WHAT IS IT?

• 5,10-methylenetetrahydrofolate reductase (MTHFR) enzyme catalyzes 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate and is therefore critical to reactions and processes involving folate
  • MTHFR converts the amino acid homocysteine to methionine
  • MTHFR and consequent folate status impacts pathways involving DNA methylation and gene regulation
• Two polymorphic variants are known to decrease enzyme activity
  • 677C>T (“thermolabile” variant – enzyme less active at higher temperatures)
    • Commonly, a C is at position 677 that codes for an alanine
    • T at position 677 leads to a valine substitution
  • 1298A>C is also common but does not cause increased homocysteine levels in heterozygous or homozygous individuals
  • Combined heterozygosity of 1298A>C and 677C>T results in an outcome like 677C>T homozygous individuals
• 677C>T is common and found throughout the world
  • 10 – 15% of North American Caucasians are homozygous
  • > 25% of Hispanics are homozygous with the highest allele frequencies
  • 6% in individuals of African descent are homozygous
  • 20 to 40% of Caucasians or Hispanics in the US are heterozygotes (one allele)
• Reduced MTHFR activity, especially when folate levels are low, is a risk factor for hyperhomocysteinemia
  • Hyperhomocysteinemia has been weakly associated with venous thrombosis and coronary artery disease
  • Other factors can elevate homocysteine levels (e.g. deficiencies of folate, vitamins B6 and B12)
  • Hyperhomocysteinemia may be mild to moderate in individuals who are homozygotes for MTHFR polymorphisms with limited clinical significance

KEY POINTS:

Is MTHFR genotype status related to disease?

• Until recently, it was thought that MTHFR deficiency, by causing elevated homocysteine levels, led to an increased risk of venous thrombosis, coronary heart disease, recurrent pregnancy loss and adverse pregnancy outcomes
• More recent analysis has found no evidence for consistent associations or causation
• Furthermore, there is no association with MTHFR variants and mortality
• Homocysteinemia should not be confused with homocystinuria, a rare genetic disease usually seen in childhood, which presents with extremely high homocysteine levels and is associated with severe, early onset vascular disease and venous thromboembolism
• There is no evidence that it is dangerous to vaccinate children with MTHFR mutations nor is testing of children for this reason indicated

Is there clinical utility to clinical testing for MTHFR variants?

• MTHFR is only one factor in hyperhomocysteinemia
• Fortification of cereals has led to higher folate levels and therefore reduced homocysteine levels
  • Due to gene-nutrient interaction, previous associations between MTHFR variants and disease may no longer be relevant
  • For example, the association between 677C>T and venous thromboembolism is no longer seen in the US
• Lowering homocysteine levels through vitamin supplementation does not reduce the risk of blood clots or cardiovascular disease

RECOMMENDATIONS:

MTHFR polymorphism genotyping should not be ordered as part of the clinical evaluation for thrombophilia, recurrent pregnancy loss, or for at-risk family members.

• ACOG
  • Testing for MTHFR mutations in not recommended for recurrent pregnancy loss, as only antiphospholipid syndrome has shown consistent associations
  • MTHFR variants in isolation do not confer additional risk for thrombosis in either pregnant or nonpregnant women and therefore testing for MTHFR variants or fasting homocysteine levels in not recommended for the work up of venous thromboembolism
  • There is lack of association between heterozygosity or homozygosity for 677C>T and any negative pregnancy outcomes
• ASRM and NSGC
  • Testing for MTHFR variants for recurrent pregnancy loss is not recommended
• ACMG
  • MTHFR polymorphism genotyping should not be ordered as part of the clinical evaluation for thrombophilia or recurrent pregnancy loss or for at-risk family members
  • Do not adjust preventative folic acid supplementation dose for NTDs based on MTHFR results
• Thrombosis Canada
  • Due to lack of clinical utility and available data, treating hyperhomocysteinemia in patients with cardiovascular disease or VTE is not recommended, nor is vitamin supplementation for primary prevention of cardiovascular disease recommended
• Joint Statement on Expanded Carrier Screening (ACOG/ACMG/NSGC/PQF/SMFM)
  • It may be preferable not to include variants on expanded prenatal genetic carrier panels that have high allele frequencies and low penetrance of a phenotype such as MTHFR

Learn More – Primary Sources:

Prevalence of methylenetetrahydrofolate reductase 677T and 1298C alleles and folate status: a comparative study in Mexican, West African, and European populations 

MTHFR related hyperhomocysteinemia

ACOG Committee Opinion 197: Inherited Thrombophilias in Pregnancy

Evaluation and treatment of recurrent pregnancy loss: a committee opinion 

ACMG Practice Guideline: lack of evidence for MTHFR polymorphism testing

MTHFR: Addressing Genetic Counseling Dilemmas Using Evidence-Based Literature 

Genetic evaluation and counseling of couples with recurrent miscarriage: recommendations of the National Society of Genetic Counselors

Meta-analysis of MTHFR 677C->T polymorphism and coronary heart disease: does totality of evidence support causal role for homocysteine and preventive potential of folate?

Expanded carrier screening in reproductive medicine-points to consider: a joint statement of the American College of Medical Genetics and Genomics, American College of Obstetricians and Gynecologists, National Society of Genetic Counselors, Perinatal Quality Foundation, and Society for Maternal-Fetal Medicine

AAP: Immunizations and Common Parental Concerns

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