Vitamin B12, Folate Deficiency Symptoms and SNPs

A key tenant of functional medicine understands the connection between different parts and systems of the body. While you may be used to going to a gastroenterologist for GI issues, and endocrinologist for your hormones and a cardiologist for heart health, it’s likely that physiological imbalances or disease that affect different areas of the body have some of the same root causes.  Functional medicine assumes that each system in the body is actually interconnected and that the body only functions as intended to when all systems work together as a whole.  When we isolate the parts of the body, we may miss key opportunities to achieve true healing and wellness.

If you suffer from migraines, depression, insomnia, fertility challenges or heart disease (along with many other diagnoses that I’ll discuss below), a root cause to consider is your vitamin B12 and folate status. These are important B vitamins that are essential for the minute to minute function of every cell in the body. Sometimes, because of genetic or environmental reasons, we need more of these specific nutrients.

This is exactly what we are going to dive into understanding in today’s article. Keep reading to learn more about:

• Methylation cycle basics
• Vitamin B12 and folate deficiencies
• What SNPs are and how they relate to vitamin B12 and folate
• The role of betaine in methylation
• Overmethylation symptoms to watch out for
• Action steps you can take in order to optimize your personal methylation status

Methylation Cycle Definition

Let’s start with the methylation definition. In a previous article on methylation, I dove into the biochemistry of this important biochemical pathway. As a recap, methylation is a critical process by which a methyl group, composed of one carbon and three hydrogen atoms, is added to another molecule.

Methylation is incredibly important for DNA expression, cell division, neurotransmitter production, detoxification and a host of other cellular processes. In addition methylation is required to make key compounds in the body including SAMe, creatinine, glutathione and others.

To learn more on this topic, please read: The Methylation Cycle And Active Methyl B12 and Methyl Folate.

Vitamin B12 And Folate Deficiency Symptoms

As mentioned, vitamin B12 and folate are key regulators for methylation. If you have a vitamin B12 deficiency or folate deficiency, methylation will be impaired.

Vitamin B12 is a relatively common deficiency, especially as we get older. B12 deficiency rates in the United States affect at least three percent of those aged 20 to 39 years, four percent of those 40 to 59 years and over six percent over the age of 60. Marginal deficiency affects more than 20 percent of older adults. (Source 1) Subclinical deficiency likely affects many more.

Folate, or vitamin B9, is another common deficiency affecting methylation. Data around folate deficiency levels is scant, but we know that it is widespread. For example, folate supplementation prevents about 90 percent of neural tube defects and 40 percent of congenital heart defects, suggesting that many pregnant women are not meeting their needs through food alone. (Source 4).

Often, B12 and folate deficiencies go hand-in-hand in terms of symptoms and consequences of deficiency due the role they both play in methylation.

B12 deficiency symptoms and/or folate deficiency symptoms include:

• Elevated homocysteine, a marker for heart health
• Neurological symptoms, such as changes in mobility (Source 1)
• Mood changes (Source 2)
• Impaired cognition
• Fatigue
• Tingling sensation in the extremities (related to B12)
• Dizziness
• Poor growth

These deficiencies may result in:

• Osteoporosis
• Cardiovascular disease
• Permanent neurological disorders
• Psychiatric disorders
• Megaloblastic anemia
• Birth defects including spina bifida
• Dementia
• Infertility and miscarriage
• Cancer
• Autoimmune disease (Source 1, 2, 3, 4, 5, 6, 7, 8, 9, 10)

In a functional medicine approach, we not only want to assess for B12 levels and deficiency symptoms, but we want to answer the question: Why? What factors contribute?

Here are some possible root causes of folate and/or vitamin B12 deficiency:

• Low dietary intake of folate and/or vitamin B12
• Vegetarian or vegan diet (naturally low in B12)
• Poor absorption of vitamin B12 or Food Bound Cobalamin Malabsorption (FBCM)
• Poor absorption of nutrients due to bariatric surgery
• Overuse of alcohol that depletes B vitamins
• Use of common prescription medications that deplete vitamin B12 including: birth control, diabetes medications like metformin, antacids such as proton pump inhibitors (PPIs) and Histamine H2 receptor agonists
• Pernicious anemia, an autoimmune disease that decreases intrinsic factor, a molecule needed for B12 absorption
• Increased need for folate and B12 during times of growth, including pregnancy
• Mutations called SNPs, in the genes coding for enzymes needed to make active (methylated) vitamin B12- (Source 1, 3)

While many root causes are possible, I’m going to focus on SNPs next.

