Reddy, Mechanism of interaction of vitamin E and glutathione in the protection against membrane lipid peroxidation. Ann NY Acad Sci 1989:570:514-7.

5,10-Methylene-THF is further reduced to 5-methyl-THF by  [EC and EC].

Due to its role in the conversion of L-tyrosine in to L-dopa, which is the precursor for dopamine, a deficiency in tetrahydrobiopterin can cause serious neurological issues including dopa-responsive dystonia (DRD). A mutation in the gene GCH1, which encodes the enzyme GTP cyclohydrolase I, disrupts the production of BH4, decreasing dopamine levels .

Patent EP A Rubreserine and its derivates with Figure imgb

Methotrexate and aminopterin are potent inhibitors of DHFR in  (Prabhu et al, 1998).

Along with vitamin B12, 5-MTHF serves as a donor of methyl groups, which the body utilizes in many nervous system and metabolic processes

In me, an HEDS patient who has compound heterozygosity for MTHFR variants C677T (+/-) and A1298C (+/-), excess folate appears to accumulate in the blood and interferes with normal metabolic function like in other disorders of metabolism. Symptoms include metabolic derangement, inflammation, visual disturbances, increased muscle tension, spasticity, muscle, bone and joint pain, nausea, dysmotility/constipation alternating with diarrhea, frequent and excessive urination, foul smelling urine and worsening of thermal regulation disturbances.

5-MTHF regulates biosynthesis of BH4.

This suggests the symptoms that improved or resolved were related to accumulation of folate in the blood rather than the folate deficiency.

Folate Deficiency

Folate deficiency is most often caused by a dietary insufficiency.

This results in autosomal-dominant DRD.

Reduced MTHFR activity limits the conversion and thus results in intracellular deficiency of folate, which has a number of health implications.

After restricting folic acid intake, my blood folate level dropped to below normal range.

NO deficit is associated with POTS.


Folate is necessary for the production and maintenance of new cells, for DNA synthesis and RNA synthesis, and for preventing changes to DNA, and, thus, for preventing cancer. [12] It is especially important during periods of rapid cell division and growth, such as infancy and pregnancy.

NO is one of the most important of these metabolic factors.

It appears folate builds up in blood if and when intake exceeds availability of the MTHFR enzyme that is needed to convert it to 5-MTHF, the biologically active form that is useable by the body.

Osteoporosis and Dysautonomia in the Joint Hypermobility Syndrome.

Other intracellular deficiencies reported by the lab as either significant or severe include vitamins A, C, E and B-carotene, lipoic acid, glutathione, iron magnesium manganese, and molybendum. I imagine these deficiencies may be due in part to malabsorption as I have mastocytosis in my small intestine.

The elevated blood folate levels and intracellular folate deficiency coexisted.