The MTHFR Gene Mutation and Methylation

What Is MTHFR?

MTHFR is a common genetic “mutation” with two primary variants: C677T and A1298C. If you get two copies of one variant, you are called homozygous; just one copy makes you heterozygous. People with a mutation have at least one variant (either with a single or double copy). These variants do not cause disease, but they can create a bottleneck for an important process in the body called methylation. Methylation relies on the enzyme MTHFR (or methylenetetrahydrofolate reductase) for a whole host of biochemical activities including those involved with our children’s brain health, DNA repair, and ability to eliminate harmful products like synthetic chemicals and metals.

Take the C677T variant for example. This mutation can impair the body’s ability to convert homocysteine to methionine, which in turn is often associated with cardiovascular dysfunction, heart disease and stroke, especially when a person is homozygous. The role of the C677T variant has been studied in pregnancy and for developmental outcomes in infants – including the risk for neural tube defects and placental vascular complications. Many children with autism have trouble with this conversion which can be reflected in abnormal levels of homocysteine on blood testing.

The A1298C variant is often associated with chronic illnesses. It typically has a milder effect on enzyme function (less impact on homocysteine) but is more commonly linked to neurotransmitter imbalances and mood-related patterns.

People with an MTHFR variant are often described as poor methylators. For example, MTHFR allows our body to activate certain B vitamins (via methylation). Children’s bodies need the activated (or methylated) form of B vitamins for brain development, growth and repair. MTHFR is needed to make methylfolate (the active form of vitamin B9) to cross the blood-brain barrier. Carrying one or more MTHFR variants can limit a child’s access to key vitamins especially if they don’t get enough of the right form through diet or supplementation.

What Is Methylation?

Methylation is the term used by biochemists to describe the addition of a carbon-hydrogen, or -CH group (methyl group), onto a molecule. The -CH group, once added, allows certain molecules in the body to carry out a particular role. Methylation is not only used to activate B vitamins, but also to synthesize, regulate and degrade neurotransmitters like serotonin, melatonin, epinephrine, nor-epinephrine, and dopamine. Our bodily functions rely on the right balance of these vitamins and neurotransmitters for both physical and mental health.

Methylation plays an important role in healthy elimination, It supports active detoxification cofactors, including vitamin C, vitamin E, and our body’s master antioxidant – glutathione. Glutathione plays a critical role in how the body excretes environmental toxins and is an important support for many immune factors and processes that the body relies on to eliminate pathogens. MTHFR and methylation directly or indirectly impact other pathways too, such as sulfation, an important pathway for detoxifying metals and resolving allergies.

Defects in the methylation process can affect many areas including:

• Immune system function
• DNA repair
• Homocysteine regulation
• Inflammation
• Recycling and regulation of key antioxidants
• Glutathione production and utilization
• Sulfation and other metabolic pathways (see lab section below)

What About MTHFR and Autism or Other related Conditions?

MTHFR may play an important role in some children developing autism. Studies have shown (see Sources & References, below) that 98% of children with autism have an MTHFR genetic mutation defect (over twice the percentage of the general population), and the mutation is not exclusive to autism. Families that are susceptible to autoimmune disorders are also often affected by the MTHFR anomaly. Critical immune functions may be compromised if there are any defects found in the methylation process. Many children on the autism spectrum are suffering from chronic symptoms of immune dysfunction and inflammation.

Some children with autism have also been found to have a shortage of adequate folate in the brain and are diagnosed with Cerebral Folate Deficiency (CFD). This can be due to poor methylation and exacerbated by mitochondrial dysfunction or poor access to co-factors. A FRAT (Folate Receptor Antibody Test) is available to check for the presence of antibodies that limit access, or completely block, folate receptors in the brain.

Children who have a problem with their folate receptors may benefit from the judicious use of leucovorin – an alternative version of folate that is taken up by the brain through a secondary, albeit less efficient, pathway. The role of diet and nutrition should never be overlooked. Access to other vitamins and minerals like vitamin D, magnesium and lithium are crucial for transporting methylfolate and methylcobolamin (methyl-B12) into the brain. When adequate, these cofactors will make methylation more efficient and should decrease the amount of leucovorin required. It is important to note that folic acid, a synthetic form of folate found in many “fortified” foods DOES NOT substitute for folate and may exacerbate symptoms of folate deficiency.

