MTHFR in Children: Signs and Risk Factors

Every year, an estimated 7.9 million children¹ are born with serious birth defects. More than half of these defects are due to unknown causes, which makes prevention difficult.

Recently, research has drawn possible links between certain health conditions and the MTHFR gene.

MTHFR stands for methylenetetrahydrofolate reductase, an enzyme required for numerous biological processes in the body. This enzyme converts ingested folate into the active form of folate, L-5-Methyltetrahydrofolate (sometimes called 5-MTHF). This is the dominant form used by the body at a cellular level.

A mutation on the MTHFR gene may lead to impaired function of the MTHFR enzyme, which may lead to a deficiency in folate and several other nutrients.

Folate is crucial for the methylation process, which underpins many bodily systems involved with neurological development and function. Methylation is required for switching genes ‘on’ and ‘off,’ as well as building and repairing DNA and converting homocysteine to methionine.

Undermethylation may have serious implications for a child’s development and long-term health. The MTHFR polymorphism has been linked to behavioral disorders (ADHD, autism)², food allergies, asthma, mood disorders (depression, anxiety), congenital heart defects, and spinal deformities. It may also influence susceptibility³ to vascular disease, neural tube defects, colon cancer, and acute leukemia.

This article will explain the significance of the MTHFR enzyme regarding children’s health and the most common signs of an MTHFR mutation in children and babies. We will then discuss potential strategies for reducing the risk of MTHFR-related complications through supplementation. 

Behavioral disorders such as Attention Deficit Hyperactivity Disorder⁴ (ADHD) and autism may show within the first 12 months⁵ of life or not until 24 months or later. This may be the first clue that the child has an MTHFR mutation. The MTHFR enzyme is required for regulating neurotransmitters such as dopamine, serotonin, and norepinephrine which control mood, behavior, and sleep. Impairment of this enzyme has been linked to behavioral disorders in children, including autism and ADHD.

There is also evidence of a link between MTHFR, hyperhomocysteinemia, folate, B12 and B6, and pediatric stroke⁶. The prevalence of homozygous 677TT was twice as high in children with stroke, and total plasma homocysteine levels were also significantly higher in children aged 2 months to 15 years with stroke. This suggests that the 677TT genotype may predispose children to both elevated homocysteine and recurrent risk of stroke.

MTHFR polymorphisms have also been implicated in the risk of childhood acute lymphoblastic leukemia, with some evidence that the C677T (but not A1298C) polymorphism is a potential biomarker for the risk of leukemia in children⁷.

Spina bifida is a type of neural tube defect that affects 1 in every 2,758 births⁸ in the U.S. MTHFR polymorphisms are strongly associated with increased risk of spina bifida due to an inability to process methylenetetrahydrofolate reductase.

Other defects in neural tube development are also thought to result from genetic influences of folic acid. Some of these may lead to chromosomal syndromes, usually trisomy 13 and 18. One study found a higher prevalence of MTHFR polymorphisms in mothers of trisomy 18 fetuses⁹ compared with other groups.

Mothers of children with Down syndrome¹⁰ also tend to have impaired folate metabolism, which may be due to a mutation in the MTHFR gene.

Some sources have claimed a relationship between MTHFR mutations and physical characteristics such as tongue ties, stork bites, sacral dimples, and other defects. However, there are no studies to support these claims. A ‘stork bite’ is actually a nevus simplex (pink patches on the face), which is present in 30-50% of all newborns¹¹, regardless of whether the baby has an MTHFR polymorphism. The MTHFR polymorphism is also common, occurring in 30-40% of people. However, having both a nevus simplex and an MTHFR nevus simplex does not make the two related.

MTHFR gene mutations have been implicated as risk factors for neural tube defects (NTDs). Some research suggests that women with the homozygous 677TT are twice as likely to give birth to a child with a neural tube defect¹², though the risk is still low. Other studies claim that homozygous 677TT is associated with a 2–4 fold increased risk of NTD¹³, while the 1298A→C mutation has a smaller relative risk. Researchers also note that the risk is much higher in conditions in which folate intake is low, or there is a greater demand for folate by the body, such as pregnancy.

This study found evidence that Hispanic mothers with the homozygous 677TT¹⁴ MTHFR genotype had a significantly higher risk of having babies with upper-level spina bifida defects.

An earlier analysis suggested that homozygosity for the 677TT allele in infants is associated with approximately a 70% increased risk¹⁵ for spina bifida.

