MTHFR Gene mutation.

NSW Government | Health | Centre for Genetics Education

WHAT DOES IT MEAN IF A MTHFR VARIANT IS FOUND FOLLOWING A DNA TEST?

DNA testing may reveal that a person has either one or two MTHFR variants.  There are currently no recommended changes in clinical management based on a MTHFR test result.

Some people that are homozygous for the MTHFR C677T variant may develop a mild to moderate increased blood homocysteine level or hyperhomocysteinaemia.  This alone does not usually cause any symptoms or health problems, however further testing may be considered, such as B12, red blood cell folate and homocysteine.

Table 2 – Potential MTHFR variant test results
Remember some results will be completely normal – i.e. no variant found

MTHFR genetic testing: Controversy and clinical implications

 RACGP Publication.

Sarah Long

Jack Goldblatt

Background

A polymorphism is a variant within a gene that does not necessarily affect its function, unlike a pathogenic mutation. Genetic testing for two common polymorphisms in the methylenetetrahydrofolate reductase gene (MTHFR), 677C>T and 1298A>C, is being accessed by general practitioners (GPs) and alternative medicine practitioners (based on in-house records from referrals), and promoted through some pharmacies in Western Australia (based on the authors’ personal communication). Due to the large, varied and often conflicting data reported on MTHFR, these polymorphisms have been weakly associated with multiple conditions, including autism, schizophrenia, cardiac disease, fetal neural tube defects, poor pregnancy outcomes and colorectal cancer.

Objective/s

The aim of this review is to explain the difficulty in translating inconclusive results – and results of uncertain clinical relevance – of genetic-association studies on common polymorphisms into clinical practice. We will also explore why testing for polymorphisms needs to be reconsidered in a diagnostic clinical setting.

Discussion

On the basis of the available scientific evidence, we propose that there are very limited clinical indications for testing for the 677C>T and the 1298A>C polymorphisms in the MTHFR gene, and that testing is not indicated as a non-specific screening test in the asymptomatic general population.

The MTHFR gene is responsible for the production of the enzyme methylenetetrahydrofolate reductase (MTHFR).1 Numerous studies have reported associations of MTHFR polymorphisms with an array of conditions including autism, schizophrenia, cardiac disease, fetal neural tube defects, poor pregnancy outcomes (eg preterm birth) and colorectal cancer.14 Over the past 24 months, Genetic Services of Western Australia has seen an increase in referrals for MTHFR polymorphism testing and counselling. Referrals have been received from general practitioners (GPs), obstetricians and alternative health practitioners. In addition, there have been cases of clients self-referring after a family member has had testing, or after a pregnancy loss or pregnancy with a neural tube defect (based on in-house records). Providers ordering testing for MTHFR polymorphisms are generally using the Medicare Benefits Schedule (MBS) item number 73308.5,6 However, this MBS item number is not specifically for MTHFR testing. It has the descriptor ‘Characterisation of the genotype of a patient for Factor V Leiden gene mutation, or detection of the other relevant mutations in the investigation of proven venous thrombosis or pulmonary embolism’.7

Scientific evidence and review

Folate (the salt of folic acid) is a vitamin the body needs for day-to-day functioning. It is required at higher doses during pregnancy, when it has an important role in preventing the formation of neural tube defects.8 Folate deficiency can cause glossitis, diarrhoea, gastrointestinal lesions, anaemia and poor growth.9,10

The enzyme MTHFR is involved in the conversion of 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate, which is the primary form of circulating folate in the blood.11 5-methyltetrahydrofolate is involved in the remethylation of homocysteine to methionine, which is then converted to S-adenosylmethionine. This S-adenosylmethionine is then able to serve as a methyl donor in many varied methyl donor reactions throughout the cellular system.10,11

There are two predominant MTHFR polymorphisms, 677C>T and 1298A>C. In the general population, 60–70% of individuals will have at least one of these variants, 8.5% will be homozygous for 677C>T or 1298A>C, and 2.25% will be compound heterozygous. Overall, 10% of the population will be homozygous or compound heterozygous for these two polymorphisms.4,12

