The Most Important Medical Breakthrough of the 21st Century (So Far)

Written by Andrew Lenhardt

               In America, you can’t go wrong with a baseball analogy, so that’s how we’ll begin.  Let’s say there’s a baseball phenom coming up through grade school.  He shows great promise and the scouts think he could be the next big thing in baseball.  He moves quickly through the minor leagues and arrives in the majors under great fanfare.  In his first game, his team is down 5-2 in the bottom of the ninth with the bases are loaded.  The prodigy comes to the plate.  On the first pitch, he makes a pure swing driving the ball far and deep over the fence for a grand slam to win the game.

               The human genome project would be the upstart with great potential and the grand slam may be MTHFR.  You’ll have to forgive a bit of science, but it is important to give some foundation for what’s ahead.  The human genome project ran from 1990 to around 2003.  It catalogued each base pair of human DNA.  Evaluating the DNA in detail allowed us to identify anomalies in human DNA (known as single-nucleotide polymorphisms or “Snips” to scientists).  One of the major developments has been variation in a certain enzyme called methylene tetrahydrofolate reductase or MTHFR.  This enzyme is active in a process called methylation that takes place within our cells.  Methylation is important for over 200 cellular processes and takes place over a billion times per second within the human body.

               When I was in my family practice residency in the late 1990s, elevated serum homocysteine got some attention as a cardiovascular risk factor.  The treatment to reduce homocysteine levels—and presumably reduce risk—was a B-complex vitamin.  The studies did not show, however, that reducing homocysteine levels reduced risk, so the issue was mostly dropped.  It is still not clear whether homocysteine is an independent risk factor or just an indicator of an impaired folate/methionine/MTHFR cycle.

               It has been established for some time that folic acid supplementation for women who become pregnant lowers the risk of birth defects such as spina bifida.  There is also a link between B12 deficiency and dementia.  We have been nibbling at the edges of MTHFR for years.  Homocysteine, folic acid and B12 are part of a larger, more complex cellular issue with MTHFR in the middle.

               If a person gets a mutated gene from both either their mother and father, they are then heterozygous.  Researchers estimate that someone heterozygous for the most common MTHFR abnormality (C677T) has 40-50% reduced activity of the enzyme.  If a person get a mutated gene from both parents, they are homozygous.  The person who is MTHFR homozygous has 70-90% reduced activity of the MTHFR enzyme.  There is evidence that someone with MTHFR anomalies has a higher risk of blood clots, strokes, heart attacks and miscarriages.  There is a strong likelihood that abnormal MTHFR activity plays a role in depression, bipolar illness, addiction, dementia and an increased the risk of certain cancers.  In his lecture on Youtube, Neil Rawlins, M.D. connects MTHFR problems with fibromyalgia and chronic pain.  He also makes the claim that 98% of children with autism have a problem with MTHFR and their methylation cycles.

               The folate/methionine/MTHFR cycles within cells are complex involving the biochemical process of methylation, but some of the endpoints likely explain why MTHFR is so important.  One pathway out of the cycle leads to production of serotonin, norepinephrine and dopamine.  These are the chemicals implicated in depression, anxiety and mental health.  The standard “antidepressants” used for depression and anxiety are serotonin reuptake inhibitors (SSRIs).  Dopamine is the chemical in the body most associated with addiction.  Drugs of addiction like heroin lead to a large release of dopamine into the system.  Other less addictive substances and pastimes like coffee, sugar, wheat, texting and email lead to a smaller release of dopamine.

               For some period of time now, If I see a patient in the office with a history of premature clotting or some odd family history of strokes and cardiac events at a young age, the most likely abnormal test result by far is an MTHFR defect.  A 44-year-old male non-smoker patient of mine developed a blood clot in his leg (a.k.a. a deep venous thrombosis or DVT).  Blood thinners were started and the specialists ordered a standard panel of tests looking for hypercoagulability or an increased tendency to form clots.  All of the tests came back normal, so I ordered the MTHFR blood test.  He was homozygous positive.  A week later, I saw a 35-year-old male with history of a DVT who had a daughter born with spina bifida.  The only abnormal test for him was a positive MTHFR.  I saw a Chinese man whose two sisters and mother all had strokes around 50 years old.  He was positive as well.  It is a relatively small sample, but so far every patient I have tested with a strong personal or family history of depression, anxiety, bipolar, addiction and/or early strokes, cardiac events and dementia has come up positive for MTHFR.  For the skeptic, does this automatically mean that MTHFR is the primary issue putting these individuals at risk?  No.  Could there be other genetic and lifestyle factors in play?  Yes, of course and that is probable.  At this point in time, however, for me in my medical career, MTHFR seems implicated in a higher risk of these important medical problems.

