MTHFR and Migraine

Migraine is one of the most prevalent health conditions in the world, and ranked as the sixth most disabling condition by the World Health Organization.

The International Headache Society defines migraine as falling within two major categories, namely migraine with aura (MA) and migraine without aura (MO). Women are three times more likely than men to be affected by migraine, and the age range with the highest prevalence includes those aged between 25-50.

While the exact causes and mechanisms of migraine are still largely unknown, research suggests that migraine is a genetic, neurological condition. Evidence that migraine runs in families has supported a theory that a combination of genetic factors may be to blame—namely genes involved in regulating the vascular system.

The MTHFR gene (methylenetetrahydrofolatereductase) has been found to play a significant role in migraine with aura (MA). MA often occurs in people who are also at a high risk of stroke, which has highlighted the vascular class of genes in migraine studies.

This article will discuss the role of both the mutated and unmutated MTHFR gene in causing migraine and the risk of developing migraine when a mutated MTHFR gene is present. We will also cover the importance of managing homocysteine levels and other health concerns in reducing the risk of migraine.

Migraine attacks may have a connection to MTHFR gene mutations because those with the mutation are unable to convert the amino acid homocysteine into methionine.

The MTHFR gene is responsible for making an enzyme called methylenetetrahydrofolate reductase. This enzyme plays a huge range of important roles within the body, from synthesizing DNA to processing amino acids. The MTHFR enzyme is also required for the conversion of a form of folate called 5,10-methylenetetrahydrofolate to a form called 5-methyltetrahydrofolate.This is the primary active form of folate in your body required for homocysteine conversion.

Homocysteine is a type of sulfur-containing amino acid that the body produces from the breakdown of another amino acid, methionine. When the MTHFR gene is functional, the body is able to maintain homocysteine at low levels by converting it into other products. To do this, your body requires the help of certain B vitamins, namely folate, B6, and B12.Each of these nutrients works together in the methionine-homocysteine pathway.

Elevated homocysteine plasma levels can cause endothelial cell injury, a higher risk of blood clotting. Inflammation in the meninges and dilation of cerebral vessels is thought to play a part in migraine onset, which suggests homocysteine dysfunction may increase the risk for developing migraine. Oxidative damage to the vascular endothelium may also increase the likelihood of migraine headaches and other vascular disorders such as stroke.

Many of the vascular-type genes associated with migraines tend to overlap with genes involved in the risk of stroke and heart disease.

Mutations of the MTHFR gene(methylenetetrahydrofolate reductase) are a significant risk factor in elevated homocysteine. A mutation on the MTHFR gene can significantly affect the ability of the MTHFR enzyme to function normally, which can lead to elevated homocysteine in the blood.

MTHFR polymorphism also impairs the body’s ability to convert folic acid into a usable form of folate. Folate is also needed to drive the homocysteine pathway, and low folate levels and/or reduced MTHFR enzymatic activity are linked to an increase in homocysteine levels. This is termed hyperhomocysteinemia and has been associated with a variety of metabolic disorders and increased risk for complex diseases, including heart disease, stroke, and migraines with aura.

The MTHFR gene variant C677T has been implicated as a genetic risk factor in migraine susceptibility, particularly in migraines with aura.

A 2000 Japanese study found a significant association between the MTHFR C677T variant and migraine. The homozygous single nucleotide polymorphism (SNP) was found in 20.3% of migraine sufferers compared with 9.6% in controls and was particularly high in those suffering from MA (40.9%).

Another study involving Spanish patients with MA also found a significant association with the C677T/TT genotype. Patients were recorded as having elevated homocysteine

blood plasma levels and were therefore also considered to be at risk of stroke and other vascular anomalies. The authors concluded that the homozygous mutation was linked to MA.

Further analytical reviews have shown that theC677T variant in the MTHFR gene influences susceptibility to MA, but not MO. This has provided compelling evidence that the MTHFR gene plays a critical role in MA pathogenesis.

The genotypes 677TT and 1298CC (both double mutations) were the only genotypes significantly associated with migraine. This may be because the A1298C variant results in decreased MTHFR activity to a somewhat lesser degree than the C677T variant.

High homocysteine is a major risk factor for not only migraine but other vascular-related conditions, including cardiovascular disease, stroke, and also mental health impairment such as cognitive disorders, dementia, depression, Alzheimer’s and Parkinson’s disease.

One of the key means of reducing migraine attacks is to manage homocysteine levels. Homocysteine catalyzation requires adequate levels of vitamins B6, B12, and folate in the blood, which have been shown to decrease the severity of migraines with aura.