The MTHFR polymorphisms in the homozygous or compound heterozygous form only reduce enzyme production mildly and are thus of limited pathogenicity.12 The 677C>T polymorphism in the homozygous form may result in mild homocystinuria due to decreased MTHFR activity.13 The 1298A>C polymorphism does not cause homocystinuria in a heterozygous or homozygous form, but may affect enzyme activity when inherited with the 677C>T polymorphism.13

Severe MTHFR deficiency (<20% of the enzyme) results in the clinical picture of homocystinuria. This is a severe, autosomal recessive genetic condition that can present with early, significant neurological defects, or with gait abnormalities and psychiatric disorders later in life.12 This condition is not caused by the 1298A>C or the 677C>T MTHFR polymorphisms.

Neural tube defects

The important role of folate in the prevention of neural tube defects is well known.14 Intuitively, therefore, polymorphisms that interfere with folate metabolism could potentially result in an increased risk of neural tube defects. However, in practice, studies both supporting and refuting this hypothesis exist.1,15

Given the prevalence of the MTHFR polymorphisms (60–70% of the population) and the frequency of neural tube defects (approximately 1 in 1000 in Australia),14 it is unlikely that the polymorphisms alone have a significant role in the formation of neural tube defects. While there may be some increased risk of neural tube defects in individuals with the homozygous 677C>T variant,11 the level of risk has not been quantified and the impact of environmental factors, such as folate supplementation, has a more significant role. This has been demonstrated through a significant drop in neural tube defects when population-level fortification of folate occurs,14,16 with a decrease in the incidence of neural tube defects by about 70%.8

Practically, it would seem to be more useful to measure maternal serum folate levels and supplement as appropriate, rather than test for the presence or absence of the polymorphisms. Alternatively, measuring levels of homocysteine rather than MTHFR polymorphisms may give useful information regarding the risk of neural tube defects.17 Regardless of the mother’s MTHFR polymorphism status, 400 µg of folate daily for women of reproductive age is recommended.16 Thus, knowing a couple’s MTHFR polymorphism status has no effect on their pregnancy-related management in terms of the prevention of primary or recurrent neural tube defects.

Fertility and poor pregnancy outcomes (other than neural tube defects)

Hyperhomocysteinaemia in pregnancy has been associated with poor pregnancy outcomes,18,19 yet studies have produced conflicting results.20 In 2012, Bergen et al reported that high homocysteine levels increase the risk of prematurity, small size for gestational age and preeclampsia, although the P value was not significant for any of these associations (except for folate in the lowest quintile being associated with prematurity).21 However, even if homocysteine was conclusively linked with poor pregnancy outcomes, the MTHFR polymorphisms have been shown to result in only mildly elevated hyperhomocysteinaemia.13 Therefore, on the basis of the available evidence, genetic testing for either of the two MTHFR polymorphisms would not appear to provide any useful information as a substitute for, or in addition to, measuring serum homocysteine levels in this clinical situation.

MTHFR polymorphisms have been associated with a higher risk of preterm labour,22 but the findings have also been contradicted in different populations.23,24 Therefore, on the basis of association studies, MTHFR polymorphisms are not useful in predicting pregnancy outcomes2528 or for the management of pregnancies. While sufficient folate is an important factor in preventing neural tube defects, increased folate levels in the presence of MTHFR polymorphisms do not seem to be associated with helping women undergoing in vitro fertilisation (IVF) treatment to achieve pregnancy.29 Therefore, testing for the polymorphisms may result in increased anxiety during pregnancy without any clinical benefit.