What is Single Nucleotide Polymorphism (SNP)? SNP And the Methylation Cycle

What is single nucleotide polymorphism? SNP, pronounced “snip”, is a small change in genetic code. These are the most common genetic variations. While most SNPs are often benign, some SNPs affect key enzymes in biochemical processes, including methylation.

Take a look at this diagram of the methylation cycle. The enzymes are in the rectangular boxes and are required to convert one molecule into the next. A SNP found in the genetic code for the enzyme might affect the enzyme’s function.

SNP, B12 and Folate Enzymes

Let’s take a look at some specific SNPs related to vitamin B12 and folate.

MTHFR is the most common SNP discussed in terms of methylation as both vitamin B12 and folate are required for this enzyme’s function. The most common variations in MTHFR are C677T and A1298C. The presence of these SNPs may correlate with decreased methylation, higher homocysteine levels and increased needs for both nutrients. (Source 11)

SNPs in the codes for MTRR and MTR, methionine synthase reductase and methionine synthase respectively (as seen above) may also influence methylation.

There are also specific SNPs that affect folate and vitamin B12 metabolism individually. One study identified 48 genes involved in the folate pathway, along with 287 possible SNPs! (Source 12)

Commonly discussed SNPs affecting B12 include:

• FUT2 – an enzyme required for vitamin B12 absorption (Source 13)
• TCN2 – a important protein for B12 transport
• TCbIR – a receptor protein (Source 14)

SNPs in MTHFR and other important genes related to vitamin B12 and folate may be a root cause to explore in fertility, migraines, mood disorders, metabolic syndrome and a host of other health concerns.

It’s also important to note that nature isn’t the whole story, nurture, that is to say the environment, also plays a leading role. It is possible to have perfect methylation genetics, but poor methylation. Conversely, someone may have many SNPs present, but a well-functioning methylation cycle. It’s not just about your genes, but mostly due to diet and lifestyle.

Diet, stress, gut health, toxin exposures, medication use and other lifestyle factors play a leading role in determining methylation status and overall health.

The Role of Betaine and Glycine

In the methylation cycle, pictured above, MTHFR is associated with the “long way” around the cycle. This is dependent upon adequate levels of folate and vitamin B12 to support genetics.

You’ll also notice a “shortcut” via the enzyme BHMT, or betaine-homocysteine S- methyltransferases, that bypasses MTHFR all together. This shortcut may be particularly important for those who happen to have SNPs in both B12 and folate-related enzymes.

BHMT relies on a nutrient called betaine that is derived from choline. Betaine is also known as trimethylglycine (TMG) because it is composed of three methyl groups connected to a glycine molecule.

Much of the focus of methylation support is on folate and B12; however, betaine is another compound to consider. Strong evidence supports the use of betaine for lowering homocysteine levels and improving metabolic health. (Source 15, 16)

Risks of Overmethylating

While much of the focus with methylation is undermethylation, often due to folate and B12 deficiencies, overmethylation deserves attention as well. Overmethylation is known as Hypermethylation and has been well studied. It refers to a situation where the body has an abundance of methyl groups which get added to enzymes or DNA gene promoter regions as the methylation cycle is “turning” faster than needed.

Hypermethylation of DNA “promoter” regions (the DNA sequence immediately preceding the actual gene sequence) turns genes “on” permanently which is dangerous. Hypermethylated DNA segments have been associated with cancer and testing is being developed as an early diagnostic tool to measure blood levels of such hypermethylated DNA as an early detection tool for cancer (19). Having adequate levels of Vitamin C is important in preventing hypermethylation, as vitamin C catalyzes enzymes that reverse methylation, called TET (demethylases).

You can read more about demethylation and vitamin C here:

Hypermethilation can also result in low levels of homocysteine, instead of high. The primary factor that drives Hypermethylation is supplementation of active B12 vitamin and folate that is too high for a specific individual.

