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The activity of the enzyme MTRR is so critical for regeneration of MethylCo(III)B12, that certain mutations in the gene have been found to be conditionally lethal in the womb, or are associated with much higher rates of Down Syndrome, Neural Tube Defects, increased homocysteine (Garcia-Minguillan etal, 2014

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This adverse effect on B12 status has only been implicated with synthetic folic acid and not with natural folate from food sources (i.e., methyl­tetra­hydrofolate) (Selhub et al., 2022)