A Chinese study suggested that genetic variants in the folate metabolism pathway constitute a significant risk factor for congenital heart defects (CHD). The polymorphism A1298C MTHFR was found to be linked to CHD susceptibility¹⁶, with a higher prevalence of this genotype in mothers who gave birth to children with CHD.

It is important to note that the C677T variant results in a less active form¹⁷ of the MTHFR enzyme and a reduced ability to process folate. Both the homozygous MTHFR 677TT and compound heterozygous variants (one copy of C677T and one copy of A1298C) also significantly decreases MTHFR enzyme activity¹⁸.

Autism affects an estimated 14.7% of children in the USA¹⁹. There is some evidence that the genes involved in the folate/homocysteine pathway may increase the risk of autism in children, particularly the C677T polymorphism. One study found that the frequency of the C677T allele was slightly higher in autistic children²⁰ than non-autistic children (29% versus 24%).

A 2020 meta-analysis²¹ indicated that MTHFR C677T polymorphism is strongly associated with an autism spectrum disorder. However, the MTHFR A1298C polymorphism was not found to be significantly related to autism.

MTHFR supplements generally include methylated multivitamins that support the methylation process in the body. L-Methylfolate is a key ingredient as it has a bioavailability much higher than folic acid alone, particularly in those with an MTHFR polymorphism. This form is often labeled as L-MTHF, L-5-Methylfolate, L-5-MTHF, and (6S)-5-Methylfolate.

Folic acid is a synthetic form of folate and should not be given to children with an MTHFR variant, as it will not be processed adequately in the body.

L-methylfolate supplementation has been shown to improve symptoms of aggression and disruptive behavior²² in children with autism who have the C677TT variant.

An MTHFR mutation occurs due to one (or more) single nucleotide polymorphisms (SNPs). SNPs are the variation in a single-nucleotide that occurs at a specific position in the genetic material.

Abnormal variations of MTHFR can be either heterozygous (one variant) or homozygous (two variations). A child will inherit one copy of each SNP from each biological parent. The more variations, the more potential problems with methylation.

Although there are over 70 different MTHFR SNPs involved in folate metabolism, testing will likely only be for the two well-known SNPs (677 and/or 1298), even though more may be present.

If a mother is found to have an MTHFR SNP, there may be some options for reducing the risk of having a child with an MTHFR-related disorder. Prenatal dietary intervention²³ in mothers with MTHFR genotypes has been shown to help reduce the risk of children being born with autism-like behavior.

Disorders related to MTHFR polymorphisms are increasingly common, and the presence of an MTHFR variant in the family may not be realized until a child shows symptoms of a disorder. Such disorders may affect a child’s nutritional status to the point of influencing their development, behavior, cardiovascular function, and other aspects relating to long-term health.

While not all genetic disorders are preventable, there is some evidence that nutritional interventions can help reduce the risk of MTHFR-related behavioral disorders and also treat symptoms later in life.

Vitamin and mineral supplements are among the most widely recommended medical interventions for autism, with 49% of physicians²⁴ suggesting supplementation for children with autism. In particular, L-methylfolate has been found to help alleviate the symptoms of ADD/ADHD and may be used as an adjuvant to stimulants.

In a study involving patients with autism disorder, it was found that taking a high-dose L-methylfolate chewable tablet²⁵ for six weeks helped to reduce behavioral symptoms on average by 27%. Sixteen of the patients showed a 50% reduction in their symptoms.

Another study highlighted the potential for L-methylfolate calcium²⁶ in treating a range of psychiatric and neurologic conditions in children’s and adolescent mental health.

Gut health also plays an essential role in MTHFR-related disorders due to the way in which nutrients are absorbed through the gut lining. Supplementing with probiotics and gut-healing nutrients is beneficial for children with autism spectrum disorders²⁷.

Dietary Reference Intakes²⁸ established by the Health and Medicine Division of the National Academy of Sciences for dietary equivalent folate (DFE) are:

• 0 - 6 months - 65 mcg DFE
• 6 - 12 months - 80 mcg DFE
• 1 - 3 years - 150 mcg DFE
• 4 - 8 years - 200 mcg DFE
• 9 - 13 years - 300 mcg DFE

Some of the most highly recommended methylfolate supplements are in the Methyl-Life® product suite, including a range of dosage levels. Methylfolate 7.5+ and the Methylated Multi may be given at lower doses that are safe for children.

Each of the methylfolate products in the Methyl-Life® collection contains the internationally-patented Magnafolate® PRO  [(6S)-5-methyltetrahydrofolic acid, Calcium salt, Type C Crystalline molecule (L-Methylfolate)]. These best-selling products are formulated especially for those with a heightened need for bioavailable folate due to MTHFR defects.