Due to the high frequency of migraines, it is not surprising that in some families several people suffer from migraines. As early as the 19th century, it was assumed that migraines were inherited. A large body of research has been conducted to support this hypothesis.
Hereditary factors play a crucial role in the development of migraines. More than 70% of those affected know first-degree family members (parents, siblings or children) who also suffer from migraines. Children of migraine sufferers have a 2 to 4-fold increased risk of developing migraines compared to their peers. Underlying genetic defects have now been identified for a subtype of migraine, familial hemiplegic migraine. These are responsible for the hypersensitivity to a variety of internal and external stimuli, the so-called trigger factors, that is so characteristic of migraine patients.
These include, among other things, disruptions to the sleep-wake rhythm, hormonal fluctuations, changes in blood sugar levels or current stress levels, unusual physical stress or odors, noise or flickering lights. This means that although the genetic predisposition to migraines is passed down through the generations, whether migraines actually occur in individual cases and, if so, how severe and how frequently, depends largely on environmental factors.
Migraines are caused by altered signal transmission and disruption of the energy supply to nerve cells in the brain
When looking at the studies, it becomes clear that parents and children of migraine sufferers are more likely to have migraines than other people. This conclusion suggests that heredity factors play an important role, but learning factors and behavior are also important. Modern migraine and genetic research has provided very important additional insights into how migraines develop.
In 2005, a team of researchers from the Kiel Pain Clinic and the Institute for Human Genetics at the University of Bonn/Cologne discovered for the first time specific changes in the human genome on chromosome 1 in patients with the most widespread forms of migraine. These disrupt the excitability of nerve cells. If overloaded too quickly or for too long, the result can be a collapse in the energy supply to the nerves. The control of nerve function is derailed. Pain-triggering messenger substances are released unhindered by the nerve cells and cause the pounding migraine headaches.
Migraine patients are characterized by a special way in which stimuli are processed in the brain. Your nervous system is constantly under “high tension”. Stimuli are absorbed earlier and faster by the brain and processed more quickly. Until now, it was largely unknown why the brains of migraine sufferers switch differently.
With the results, the research team has discovered an important key to migraine genes.
Until now, only genetic changes for extremely rare subtypes of migraine were known. Over four years, the scientists studied families in which several people suffered from either migraine with aura or migraine without aura. These are the most common forms of migraine and are responsible for more than 99% of all migraine attacks. The Kiel-Cologne research team searched across Germany for families in which at least two members suffered from migraine with aura. The study examined members of 45 families, in which an average of four people were ill. In one family, ten affected patients were even identified. The types of migraine were diagnosed using the latest internationally standardized headache criteria. Blood samples were collected from affected and unaffected family members. After precise diagnosis of the forms of migraine, the genetic material was sent from the Kiel Pain Clinic to the Institute for Human Genetics at the University of Bonn and Cologne, where its structure was analyzed using special techniques.
In this study, the research team focused on the chromosome 1 area, in which gene changes had previously been found in an extremely rare subtype of migraine.
This focused center contains a genetic makeup for a specific ion pump of the brain, whose function is to control the excitability and supply energy to nerve cells. For the first time, the team of scientists was able to discover two previously unknown gene changes in patients suffering from the widespread migraine with aura. These changes were only found in affected members of migraine families, but not in healthy controls. Further investigations showed that one of these genetic changes actually leads to a loss of function of the ion pump and thus probably also to a disorder of nerve excitability. The result can be a collapse of the energy supply in the nerve cells if the nervous system of migraine patients is stimulated excessively or suddenly. As a result, pain-triggering nerve messengers are released excessively. These cause the migraine pain and accompanying symptoms during the migraine attack. The research results are important for the future diagnosis and treatment of migraines. Migraine sufferers should maintain a consistent day-night rhythm. Abrupt and intense changes in stimulus should be avoided. A regular, carbohydrate-rich diet with sufficient vitamin B2 can stabilize the energy supply to the nerve cells.