Thrombophilia

While homozygosity for the 677T>C MTHFR polymorphism is linked to an increase in homocysteine level, it is not clearly linked to an increase in thrombophilic events.26,30 MTHFR polymorphisms do not increase the risk of thromboembolic disease when found in a heterozygous state.30 Supplementation with folic acid and vitamin B12 does not significantly decrease the risk of thrombotic events.30

Cardiovascular disease

Increased levels of homocysteine have been associated with cardiovascular disease.10,31 The link was first hypothesised when children with severe homocystinuria were found to have vascular lesions.32 However, a meta-analysis of studies has found that the association was not as strong as previously believed.32 As stated above, while homozygosity for the 677C>T polymorphism is linked to a small increase in homocysteine levels, the increased risk of ischaemic heart disease and stroke is more closely related to the serum levels of homocysteine rather than the presence of the MTHFR polymorphisms. Importantly, there seems to be no increased risk of mortality from cardiovascular disease to MTHFR 677C>T homozygotes.11

Mental illness

Recent media attention regarding the tenuous link between MTHFR polymorphisms and depression and anxiety has garnered much interest from individuals living with these complex conditions. For example, a recent online newspaper article purports to provide an ‘easy’ fix for affected individuals, advising them that vitamin supplementation will ‘cure’ them of symptoms.33

Although some studies found evidence that MTHFR polymorphisms were associated with an increased risk of bipolar and schizophrenic disorders,2 other studies have found no convincing link.3436 In one study, an increased rate of 677C>T homozygotes was found in a population with major depressive disorder. However, no differences in vitamin B6, vitamin B12 or homocysteine levels were found in 677C>T patients with a major depressive disorder, compared with those who were unaffected. The same study found folate levels in control subjects were higher than in participants who were depressed, but this difference was not found with statistical correction for demographics.35 There is no convincing evidence linking mental illness and MTHFR polymorphisms.

Marketing to consumers

The ethics of nutritional companies and alternative practitioners offering consumers genetic testing has been debated for some time, with concerns about the clinical validity of the results. The issues involve the role of single nucleotide polymorphisms in individual genes in influencing complex nutritional conditions and, most importantly, how consumers will use the information derived from this testing.37 The position of the Academy of Nutrition and Dietetics in the US is that:

There is insufficient evidence regarding C677T polymorphism in the MTHFR gene to modify current folate recommendations from those provided in the Dietary Reference Intakes.38

Two examples of websites offering MTHFR ‘information’ are MTHFR Support Australia39 and MTHFR.net from the US.40

Recommendations for clinical practice

Folate plays a vital role in cellular health, and the MTHFR gene has an important role in the folate pathway. However, we propose that there is no statistically significant evidence that the 677C>T and the 1298A>C polymorphisms have a clinically important impact on this pathway. The American College of Medical Genetics and Genomics has issued a detailed guideline that discourages testing for the two common polymorphisms in the MTHFR gene.11 The Academy of Nutrition and Dietetics states no dietary interventions are needed, even in individuals with homozygous 677C>T mutations who have elevated levels of homocysteine. As the 677C>T and 1298A>C polymorphisms occur at high rates in the general population, and there are no clinically significant interventions that could be offered to carriers of the variants in heterozygous, homozygous or compound heterozygous states, it is not useful to offer genetic testing for these variants.

Authors

Sarah Long BSc (Hons)(Biomed Sci), PostGradDip (Gen Couns), FHGSA, Genetic Counsellor, King Edward Memorial Hospital – Genetic Services of Western Australia, Subiaco, WA. Sarah.Long@health.wa.gov.au

Jack Goldblatt MBChB, MD, FRACP, Clinical Professor, School of Paediatrics and Child Health, University of Western Australia, Genetic Services of Western Australia, King Edward Memorial Hospital, Perth, WA

Competing interests: None.
Provenance and peer review: Not commissioned, externally peer reviewed.

Science-Based Medicine

Exploring issues and controversies in the relationship between science and medicine

Jann Bellamy on June 11, 2015

Just what is the MTHFR gene? Allow me to introduce some actual scientific information here. According to Genetics Home Reference, a service of the National Library of Medicine,

the MTHFR gene provides instructions for making an enzyme that plays a role in processing amino acids, the building blocks of proteins. This particular enzyme is important for a chemical reaction involving forms of the vitamin folate (also called vitamin B9), a reaction required for the multistep process that converts the amino acid homocysteine to another amino acid, methionine. The body uses methionine to make proteins and other important compounds.

