More than 50% of your patients are affected by genetic mutations in the methylation pathway.1 Standard MTHFR genotyping only evaluates folic acid metabolism. The MethylDetox Profile makes it easy to understand the complicated methylation process by giving comprehensive insights into the functional status of the methylation pathway.
The MethylDetox Profile includes genetic markers involved in methylation and homocysteine metabolism provided in a detailed lab report with personalized commentary. Additionally, continued homocysteine testing enables easy monitoring of patient progress.
Genetic variations in this pathway are associated with elevated homocysteine levels, impaired methylation processes and limited detoxification capacity. 1, 3 As a result, these SNPs (single nucleotide polymorphisms) may contribute to accelerated aging, certain chronic diseases like cardiovascular disease and neurodegenerative disorders, impaired gene-regulation, poor drug clearance, and impaired neurotransmitter metabolism. 1, 3-21Get Starter Test Kit
Methionine and homocysteine metabolism are areas of active scientific and medical investigation. In addition to the MTHFR gene, specific SNPs in other genes also affect individual methylation capacity and homocysteine levels. 1-3
Methionine and homocysteine balance is important for optimal health. Homocysteine is resynthesized from the amino acid methionine. In general, amino acids are supplied from a balanced diet or supplementation. However, a certain amount of methionine is recycled for methylation in the methionine/ homocysteine pathway.
Therefore, the primary purpose of methionine/ homocysteine balance is to ensure proper methylation by donating methyl groups for:
Elevated serum homocysteine is a widely accepted marker for methionine/homocysteine imbalance, which is a genetically controlled process.28 Elevated homocysteine levels can lead to accelerated aging, cardiovascular disease and neurodegenerative disorders among others. 20, 21, 29
Sequence Specific Real-Time Polymerase Chain Reaction (SSP-PCR) Enzyme
Individuals with a manifestation and/or family history of:
1. MTHFR (Methylenetetrahydrofolate reductase)
Folic acid (vitamin B9) passes through a complex metabolic pathway in order to be used in the methionine/homocysteine cycle. It is first converted to tetrahydrofolate (THF) then to 5,10-methylenetetrahydrofolate (5,10-CH2- THF).
MTHFR is needed to further convert 5,10-CH2-THF into active 5-methyltetrahydrofolate (5-MTHF), in order to convert methionine from homocysteine. This is where one genetic problem can occur. If the patient has particular genetic polymorphisms in the MTHFR gene, challenges can occur, converting folic acid into its active form 5-MTHF. If the patient acquired the SNPs from both parents (called homozygous positive), she/he probably has significantly reduced MTHFR activity and a marked deficiency in active 5-MTHF. If the patient received the SNP from only one parent (heterozygous positive) he/she may have suboptimal MTHFR function.
The SNPs investigated here are at position C677T and A1298C (Ala222Val and Glu429Ala). Testing these SNPs indicate how well homocysteine is cleared from the blood.30 Approximately 10% of Caucasian and Asian populations have 70% less activity (homozygote positive, diminished function). About 40% of the population (heterozygous appearance) have a diminished enzyme capacity to convert folic acid into (levomefolic acid) 5-MTHF.
Supplementation: When genetic mutations are present, supplementation of 5-MTHF is recommended.
2. MTR (5-methyltetrahydrofolate-homocysteine methyltransferase)
The MTR gene encodes the methionine synthase (MS) enzyme. MS regenerates methionine from homocysteine using 5-MTHF as a methyl donor and vitamin B12 as the methyl transfer compound. In a first reaction, MS attaches the methyl group from 5-MTHF to vitamin B12, forming a MSmethylcobalamin complex. The MS-methylcobalamin complex then transfers this methyl group to the homocysteine, thus converting it into methionine.
During this process, MS becomes oxidized over time and has to be reduced again to maintain proper function. This step is performed by methionine synthase reductase (MSR) which is encoded by the MTRR gene (see MTRR). MTR gene mutations, C3518T and A2756G, affect function of the enzyme even in the heterozygous form. They are associated with higher homocysteine levels and may lead to hypomethylation. Reported prevalence of A2756G in the Caucasian population is 1.7% in the homozygous form.
Supplementation: When genetic mutations are present in the MTR gene, supplementation with methylcobalamin (methylated vitamin B12) is recommended.
3. MTRR (5-methyltetrahydrofolate-homocysteine methyltransferase reductase)
The MTRR gene encodes the enzyme methionine synthase reductase (MSR). Its task is to support MS in the remethylation of homocysteine into methionine by keeping the MS enzyme in an active (reduced) form (see MTR). Over time, MS becomes oxidized and loses its ability to transfer methyl groups from the MS-methylcobalamin complex to homocysteine. The MS has to be activated (reduced) again by MSR in a so called “ping-pong” reaction that uses SAMe (S-adenosyl methionine) as the activating (reducing) agent.
The common MTRR polymorphism, A66G, has a prevalence of 26.58% (GG), 48.84 %(AG), 24.58% (AA) in the Caucasian population. In combination with the C677T polymorphism in MTHFR, MTRR genotypes AG, GG influence total plasma homocysteine levels. Additionally, the combination of the genetic polymorphisms in MTRR and MTHFR was linked to an increase in DNA damage as measured by micronucleus frequency (MN).
Supplementation: When genetic mutations are present in the MTRR gene, supplementation with SAMe (S-Adenosyl Methionine) is recommended.
4. COMT (Catechol-O-Methyltransferase)
COMT is the major enzyme involved in the methylation process. COMT catalyzes the transfer of the functional methyl group from S-adenosyl methionine (SAMe) to a substrate, which has to be methylated. Two SNPs, Val108/158Met and Ala52/102Thr, are known to alter COMT methylation capacity. 41
These 2 SNPs of the COMT gene are associated in literature with:
Supplementation: When genetic mutations are present, supplementation with S-Adenosyl Methionine (SAMe) is often recommended. Attention should be paid to other medications being taken, including anti-depressants.
5. AHCY (S-Adenosylhomocysteine hydrolase)
The AHCY gene encodes an enzyme called S-adenosylhomocysteine hydrolase and is the only enzyme known to convert S-adenosylhomocysteine (AdoHcy) to homocysteine.
AdoHcy is an inhibitor of methylation processes. The ratio between AdoMet and AdoHcy is referred to as methylation potential. Therefore, it is crucial that AHCY immediately converts AdoHcy to homocysteine and adenine in order to maintain an optimal methylation potential. Several genetic polymorphisms (SNPs) in this gene are known to alter activity and expression of this enzyme, leading to elevated AdoHcy concentrations and impaired methylation potential. Recent studies show association between those mutations resulting in poor methylation potentials, severe myopathies, developmental delays and hypermethioninemia.
Supplementation: When genetic mutations are present, supplementation with NADH (nicotinamide adenine dinucleotide + hydrogen) is often recommended. Supplementation with SAMe may also be recommended.
Monitoring of patient progress is done by testing homocysteine levels before, during and after the implementation of personalized therapy or supplementation.
Patient test results are provided both in the context of the methylation pathway and personalized commentary. Commentary includes supplementation recommendations for personalized treatment. Throughout treatment, homocysteine testing is recommended to monitor patient outcomes.
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