C Sjostrand (2009) “Genetic Aspects of Cluster Headache” Expert Rev Neurother, 2009. 9(3) 359-368. (Click author to see paper)
AUTHORS’ ABSTRACT: Cluster headache (CH), a primary neurovascular headache syndrome, is characterized by recurrent, unilateral, short-lasting attacks of excruciating pain in the temporal and/or orbital region. The pain is considered one of the most severe pain conditions known to humans. Compared with the general population, first-degree relatives of probands with CH have a significantly increased risk of the same disorder. However, there seems to be no clear mode of inheritance, suggesting that both genetic and environmental factors are of importance, with the pathophysiology being multifactorial. Despite the genetic influence of the disease, a low prevalence and small pedigrees complicate the feasibility of genetic studies. To date, only genetic studies with limited sample sizes have been performed, but results have indicated an association with the HCRTR2 gene, which is involved in the regulation of chronobiological rhythms. Collaborative multicenter studies on large clinically well-defined materials are needed to reach a better understanding of the complex genetic background of CH.
Dr. Sewell’s comment:
Is cluster headache genetic? Migraine certainly is. However, the current thinking is that cluster headache is not. But we all know families where both parent and child have cluster headache—what explains that? In this recent paper, Dr. Sjostrand reviews what’s known about the genetics of cluster headache.
First, she points out that just because several members of a family have a disease, it is not necessary genetic. It could be from the environment (which all the family members share) or even from the same culture (as there are “culture-bound syndromes”, particularly in psychiatry). But then she also points out that when diseases have no clear mode of inheritance, like cluster headache, it can also be because several different genes are interacting together, or else a gene might make someone susceptible to something in the environment that wouldn’t affect someone without the gene. Both of these factors can make it difficult to tell if cluster headache is heritable or not.
The idea that cluster headache might have a genetic component was first introduced in 1994 by Dr. Kudrow, the “grand old man” of cluster headache research (who incidentally suffers from cluster headache himself). He discovered that first-degree relatives of cluster headache patients (in other words—parents, children, or siblings) were forty-five times as likely to have cluster headache as non-relatives. The following year, Dr. Russell in Denmark also found an increased risk in first-degree relatives—a fourteenfold increase, not quite as high as Dr. Kudrow—and also a doubled risk in second-degree relatives (cousins and the like). Then, an Italian study by Dr. Leone (of deep brain stimulation fame) in 2001 found a 39-fold increased risk in first-degree relatives, matching Dr. Kudrow’s figures, and an eightfold increased risk in second-degree relatives. (A fifth of the relatives didn’t quite meet criteria for cluster headache, though, but were included anyway). The following year, a French study by Dr. El Amrani found an 18-fold increase in cluster headache in first-degree relatives. No clear mode of inheritance was directed, but all the studies agree: Something is Clearly Up. But what?
Genes can’t be the only answer. Although there have been seven cases reported of identical twins, both with cluster headache, it’s not clear how many twins don’t share cluster headache. When the Dr. Svensson took a look through the Swedish Twin Registry to find out, he discovered eleven sets of twins in which one had cluster headache and the other didn’t, and none in which both twins had cluster headache. So much for genes alone.
Could there be two forms of the disease, a “familial form” and a “sporadic form”, which differ in other ways as well? It’s been suggested that the familial form seems to appear earlier (in children), have more attacks per day, and get worse in successive generations, but there are plenty of examples of cluster headache in families where that’s not true. Cluster headache patients mostly smoke like chimneys, and it’s been noticed that family members of cluster headache patients also smoke more than usual as well, so perhaps smoking is a trigger for “cluster headache genes”—it’s just a thought, though; nobody’s sure.
