What is a DHFR deficiency?

What is a DHFR deficiency?

Katie Stone - Naturopath

Written By:

Katie Stone - Naturopath
Kari Asadorian - Bachelor of Science in Nursing

Medical Reviewer:

Kari Asadorian - Bachelor of Science in Nursing
Jamie Hope - Founder of Methyl-Life

Edited By:

Jamie Hope - Founder of Methyl-Life

Updated On:

September 09, 2025

What is DHFR?

The DHFR gene (dihydrofolate reductase) provides instructions for creating the enzyme dihydrofolate reductase.

Dihydrofolate reductase is the enzyme required for converting dihydrofolate (a derivative of folic acid) to tetrahydrofolate. This is the first step in the process of converting folic acid and dietary folate to active folate, which is critical if folic acid is consumed in supplements or in fortified foods.


Tetrahydrofolate is then used to make several substances required for methylation, including methyl-tetrahydrofolate (also known as methylfolate, also known as 5-methylenetetrahydrofolate or 5-MTHF). Many of these substances take part in the production of purines, amino acids, and thymidine.1

These functions are particularly vital in tissues with high cell turnover, such as bone marrow and the brain. Deficiencies in DHFR can therefore lead to megaloblastic anemia and neurological problems.2

What is DHFR deficiency?

A DHFR deficiency means that the body doesn’t produce enough of the DHFR enzyme. This can happen when there is a mutation on the DHFR gene. DHFR deficiency is a rare autosomal recessive metabolic disorder, in which two copies of a mutated gene, (one from each parent) are passed down. The prevalence is uncertain as very few cases have been reported, but DHFR is thought to be rare.


DHFR is necessary for maintaining sufficient cerebrospinal folate and red blood cell folate levels, even if someone is eating plenty of dietary folate and has normal plasma folate.3 This is because impaired DHFR activity may prevent dietary folate from being used effectively in the brain and red blood cells.


Some research has linked DHFR deficiency to megaloblastic anemia, as lack of DHFR disrupts the production of THF and impairs DNA synthesis. This can affect rapidly dividing cells such as red blood cell precursors.

DHFR mutations have also been linked to cerebral folate deficiency and cerebral tetrahydrobiopterin deficiency. As DHFR activity is required for methylfolate synthesis, a deficiency can impair the methylation cycle, affecting DNA synthesis, neurotransmitter production, and many other important biological processes. It may also affect homocysteine levels and other methylation processes, as methylfolate is needed for the remethylation of homocysteine to methionine.4

Symptoms of DHFR deficiency & health implications

Some research has suggested that the homozygous DHFR mutation can cause deficiency in the DHFR enzyme. If untreated, this may potentially lead to hematological conditions such as megaloblastic anemia, and/or cardiovascular disease, neural tube defects, and mental health disorders.5


This is because DHFR is necessary for maintaining sufficient CSF and RBC folate levels, even in the presence of adequate nutritional folate supply and normal plasma folate. Fortunately, DHFR deficiency can be successfully treated with folinic acid.


However, DHFR deficiency does not cause physical malformations like neural tube defects.

Cerebrospinal fluid (CSF) levels in patients with DHFR deficiency appear to be similar to those with cerebral folate deficiency (CFD), which is usually diagnosed at a very early age. CFD is a condition marked by low folate levels in the cerebrospinal fluid despite normal blood levels, often linked to folate transport or metabolism issues, including DHFR mutations.

Other neurological symptoms (in very severe cases) may include developmental delay, seizures, and other cognitive issues, depending on the severity of CSF levels.6

Treatment of DHFR deficiency

Folinic acid (Leucovorin) has been used successfully to treat hematological issues such as anemia and normalize CSF folate levels, which can then improve neurological symptoms.7

Folinic acid is a derivative of tetrahydrofolic acid (THF) that bypasses the need for DHFR and is readily converted to methylfolate.8 However, early intervention may be required to prevent long-term neurological damage.

