Gene Mutation - The role of genetics in migraines

Gene mutations and the role of genetics in migraine

Migraine is a brain disorder that causes moderate to severe headaches concentrated on one side of the head. Migraine is very common, affecting 15–20% of the world’s population throughout their lifetime, and is ranked as the second most disabling condition in terms of years lived with disability.  [1] It is three times more prevalent in females than in males. [2]

Migraine can have a major impact on one’s life, affecting their ability to function properly at work and socially. 

The causes of migraine are difficult to pinpoint due to the tendency for symptoms to overlap with other neurological disorders. This difficulty has led researchers to investigate the role of genetics in migraine etiology. It appears that migraine has a strong genetic component, and there are many common polygenic forms of the disorder. 

Understanding migraine

A typical migraine attack involves a severe throbbing headache on one side of the head and can last for a few hours or days. It may be accompanied by other symptoms, such as nausea, vomiting, and sensitivity to light and sound, and is aggravated by physical activity.

Around a third of migraine patients also experience an aura phase, which involves transient neurological symptoms such as scintillations (sparkles or flashes of light). For this reason, the two main migraine subtypes are defined as migraine with aura (MA) and migraine without aura (MO).

Triggers can include stress, hormonal imbalance, poor sleep patterns, hunger, or sensory overload. However, scientists are still uncertain of the neural and vascular mechanisms that set off a particular migraine. [3]

Some research suggests that migraine headache occurs in those with a brain state of altered excitability capable of activating the trigeminovascular system, the major pain-signaling pathway of the brain. [4]

Is migraine always genetic?

Not always. 

Familial studies show that migraine has a significant genetic component. Migraine has strong genetic links, with heritability estimated to be between 40% and 60%. Some studies show that an immediate relative of someone who has migraine without aura (MO) is twice as likely also to have MO and 1.4 times as likely to have migraine with aura (MA). An immediate relative of someone with MA is four times more likely to have MA themselves (although the risk of MO does not increase). [5]

The high prevalence of migraine in females has suggested that hormonal or X-linked components can also contribute. The neurovascular unit plays a prominent role in the genetics of migraine, as well as other factors such as depression and high blood pressure. [6] Researchers have suggested that migraine is a polygenic disorder, and the genetic etiology is likely to include a number of genes that may act in combination. [7]

Migraine also has many non-genetic factors, with environmental factors shown to account for 40% of migraine cases. This makes migraine a multifactorial (complex) disease. [8]

Genetic mutations linked to migraines

Around 200 types of gene mutation in around 100 genes have been investigated for their links to migraine. Two gene mutation examples include MTHFR C677T and MTHFR A1298C. One of the most extensively studied mutations in relation to migraine is MTHFR C677T. 

The MTHFR C677T polymorphism is significantly associated with increased levels of circulating homocysteine, which is a risk factor for vascular disease. Both major forms of migraine (MA and MO) are known to be affected by genetically influenced hyperhomocysteinemia. [9]

The MTHFR gene is responsible for making the enzyme methylenetetrahydrofolate reductase, which is required for the conversion of folate to 5-methyltetrahydrofolate, and the conversion of homocysteine into methionine. A mutation in the MTHFR gene impairs the ability of the MTHFR enzyme to function normally, which can lead to elevated homocysteine in the blood. [10]

Migraine, stroke, and elevated homocysteine all affect the cerebral circulatory system. Elevated homocysteine plasma levels can lead to endothelial cell injury, while inflammation in the meninges and dilation of cerebral vessels is associated with migraine onset, which may be due to homocysteine dysfunction. Oxidative damage to the vascular endothelium is also shown to increase the likelihood of migraines and other vascular disorders such as stroke. [11]

A 2004 study found that the C677T variant increases susceptibility to MA, but not MO. 

Previously, a 2001 study found that 40.9% of those with migraine with aura also had the homozygotic C677T genotype, which they described as remarkably high. This homozygous genotype was also present in 20.3% of migraine sufferers compared with 9.6% in controls. [12]

MTHFR gene mutation symptoms may include depression, anxiety, fatigue, chronic pain, headaches and/or migraine, fertility issues, and neurological and vascular issues such as seizures, thromboses, and vascular lesions.

Nutritional supplements for managing migraine

Researchers have suggested that dietary folate supplementation could help in easing migraine and reducing the risk of vascular injury by improving homocysteine levels. [13]

The homocysteine-methionine cycle requires folate, B6, and B12. Folate is often deficient in those with MTHFR, which then increases the risk of homocysteine. Supplementation with these nutrients may help decrease the severity of migraines with aura. [15]

Riboflavin (B2) is also effective for treating migraine as it increases the synthesis of flavin mononucleotide (FMN) and flavin adenine dinucleotide (FAD) to generate phosphorylation potentials.

Methyl-Life® specializes in methylated vitamin supplements for migraines, particularly for those with MTHFR mutations. Methylated nutrients are able to cross the blood-brain barrier and bypass the MTHFR polymorphism. Methyl-Life’s® Methylated Multivitamin contains both methylfolate and bioactive B12 as well as other B complex vitamins involved in proper homocysteine metabolism and overall good health. 

The takeaway 

Migraine is a painful and debilitating condition that typically runs in families. These genetic links are especially true in those with MTHFR mutations, with studies showing a higher prevalence of the C677T variant in migraine sufferers. 

The close association with MTHFR mutations and migraine has been linked to elevated homocysteine, which occurs with low folate levels and impaired homocysteine metabolism. 

Those who experience migraine should be tested for a MTHFR mutation or elevated homocysteine levels. 

Depending on these results, they may then be able to manage their migraine frequency and symptoms by supplementing with the nutrients required to reduce homocysteine levels. Methyl-Life® provides an excellent range of supplements specifically designed for managing homocysteine and supporting the nutritional needs of those with MTHFR mutations. 

References

1. https://pubmed.ncbi.nlm.nih.gov/33267788/

2. https://onlinelibrary.wiley.com/doi/10.1002/jnr.23903

3. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3858400/

4. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3858400/

5. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8075356/

6. https://pubmed.ncbi.nlm.nih.gov/34304862/

7. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC375543/

8. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8075356/

9. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8075356/

10. https://www.ncbi.nlm.nih.gov/books/NBK6561/

11. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8053543/

12. https://pubmed.ncbi.nlm.nih.gov/11121176/

13. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC375543/

14. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7564482/

15. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4359851/