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For people with Down syndrome, family members, caregivers and professionals.

Vitamin B12 and Folate

March 2025 | Brian Chicoine, MD - Adult Down Syndrome Center

Key Points

  • Vitamin B12 and folate are vitamins that serve important functions in the human body.

  • There are differences in how effectively these vitamins perform their functions in people with Down syndrome compared to people without Down syndrome.

  • There are some differences in the possible significance of blood testing for these vitamins in people with Down syndrome compared to people without Down syndrome.

 

Functions of vitamin B12 and folate

Vitamin B12 (cobalamin) and folate (vitamin B9) are vitamins that serve important functions in the human body. Folate is needed for development and growth of cells (including red blood cells) and synthesis of DNA (genetic material). Vitamin B12 is needed for maintaining healthy red blood cells, nerves, and brain function.

Methylation

Both vitamin B12 and folate are needed for a chemical process called methylation.

A few terms that are helpful to know:

  • Chromosomes – structures in our cells that are inherited from our biological parents. Most people have 23 pairs of chromosomes (46 total). Most people with Down syndrome have 47 chromosomes. Chromosomes are made up of proteins and DNA.

  • DNA (deoxyribonucleic acid) – a molecule that contains our genetic information.

  • Genes - segments of DNA that affect our physical characteristics and body functions. They control the function of our cells, replication of our cells, and formation of new cells.

Genes also pass on information and instructions to cells in the body. Methylation is involved in this passing on of information and instructions. Methylation requires vitamin B12 and folate.

People with Down syndrome have a relatively low methylation functional status compared to people without Down syndrome. This means that there is less ability in the cells of people with Down syndrome to perform the chemical reaction (methylation). The implications of this in people with Down syndrome need additional study.

 

Vitamin B12

Vitamin B12 is found in foods such as beef, poultry, fish, eggs, and milk. Some foods are also supplemented with vitamin B12. Some supplements, such as multivitamins or vitamin B12 tablets, also contain vitamin B12.

Vitamin B12 deficiency

Vitamin B12 deficiency is seen more frequently in:

  • People who follow diets that do not have enough vitamin B12 (vegetarian and vegan diets are two examples).

  • People who have digestive disorders that make it difficult for their bodies to absorb vitamin B12 (such as celiac disease which is more common in people with Down syndrome).

  • Older individuals (with aging, some individuals don’t absorb vitamin B12 as well).

Symptoms of vitamin B12 deficiency

Some of the symptoms that can be caused by a lack of vitamin B12 include:

  • Poor appetite

  • Anemia

  • Fatigue

  • Weakness

  • Numbness or tingling in the hands or feet

  • Difficulty with balance

Vitamin B12 deficiency can also contribute to depression, cognitive impairment, and dementia. Limited data indicate vitamin B12 deficiency may contribute to menstrual irregularities (but more study is needed).

 

Folate

Folate is found in foods such as:

  • Dark green leafy vegetables (e.g., spinach, kale, broccoli)

  • Asparagus

  • Beans and lentils

  • Peas

  • Quinoa

  • Fruits (e.g., oranges, bananas)

  • Nuts and seeds (e.g., almonds, sunflower seeds)

  • Liver

  • Eggs

Some foods are also supplemented with folate (e.g., breakfast cereals). Some supplements, such as multivitamins or folic acid tablets, also contain folate.

Symptoms of folate deficiency

Some of the symptoms that can be caused by a lack of folate include:

General symptoms

  • Fatigue

  • Irritability

  • Headache

  • Dizziness

Gastrointestinal symptoms

  • Sore tongue

  • Mouth ulcers

  • Diarrhea

  • Loss of appetite

Neurological symptoms

  • Numbness and tingling in the hands and feet

  • Confusion

  • Depression

  • Cognitive impairment

  • Dementia

Hematological symptoms

  • Anemia (pale skin, shortness of breath)

 

Testing for vitamin B12 and folate deficiency

When to test

Since vitamin B12 and folate affect many functions in the body and there are many possible symptoms, blood testing for vitamin B12 and folate is commonly ordered by the physicians at the Adult Down Syndrome Center. We order vitamin B12 and folate testing when a person with Down syndrome we are evaluating has symptoms described above, has a lab abnormality for which follow up testing of vitamin B12 and/or folate is indicated, or the person has a condition in which deficiency is common (e.g., celiac disease). 

How to test

A blood test is done to check for vitamin B12 or folate deficiency. Serum (the liquid portion of blood) is commonly used to test vitamin B12 and folate. Folate can also be tested in the red blood cells. Testing for vitamin B12 or folate deficiency is not routinely included in blood work ordered at an annual physical exam. This testing is added based on the criteria described above in “When to test.”

In people without Down syndrome, studies have demonstrated that red blood cell folate and serum folate testing provide equivalent data; thus, testing red blood cell folate is not necessary. However, in children with Down syndrome, one study found red blood cell folate was lower than serum folate. This suggests that it might be more beneficial to check red blood cell folate instead of serum folate in people with Down syndrome.

A decrease in vitamin B12 and/or folate results in an increase in homocysteine level. Homocysteine level is a more direct measure of the function of vitamin B12 and folic acid (compared to red blood cell or serum testing). It may be a better indicator of folate and B12 functional levels. Checking a homocysteine level in people with Down syndrome may clarify or confirm vitamin B12 and/or folate deficiency.

Further study on vitamin B12, folate, and homocysteine testing in people with Down syndrome is needed.

 

Prevention and treatment

Diet

Including foods with vitamin B12 and folate (listed above) in the diet is the first step to preventing and treating low levels of these vitamins.

