Add-On CNA + MethylDetox Profile

MTHFR catalyses the reduction of 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate, the principal circulating folate and the methyl donor for homocysteine remethylation to methionine. The C677T polymorphism produces a thermolabile enzyme with reduced activity, most pronounced in TT homozygotes. Functional impact is greater when folate status is suboptimal, leading to elevated homocysteine and reduced methylation capacity.

The TT genotype confers approximately 70% residual enzyme activity and is associated with elevated homocysteine when folate intake is inadequate. Clinical associations include increased cardiovascular risk, adverse pregnancy outcomes, and altered drug metabolism (particularly methotrexate). The CT heterozygote retains approximately 65% activity and shows intermediate effects. Many functional-medicine practitioners use this genotype to guide methylated-folate supplementation, though population screening remains controversial.

The A1298C polymorphism lies in the regulatory domain of MTHFR and affects enzyme stability rather than catalytic efficiency. Homozygosity for 1298C reduces MTHFR activity to a lesser extent than the C677T variant. Compound heterozygosity (677T/1298C) produces a more significant functional decrement than either single heterozygous state.

The CC genotype at A1298C is less strongly associated with elevated homocysteine than C677T TT, but functional practitioners interpret it in the context of neurotransmitter metabolism and mood disorders. Evidence remains mixed; compound 677T/1298C heterozygosity shows clearer biochemical impact. This variant is used to personalise folate and methylation-support protocols rather than to diagnose disease.

COMT methylates and inactivates catecholamine neurotransmitters and catechol oestrogens. The V158M polymorphism (also designated rs4680) substitutes methionine for valine at codon 158 of the membrane-bound isoform, reducing enzyme thermostability and activity by approximately 40% in Met/Met homozygotes. Lower COMT activity slows dopamine and noradrenaline clearance in prefrontal cortex, influencing executive function, stress resilience, and pain perception.

The Met/Met (AA) genotype is associated with higher prefrontal dopamine tone, superior working memory under low-stress conditions, but increased vulnerability to stress and anxiety. Val/Val (GG) confers more efficient catecholamine clearance, greater stress resilience, but lower baseline prefrontal dopamine. Functional practitioners use COMT genotype to guide methylation support, stress-management strategies, and occasionally oestrogen-metabolism protocols.

Methionine synthase catalyses the remethylation of homocysteine to methionine, using 5-methyltetrahydrofolate as the methyl donor and vitamin B12 (methylcobalamin) as a cofactor. The A2756G polymorphism may affect enzyme-substrate interaction or stability. Functional activity depends on adequate B12 and folate status, so genetic variation interacts with nutritional sufficiency.

Variants at MTR A2756G have been associated with altered homocysteine and methionine in some studies, particularly when B12 status is marginal. Functional practitioners interpret this genotype as part of a broader methylation map, guiding methylcobalamin and methylfolate dosing, though evidence for clinical utility is less robust than for MTHFR C677T.

Methionine synthase reductase regenerates the active form of methionine synthase by reductive methylation of its cobalamin cofactor. The A66G polymorphism may alter reductase efficiency, influencing the rate at which methionine synthase is restored to active service and thereby affecting one-carbon metabolism under conditions of oxidative stress or suboptimal B12.

The GG genotype has been associated with altered homocysteine and differential response to B12 supplementation in some populations. Functional medicine protocols use MTRR genotype alongside MTR and MTHFR to tailor methylated B-vitamin formulations, though the independent clinical impact of MTRR A66G is modest and context-dependent.

Cystathionine beta-synthase shunts homocysteine into the transsulphuration pathway for synthesis of cysteine and downstream glutathione production. The C699T polymorphism has been reported to increase CBS activity in some functional contexts, potentially lowering homocysteine but raising downstream sulphite, sulphate, and ammonia. Classical CBS deficiency (a separate, rare autosomal-recessive disorder) causes severe homocystinuria; the C699T variant does not.

In functional-medicine interpretation the TT genotype is sometimes linked to 'upregulated' transsulphuration, lower homocysteine, and higher taurine/sulphate production, with theoretical implications for sulphur sensitivity and ammonia load. Evidence is contested — some studies find no clear phenotype, and the direction of effect (gain vs loss of function) is debated. Practitioners may adjust sulphur-containing supplements or assess ammonia clearance accordingly, though this remains exploratory.

A composite or algorithmic score that integrates MTHFR, MTR, MTRR, and other genotypes to estimate net one-carbon/methylation flux. The index is proprietary to the performing laboratory and reflects predicted capacity to generate S-adenosylmethionine and maintain homocysteine clearance under typical dietary conditions.

Used as a personalised functional-medicine tool to guide methylated-vitamin formulations (methylfolate, methylcobalamin, trimethylglycine) and to interpret plasma homocysteine or methylmalonic acid in genetic context. The score is not validated as a standalone diagnostic marker, and clinical utility depends on integration with biochemical measures and symptoms.