Testing and Treatment

While this article focuses primarily on two common methylation variants (C677T and A1298C) and the activity of the enzyme MTHFR, there are a variety of other gene variants that can be tested to give clues into a body’s ability to methylate as well. These include COMT (involved with dopamine/estrogen metabolism), MTR/MTRR (B12 recycling), CBS (sulfur metabolism), BHMT (alternate methylation pathway), SHMT (also involved with folate metabolism), SHMT (folate metabolism), MAO-A (neurotransmitter breakdown).

Individual variants can be tested in blood through standard labs like Labcorp, genomics, or nutrigenomics testing. Testing only requires a saliva cheek-swab rather than blood samples. These test for many methylation-related genes all at once (along with genes that pertain to aging, nutrient availability, mental health risks, inflammation, and the role of numerous other enzymes and biochemical pathways). These tests can help guide therapies for bioindividual safety and efficacy, as well as highlight a person’s unique strengths and vulnerabilities.

Genomics and other tests identify variants by looking at SNPs (single nucleotide polymorphism) pronounced “snips.” SNPs are small variations in a single “letter” of DNA that can influence how our bodies uniquely function and respond to environment, diet, lifestyle, medications, and stressful situations. Whole-genome-sequencing attempts to identify every known or new gene variant and requires a much more comprehensive approach to interpretation.

Genomic testing is becoming more popular and sophisticated as more clinical tools are available to guide individualized diet and lifestyle modifications to improve people’s health outcomes. Here is an alphabetical list of some of the more popular genomic tests used by root-cause oriented, health care providers: Ancestry, Doctor’s Data, Genemetrics, Genomind, Genova Diagnostics, IntellxxDNA, Mosaic Diagnostics (formerly Great Plains), Seeking Health, and StrateGene (created by Ben Lynch, author of Dirty Genes).

An early advocate and researcher of genetic testing for children with neurodevelopmental challenges is Dr. Amy Yasko PhD, ND. She has done extensive work with methylation and offers a nutrigenomic test which identifies 30 different genetic mutations in the body including the MTHFR. Some mutations have to do with neurotransmitters like dopamine and serotonin, while others are concerned with sulfation and pathways that generate ammonia – critical issues for autism and other neurologic conditions.

Many practitioners now recognize that while genes indicate methylation potential, other measurable biomarkers (e.g., homocysteine, organic acids, individual nutrients, metals, molds and toxic elements, and hormones or neurotransmitters) reveal how methylation is truly functioning. Testing biomarkers may help prevent over-interpretation of SNPs and help practitioners prioritize bioindividual, timely, and cost-effective interventions – including wiser diet choices and lifestyle changes. Functional tests can also be repeated over time to measure and track improvements or change.

An experienced health care provider can guide the appropriate testing and suggest appropriate nutritional supplementation to support the methylation process and MTHFR. For children who require supplementation but are unable to swallow pills, powders, sprays, topical solutions and liquids can be used as alternatives. Dr. Yasko has formulated oral sprays to support a child’s methylation, and Kendall Stewart MD at Neurobiologix has formulated an effective transdermal cream called Neuro Immune Stabilizer Topical Cream that is applied to the skin.

In Short

MTHFR is a key factor in methylation. Methylation is an important pathway necessary for many active molecules and processes throughout our bodies. It supports a child’s growth, repair, detoxification, neurotransmitter balance, and vitamin status, as well as overall mental and physical well-being. Poor methylation may explain why some children survive the overload of environmental toxicity during their early stages of neurological development, while others regress or remain somewhere on the vast spectrum of neurodevelopmental disorders.

MTHFR variants combined with other factors such as toxins, stressors, or nutrient deficiencies can lead to the “perfect storm” and may explain your child’s symptoms, behaviors or ability to heal or progress. On the bright side, while genetic SNPs are present for life, their positive or negative impact on our children’s health can be modified and improved through better choices of diet, lifestyle, supplements, environmental exposures, medications and therapies.

About Heather Tallman Ruhm MD

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