Other immediate hypermethylation symptoms may include:

• Anxiety
• Poor concentration
• Panic
• Insomnia
• Paranoia
• Hyperactivity
• Inflammation

If you experience any of these symptoms immediately after taking methylated supplements, or they develop over time with prolonged use, you may need to take a break, reduce your dose or consider other supplemental support such as niacin which uses up excess methyl groups. Please work with your functional medicine provider. Curcumin is also a helpful supplement to keep on hand to calm any inflammation associated with Hypermethylation.

Prolonged overmethylation is quite concerning and often seen in cancer. (Source 1, 17) The goal is to optimize methylation for each individual and achieve balanced levels that aren’t too high or too low.

Action Steps For Methylation Support

With the goal of optimizing methylation, here are some diet and lifestyle pieces to consider.

• Meet nutrient needs through diet. Dietary intake is the main determinant of vitamin B12 and folate status. (Source 18) You may want to consider micronutrient testing to look at current levels and adjust your diet from there.

Good sources of folate: leafy green vegetables, beans and avocado

Good sources of vitamin B12: meat, fish, poultry, eggs and dairy

Good sources of choline or betaine: eggs, liver and beets

• Avoid folic acid. Folic acid is a synthetic nutrient often found in inexpensive supplements or fortified foods that isn’t the same structure as the active folate that the body needs for methylation.

• Adopt a healthy lifestyle. This means stress less, get optimal sleep, move your body and reduce exposure to toxins. All of these measures support optimal gene expression and methylation.

• Consider supplemental methylation support. Diet and lifestyle components are foundational, but often additional support is required especially when SNPs are present or you are going through a period of increased need for these nutrients.

Core Med Science Liposomal B12 Folate TMG (add link) contains methylated or “active” folate (as L-methylenetetrahydrofolate), “active” vitamin B12 (as methylcobalamin) as well as betaine (TMG) to support methylation through both the long and short routes for those individuals who have SNP’s in processing both B12 and Folate.

The liposomal delivery system assures superior absorption and delivery to cells throughout the body. Liposomal B12 Folate TMG comes in a convenient liquid pump so it is easy to adjust the dose to your specific needs.

When it comes to optimizing methylation, folate and vitamin B12 are the stars of the show. Understanding deficiency symptoms and how SNPs play a role may lead you to some new insight about your own health and healing process. Remember that everything in the body is connected and supporting methylation ultimately supports each and every cell in the body for optimal function and wellness.