Adequate intake of folate (specifically methylfolate), vitamin B6, vitamin B12, and betaine may control or alleviate the risk of elevated homocysteine.  Taking folate, B12, and B6 together has also been shown to help lower homocysteine levels more effectively than taking folate alone.

A 2009 study in which patients with MA were treated for six months with these vitamins (2 mg of folic acid, 25 mg of vitaminB6, and 400 mcg of vitamin B12 daily) resulted in lowered homocysteine by 39%and reduced headache frequency, pain severity. The prevalence of migraine disability reduced from 60% to 30%after 6 months follow-up, while no reduction was observed for the placebo group.

Treating migraines associated with MTHFR should involve therapies that help to reduce homocysteine and improve methylation. This is best done through diet and supplementation.

As mentioned above, supplementation with B vitamins (methylfolate, B6, and B12) is essential for decreasing homocysteine concentrations, which in turn may reduce the frequency of migraines.

Examining family history of cardiovascular disease and digestive disorders will help to assess your level of risk. Check for history of stroke, heart attack, thrombosis, congenital heart defects, inflammatory bowel disease, Crohn’s disease, depression, dementia, and migraine with aura.

A range of medical tests is also recommended, including:

● Blood count test: Large red blood cells (RBCs) or anemia can be a sign of poor methylation, particularly RBCs with a mean corpuscular volume (MCV) greater than 95.

● Homocysteine: Levels should be less than 13, but ideally between 5 and 8.

● Serum or urinary methylmalonic acid: This may indicate low vitamin B12.

Improving gut health will help with nutritional absorption. Digestive diseases, food allergies, and even aging can reduce the absorption of nutrients. Low stomach acid also affects the absorption of vitamin B12.

Avoid refined/processed foods, sugar, saturated fat, coffee, and alcohol, as these foods can deplete B vitamins.

Over-the-counter medications such as acid blockers and the oral contraceptive pill can affect levels of B vitamins: these should be taken only when necessary. Quitting smoking is also important, as carbon monoxide from cigarette smoke reduces folate.

The main goals in treating conditions associated with MTHFR is to improve methylation and reduce homocysteine. This can be applied to treating migraines.

Whether due to genetic influences or dietary factors, homocysteine can be lowered by increasing intake of folate, vitaminB6, and B12. Other nutrients - taurine, betaine (TMG, or trimethylglycine), DMG(dimethylglycine), NAC (N-acetylcysteine), and Omega-3 fatty acids - can also help to lower levels and support overall wellbeing.

As well as supplementation, foods that are rich in folate, B6, B12, and betaine should be included in your diet as often as possible. This includes leafy greens, whole grains, legumes, fruit, and nuts. Egg yolks, meat, liver, and oily fish are also excellent sources of vitamin B12.

Vitamin deficiency often occurs as a result of poor diet and/or weak digestive function; therefore, your diet should also include foods rich in protein and probiotic bacteria to help restore the integrity of the digestive tract. Essential fatty acids such as omega-3 can help reduce inflammation and the risk of heart disease.

A spore-based probiotic supplement is recommended as these are highly resistant to acidic pH, stable at room temperature, and able to deliver a higher quantity of viable bacteria to the small intestine than traditional probiotics.

The link between MTHFR and migraines has been confirmed in several studies. This link appears to be strongest in those with high homocysteine concentrations. Study authors have highlighted that this is likely due to the fact that homocysteine conversion is dependent on adequate levels of folate, B6, and B12: this is often lacking in those with the MTHFR mutation, particularly the C677T variant.

Supplementing with the active, methylated forms of folate, B6, and B12 is the most effective way to improve concentrations of these vitamins. Methylated nutrients are able to cross the blood-brain barrier without requiring further conversion in the body, which means they will bypass an MTHFR polymorphism.

Some of the best methylfolate supplements for those with MTHFR mutations include Methyl-Life® products (B-Methylated II, Methylated Multivitamin, also Methylfolate 7.5+ or Methylfolate 15+). This product range has been created by a team of natural health experts and contains the purest, most stable, and most potent of four of the world’s industry-leading patented L-methylfolates. It is also suitable for vegans and those with cardiovascular risks.

Methy-Life’s® B12 Complete is also ideal for those with genetic and/or absorption issues that may be affecting B12absorption. B12 Complete contains a combination of the 3 most bioactive forms of B12 (hydroxocobalamin, methylcobalamin, and adenosylcobalamin) for maximum delivery and absorption.