Back to pseudoscience. Next comes the scare tactic: telling you how a MTHFR mutation might affect your health: anxiousness, adrenal fatigue, brain fog, cervical dysplasia, increased risk of many cancers (including breast and prostate), low thyroid, leaky gut, high blood pressure, heart attacks, stroke, Alzheimer’s disease, diabetes, and miscarriages.

Well, who wouldn’t want to know if they were at risk for one of these problems, whether the real ones or those fabricated by naturopaths, like adrenal fatigue and leaky gut? What to do? Obviously, a genetic test is in order.

Fortunately for you, the naturopath will guide you through the next step. First, order an on-line genetic test. There’s a bit of a snag here. The FDA, which regulates medical tests, prohibits open access labs from offering health-related information based on your genetic panel without validation of the test used (and companies have gotten in trouble for offering unvalidated tests in the past). Not to worry: there are software programs available online that will turn the raw data into a report explaining your mutations.

At that point, the naturopath stands ready to help you understand your results and figure out what to do about them. Of course, she will have a solution. Naturopaths always do.

For example,”Dr. Doni,” (whom we’ve met before) practices in New York (even though New York doesn’t license naturopaths) and Connecticut. She offers a four-month, $3,000 package. (This also covers other genetic mutations that testing may have discovered.) Based on your “unique genetic health profile” she will ensure you understand your genetic mutations “so you can take control of your own health.”

How? With dietary supplements and other nutrients needed to address your mutations, naturally. Your $3,000 doesn’t cover these but, conveniently, she will sell them to you at a 10% discount. She will also create a “natural remedy plan” to “reduce or eliminate your symptoms.” And, best of all, she can design a long-term preventive help regimen that can help you “avoid serious illness (cancer, Alzheimer’s, heart disease, auto-immune disorders, etc.).” Not only that, you will “lessen the likelihood of needing medications and/or invasive surgical procedures (gall bladder surgery, cataracts, LEEP procedure, etc.) later in life.” And all of this can be done via Skype!

Where is this coming from?

Ben Lynch appears to be the naturopathic guru of MTHFR genetic mutations, or at least has designated himself as such, and he is intent on spreading the word. He seems convinced these mutations are something close to the “one true cause.”

Lynch runs the MTHFR.net website: “Your Expert Resource on MTHFR Mutations.” He believes that:

the MTHFR gene mutation is a highly significant health problem that is completely ignored. Yet, millions are suffering from pulmonary embolisms, addictions, fibromyalgia, miscarriages, schizophrenia, severe depression, cancer and autism to name a few.

All of these, he claims, “may” be linked to a MTHFR gene mutation. He says he is “constantly in research” and has “a solid understanding of MTHFR mutations and expanding that knowledge on a weekly basis.” He is looking forward to improving your life and “perhaps saving the life of a family member with an unknown MTHFR gene mutation.”

For a researcher, his Research page is oddly out of date, having been posted in January, 2012. His statements are conflicting. First, he says that the journal articles he’s listed support his conclusions that MTHFR genetic mutations are to be “dealt with – not dismissed.” Yet he also says he has not fully evaluated the articles.

So, is Lynch really an expert? Should we trust what he is saying? Should we trust a naturopath who cites him as a resource?

Lynch has an undergrad degree in cell and molecular biology from the University of Washington (1997). I suppose that is a good place to start if you want to develop an expertise in genetics, but it won’t make you into an expert. Lynch then graduated from Bastyr with an ND degree. Given that Bastyr’s naturopathic program is steeped in pseudoscience and the rudimentary (and also pseudoscience-filled) clinical training it offers, there is no plausible reason to conclude that an ND degree from Bastyr qualifies anyone to claim expertise in genetics, genetic mutations, genetic testing or treatment of genetically-based disease.

That’s it. Lynch didn’t do any sort of residency, fellowship or any post-undergraduate education or training in genetics (or anything else, as far as I can tell). He is not a member of any reputable organization of genetic experts that I could find. According to my PubMed search, Lynch has never published any genetics research. In fact, I can’t find that he’s published any peer-reviewed research at all.