References

1. Shipton, M. J., & Thachil, J. (2015). Vitamin B12 deficiency - A 21st century perspective . Clinical medicine (London, England), 15(2), 145–150. Full text: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4953733/
2. Coppen, A., & Bolander-Gouaille, C. (2005). Treatment of depression: time to consider folic acid and vitamin B12. Journal of psychopharmacology (Oxford, England), 19(1), 59–65. Abstract: https://pubmed.ncbi.nlm.nih.gov/15671130/
3. Langan, R. C., & Goodbred, A. J. (2017). Vitamin B12 Deficiency: Recognition and Management. American family physician, 96(6), 384–389. Abstract: https://pubmed.ncbi.nlm.nih.gov/28925645/
4. Czeizel, A. E., Dudás, I., Vereczkey, A., & Bánhidy, F. (2013). Folate deficiency and folic acid supplementation: the prevention of neural-tube defects and congenital heart defects. Nutrients, 5(11), 4760–4775. Full text: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3847759/
5. Román, G. C., Mancera-Páez, O., & Bernal, C. (2019). Epigenetic Factors in Late-Onset Alzheimer's Disease: MTHFR and CTH Gene Polymorphisms, Metabolic Transsulfuration and Methylation Pathways, and B Vitamins. International journal of molecular sciences, 20(2), 319. Full text: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6359124/
6. Zhu, Y., Wu, T., Ye, L., Li, G., Zeng, Y., & Zhang, Y. (2018). Prevalent genotypes of methylenetetrahydrofolate reductase (MTHFR) in recurrent miscarriage and recurrent implantation failure. Journal of assisted reproduction and genetics, 35(8), 1437–1442. Full text: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6086799/
7. Martinez, C. A., Northrup, H., Lin, J. I., Morrison, A. C., Fletcher, J. M., Tyerman, G. H., & Au, K. S. (2009). Genetic association study of putative functional single nucleotide polymorphisms of genes in folate metabolism and spina bifida. American journal of obstetrics and gynecology, 201(4), 394.e1–394.11. Full text: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2790326/
8. Gong, J. M., Shen, Y., Shan, W. W., & He, Y. X. (2018). The association between MTHFR polymorphism and cervical cancer. Scientific reports, 8(1), 7244. Full text: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5940696/
9. Xu, L., Qin, Z., Wang, F., Si, S., Li, L., Lin, P., Han, X., Cai, X., Yang, H., & Gu, Y. (2017). Methylenetetrahydrofolate reductase C677T polymorphism and colorectal cancer susceptibility: a meta-analysis. Bioscience reports, 37(6), BSR20170917. Full text: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5719002/
10. Arakawa, Y., Watanabe, M., Inoue, N., Sarumaru, M., Hidaka, Y., & Iwatani, Y. (2012). Association of polymorphisms in DNMT1, DNMT3A, DNMT3B, MTHFR and MTRR genes with global DNA methylation levels and prognosis of autoimmune thyroid disease. Clinical and experimental immunology, 170(2), 194–201. Full text: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3482366/
11. Levin, B. L., & Varga, E. (2016). MTHFR: Addressing Genetic Counseling Dilemmas Using Evidence-Based Literature. Journal of genetic counseling, 25(5), 901–911. Abstract: https://pubmed.ncbi.nlm.nih.gov/27130656/
12. Vohra, M., Sharma, A. R., Paul, B., Bhat, M. K., Satyamoorthy, K., & Rai, P. S. (2018). In silico characterization of functional single nucleotide polymorphisms of folate pathway genes. Annals of human genetics, 82(4), 186–199. Abstract: https://pubmed.ncbi.nlm.nih.gov/29574679/
13. Tanaka, T., Scheet, P., Giusti, B., Bandinelli, S., Piras, M. G., Usala, G., Lai, S., Mulas, A., Corsi, A. M., Vestrini, A., Sofi, F., Gori, A. M., Abbate, R., Guralnik, J., Singleton, A., Abecasis, G. R., Schlessinger, D., Uda, M., & Ferrucci, L. (2009). Genome-wide association study of vitamin B6, vitamin B12, folate, and homocysteine blood concentrations. American journal of human genetics, 84(4), 477–482. Full text: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2667971/
14. Mills, J. L., Carter, T. C., Kay, D. M., Browne, M. L., Brody, L. C., Liu, A., Romitti, P. A., Caggana, M., & Druschel, C. M. (2012). Folate and vitamin B12-related genes and risk for omphalocele. Human genetics, 131(5), 739–746. Full text: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3374579/
15. Schwab, U., Alfthan, G., Aro, A., & Uusitupa, M. (2011). Long-term effect of betaine on risk factors associated with the metabolic syndrome in healthy subjects. European journal of clinical nutrition, 65(1), 70–76. Abstract: https://pubmed.ncbi.nlm.nih.gov/20978525/
16. Brouwer, I. A., Verhoef, P., & Urgert, R. (2000). Betaine supplementation and plasma homocysteine in healthy volunteers. Archives of internal medicine, 160(16), 2546–2547. Abstract: https://jamanetwork.com/journals/jamainternalmedicine/article-abstract/485420
17. Hoffman R. M. (1985). Altered methionine metabolism and transmethylation in cancer. Anticancer research, 5(1), 1–30. Abstract: https://pubmed.ncbi.nlm.nih.gov/3888043/
18. de Batlle, J., Matejcic, M., Chajes, V., Moreno-Macias, H., Amadou, A., Slimani, N., Cox, D. G., Clavel-Chapelon, F., Fagherazzi, G., & Romieu, I. (2018). Determinants of folate and vitamin B12 plasma levels in the French E3N-EPIC cohort. European journal of nutrition, 57(2), 751–760. Abstract: https://pubmed.ncbi.nlm.nih.gov/28004270/
19. Liquid Biopsy blood test accurately detects cancer by detecting DNA methylation https://www.chemistryworld.com/news/liquid-biopsy-blood-test-accurately-spots-cancer-by-detecting-dna-methylation/4011447.article