Previous studies have shown that DHFR deficiencies can be successfully treated with folinic acid, the “non-methylated form” of folate that becomes methylfolate.9

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Frequently Asked Questions about DHFR

What is the DHFR gene mutation?

A mutation on the DHFR gene affects the production of dihydrofolate reductase, the enzyme required for converting dihydrofolate (a derivative of folate) to tetrahydrofolate. This is the first step in the process of converting folic acid to active folate (the form that can be used immediately in the body).
If untreated, a DHFR mutation can lead to severe neurological and hematological issues, although it does not cause neural tube defects. However, the prevalence of the DHFR mutation is uncertain as there are very few studies. Currently, DHFR mutations can be identified through genetic testing.

What is DHFR and why is it important?

Dihydrofolate reductase is the enzyme that converts dihydrofolate into tetrahydrofolate. This is an important part of the methylation cycle as it produces methylfolate. Methylfolate is the active form of folate required for numerous biological functions in the body, including the production of neurotransmitters and the recycling of homocysteine. These include synthesis of serotonin, dopamine, and norepinephrine, as well as DNA repair. Methylfolate also helps normalize red blood cell production, which can improve or prevent anemia.

How do you treat dihydrofolate reductase deficiency?

Previous research suggests that DHFR deficiency has been successfully treated with folinic acid.10 Folinic acid is a derivative of tetrahydrofolic acid (THF) which can be converted to methylfolate without requiring DHFR. Further research regarding the treatment of DHFR deficiency with methylfolate is pending.

What happens when DHFR is inhibited?

Certain drugs are designed to block DHFR in order to treat cancer, rheumatoid arthritis, and parasitic infections. This is because a lack of DHFR impairs folate metabolism and cell growth. DHFR inhibitors such as methotrexate (MTX) are used as anticancer agents as it can slow down cell division and growth.

References

  1. www.sciencedirect.com; "Dihydrofolate Reductase"; 2025

    https://www.sciencedirect.com/topics/neuroscience/dihydrofolate-reductase

  2. Taco W Kuijpers, Andrica CH de Vries, Ester M van Leeuwen, A(Ton) AM Ermens, Saskia de Pont, Desirée EC Smith, Mirjam MC Wamelink, Arjen R Mensenkamp, Marcel R Nelen, Hana Lango Allen, Steven T Pals, Berna HB Beverloo, Hidde H Huidekoper, Anja Wagner, NIHR BioResource Study Group; "Megalobastic anemia, infantile leukemia, and immunodeficiency caused by a novel homozygous mutation in the DHFR gene"; Blood advances; 2022 Aug

    https://pmc.ncbi.nlm.nih.gov/articles/PMC9641170

  3. Holger Cario, Desirée E.C. Smith, Henk Blom, Nenad Blau, Harald Bode, Karlheinz Holzmann, Ulrich Pannicke, Karl-Peter Hopfner, Eva-Maria Rump, Zuleya Ayric, Elisabeth Kohne, Klaus-Michael Debatin, Yvo Smulders, Klaus Schwarz; "Dihydrofolate Reductase Deficiency Due to a Homozygous DHFR Mutation Causes Megaloblastic Anemia and Cerebral Folate Deficiency Leading to Severe Neurologic Disease"; The American Journal of Human Genetics; 2011 Feb

    https://www.cell.com/ajhg/fulltext/S0002-9297(11)00008-5

  4. Kyoung-Jin Sohn, Hyeran Jang, Mihaela Campan, Daniel J Weisenberger, Jeffrey Dickhout, Yi-Cheng Wang, Robert C Cho, Zoe Yates, Mark Lucock, En-Pei Chiang, Richard C Austin, Sang-Woon Choi, Peter W Laird, Young-In Kim; "The methylenetetrahydrofolate reductase C677T mutation induces cell-specific changes in genomic DNA methylation and uracil misincorporation: a possible molecular basis for the site-specific cancer risk modification"; International journal of cancer; 2009 May

