MTHFR Genetic Mutation, Associated Illnesses and Current Medical Nutrition Therapy Research

Nutrigenomics: MNT for Methylenetetrahydrofolate Reductase (MTHFR) Deficiency

7/18/2012

Nutrigenomics: MNT for Methylenetetrahydrofolate Reductase (MTHFR) Deficiency

ABSTRACT

Background

            Having a mutation on the MTHFR gene means that the enzyme which converts 5, 10-Methylenetetrahydrofolate reductase  to 5, Methyltetrahydrofolate reductase is deficient, causing a defect in an important methylation cycle, and the conversion of  homocysteine to methionine.  This can result in a dangerous increase in serum homocysteine, leading to serious health outcomes.  It is considered an inborn error of metabolism.  The research on some of the health risks is more conclusive than others.     

            Chapter 9 Perspectives article in Advanced Nutrition and Human Metabolism describes the gene known as Methylenetetrahydrofolate reductase  (MTHFR), and the two well-known variants of mutation known as C677T and A1298C.  It describes increased risks of several chronic illnesses in people who have these two most common polymorphisms of MTHFR, mentioning neural tube defects, cardiovascular disease and dementia.   Written in 2009, it surmised that treating these MTHFR polymorphisms “has limited application to the general public….[due to] limited individualized genetic mapping [and] the impact of having an MTHFR polymorphism is not clear.” (1)  A review of the references used throughout the Perspectives article in Chapter 9 reveal that they appear somewhat outdated, with references dating between the years 2000-2003.

            As mentioned in both Perspectives articles cited in References, staying abreast of current research regarding nutrigenomics is important to the nutritional health counselor and clinician.  The wide-range of chronic illnesses associated with an MTHFR mutation make it particularly important to keep up with the latest developments and research.  Some additional health risks associated with an MTHFR deficiency are:  Down syndrome, miscarriage, psychiatric illness, epilepsy, impaired detoxification and a higher risk of developing blood clots.  It is also contraindicated with nitrous oxide use, as is used with general anesthesia. 

             When treated, the Medical Nutrition Therapy (MNT) is similar for all deficiencies and resulting diseases of MTHFR deficiency:  supplementation with folic acid (sometimes with its active form), and sometimes with other B-vitamins (2).   However, some complementary and alternative practitioners believe that the form of folic acid is important in treatment, and that the more active form, folate, or methylfolate should be used. 

OBJECTIVE

            This paper aims to explore the continuation of the research that has since been published, and is two-fold:  1) To explore and discuss more current research on which aspects of health may be affected by MTHFR mutation (and mechanisms), and 2) Attempt to determine which form of folate is most beneficial in treating those with the mutation, between dietary folate, supplemented folic acid and 5-methyltetrahydrofolate (5-MTHF).  

MTHFR Mutation in Chronic Illness

            Blood clots, neural tube defects and miscarriages are some of the better known events and illnesses associated with the MTHFR mutation, but more recent research has shed light on a myriad of other adverse and serious conditions associated with the defective enzyme.  A common medical practice, using nitrous oxide-containing anesthesia, has even been found to have disastrous results in someone with a variant of MTHFR mutation.

            A normal appearing 3-month old child was placed under anesthesia containing 0.75 percent halothane and 60 percent nitrous oxide for 45 minutes to biopsy a large mass that had grown on his leg.  Subsequently, four days later, he was again anesthetized to remove the mass for 270 minutes with the same ratio of halothane and nitrous oxide.  Twenty-five days after the surgery, he was admitted to the hospital with seizures and apnea.  He was found to be severely hypotonic with other severe neurological problems.  He passed away 46 days after the surgery, and severe demyelination was found in his midbrain, medulla and cerebellum.  It was then discovered that he had inherited a novel MTHFR mutation, but one that is coinherited with the two more common MTHFR mutations, C677T and A1298C.  It’s interesting to note that the autopsy revealed his serum folate and B12 were within normal limits; however his homocysteine (Hcy) was elevated.  The authors of the study concluded that “a nitrous oxide-induced defect of methionine synthase superimposed on an inherited defect of MTHFR,” which was, in effect, a sort of “double-whammy,” against converting hcy to methionine.  It caused his death, and the authors related two other cases of infants with MTHFR mutation that were severely injured neurologically after receiving nitrous oxide.  The authors asserted that nitrous oxide is contraindicated in those with MTHFR mutations (3).

