National Center for Advancing and Translational Sciences Genetic and Rare Diseases Information Center, a program of the National Center for Advancing and Translational Sciences

Homocystinuria due to MTHFR deficiency


Other Names:
Homocysteinemia due to methylenetetrahydro-folate reductase deficiency; Methylenetetrahydro-folate reductase deficiency; Homocysteinuria due to methylenetetrahydro-folate reductase deficiency; Homocysteinemia due to methylenetetrahydro-folate reductase deficiency; Methylenetetrahydro-folate reductase deficiency; Homocysteinuria due to methylenetetrahydro-folate reductase deficiency; 5,10-alpha-methylenetetrahydro-folate reductase deficiency; 5,10 alpha methylenetetrahydro-folate reductase deficiency See More
Categories:
Homocystinuria due to MTHFR deficiency is a genetic condition that results from poor metabolism of folate (also called vitamin B9), due to a lack of working enzyme called MTHFR. The gene that tells our body how to make the enzyme is also called MTHFR. At least 40 rare MTHFR gene variants have been found in people with decreased or no working enzyme.[1]

Very common gene variants (C677T and A1298C) can cause some decrease in enzyme function. People with homocystinuria due to MTHFR deficiency tend to have two rare variants or sometimes a rare variant and a common variant. Very rarely people inherit a combination of three or four common variants from their parents (for example two C677T variants and two A1298C variants) and may also develop very high levels of homocystine in their body. 

Homocystinuria usually does not show symptoms in a newborn baby. If untreated, children show signs and symptoms of severe homocystinuria in infancy. Newborn screening in most states includes a screening test for homocystinuria so that newborn infants can be treated early in their lives.

However, homocystinuria due to MTHFR variants can be milder, presenting in later childhood or in adulthood. Symptoms may include abnormal clotting, developmental delay, seizures, intellectual disability, and microcephaly.[1] Severe homocystinuria can also be caused by gene variants in other genes besides MTHFR. For more information about other causes of homocystinuria, see the GARD page:
https://rarediseases.info.nih.gov/diseases/10770/homocystinuria 

For more information on having two common MTHFR gene variants (specifically, C677T and A1298C) visit our page: MTHFR gene variant
Last updated: 1/30/2018
Signs and symptoms of severe MTHFR deficiency may include:

Global developmental delays (46% of cases)
Low muscle tone (35%)
Seizures (33%)
Failure to thrive (17%)
Blood vessel disease (16%) (blood clots)
Small head size (15%)
Ataxia (9%)
Peripheral neuropathy (7%)

Other possible symptoms include bone disease (scoliosis), mental health problems, and behavior problems (e.g., attention deficit disorder and hyperactivity). Life expectancy will vary depending on the severity of the deficiency.[2]

For information on signs and symptoms reported in association with having two common MTHFR gene mutations, such as C677T and A1298C, please visit our MTHFR Gene Mutation resource page.
Last updated: 1/25/2018

This table lists symptoms that people with this disease may have. For most diseases, symptoms will vary from person to person. People with the same disease may not have all the symptoms listed. This information comes from a database called the Human Phenotype Ontology (HPO) . The HPO collects information on symptoms that have been described in medical resources. The HPO is updated regularly. Use the HPO ID to access more in-depth information about a symptom.