    https://pubmed.ncbi.nlm.nih.gov/19123462/

  5. Holger Cario, Desirée E C Smith, Henk Blom, Nenad Blau, Harald Bode, Karlheinz Holzmann, Ulrich Pannicke, Karl-Peter Hopfner, Eva-Maria Rump, Zuleya Ayric, Elisabeth Kohne, Klaus-Michael Debatin, Yvo Smulders, Klaus Schwarz; "Dihydrofolate reductase deficiency due to a homozygous DHFR mutation causes megaloblastic anemia and cerebral folate deficiency leading to severe neurologic disease"; American journal of human genetics; 2011 Feb

    https://pubmed.ncbi.nlm.nih.gov/21310277/

  6. Holger Cario, Desirée E.C. Smith, Henk Blom, Nenad Blau, Harald Bode, Karlheinz Holzmann, Ulrich Pannicke, Karl-Peter Hopfner, Eva-Maria Rump, Zuleya Ayric, Elisabeth Kohne, Klaus-Michael Debatin, Yvo Smulders, Klaus Schwarz; "Dihydrofolate Reductase Deficiency Due to a Homozygous DHFR Mutation Causes Megaloblastic Anemia and Cerebral Folate Deficiency Leading to Severe Neurologic Disease"; The American Journal of Human Genetics; 2011 Feb

    https://www.cell.com/ajhg/fulltext/S0002-9297(11)00008-5

  7. Holger Cario, Desirée EC Smith, Henk Blom, Nenad Blau, Harald Bode, Karlheinz Holzmann, Ulrich Pannicke, Karl-Peter Hopfner, Eva-Maria Rump, Zuleya Ayric, Elisabeth Kohne, Klaus-Michael Debatin, Yvo Smulders, Klaus Schwarz; "Dihydrofolate Reductase Deficiency Due to a Homozygous DHFR Mutation Causes Megaloblastic Anemia and Cerebral Folate Deficiency Leading to Severe Neurologic Disease"; American journal of human genetics; 2011 Feb

    https://pmc.ncbi.nlm.nih.gov/articles/PMC3035706

  8. Yves Menezo, Kay Elder, Arthur Clement, Patrice Clement; "Folic Acid, Folinic Acid, 5 Methyl TetraHydroFolate Supplementation for Mutations That Affect Epigenesis through the Folate and One-Carbon Cycles"; Biomolecules; 2022

    https://www.mdpi.com/2218-273X/12/2/197

  9. Holger Cario, Desirée E C Smith, Henk Blom, Nenad Blau, Harald Bode, Karlheinz Holzmann, Ulrich Pannicke, Karl-Peter Hopfner, Eva-Maria Rump, Zuleya Ayric, Elisabeth Kohne, Klaus-Michael Debatin, Yvo Smulders, Klaus Schwarz; "Dihydrofolate reductase deficiency due to a homozygous DHFR mutation causes megaloblastic anemia and cerebral folate deficiency leading to severe neurologic disease"; American journal of human genetics; 2011 Feb

    https://pubmed.ncbi.nlm.nih.gov/21310277/

  10. Holger Cario, Desirée E C Smith, Henk Blom, Nenad Blau, Harald Bode, Karlheinz Holzmann, Ulrich Pannicke, Karl-Peter Hopfner, Eva-Maria Rump, Zuleya Ayric, Elisabeth Kohne, Klaus-Michael Debatin, Yvo Smulders, Klaus Schwarz; "Dihydrofolate reductase deficiency due to a homozygous DHFR mutation causes megaloblastic anemia and cerebral folate deficiency leading to severe neurologic disease"; American journal of human genetics; 2011 Feb

    https://pubmed.ncbi.nlm.nih.gov/21310277/

Katie Stone - Naturopath

About the Author

Katie is a qualified Naturopath (BNatMed) and freelance writer from New Zealand. She specializes in all things health and wellness, particularly dietary supplements and nutrition. Katie is also a dedicated runner and has completed more half-marathons than she can count!

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