            The above story illustrates an extreme example of the extent to which an individual can be adversely affected by having one of the polymorphisms of MTHFR mutation.   However, an individual can experience other neurological adverse effects from the MTHFR mutation, mainly due to two factors:  the neuroexcitatory effects of even low to moderate levels of serum Hcy, and the effects having the mutation has on the proper formation of the myelin sheath of neuronal axons.  Some types of epilepsy have been linked to MTHFR mutation, especially when the EEG pattern is of the ‘burst suppression’ type (4).  The association between high Hcy levels (as having excitatory or even toxic effects on the nervous system) dates back to the 1960’s, but recent research correlates having even mild to moderate levels of Hcy with epilepsy, and finds an elevated percentage of people in the study with epilepsy have MTHFR mutations (5). 

            An Australian study showed subjects with multiple sclerosis (MS) were slightly overrepresented for having MTHFR mutations, but they cited their own study’s limitations in being able to report a positive correlation, and conceded that more research was needed, perhaps with a larger sample size and that the gene should not be ruled out as a causal factor for MS (6).  A Case Report in the British Journal of Anesthesia reported on the adverse neurological effects of nitrous oxide during surgery on an adult male with MTHFR mutation, and the resulting myelopathy, which was reversed with supplementation of folic acid and B12 after “several weeks of profound neurological impairment.”  Again, it is interesting to note, as with the earlier description of the infant dying after repeated surgeries with nitrous oxide, the man in the Case Report had normal folate levels (7).

            The mechanism by which the myelin sheath, the protective coating around neuronal axons, is created is dependent upon the ability of the MTHFR enzyme 5, 10-methylenetetrahydrofolate reductase  to catalyze the reduction of 5, 10-methylenetetrahydrofolate to 5-methyltetrahydrofolate, which is a carbon donor for converting homocysteine to methionine.  Then the activated form of methionine, which is S-adenosylmethionine (SAM), is created.  SAM is the main substrate in several important neurological functions.  If this is deficient, and further suppressed by a toxic substance, or as in the case of nitrous oxide, then myelin sheath assembly and neurotransmitter methyl substitutions (and DNA synthesis) can be impaired.

            Other chronic diseases that recent research has shown a correlation with having an MTHFR mutation are:  autism, psychiatric illnesses such as schizophrenia, bipolar disorder, and depression, as well as Down syndrome, other congenital birth defects and cancer (8,9).

DNA Hypomethylation

            Hypomethylation of a gene is believed to cause its increase for expression, and this figures prominently in the case of cancer proliferation in the case of MTHFR mutation and even psychiatric illness through its interaction with decreased folate status.   Possibly supporting the hypothesis that hypomethylation has a larger part to play in psychiatric illness, a recent study found that among people who had schizophrenia and smoked, the smoking preceded the onset of schizophrenia. Other studies have shown that smoking and alcohol consumption are associated with decreases in methylation, and folic acid serum status, an outcome that becomes even more important when considering MTHFR mutation associations with people who have psychiatric illness.  People with mental illness account for almost half of all cigarettes smoked in the U.S and alcohol addiction is a frequent co-morbidity with mental illness.  In fact, for the purposes of the research, The AMA classified alcohol abuse as a mental illness.  Alcohol also depletes folate status (10, 11).

Researchers found indications suggesting that hypomethylation is an early event in colon carcinogenesis.  And in a Brazilian study, acute lymphoid leukemia (ALL), chronic myeloid leukemia (CML), and cancer of white blood cells (WBCs), showed a correlation with MTHFR.  Some, like ALL, CML are in certain populations, like Brazilian, but a study done with Italians did not show a correlation, suggesting other genetic or environmental factors are at play.  Clearly, recent research confirms correlations between chronic illness, adverse events and having one of the MTHFR polymorphisms.  Several have been discussed here, but even this discussion is not all-inclusive. 

                As the study of genetics progresses, more and more underlying causes of many illnesses are being uncovered, and with that, the ability for the individual to get genetic testing.  Genetic testing for MTHFR polymorphisms has become more widely available, particularly for the two most common, C677T and A1298C, with insurance covering it.   Out of pocket fees for MTHFR testing can be pricey, upwards of $400.  However, an online genetic testing service known as 23andme, offers genetic testing which includes polymorphisms for MTHFR mutations using an individual’s saliva, and the individual is able to perform the saliva collection at home without a prescription from their doctor.  This offers a lower-cost alternative, as current prices for 23andme testing are $100, with a low monthly fee, which covers updates to a person’s DNA information as new research allows.

  

MNT-Supplementation

             The standard Medical Nutrition Treatment (MNT) for individuals with MTHFR mutations is to supplement with folic acid and sometimes other B vitamins, like B6 and B12.  This supplements the deficient enzyme, supporting the methylation pathways to help lower Hcy levels in the body.