Supplements

We recommend discussing vitamin B12 and/or folate supplements with a health care professional before starting supplementation. Additional information is provided below.

Can a person have too much vitamin B12 or folate?

Too much vitamin B12 intake can cause headache, nausea and vomiting, diarrhea, fatigue, weakness, and tingling. Vitamin B12 supplements can interact with some medications, too. Too much folate can cause nausea, loss of appetite, confusion, irritability, and changes in sleep.

Taking a folate supplement can mask vitamin B12 deficiency. This is problematic because vitamin B12 deficiency can cause permanent neurological effects. If the symptoms of vitamin B12 deficiency are not evident earlier because of the folate intake, the effects may become irreversible.

When treating with supplements, repeat blood testing of vitamin B12 and folate levels is done to monitor and confirm adequate treatment. Homocysteine level may also be repeated.

 

Supplements

For each of these vitamins, there is an active form in the body that performs the functions (such as methylation noted above). There are also inactive forms that are synthetically made (human-made). The supplements of these vitamins may be in the active or inactive form. When supplemented with an inactive form, it is converted to the active form in the body.

Studies have found mixed results on whether one form is absorbed better or is more effective. Information specific to people with Down syndrome is included below.

Vitamin B12 supplements

Active: Methylated B12 (methyl cobalamin) is the active, natural form of vitamin B12. It is available in oral forms (capsules, lozenges, chewable tablets, and dissolving tablets).

Inactive: Cyanocobalamin is the synthetic form of vitamin B12. It is available in oral forms (tablets, capsules, liquid, dissolving tablets, chewable tablets) and injection.

Vitamin B12 oral forms are available without a prescription. The injectable form requires a prescription.

Folate supplements

Active: Levomefolate (5-methyltetrahydrofolate) is the active, natural form of folate. It is available in oral forms (liquid, tablets, and capsules).

Inactive: Folic acid is the synthetic form of folate. It is available in oral tablets and/or injection.

Lower doses are available without a prescription. Higher doses and the injectable forms require a prescription.

Supplements and Down syndrome

There are mixed data regarding whether people with Down syndrome require the active forms (versus inactive forms) of vitamin B12 and folate when taking a supplement.

Some studies have shown that, if people with Down syndrome take the inactive oral forms of vitamin B12 and folate, their bodies may have difficulty converting from the inactive to the active form and the inactive form may not be as effective. For example, this study by Funk et al. found that supplementation with folic acid (the synthetic form) in girls with Down syndrome may not be as effective as the active form. The study measured red blood cell folate level before and after supplementation.

However, other studies found that the inactive forms were effective. In this study by Fillon-Emery et al., a multivitamin with folic acid (the synthetic form) was shown to be effective in people with Down syndrome. It reduced homocysteine levels.

Further study is needed to clarify the best methods of supplementing.

 

Resources

Down syndrome

Balance

Celiac disease

Depression

General

Folate (NIH Office of Dietary Supplements)

Folate (folic acid) (Mayo Clinic)

Vitamin B12 (NIH Office of Dietary Supplements)

Vitamin B12 (Mayo Clinic)

 

References

Yassaee F, Hadadianpour S. The effects of Cobalamin and B-complex on hypermenorrheaJ Res Med Sci. 2020;25:30. doi:10.4103/jrms.JRMS_862_18

De Bruyn E, Gulbis B, Cotton F. Serum and red blood cell folate testing for folate deficiency: New features?Eur J Haematol. 2014;92(4):354-359. doi:10.1111/ejh.12237

Dixon N, Kishnani PS, Zimmerman S. Clinical manifestations of hematologic and oncologic disorders in patients with Down syndromeAm J Med Genet C Semin Med Genet. 2006;142C(3):149-157. doi:10.1002/ajmg.c.30096

Fillon-Emery N, Chango A, Mircher C, et al. Homocysteine concentrations in adults with trisomy 21: Effect of B vitamins and genetic polymorphismsAm J Clin Nutr. 2004;80(6):1551-1557. doi:10.1093/ajcn/80.6.1551

Funk RS, Jones J, Polireddy K, et al. Folates in children with Down syndrome and the impact of dietary supplementation. J Hum Clin Gen. 2020;2(1):1-8. doi:10.29245/2690-0009/2020/1.1110

Galloway M, Rushworth L. Red cell or serum folate? Results from the National Pathology Alliance benchmarking reviewJ Clin Pathol. 2003;56(12):924-926. doi:10.1136/jcp.56.12.924

Hamaguchi Y, Kondoh T, Fukuda M, et al. Leukopenia, macrocytosis, and thrombocytopenia occur in young adults with Down syndromeGene. 2022;835:146663. doi:10.1016/j.gene.2022.146663

Langan RC, Goodbred AJ. Vitamin B12 deficiency: Recognition and managementAm Fam Physician. 2017;96(6):384-389.

Lauer AA, Grimm HS, Apel B, et al. Mechanistic link between vitamin B12 and Alzheimer's diseaseBiomolecules. 2022;12(1):129. doi:10.3390/biom12010129

Pogribna M, Melnyk S, Pogribny I, Chango A, Yi P, James SJ. Homocysteine metabolism in children with Down syndrome: in vitro modulationAm J Hum Genet. 2001;69(1):88-95. doi:10.1086/321262

Reynolds EH. Folic acid, ageing, depression, and dementiaBMJ. 2002;324(7352):1512-1515. doi:10.1136/bmj.324.7352.1512

Song C, He J, Chen J, et al. Effect of the one‑carbon unit cycle on overall DNA methylation in children with Down's syndromeMol Med Rep. 2015;12(6):8209-8214. doi:10.3892/mmr.2015.4439

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