Instead, his “research” seems to consist of collecting anecdotes from individuals in blog format and posting them online. These posts, which are sometimes identified by name, have all sorts of personal medical information in them, both of the writer and others who could be identified by their connection to the writer. What he is doing with this “research” is unclear, other than it is not being published in a reputable journal. Nor do I find that he is, or has been, involved in research listed on clinicaltrials.gov. There is no reference indicating that any of his research has been approved, or exempted from approval, by an Institutional Review Board, even though it obviously involves human subjects.

What you do see on his website are stories of people who are being horribly exploited by naturopaths and other health care practitioners. They are taking expensive nutritional supplements (some available only from their ND), have gone through other quack testing, like hair analysis and manual muscle testing by chiropractors, and they are on highly restrictive diets, “detox” protocols and other costly treatment regimens.

They express anger at medical doctors who won’t order the (worthless) tests they want. They claim that medical doctors couldn’t really fix the problem and are now being properly treated by a CAM practitioner, usually a naturopath.

An example posted May 6th by Erica:

I am 24 years old and have the homozygous a1298c gene mutation. I have experienced a wide range of health problems through out [sic] my life. After seeing a neurologist for 7 years, I finally sought out a naturopath. I was able to fix the majority of my weird symptoms with a STRICT DIET. I cut out gluten, dairy, corn, soy, nuts, eggs, and yeast for four months. I felt incredible. My naturopath’s theory was that because this mutation leads to detoxing issues, food and chemical sensitivities… that I probably had a ton of digestive damage and really had a bunch of food intolerances that I wasn’t connecting the dots too. I started taking quercetin 3 times a day (it helps heal digestive damage). I also take magnesium and a methylated folate and b12.

One poster got her 23andme results, then apparently (it’s not easy to follow what she is saying) uploaded them to software programs (Prometheus and Genetic Genie) for further interpretation. She is seeking help in interpreting the results on her own.

There were several posts of this nature: people who do their own testing, are concerned when they find a mutation, and don’t know what to do about it, so they are asking others on Lynch’s blog for advice. Or, they ask other bloggers for assistance in finding the “right” doctor.

In addition to Lynch’s “research,” and providing information on getting tested for MTHFR mutations, Lynch helps readers “Find a Doctor,” but to be listed you must have attended or purchased one of Lynch’s courses. Most of the “doctors” are NDs, with a smattering of MDs, DCs, RNs, LAcs, and homeopaths. (It is always interesting to see how many naturopaths are openly diagnosing and treating patients in states where they are not licensed.)

Other dubious resources Lynch provides include:

Lynch offered phone consultations at one time, but does not seem to be doing that anymore. In this consult, he advised someone to take 6 different “Seeking Health” products. If you go to the Seeking Health website, guess who appears on the home page? Ben Lynch. You’ll also see more Ben Lynch videos for sale. Lynch is the “Medical Director” of Seeking Health and, as you will find if you go to the public records of Washington State, he has an ownership interest in the company.

Lynch is not currently a practicing naturopath. Rather, he sells his “expertise” to others through online courses and talks. He taught continuing education courses to naturopaths and chiropractors at Bastyr. Unfortunately, this course was also approved as CME for MDs, PAs, ARNPs and RNs licensed in Washington.

He also speaks at conferences, such as the upcoming SHEICon (SHEI stands for “Seeking Health Educational Institute”), which features “Vaccine Presenters” Kelly Brogan, MD, and Sayer Ji, fresh from, as Orac puts it, “the yearly autism quackfest known as Autism One.” “Vaccine Presenter” must be a new euphemism for anti-vaccine crank.

Hmm. Is there connection between anti-vaccinationist “theory” and genetic mutations? Why, yes there is. Turns out it is one of the factors that increases “vaccine risk” according to Barbara Loe Fisher, queen of the anti-vaccination movement.

