: It’s very exciting. There was an article in Science 2 weeks ago about this extraordinarily giant human. They were finally able to do a genetic analysis that showed that she had a very rare combination of multiple genes that can’t be but 1 in a billion. Those individual gene variants added together made them extraordinarily tall, which is interesting because the height was related to genetics, just like with migraines—multiple factors contribute to one thing.
David Dodick, MD: This also becomes important regarding comorbid diseases. There was a beautiful study this year published where they looked at the genetic relationship between psychiatric disorders like depression, anxiety, bipolar disorder, and compared it with multiple neurologic diseases from ALS amyotrophic lateral sclerosis and Lou Gehrig disease, to Alzheimer disease and Parkinson disease. The only neurological disease that had a genetic relationship with some of these psychiatric diseases was migraine. It’s important for neurologists in general to be aware that these people are not necessarily depressed or anxious because they have migraine, but there’s a shared underlying genetic risk that’s responsible for the sort of comorbid relationship between these diseases.