Can MTR and MTRR variants raise homocysteine despite adequate B12 and folate?

The methionine synthase (MTR) and methionine synthase reductase (MTRR) enzymes coordinate the vitamin B12-dependent remethylation of homocysteine to methionine. Polymorphisms in these genes can disrupt this essential pathway, leading to elevated systemic homocysteine even in patients with optimal serum folate and B12 levels.

Clinical evidence

• Resistance to cofactor therapy: Genetic variations in MTR and MTRR compromise remethylation efficiency, meaning systemic homocysteine accumulation can persist despite adequate or supplemented cofactor levels.
• Folate treatment failure: Specifically, individuals carrying the MTRR rs1801394 G-allele exhibit a reduced response and a higher risk of treatment failure during folic acid supplementation, failing to achieve expected reductions in homocysteine.

Mechanistic explanations

• Enzymatic kinetic slowdown: The MTR A2756G (rs1805087) variant alters the enzyme's cobalamin-binding domain, reducing the rate of remethylation. Meanwhile, the MTRR A66G (rs1801394) G-allele reduces the enzyme's activity, which impairs the essential reactivation of methionine synthase.
• Impaired cellular methylation: This enzymatic deceleration blocks the conversion of homocysteine to methionine. Beyond elevating systemic homocysteine, this blockade limits the synthesis of S-adenosylmethionine (SAM), ultimately leading to cellular DNA hypomethylation.

Bottom line

• Genetic variants in MTR and MTRR impair the biochemical recycling of homocysteine, meaning elevated plasma levels can persist despite clinically normal or supplemented serum vitamin B12 and folate.