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Medical Terms Other Names
Learn More:
HPO ID
Percent of people who have these symptoms is not available through HPO
Autosomal recessive inheritance 0000007
Behavioral abnormality
Behavioral changes
Behavioral disorders
Behavioral disturbances
Behavioral problems
Behavioral/psychiatric abnormalities
Behavioural/Psychiatric abnormality
Psychiatric disorders
Psychiatric disturbances
[ more ] 		0000708
Gait disturbance
Abnormal gait
Abnormal walk
Impaired gait
[ more ] 		0001288
Global developmental delay 0001263
Homocystinuria
High urine homocystine levels
0002156
Hyperhomocystinemia
Elevated blood homocystine
0002160
Incoordination
Difficulties in coordination
Incoordination of limb movements
Limb incoordination
[ more ] 		0002311
Microcephaly
Abnormally small skull
Decreased circumference of cranium
Decreased size of skull
Reduced head circumference
Small head circumference
[ more ] 		0000252
Muscle weakness
Muscular weakness
0001324
Paresthesia
Pins and needles feeling
Tingling
[ more ] 		0003401
Seizure 0001250
Stroke 0001297
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Last updated: 7/1/2020
Homocystinuria due to MTHFR deficiency is caused by mutations in the MTHFR gene. This gene tells the body how to make an enzyme, also called MTHFR. MTHFR is important for a chemical reaction in the body involving forms of the vitamin folate. Mutations in the MTHFR gene result in an enzyme that doesn't work like it should, causing a buildup of homocysteine in the body.[3]
Last updated: 4/14/2015
Homocystinuria due to MTHFR deficiency is inherited in an autosomal recessive fashion, which means that both copies of the gene in each cell have mutations in the MTHFR gene.[1]

For more information on the inheritance of common MTHFR gene mutations (such as C677T) visit our page: MTHFR gene mutation
Last updated: 4/14/2015

Making a diagnosis for a genetic or rare disease can often be challenging. Healthcare professionals typically look at a person’s medical history, symptoms, physical exam, and laboratory test results in order to make a diagnosis. The following resources provide information relating to diagnosis and testing for this condition. If you have questions about getting a diagnosis, you should contact a healthcare professional.

Testing Resources

  • The Genetic Testing Registry (GTR) provides information about the genetic tests for this condition. The intended audience for the GTR is health care providers and researchers. Patients and consumers with specific questions about a genetic test should contact a health care provider or a genetics professional.
Treatment of MTHFR deficiency involves taking betaine, folinic acid, Vitamins B6 and B12, methionine, and methyltetrahydrofolate supplements.[2][4] If MTHFR deficiency is diagnosed early and betaine treatment is started right away, affected infants have a much better developmental outcome.[2] Treatments started later do not reverse symptoms but can cause favorable improvements in symptoms.[2]
Last updated: 9/10/2015

FDA-Approved Treatments

The medication(s) listed below have been approved by the Food and Drug Administration (FDA) as orphan products for treatment of this condition. Learn more orphan products.

If you need medical advice, you can look for doctors or other healthcare professionals who have experience with this disease. You may find these specialists through advocacy organizations, clinical trials, or articles published in medical journals. You may also want to contact a university or tertiary medical center in your area, because these centers tend to see more complex cases and have the latest technology and treatments.

If you can’t find a specialist in your local area, try contacting national or international specialists. They may be able to refer you to someone they know through conferences or research efforts. Some specialists may be willing to consult with you or your local doctors over the phone or by email if you can't travel to them for care.

You can find more tips in our guide, How to Find a Disease Specialist. We also encourage you to explore the rest of this page to find resources that can help you find specialists.

Healthcare Resources

Related diseases are conditions that have similar signs and symptoms. A health care provider may consider these conditions in the table below when making a diagnosis. Please note that the table may not include all the possible conditions related to this disease.

Conditions with similar signs and symptoms from Orphanet
The differential diagnosis should include other homocysteine remethylation disorders.
Visit the Orphanet disease page for more information.

Research helps us better understand diseases and can lead to advances in diagnosis and treatment. This section provides resources to help you learn about medical research and ways to get involved.

Clinical Research Resources

  • ClinicalTrials.gov lists trials that are related to Homocystinuria due to MTHFR deficiency. Click on the link to go to ClinicalTrials.gov to read descriptions of these studies.

    Please note: Studies listed on the ClinicalTrials.gov website are listed for informational purposes only; being listed does not reflect an endorsement by GARD or the NIH. We strongly recommend that you talk with a trusted healthcare provider before choosing to participate in any clinical study.