            Folate is the generic term to describe both dietary folate and the synthetic supplement folic acid.  Dietary folate is less bioavailable than folic acid, by about 50%, so supplementation is usually recommended with folic acid.  Since 1998, folic acid has been added to most of the grain products in the USA per a federal mandate (12). 

            Other countries, like the Netherlands, have not required this supplementation.  A recent government report, however, details their consideration of requiring the fortification of grain products.  The report details their concerns with different folate requirements of people with MTHFR mutations, and specifically details their knowledge of the differing folate requirements among the various polymorphisms.  Further, they are concerned with the amount of folic acid that all members of the population will be ingesting with this requirement, and the proliferation of certain cancers.  From the report: “The committee advises doctors to warn patients with benign colorectal tumours against using dietary supplements containing folic acid. It cannot be ruled out that a high folic acid intake may accelerate the transformation of a benign tumour into a malignant one” (14).  A 2009 study showed that higher levels of folate in women with MTHFR polymorphisms, except in the case of heterozygosity,  increased risk for breast cancer (15).

In the Netherlands report, they were also concerned of the effects of too high of an intake of folic acid-enriched products on the elderly, because of cognitive deficits associated with high intake of folic acid and “inadequate B12 status.”  B12 deficiencies are common among the elderly.  They also were concerned with the lack of research on the effects high levels of folic acid, as might be consumed in fortified products, would have on children.

L-5-methyltetrahydrofolate (5-MTHF)

            The body needs to convert folate and folic acid to their active form, which is L-5-methyltetrahydrofolate (5-MTHF).  The Netherland report mentions a synthetic form of this in 2008 as a “newer” form of folate to hit the market. At the time of their report, they reported that there was little to no research shedding light on positive or negative effects, and they considered it as effective as folic acid.  The rest of the report does not mention this active form of supplement.   A study done in 2002 has similar findings, noting that in the MTHFR polymorphisms, supplementing with folic acid can lower the homocysteine levels, but there wasn’t enough data on the effects of synthetic 5-MTHF.  In fact, with a certain polymorphism, the CT or CC genotype, folic acid supplementation was found to be superior over 5-MTHF in lowering plasma homocysteine (16).

            Conversely, a 2009 study did conclude that supplementation with 5-MTHF form of folate was more effective at increasing plasma folate without leaving unmetabolized folate.  Folic acid was found to leave unmetabolized folic acid in the plasma of healthy young women with the homozygous or wild type C677T polymorphism of MTHFR.  Both did raise plasma folate levels effectively (17).  A later study in 2010 confirmed that both synthetic forms, folic acid and 5-MTHF, worked efficiently, however 5-MTHF did have the added benefit of not masking B12 deficiencies, and also may have less drug-nutrient interactions (18).

Conclusion

          Much has been learned in the field of genetics in the last ten years, specifically regarding the MTHFR mutation and its effects on health and disease.   MTHFR has been implicated in adverse events and chronic illnesses much more so than when the mutation was discovered over a decade ago.  Nutritional intervention is the treatment of the various polymorphisms, but much of that depends on folate status levels.  However, just knowing of the mutation may warrant proper supplementation and avoidance of certain compounds, as in the case of nitrous oxide use during anesthesia. 

            Contrary to the Perspectives article concluding that knowing one’s MTHFR polymorphisms, if any, “has limited application to the general public….[due to] limited individualized genetic mapping [and] the impact of having an MTHFR polymorphism is not clear” no longer seems valid.  Advances in research have allowed for wider genetic mapping through 23andme and laboratories, and the impact of having an MTHFR polymorphism, and not knowing it, can be very debilitating to tragic in some cases.

            Research regarding the form of folate ingested seems to be increasing as well.  There does seem to be clear benefits of supplementing with the more active form, 5-MTHF, rather than the traditional folic acid.  Future research in this area may be needed to draw further comparisons.   The MTHFR mutation is a complicated one, and so is the remedy, as it turns out.  Lastly, there are many implications and variables of the fortification program that need to be examined in this country, and considered to account for individual differences.

REFERENCES

1)       Gropper, S., Smith, J. Groff, J., Advanced Nutrition and Human Metabolism, Fifth Edition, Perspectives, Chapters 1, 9.  Wadsworth, 2009. 

2)      Mahan, L.K., Escott-Stump, S. Krause’s Food & Nutrition Therapy, Chapter 13, Saunders Elsevier, St. Louis, 2008.

3)       Selzer, R. R., Rosenblatt, D. S., Laxova, R., and Hogan, K.,  Adverse Effect of Nitrous Oxide in a Child with 5,10-Methylenetetrahydrofolate Reductase Deficiency, N Engl J Med 2003; 349:45-50  2003.

