Remethylation defects are primarily those in which homocysteine cannot be converted to the amino acid methionine. The most common problems are with the gene encoding methylene tetrahydrofolate reductase (MTHFR). Genes which process cobalamin/vitamin B12 or folate can also lead to disease. Folate provides the methyl part of remethylation and vitamin B12 is necessary for MTHFR and several other enzymes to work.
Genetic differences in MTHFR can totally wipe its function out (severe) or the impact can be milder. Two common mild variants are found in the gene in approximately 10-15% of the population (1 in every 10 people to 3 in every 20 people). These “common” variants are specifically labelled “C677T” and “A1298G” based on where the genetic difference is located. These common variants have MTHFR function which is only slightly less than those with typical MTHFR function. Only when these patients are folate deficient will their homocysteine levels be elevated. These are so common and so unlikely to cause disease, the American College of Medical Genetics and Genomics recommends that NO ONE is tested for these.
Those with severe MTHFR (no MTHFR or extremely low, like <1% activity) are in a different category. Individuals with severe MTHFR have homocysteines that are elevated even when they are adequately supplemented with folate and Vitamin B12. Many will present with apnea (stop breathing), blood clots (especially in the brain), seizures and hydrocephalus (extra fluid on the brain). Older individuals can have learning problems, feeding problems, and behavior problems. Individuals with severe MTHFR are treated with the medication Betaine (Cystadane ®). Some will be supplemented with folate (or folinic acid), vitamin B12, and other vitamins. Different metabolic/genetic clinics have different approaches to diet. If you want to read more (warning this is a copy of the document your medical professional will use so it is long and technical), the guidelines for management and diagnosis are: here .
There are more rare remethylation defects from changes in genes that encode methionine adenosyltransferase I/III, glycine N-methyltransferase, S-adenosylhomocysteine hydrolase and adenosine kinase deficiencies. We are still learning about these disorders so information is limited. If you are interested, contact HCU Network America and we will reach out for input to update you and your care team.