Nutrigenomics:
MNT for Methylenetetrahydrofolate Reductase (MTHFR) Deficiency
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7/18/2012
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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A review of the references used throughout the Perspectives article in Chapter 9 reveal that they appear somewhat outdated,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.
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