Not many molecular genetic studies have been done on cluster headache patients over the years, because nobody thought the disease was genetic, but since 2001 there have been a few. A couple of patients have had their genes sequenced, and a few deletions found, but nothing that seemed to be true of everyone. There is a gene, CACNA-1A, that appears to be responsible for familial hemiplegic migraine, so that gene has also been studied in cluster headache also. Nothing there. The gene for nitric oxide (which seems to be what causes dilation of blood vessels in neurovascular headache, of which cluster headache is one) didn’t seem to be different in cluster headache either. The hemochromatosis gene, HFE? Nope. Trace amines? Nada. What about genes involved in the hypothalamus, which we know is abnormal in cluster headache? Any differences in the Clock gene (one of the five genes that regulates the circadian rhythm, or day-night cycle)? Nope. What about hypocretin-1 and hypocretin-2 (from the HCRTR1 and HCRTR2 genes), which are found in the hypothalamus, are involved in regulating the sleep-wake cycle, and are abnormal in narcolepsy? In 2004, an Italian study led by Dr. Rainero reported that a particular allele (variant) of the hypocretin-2 gene was associated with cluster headache—specifically, one nucleotide substitution appeared to increase the risk for cluster headache sevenfold. Dr. Schurks repeated this study in 2006 in Germany and verified that this “G-allele” increased the risk for cluster headache—he found it doubled it. The Italian group also replicated their own study in 2008 and confirmed the link.
As always in science, not every line of evidence says the same thing. Intrigued by this hypocretin-2 link, Dr. Baumber did a linkage analysis (a genome-wide scan) on 259 cluster headache patients in Denmark, Sweden, and Britain… but didn’t find any link with hypocretin-2, or any other gene for that matter. It’s not clear why. My suspicion is that he might not have examined enough patients. These linkage analyses seem to work best when you have several thousand patients, not several hundred.
So where does that leave us? We don’t have a simple genetic explanation for cluster headache, but we’ve known for years that the hypothalamus is involved, and now we seem to have found a gene, HCRTR2, that’s abnormal in some cluster headache patients. Unfortunately, there aren’t too many genetic investigations into headache being done, and those that are tend to focus on migraine. Luckily, the cost of microarrays, which are used in genetic studies, gets less and less every year, so such studies will become cheaper and cheaper as time goes by. Hopefully that will lead to more genetic studies of cluster headache!
Excellent explanation, thank you very much!
New research results, published yesterday:
http://dx.doi.org/10.1111/j.1526-4610.2009.01569.x
I agree that you have to look at the big picture. Variables such as environment and culture should be considered when looking at the genetic factor in CH. But I believe that CH is genetic. I have two brothers diagnosed ECH. I was diagnosed primary chronic CH. I can also remember my paternal grandmother tying cayenne peppers around her head for her “headaches. At some point, one has to consider the genetic aspect of CH, as opposed to coincidences.
It is also possible that there is a familial form, and a non-familial form. We see this in such things as Lou Gehrig’s disease, in which there is a familial form caused by a mutation in the superoxide dismutase gene (SOD1), but most have nothing to do with it. The same could be true of cluster headache; we just haven’t pinned down the gene yet.
In my case genetically, there have to be some link. My late Grandfather (Mothers side), although never diagnosed, suffered from exactly the same symptoms and attacks as me, that has been diagnosed with CH.
He had these symptoms until he died at a very ripe age. My middle daughter started with Migraine at the age of 6 and my youngest, my son suffer from periodic one sided headaches since puberty.
Coincidence? I do not think so.
Environment in our case… No.
We all have lived apart for years at a time in different countries, except for my son that has been with me since birth.
Culture… No.
My Grandfather was French, my daughter is Flemish, I am Dutch/Afrikaans, my son has been adopting all the cultures he has lived in or was schooled in since birth. British, American, Portuguese, South African and now Australian.
I experienced my first cluster headache attack when I was 23 years old. My mother had migraines. Her mother, too. My daughter has migraines, and my great-great grandfather had what sounds like cluster headaches, and used Laudanum regularly for pain relief.
Great. Thanks for posting this. It is always awesome to see someone educate the public.