Friday, 20 January 2017

The methylenetetrahydrofolate reductase (MTHFR) variant c.677C>T influences overall survival of patients with glioblastoma multiforme

This was a 2008 article published in Neuro Onc 10.1215/15228517-2008-020.  PMCID: PMC2666227.

From what I gather, the C/T (C677T) A/C (A1298C) genotype (Greatly Reduced Activity, GRA) of the MTHFR gene is a risk factor for survival in GBM. C/C is considered normal. 

I did test our survivor for the MTHFR gene and he has the C/T polymorphism noted above.  It should be noted that this polymorphism is common in the general population.  

Individuals with the GRA MTHFR type mutation are expected to have greatly decreased folic acid metabolism and low folate levels. 

The authors of the study concluded that "folate supplementation or dietary strategies influencing methionine and further metabolites of methionine metabolism might be interesting candidate supportive therapies for GBM patients".  There is a product on the market known at L-methylfolate or Metafolin and also marketed as Deplin 7.5 mg or 15 mg.   Supplementing with regular folic acid would seem to be much less effective if one does not have enough MTHFR to convert folate to its active form that can pass the blood brain barrier.  My question is if anyone has any further information or experience with L-methylfolate supplementation in their BTcocktail. 


  1. There was some discussion of this same study here:

  2. Was he heterozygous or homozygous for the MTHFR c.677C>T variant (was the variant found in only one or both copies of the gene)? The study shows that the greatest impact on survival is for patients homozygous for the c.677C>T variant (TT genotype). If only one copy of the gene was thus affected (CT genotype), median survival was the same as for those without the variant (CC genotype).

    1. Mine was the C/C "normal" and his was the C/T "greatly reduced activity" phenotype.

    2. He has the C/T variant, "greatly reduced activity" or heterozygous" phenotype. The common 677C to T genetic variant has reduced catalytic activity and is associated with a low tissue concentration of folate. The resulting impairment of DNA methylation could then affect many physiologic processes. Hyperhomocysteinemia is not an uncommon finding and is known to lead to DNA hypomethylation and altered gene expression, many can be corrected by administration of folate.

    3. You're saying he is heterozygous for the variant, meaning he has one copy of the normal C allele and once copy of the variant T allele. His MTHFR activity would therefore not be as impaired as someone homozygous for the variant (having 2 copies of the mutant T allele).

      An individual homozygous for the 677C>T variant (having two copies of the impaired T allele) is much more likely to have clinical complications than someone heterozygous for the variant (having one impaired T allele and one normal C allele). In a case like this (such as your brother's case) the normal C allele could compensate for the impaired activity of the T allele. This is also reflected in the GBM retrospective study in which patients homozygous for the 677C>T variant (two copies of the T allele, or TT or T/T genotype) had worse median survival, but patients heterozygous for the variant (only one copy of the impaired T allele, or CT, or C/T genotype) had median survival similar to patients without the variant (two copies of the normal C allele, or CC genotype).

      In short, I'd expect L-methylfolate supplementation to be more important for someone with two mutant T alleles (homozygous for the variant) than someone with only one mutant T allele (heterozygous for the variant).

      "Homozygous mutations often increase methylfolate requirements compared with heterozygous mutations."

    4. Of course it's also possible a person could inherit one variant of the MTHFR gene (c.677C>T for example) from one parent, and a different variant (for example c.1298A>C) from the other parent. I'm not sure whether your testing was looking for other variants besides c.677C>T.

  3. Also note that L-methylfolate is the same thing as 5-methyltetrahydrofolate (5-MTHF) which was discussed in the previous post (click on the 5-MTHF label from the labels menu). This molecule is the normal end product of the MTHFR enzyme, which converts 5,10-methyleneTHF to 5-MTHF. I'm not aware of anyone on the blog taking L-methylfolate (5-MTHF) supplements as part of their GBM cocktail, but perhaps there is someone out there that has.


    A Phase I/II Study of High-dose L-methylfolate in Combination With Temozolomide and Bevacizumab in Recurrent High Grade Glioma