4)      Pearl, P., Bennett, H., Khademain, Z., Seizures and Metabolic Disease, Pediatric Neurology, Current Neurology and Neuroscience Reports 5:127–133, 2005.

5)      Kolínová M, Dvoráková J, Hladíková E, Preiss J, Hyánek J., Moderate hyperhomocysteinemia in patients treated for epilepsy, Prague Med Rep. 41:107(2):227, 2006.

6)      Lotti Tajouri, Virginie Martin, Claudia Gasparini, et al.  Genetic Investigation of Methylenetetrahydrofolate Reductase (MTHFR) and Catechol-O-methyl

      Transferase (COMT) in Multiple Sclerosis Brain Research Bulletin (2006) 69 (3): 327-       331. doi:10.1016/j.brainresbull.2006.01.005

7)      H. J. Lacassie, C. Nazar, B. Yonish, Case Report: Reversible nitrous oxide myelopathy and a polymorphism in the gene encoding 5,10-methylenetetrahydrofolate reductase  British Journal of Anaesthesia 96 (2): 222–5 (2006)

            doi:10.1093/bja/aei300 Advance Access publication December 16, 2005

8)      Peerbooms, O.L., van Os J, Drukker, M, Kenis, G, Hoogveld,  L; MTHFR in Psychiatry Group, de Hert, M., Delespaul. P., van Winkel, R., Rutten, B.P. ,  Meta-analysis of MTHFR gene variants in schizophrenia, bipolar disorder and unipolar depressive disorder: Evidence for a common genetic vulnerability?  Brain, Behavior and Immunity,  25: Issue 8, 1530-1543, 2011.

9)      James, S.J., Pogribna, M.,  Pogribny I.P., et al., Abnormal folate metabolism and mutation in the methylenetetrahydrofolate reductase gene may be maternal risk factors for Down syndrome, Am J Clin Nutr 70:495–501, 1999.

10)  Kelly C, McCreadie RG. Smoking habits, current symptoms, and premorbid characteristics of schizophrenic patients in Nithsdale, Scotland.  Am J Psychiatry.1999;156:1751-1757.) 
11)   Smoking and Mental Illness A Population-Based Prevalence Study 

            Karen Lasser, MD; J. Wesley Boyd, MD, PhD; Steffie Woolhandler, MD, MPH; David    U. Himmelstein, MD; Danny McCormick, MD, MPH; David H. Bor, MD

      JAMA. 2000;284(20):2606-2610. doi:10.1001/jama.284.20.2606

12)  Flavio Jose da Costa Ramos Maria Tereza Cartaxo Muniz, Vanessa Cavalcante Silva, et al,  Association between the MTHFR A1298C polymorphism and increased risk of acute myeloid leukemia in Brazilian children Leuk Lymphoma. 2006 Oct;47(10):2070-5.

13)  Federal Register. Food Standards: amendment of standards of identity for enriched grain products to require addition of folic acid. 1996;61:8781-8797.

14)  He a l t h  C o u nc i l o f  t h e  N e t h e r l a n d s, Towards an optical use of folic acid,

      http://www.gezondheidsraad.nl/sites/default/files/200802E_0.pdf, Accessed 7/18/12.

15)  Ulrika Ericson, Emily Sonestedt, Malin I.L. Ivarsson, et al.

      Folate Intake, Methylenetetrahydrofolate Reductase Polymorphisms, and Breast Cancer   Risk in Women from the Malmö Diet and Cancer Cohort  Cancer Epidemiol Biomarkers          Prev 2009;18:1101-1110. Published online March 31, 2009

16)  Fohr, I, Prinz-Langenohl, R., Bronstrup, A.  5, 10-Methylenetetrahydrofolate reductase genotype determines the plasma homocysteine-lowering effect of supplementation with

      5-methyltetrahydrofolate or folic acid in healthy young women Am J Clin Nutr;75:275–   

      82, 2002

17)  Prinz-Langenohl R, Brämswig S, Tobolski O, et al. [6S]-5-methyltetrahydrofolate increases plasma folate more effectively than folic acid in women with the homozygous or wild-type 677C-->T polymorphism of methylenetetrahydrofolate reductase. Br J Pharmacol. 2009 Dec;158(8):2014-21.

18)   Pietrzik K, Bailey L, Shane B et al. Folic acid and L-5-methyltetrahydrofolate: comparison of clinical pharmacokinetics and pharmacodynamics  Clin Pharmacokinet. 2010 Aug;49(8):535-48. doi: 10.2165/11532990-000000000-00000.