               The most dramatic patient thus far with MTHFR-related health issues is a middle aged woman I have seen for years.  She came in for a recent visit to follow-up on some cardiac issues.  I looked at her family history in the record and there were a lot of first degree family members (parents, siblings and children) with health problems at a relatively young age.  My MTHFR antennae went up.  More questioning revealed this:

               Mother had pulmonary embolism (blood clot in the lungs), melanoma and a stroke.

               Father had coronary disease, stroke and lymphoma.

               One brother had bipolar illness, addiction problems and died of a stroke.

               The second brother had depression and coronary artery disease.

               A third brother had mental health issues and a pulmonary embolism.

               One sister with depression, hypothyroidism, fibromyalgia and pulmonary embolism.

               The second sister had the same four medical conditions.

               Her daughter had hypothyroidism and a pulmonary embolism in her 30s.


               I ordered the MTHFR test and she was, not surprisingly, homozygous positive.

               One could ask why an issue of this importance gets so little attention.  Perhaps there isn’t enough profit potential in finding the optimal combination of methylated B-vitamins (which is the primary mode of treatment).  I could guess that if the pharmaceutical industry thought a drug could be developed to manage MTHFR and methylation, they would have pursued it upside down and sideways.  It may be that patients and informed practitioners will have to manage these issues without the blessing of the medical establishment.

               If you ask your primary care physicians about MTHFR/methylation, the conversation may center on the failings of homocysteine management.  They may have little or no understanding of the topic.  A few points are crucial: (1) My sense is that the management of elevated homocysteine levels was too narrow in focus, using an inadequate treatment regimen;  (2) MTHFR is a complex issue with homocysteine likely playing only a minor, tangential role; (3) There are experts working on protocols to manage genetic MTHFR anomalies and associated imbalances/deficiencies of methylation, but they are not necessarily working at your friendly neighborhood medical research facility; (4) It is important to note that the risks associated with MTHFR are associated not only with an individual’s genetics, but also a wide variety of environmental and lifestyle factors.

               If there seems to be a strong family history of anxiety, depression, bipolar, addiction, blood clots, cardiac events, strokes, fibromyalgia, autism and certain cancers, it is worth doing some research on MTHFR.  Youtube is an accessible source for videos and lectures.  I would probably start with Carolyn Ledowsky, and then perhaps Fred Smith, as they have relatively short introductory pieces.  Beyond that Neil Rawlins, Ben Lynch and Amy Yasko are the best I have come across so far.  MTHFR will come up in many future blogs as well in my effort to distill the most relevant information into a tight summary.

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3 Responses to “The Most Important Medical Breakthrough of the 21st Century (So Far)”

  1. Ms. A August 1, 2014 at 12:56 am #

    I begged and pleaded with my doctor to do further testing on me, because of too many coincidental things in my family history and he refused. I started questioning a link 30 years ago. When my son ended up in the hospital with clots and heart failure, once again I begged and pleaded for them to test for more than viruses as the cause. It took months of failed balloon pumps and two failed LVADs, hundreds of procedures and serious consequences before they finally took me serious and did further testing. Unfortunately, we didn’t find out those results until he was in the hospital for a heart transplant. He is homozygous for C677T. I can’t help wondering if they had found out sooner, perhaps something could have been done before it got that far and I am more than a little bitter that they wouldn’t listen sooner.

  2. Mara August 14, 2014 at 3:17 am #

    I believe I have one of the mutations, but someone said that if I was born with this mutated gene, and it’s the cause of my problems, I should have suffered those since childhood, not in my thirties. Is this true?

    • Rita August 21, 2014 at 5:09 pm #

      Hi Mara, I have a homozygous 1298C mutation.Follow your instincts. I didn’t suffer during childhood–I didn’t have any apparent symptoms until I was in my 40’s. Rita

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