“Conventional” medical advice

Let’s see what conventional medicine thinks about MTHFR genetic testing. And while Lynch’s naturopathic modus operandi was easy enough to understand, once I get into the real science I must tread carefully and apologize to my colleagues and readers if I go astray here.

First, genetic testing from on-line do-it-yourself companies can be inaccurate. Although the NY Times article linked here was written before the FDA started clamping down on direct-to-consumer genetic testing, the raw data can still be fed into software like Genetic Genie and – voila – your results.

(23andme now advertises its testing as determining your ancestry and helping you get in touch with other members of your family tree. However, in February, the FDA approved its first direct-to-consumer carrier testing from the company.)

According to Genetics Home Reference, at least 40 MTHFR mutations can cause homocystinuria, a disorder that can affect the eyes, joints and other parts of the body. MTHFR genetic mutations have been associated with neural tube defects in babies, but most people with these mutations do not have neural tube defects. They have been studied in connection to stroke, high blood pressure and heart disease, and mental conditions such as bipolar disorder, but the associations are not clear cut.

For a really wonky discussion, try the Online Mendelian Inheritance in Man website. Even if you don’t understand a word of it, you will get a flavor of just how difficult, and nuanced, the matter is. And why those who don’t know what they’re taking about should stay out of the whole business.

As a real geneticist, Charis Eng, MD, PhD, points out, none of this means genetic testing is necessary. For some problems, there are cheaper alternatives that give better information. If high homocysteine levels are suspected, the simple solution is a blood test. If the blood test bears this out, supplementation with vitamins such as B6, B12, and folate or folic acid can be recommended. If the levels are normal, nothing need be done, whether the mutation is present or not.

As for neural tube defects, rather than having an unnecessary test, she advises that pregnant women should take prenatal vitamins that contain higher folate levels (from a drug store, not a naturopath). Until a connection between other disorders and MTHFR mutations are established, most geneticists feel that a test is unnecessary.

One insurer summed up the current evidence nicely:

Genetic testing for inherited thrombophilia or recurrent pregnancy loss to include testing for mutations in the MTHFR gene is considered investigational.

Genetic testing for MTHFR for diagnosis or management of all other indications, including but not limited to, depression, coronary artery disease, cancer, congenital heart defects, Alzheimer’s, dementia, hepatitis, stroke, infertility, Parkinson’s, migraines, peripheral neuropathy, diabetic retinopathy, autism spectrum disorder, nitrous oxide use, schizophrenia and vascular disease is considered investigational.

There are no recommended changes in management that are linked to specific test results. Management changes that might be made include selection of specific medications according to test results, discontinuation of medications, changes in dosing of medications among other ill-defined management changes. However, these management changes are not well-defined and may vary according to the judgment of the treating clinician. Since management changes are ill-defined, it is not possible to determine whether management changes associated with the test lead to improvements in health outcomes. In conclusion, there is insufficient evidence in the published peer reviewed scientific literature regarding the clinical utility and its impacts on health outcomes. Therefore, genetic testing for MTHFR for any indication would be considered investigational.

In coming to this determination, last reviewed in 2014, the company relied on research and recommendations from:

So, let’s compare and contrast. On the one hand, you could take the advice of geneticists with advanced degrees who’ve spent their careers researching genetic mutations and their effects on human health, plus several medical organizations and other reputable research sources. They think testing is unnecessary and offer lower-cost options where there is genuine concern.

On the other hand, you could listen to a naturopath with no particular background in anything, who never published a single article in a reputable journal, who has fashioned himself into a genetics expert, who tells patients to get online testing then sells them dietary supplements to treat their “condition,” who promotes a number of dubious organizations and products, lectures with notorious anti-vaccination cranks, and sells online courses to the public and “professionals” to promote his views, and, in case of the latter, get themselves listed on his website as experts.

Your choice.

(Note: I didn’t realize until I was almost finished writing this post yesterday that Skeptical Raptor had its own post on the subject just last month. You won’t be surprised to learn that Skeptical Raptor and I came to remarkably similar conclusions about Lynch.)

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