MTHFR Gene Mutations and Multiple Sclerosis: Is There a Connection?

Multiple sclerosis (MS) is a complex autoimmune disease of the central nervous system (CNS) that leads to CNS inflammation and demyelination of nerve axons. MS affects about 2.8 million people worldwide and around 1 million people in the US. 

Genetic factors  have long been suspected in MS, and recent studies have provided evidence of a link to MTHFR polymorphisms. 

A major factor in the development of MS is elevated homocysteine, which causes dysregulation of the blood-brain barrier and endothelial dysfunction. Homocysteine also contributes to the damage of neurons through excitotoxicity (excessive stimulation) and apoptosis of neurons. The result is neurodegenerative brain damage, which plays a leading role in the progression of MS. 

This article will explain the pathophysiology of MS and how it may be linked to MTHFR genetic mutations. We will also discuss how an MTHFR polymorphism can increase the risks of developing MS and potential options for treatment and prevention. 

MS is a neurodegenerative disease in which the immune system attacks myelinated axons in the central nervous system. Specifically, the immune system attacks the insulating layer or sheath that protects nerves fibers, including those in the brain and spinal cords. This damage disrupts the flow of information between the brain and the body. 

Symptoms are unpredictable, and each patient is affected differently. Some may suffer only mild symptoms, while others may be unable to write, speak, or walk. Most patients suffer initial episodes of reversible neurological deficits, often followed by progressive neurological deterioration over time. Up to 50% will need help walking within 15 years after the onset of the disease.

When diagnosed, around 85% of patients will experience a relapsing-remitting form of MS, characterized by neurological symptoms that continue for hours to days. Relapse symptoms include fatigue, numbness, tingling, blurred vision, double vision or loss of vision, unsteady gait, and weakness. 

Other forms of MS include secondary progressive, primary progressive, and progressive-relapsing.

The cause of MS remains unknown, but research has indicated that it may involve a combination of genetic susceptibility and an external trigger, such as a virus or environmental factors. This can lead to autoimmune dysfunction in which the immune system attacks the CNS.

Genetic influences appear to play a major role in the development of MS, mainly in relation to homocysteine. Previous studies have shown that MS patients have elevated levels of homocysteine, reduced folate, and reduced vitamin B levels. A large meta-analysis showed that MS patients tend to have elevated homocysteine blood levels compared to healthy controls. 

Excess homocysteine can increase the sensitivity of neurons to oxidative stress, leading to apoptosis, hypersensitivity to excitotoxicity, and neuronal damage.

MTHFR (Methylenetetrahydrofolate reductase) is the enzyme required for metabolizing folate to 5-methyltetrahydrofolate, which is then required for remethylation and conversion of homocysteine to methionine.

A mutation on the MTHFR gene impairs the ability to process folate, leading to low folate levels and elevated homocysteine levels, particularly in those who inherit MTHFR variants from both parents. 

The two most common MTHFR mutations include C677T and A1298C. Both are associated with decreased MTHFR enzyme activity and increased levels of homocysteine. Some studies suggest the C677T has a more severe effect than the A1298C variant.

MTHFR mutations also may result in a three- to four-fold decreased activity of the COMT enzyme, which may also play a role in MS inflammation.

One study showed that MTHFR C677T and A1298C polymorphisms were strongly associated with a higher risk of MS in some populations of people. The study also found a higher risk associated with the MTHFR 1298AC genotypes than controls. 

A previous study also found that subjects with the combined 677CT/1298AC heterozygosity had significantly higher homocysteine levels than those of C677T heterozygous.

An Iranian study also found that MS patients with the C677T may be prone to higher levels of serum inflammatory mediators and a vulnerability to an earlier age of onset of disease. 

One study indicated no association between the C677T variants and MS, but it did find a significant association between A1298C and MS. An Australian study also showed a non-significant increased MS risk associated with the C677T variant.

Multiple sclerosis may amplify some of the symptoms already associated with MTHFR, including fatigue, weakness, impaired sensation, cognitive impairment, and mood changes.

Gastrointestinal function is ultimately regulated by the brain and spinal cord, which means that neurologic illnesses such as MS may affect digestive function and nutritional status. Several substantial studies have shown that MS patients are often deficient in vitamin A, B12, and D3.