Relaxation training, biofeedback therapy and stress management training prevent excessive nerve excitation and reduce energy consumption in the nerve cells. During an attack, specific migraine medications, triptans, stop the release of pain-triggering neurotransmitters. Preventive medications can normalize energy consumption in nerve cells.
Risk factor for migraine without aura and migraine with aura on chromosome 8
Scientists from the Kiel Pain Clinic and the University of Cologne/Ulm identified a genetic risk factor for the first time in 2010 as part of an international collaboration with researchers from the Wellcome Trust Sanger Institute (Cambridge), the Ludwig Maximilian University of Munich and the Leiden University Medical Center, among others , which is associated with migraines with and without aura.
The genetic variant found on chromosome 8 controls the amount of the nerve transmitter glutamate in the nerve junctions via the nearby genes PGCP and MTDH. Glutamate activates important nerve functions such as attention, memory, concentration and perception.
The new discovery is considered crucial in starting the most common migraine attacks. It provides new insights into the causes and treatment options for the widespread disease migraine. Through a unique international network of 65 researchers from 13 countries in the world's largest migraine study to date, it has been possible for the first time to discover a gene variant for the most common forms of the widespread disease migraine. Previous studies have only been able to find genetic changes in rare subtypes of migraine with aura. The now discovered gene variant on chromosome 8 can be found in migraines with or without accompanying neurological symptoms.
In previous studies, the researchers had already discovered gene locations that could be responsible for very severe but rare subtypes of migraine. However, it was unclear which risk factors in the genetic material are responsible for the widespread common migraines, i.e. migraines with and without aura. To develop the data, a research group from the Kiel Pain Clinic collected and classified blood samples from affected patients and their family members over several years in Germany.
In the search for the key to common migraines, the genomes of over 6,000 migraine patients were compared with those of healthy control subjects. Researchers from over 13 countries were internationally networked. The patient group from the Kiel Pain Clinic was one of the largest subgroups in the network, which made the current identification of the gene variant possible.
Completely unexpectedly, basic researchers were able to identify a variant on chromosome 8, called rs1835740, as the first known genetic risk factor for migraines. In the original study, genetic material from over 2,500 migraine patients and 10,000 healthy people was initially compared. Due to the unexpected finding, this gene locus was checked again in a second, very extensive replication study on over another 3,200 migraine patients and 40,000 control subjects. The international migraine network was able to confirm his initial suspicions.
Nervous excitability and glutamate
Due to a genetically determined high glutamate level, it seems possible that the transmission of nerve impulses via the so-called synaptic gap between the nerves occurs very quickly, sustainably and intensively. Stress and irregular daily rhythms are the strongest migraine triggers.
If the nervous system is activated too strongly, too intensively, too excessively and too suddenly, overactivation and ultimately exhaustion of the transmitter substances can result. The nervous control could be derailed and secondarily release inflammatory substances in the nervous system. These can lead to painful inflammation of blood vessels in the meninges, which causes the pulsating and throbbing migraine headache.
The research approaches now found will make it easier to intervene more specifically in the fundamentals of migraine development in the future. It is known from current clinical studies that those affected by frequent attacks are characterized by a high sensitivity of the nervous system and the pain perception system. Both behavioral and experiential factors that cause the excessive activation of glutamate levels could now be targeted in clinical research programs. The specific development of groups of substances that lead to normalization of glutamate levels could represent a further step in the successful future prevention of migraine attacks.
Migraines are now viewed as a progressive disease of the central nervous system. Long-lasting and high-frequency migraine attacks cause structural changes in the nervous system. This promotes a number of comorbidities. In the neurological field, these include epilepsy, medication overuse headaches and strokes, in the psychiatric field, depression, anxiety and panic disorders, and in the internal medicine field, heart attacks, coronary heart disease and high blood pressure.
The constant overactivation of the nervous system due to increased glutamate levels could also play a decisive role in the occurrence of other diseases in addition to migraines. The genetic risk factor found on chromosome 8 could be relevant as a common basis for these diverse diseases.