MTHFR: Hope or Hype?

Once upon a time, variants in the MTHFR gene were thought to be linked to more than 400 diseases, but the mainstream scientific community now thinks otherwise.

By Heather Millar

Last spring, a woman in her early 30s came into the office of Jay Flanagan, a genetic counselor in a reproductive clinic at Sanford Health in Sioux Falls, South Dakota. She was trying to get pregnant, and she brought a bag with all the supplements she was taking in her effort to start a family.

“The first thing I asked her was, ‘Why are you taking $800 worth of supplements every month?’ ” says Flanagan. “Someone in her family had tested positive for a mutation in a gene called MTHFR. So she had gone to a homeopathic group and asked to get the same test. Her test came back positive, and they told her that she had to take all these supplements in order to reduce her risk of pregnancy loss.

“So then I had to explain that MTHFR helps change folic acid from one form to another form,” says Flanagan. (For more details on the science of MTHFR, see “Breaking it Down,” page 42.) “It helps to change one amino acid building block, homocysteine, into another, methionine. The problem isn’t the MTHFR, it’s the amount of homocysteine in your blood.”

Flanagan had the woman stop taking all her supplements so that he could measure the level of homocysteine in her blood. Despite the variation in her MTHFR gene, her homocysteine blood level came back normal.

“As a geneticist and a researcher, I believe in the power of genetic testing in the right clinical context,” says Charis Eng, the founding director of the Center for Personalized Genetic Healthcare at Cleveland Clinic. “But just because you can test for something doesn’t mean you should. Most MTHFR testing is unnecessary.”

Ironically, just as the mainstream scientific community has decided that the test for MTHFR variations is not very useful except in rare cases, it has become a popular test for naturopaths, homeopaths, and alternative medicine companies to recommend. Several direct-to-consumer DNA testing labs screen for MTHFR variations. And at least a handful of supplement companies and alternative medicine websites maintain that MTHFR variations could be the key to everything from fatigue to schizophrenia to cancer.

What’s Going on Here?

About 20 years ago, just after the human genome was fully sequenced and enthusiasm for the idea of personalized medicine was beginning to grow, researchers noticed that two variations in the MTHFR gene — 677C>T and 1298A>C — seemed to be linked to thromboembolism, a blood clotting condition that obstructs blood vessels.

Researchers around the world leapt to figure out how MTHFR might affect various diseases. Since then, more than 5,000 studies have tried to link MTHFR variants to a terrifying grab bag of more than 400 health problems: heart disease, stroke, autism, depression, pregnancy loss, cancer, cognitive problems, underdeveloped spinal cords and brains, and developmental disorders.

Most of these research papers found associations between many conditions and MTHFR — that is, people who had an MTHFR variant might also have one of these other problems. But almost none could show that the variants caused those conditions. Or, one study might hint that the variant caused a problem, and then a later paper would fail to support that causal link.

Meanwhile, researchers found that approximately 60 to 70 percent of us carry at least once copy of at least one variant of the MTHFR gene that differs from a reference genome. And about 20 to 30 percent of us carry two copies of an MTHFR variant.

Since they’re so common, most geneticists and genetic counselors have become skeptical that these variants can actually explain the various health problems to which they’ve been ostensibly linked. “We usually say if it’s associated with everything, it’s probably not associated with anything,” explains Flanagan of Sanford Health.

In the vast majority of people, the presence of an MTHFR variant, even if it leads to moderately high homocysteine levels, really doesn’t cause problems, experts say. Slightly high homocysteine levels (15-30 micromoles per liter) are quite common. And even moderately high levels (30-60 micromoles per liter) don’t lead to serious problems and usually can be treated with a folic acid supplement, such as a multivitamin with folic acid, geneticists say.

We usually say if it’s associated with everything, it’s probably not associated with anything.”

In rare cases, a different, more severe MTHFR mutation can lead to elevated homocysteine levels, and this has been linked to some cardiovascular and neurological problems. While it sometimes may occur in adults who haven’t had symptoms before, usually the condition presents very early in infancy, doctors say.