Support and advocacy groups can help you connect with other patients and families, and they can provide valuable services. Many develop patient-centered information and are the driving force behind research for better treatments and possible cures. They can direct you to research, resources, and services. Many organizations also have experts who serve as medical advisors or provide lists of doctors/clinics. Visit the group’s website or contact them to learn about the services they offer. Inclusion on this list is not an endorsement by GARD.

Organizations Supporting this Disease

These resources provide more information about this condition or associated symptoms. The in-depth resources contain medical and scientific language that may be hard to understand. You may want to review these resources with a medical professional.

Where to Start

  • Genetics Home Reference (GHR) contains information on Homocystinuria due to MTHFR deficiency. This website is maintained by the National Library of Medicine.
  • LabTests Online provides information on testing homocysteine levels in general. Click on LabTests Online to view the information page.

In-Depth Information

  • The Monarch Initiative brings together data about this condition from humans and other species to help physicians and biomedical researchers. Monarch’s tools are designed to make it easier to compare the signs and symptoms (phenotypes) of different diseases and discover common features. This initiative is a collaboration between several academic institutions across the world and is funded by the National Institutes of Health. Visit the website to explore the biology of this condition.
  • Online Mendelian Inheritance in Man (OMIM) is a catalog of human genes and genetic disorders. Each entry has a summary of related medical articles. It is meant for health care professionals and researchers. OMIM is maintained by Johns Hopkins University School of Medicine. 
  • Orphanet is a European reference portal for information on rare diseases and orphan drugs. Access to this database is free of charge.
  • PubMed is a searchable database of medical literature and lists journal articles that discuss Homocystinuria due to MTHFR deficiency. Click on the link to view a sample search on this topic.

Questions sent to GARD may be posted here if the information could be helpful to others. We remove all identifying information when posting a question to protect your privacy. If you do not want your question posted, please let us know.

  1. Homocystinuria. Genetics Home Reference (GHR). March, 2016; https://ghr.nlm.nih.gov/condition=homocystinuria.
  2. Munoz T, Patel J, Badilla-Porras R, Kronick J, Mercimek-Mahmutoglu S. Severe scoliosis in a patient with severe methylenetetrahydrofolate reductase deficiency. Brain Dev. 2015 Jan; 37(1):168-70. Accessed 9/10/2015.
  3. MTHFR. Genetics Home Reference (GHR). November, 2014; http://ghr.nlm.nih.gov/gene/MTHFR.
  4. Physician's Guide to The Homocystinurias. The National Organization of Rare Disorders. http://nordphysicianguides.org/wp-content/uploads/2012/02/Homocystinuria_11_29b.pdf. Accessed 9/10/2015.
  5. Homocystinuria due to deficiency of N(5,10)-Metylenetetrahydrofolate Reductase Activity. Online Medelian Inheritance of Man (OMIM). 2014; http://www.omim.org/entry/236250.
  6. Varga EA, Sturm AC, Misita CP & Moll S. Homocysteine and MTHFR Mutations: Relation to Thrombosis and Coronary Artery Disease. Circulation. 2005; 111:e289-e293. http://circ.ahajournals.org/content/111/19/e289.full.
  7. Rosenson RS & Kang DS. Overview of homocysteine. UpToDate. July 21 2017; https://www.uptodate.com/contents/overview-of-homocysteine.
  8. Homocysteine. American Academy of Family Physicians. 2006; http://familydoctor.org/online/famdocen/home/articles/249.html. Accessed 5/13/2009.
  9. Homocystinuria due to deficiency of N(5,10)-Methylenetetrahydrofoloate reductase activity. Online Mendelian Inheritance in Man. 2007; http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=236250.
  10. Liew SC & Gupta ED. Methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism: epidemiology, metabolism and the associated diseases. Eur J Med Genet. January 2015; 58(1):1-10. https://www.ncbi.nlm.nih.gov/pubmed/25449138.