Folate, Folate Receptor Autoantibodies and a Genetic Connection?

There has been quite a bit of interest in what is termed MTHR polymorphisms in recent years. A plethora of articles have been published in scientific journals with respect to the topic and its connection to neurological health including its relevance to autism spectrum disorders.

So, what exactly is MTHFR, and what are MTHFR polymorphisms?

MTHFR polymorphisms refer to variations in the MTHFR gene (methylenetetrahydrofolate reductase), which plays a key role in processing certain vitamins and amino acids, particularly folate (vitamin B9) and homocysteine. Variations in this gene can affect how well the enzyme works, potentially influencing a person’s risk for certain health conditions.

1. C677T (rs1801133):
   • A substitution of cytosine (C) with thymine (T) at position 677.
   • Homozygous individuals (TT) may have reduced MTHFR enzyme activity.
   • Associated with higher homocysteine levels, which can increase cardiovascular risk.
2. A1298C (rs1801131):
   • A substitution of adenine (A) with cytosine (C) at position 1298.
   • May affect enzyme activity but typically less than the C677T variant.

Reduced enzyme activity can:

• Elevate homocysteine levels: This amino acid, if not properly metabolized, may contribute to cardiovascular disease, stroke, and other health concerns.
• Affect folate metabolism: May lead to a deficiency in active folate, impacting DNA synthesis, repair, and methylation.
• Influence pregnancy outcomes: Associated with an increased risk of neural tube defects, preeclampsia, and miscarriage.

Genetic testing can identify MTHFR variants. However, testing is generally not routine unless there is a specific medical reason, such as:

• Recurrent pregnancy loss.
• Elevated homocysteine levels with no clear cause.
• A strong family history of conditions linked to these polymorphisms.

For individuals with MTHFR polymorphisms:

• Dietary changes: Ensure adequate intake of bioavailable folate (e.g., leafy greens, legumes) and B vitamins (B6, B12).
• Supplements: Methylated forms of folate (L-methylfolate) may be recommended instead of folic acid.
• Medical monitoring: Regular checks for homocysteine levels and cardiovascular health.

Cleary, MTHFR may affect folate cycles and transport, which is an exceedingly important aspect in human health and wellbeing. MTHFR would fall in the domain of genetics. And there are other genetic variants that would affect folate transport, such as variants in the FOLR1 gene. Again, folate transport may be perturbed if the FOLR1 gene is affected.

The question now becomes, is there a connection between folate receptor autoantibodies and MTHFR genetic polymorphisms?

Recent evidence may point to a potential connection between certain gene variants and folate receptor autoantibodies (FRA). This connection is of interest, particularly in the context of conditions such as autism spectrum disorder (ASD), developmental delays, and certain neurological and metabolic conditions.

• What are they? FRA are autoantibodies that interfere with the function of folate receptors. These receptors are critical for the transport of folate (vitamin B9) into cells, especially across the blood-brain barrier.
• Impact: The presence of these autoantibodies can lead to reduced folate levels in the central nervous system, a condition known as cerebral folate deficiency (CFD). CFD has been implicated in developmental delays, ASD, and other neurological disorders.

Certain genetic polymorphisms affect folate metabolism, transport, and utilization. Examples include:

• MTHFR gene variants (e.g., C677T, A1298C):
  • These polymorphisms can reduce the activity of methylenetetrahydrofolate reductase (MTHFR), an enzyme critical for converting folate into its active form, 5-MTHF.
  • Reduced MTHFR activity can lead to elevated homocysteine levels and impaired folate-dependent processes like DNA methylation and neurotransmitter synthesis.
• FOLR1 gene variants:
  • FOLR1 encodes the folate receptor alpha, which is the target of folate receptor autoantibodies.
  • Mutations or polymorphisms in this gene may increase susceptibility to the development of FRA.

• Studies suggest individuals with FRA and polymorphisms like MTHFR mutations may have compounded disruptions in folate metabolism, worsening folate deficiency symptoms.
• FRA and gene variants may act synergistically, particularly in children with ASD. For example:
  • FRA can block folate transport to the brain, while MTHFR polymorphisms can impair systemic folate metabolism.
  • This combination may lead to a greater risk of cognitive and neurological issues.

• Testing: Screening for FRA and genetic polymorphisms can provide insight into folate metabolism issues. FRAT^® will screen for folate receptor autoantibodies.
• Treatment:
  • Supplementation with high-dose folinic acid (a bioavailable form of folate) may bypass these metabolic blockages and improve outcomes in individuals with FRA or folate-related gene variants.
  • Monitoring homocysteine levels can guide the management of folate-related deficiencies.

Gene variants in the folate pathway are associated with increased levels of folate receptor autoantibodies

Yuqi Dong ¹, Linlin Wang ¹, Yunping Lei ², Na Yang ¹, Robert M Cabrera ²,
Richard H Finnell ², Aiguo Ren ¹