The C677T variant is significantly associated with vitamin B12 deficiency, which may increase the risk of megaloblastic anemia. Low B12 plays a part in many other MTHFR symptoms. It has been linked to neurological and hematological disorders such as neural tube defects, cardiovascular diseases, dementia, and some types of cancer. 

Although MS is not considered to affect the immune system directly, medications used to treat the disease, such as steroids and immunomodulators, can suppress immune function, increasing vulnerability to infection. 

Those with low folate levels due to MTHFR are already at risk of reduced immune function. Folate deficiency leads to a reduced response of T lymphocytes and antibodies to several antigens. This suggests that those with MS who also have MTHFR may be at greater risk of infection. 

Although it is impossible to change genetic determinants, reducing the risk of developing MS may be possible through nutritional supplementation.

It is already well-established that elevated homocysteine may contribute to the pathogenesis of MS. 

Managing homocysteine may be key to reducing the risk and progression of MS. Folate and vitamin B12 play critical roles in CNS function at every stage of life, especially the conversion of homocysteine to methionine, which is essential for nucleotide synthesis and methylation. 

MTHFR mutations are typically associated with low folate and B12 levels. 

Folate is intimately involved in healthy nervous system development and function. Vitamin B12 is necessary for the production of red blood cells, nervous system maintenance, and the metabolism of fatty acids essential for maintaining myelin. 

Both nutrients are required to properly function the methionine and folate cycles and methylation cycle, and monoamine oxidase production. Dysfunction in monoamine oxidase is thought to be responsible for many psychiatric and neurological disorders, including MS.

Low B12 will lead to methionine and S-adenosylmethionine deficiencies: both of which are required for myelin synthesis.

In a study investigating the effect of Vitamin B12 and folic acid supplementation on patients with  MS, it was found that the patients’ homocysteine levels decreased along with their risk of developing anemia. As a result, their quality of life also improved.  

Vitamin D status may also contribute to the risk of developing MS. A study followed 182,000 women and found that 173 cases of MS. The risk was 40% lower among those women who reported regular use of at least 400 IU/day of vitamin D from supplements. 

Avoiding smoking is also crucial. The risk of developing MS is about 50% higher for smokers than people who have never smoked.

The vitamin B complex has been implicated to have a modulatory role in the pathophysiological process of MS. Researchers have suggested close monitoring of folate and vitamin B12 levels in people with MS, as well as supplementation. 

Folic acid and vitamin B12 may have roles in preventing disorders of CNS development, mood disorders, and dementia. Increasing intake of vitamin B12 and folate alongside immunotherapy treatments in patients with MS has so far shown to be promising. 

Folic acid supplementation (200-300 mcg/day) to patients with MS improved the neurological status of patients, promoted myelin regeneration and the overall general condition and symptoms.

High B12 supplementation in patients with chronic progressive MS resulted in improved visual and brainstem auditory evoked potentials.

Higher vitamin D levels are associated with reduced risk for developing MS and reduced clinical activity in established MS. 

While further research into supplementation for MS is pending, it has been indicated that folate and B12 may play a part in preventing and slowing the progression of the disease. 

Although folic acid supplementation has been used in most of the studies mentioned above, folate is a superior form of the nutrient. Folic acid is not recommended for those with MTHFR polymorphisms as it cannot cross the blood-brain barrier, has no coenzyme activity, and must be reduced to tetrahydrofolate form (the metabolically active form) before the body can use it.

Methylfolate can bypass impaired folate metabolism caused by an MTHFR mutation. Unlike folic acid, it can enter the folate cycle directly without the need for further enzymatic modification.

The Methyl-Life® product range is made with the internationally-patented Magnafolate® PRO, clinically tested as the world’s purest methylfolate and the most active form of folate in plasma circulation. Compared with ordinary folate, Magnafolate® PRO was absorbed faster and utilized more quickly in the body.

In addition, Methyl-Life’s® B12 Complete is ideal for those who are also low in folate or have any form of health condition or gene mutation that may be affecting B12 absorption. B12 Complete combines the three most active forms of B12: Methylcobalamin (2,500 mcg), Hydroxocobalamin (1,250 mcg) and Adenosylcobalamin (1,250 mcg). Previous studies have suggested that those with genetic mutations affecting B12 absorption might raise their B12 status more efficiently by supplementing with these three naturally occurring forms of B12.