“It was a compelling idea 20 to 30 years ago that MTHFR causes heart problems,” says Jim Evans, the Bryson Distinguished Professor of Genetics and Medicine at the University of North Carolina, Chapel Hill. “This one didn’t pan out. But we all engage in wishful thinking; these things die hard. That may be why MTHFR testing remains popular.”

The U.S. Preventive Services Task Force, which seeks to outline the national standard of care in medical practice, has concluded that testing for the MTHFR gene is not clinically useful for most people. The American Academy of Family Practitioners, the American Heart Association, and the American College of Medical Geneticists have all released statements saying that MTHFR testing for people who don’t have any symptoms shouldn’t be done.

“If a patient comes to me saying they have an MTHFR variant, I say, ‘Let’s measure homocysteine, the end product of that process,’ ” says Eng. “If homocysteine is even slightly elevated, then we’ll talk. But it’s never elevated.”

Selling the Diagnosis and the Cure

Companies who remain in favor of MTHFR testing tend to be passionate about it.

Several websites mix medical advice and marketing, including,, and Some of these sites sell genetic testing, or analyze genomic data from direct-to-consumer genetic testing companies like 23andMe. Some claim that those with an MTHFR variant should take expensive natural supplements (called 5-MTHF) instead of folic acid, which is synthetic. Several labs offer direct-to-consumer MTHFR testing, including SpectraCell and

“People need to be skeptical when somebody is selling them the diagnosis and the cure,” says Scott Hickey, an assistant clinical professor of pediatrics at Ohio State. Hickey says that 5-MTHF is the “thing du jour” that’s recommended, especially for depression. But while there’s some evidence that 5-MTHF may more easily penetrate the blood-brain barrier, the supplement’s effectiveness hasn’t been proven, he says.

Some “functional medicine” specialists, that is, medical doctors who cultivate a holistic approach toward health care, contend that if MTHFR variants are associated with many things, there must be some process at work that we don’t yet understand. That’s a position completely at odds with the conclusion of the medical establishment.

Genetic counselors and geneticists say that if there’s no evidence to back these treatments, then they shouldn’t be recommended.

“It’s pretty poor science, leading to even worse medicine,” says Eng of the Cleveland Clinic.

Amy Shealy, a genetic counselor at the Cleveland Clinic, recently counseled a well-educated middle-age woman. “She was having problems with fatigue,” Shealy says. “She went to a functional medicine clinic, and they recommended doing some blood work including testing for MTHFR.”

The blood results came back with two MTHFR variants, and the functional medicine doctor reportedly told her these were causing her to have depression. Moreover, she reported that when she told the physician she was not depressed, she was told she’d probably been depressed for so long that she didn’t even realize she was depressed, according to Shealy. The functional medicine practitioners said that the woman should take supplements for depression, but she wanted her fatigue treated, not her depression, and became suspicious the more the doctors told her she was depressed. To be clear, the doctors were not selling her the supplements.

“That’s when she came to us,” Shealy says. “When she found out that national medical societies do not recommend MTHFR testing, she was not happy that the previous physician had tested her.”

Brooke Levenseller Levin, a genetic counselor at MD Anderson Cancer Center at Cooper in Voorhees, New Jersey, says that she’s had some difficult conversations with people who have come in thinking that their MTHFR variations explain their health problems.

“There’s disbelief and disappointment,” says Levenseller Levin, who co-authored a paper, “MTHFR: Addressing Counseling Dilemmas Using Evidence-Based Literature.” “People don’t want to know that what they’ve been led to believe is not supported by evidence. … My best advice is to check out good websites like the National Society of Genetic Counselors, the National Institutes of Health, Genetics Home Reference, and the Centers for Disease Control. Talk to a genetic counselor.”

“It’s giving patients false hope,” says Flanagan. “About 50 percent of people will test positive. They will go to Google and find articles that say this is a problem. People who have major genetic diseases are often more worried about MTHFR than about their actual disease.

“Everything good to come out of medicine — antibiotics, chemo, penicillin — is based on years of research. That’s evidence-based medicine,” he says. “You need to articulate what the research has shown. In MTHFR, there is no evidence that it causes all these conditions.”