CBS (cystathionine beta synthase) catalyzes the first step of the transsulfuration pathway, from homocysteine to cystathionine. CBS defects are actually an upregulation of the CBS enzyme. This means the enzyme works too fast. In these patients, it's common to see low levels of cystathionine and homocysteine since there is a rapid conversion to taurine. This leads to high levels of taurine and ammonia. The CBS upregulation has been clinically observed to result in sulfur intolerance in some patients. It has also been observed that BH4 can also become depleted with a CBS upregulation. BH4 helps regulate neurotransmitters and mood. Other mutations, such as MTHFR A1298C, Chronic bacterial infections, and aluminum can also lead to low BH4 levels. Lack of BH4 can lead to mast cell degranulation and possibly mast cell activation disorder (MCAD).

Note: While some physicians think the CBS mutation is one of the most important mutations to address, there is very little medical research to support these claims and some doctors in the field disagree. In normal populations, studies have shown CBS upregulations to be protective against high homocysteine. However, CBS upregulations have shown to be harmful in Down Syndrome. Medical research has not determined if CBS upregulations are harmful in those with syndromes or disorders leading to impaired methylation.


One function of MTHFR (Methylenetetrahydrofolate reductase) is to help convert homocysteine to methionine. A MTHFR C677T mutation means that the MTHFR enzyme may have trouble performing its task leading to high levels of homocysteine. According to Dr. Ben Lynch, impaired function of the enzyme can cause or contribute to conditions such as Autism, Chronic Fatigue Syndrome, Fibromyalgia, Miscarriages, IBS, many birth defects, Multiple Sclerosis, Alzheimer's, Bipolar Disorder, blood clots, Stroke, Chemical Sensitivity, and many other conditions.

MTHFR C677T can also lead to high homocysteine. High levels of homocysteine can be related to MTHFR C677T mutations. While homozygous (+/+) or heterozygous (+/-) mutations indicates reduced activity of this enzyme, it does not necessarily mean there will be high homocysteine levels in a clinical setting.

As S-adenosylhomocysteine (SAH) accumulates, the COMT enzyme may become impaired. Inhibitiion of COMT can increase dopamine levels in COMT V158M (-/-), but for those with COMT V158M (+/+), the high level of SAH can lead to behavior problems and mood swings according to Dr. Amy Yasko.


There is currently not enough data to draw conclusions about the significance of this SNP.


MTHFR A1298C is involved in converting 5-methylfolate (5MTHF) to tetrahydrofolate (THF). Unlike MTHFR C677T, the A1298C mutation does not lead to elevated homocysteine levels. This reaction helps generate BH4. BH4 is important for the detoxification of ammonia. The gene is compromised about 70% in MTHFR A1298C (+/+) individuals, and about 30% in people with a heterozygous (+/-) mutation.

BH4 acts as a rate limiting factor for the production of neurotransmitters and catecholamines including serotonin, melatonin, dopamine, norepinephrine, and epinephrine. A MTHFR A1298C + status may cause a decrease in any of these neurotransmitters or catecholamines. BH4 is also a cofactor in the production of nitric oxide. A dysfunctional BH4 enzyme may lead to mental/emotional and/or physical symptoms. Mercury, lead, and aluminum may act as a drain on BH4.


COMT (catechol-O-methyltransferase) helps break down certain neurotransmitters and catecholamines. These include dopamine, epinephrine, and norepinephrine. Catechol-O-methyltransferase is important to the areas of the pre-frontal cortex. This area of the brain is involved with personality, inhibition of behaviors, short-term memory, planning, abstract thinking, and emotion. COMT is also involved with metabolizing estrogens.

COMT (-/-) individuals can usually break down these neurotransmitters efficiently, but COMT (+/+) individuals may have trouble breaking these chemicals down from impaired function of the enzyme. With a COMT + status, it has been clinically observed by physicians that people may have trouble with methyl donors. This can lead to irritability, hyperactivity, or abnormal behavior. They may also be more sensitive to pain.


VDR (Vitamin D Receptor) encodes the nuclear hormone receptor for vitamin D3. Low or low normal vitamin D values are often seen in those with chronic illness and even the general population. Low vitamin D is related to a lot of neurological and immunological conditions. Vitamin D stimulates enzymes that create dopamine.

VDR Tak and VDR Bsm are usually inverse from eachother. So if there is a (+/+) VDR Tak, there would be a (-/-) VDR Bsm. However, this is not always the case.

It has been clinically observed that the body may have trouble tolerating methyl donors with a COMT V158M + and a VDR Taq + status. VDR Taq (-/-) individuals may already have higher levels of dopamine, and combinations of variations COMT and VDR Taq can lead to a wide range of dopamine levels. Those that are VDR Taq (+/+) and COMT (-/-) may have lowest dopamine levels.

Note: Some have pointed out that VDR Taq is reported backwards since majority of medical journals report a different risk allele or use different notation. These arguments are well-founded, but Genetic Genie reports this way so results are compatible with existing methylation nutrigenomics literature. Many claims about VDR and methylation are clinical observations. There are no medical studies to support some of the observations.


MAO-A (Monoamine oxidase A) is a critical enzyme involved in breaking down important neurotransmitters such as serotonin, norepinephrine, and dopamine. Males only have one allele since the gene is inherited through from their mother since it is located on the X chromosome. Only females can be heterozygous (+/-) for this mutation. When a (+/+) MAO-A mutation is combined with a (+/+) or (+/-) COMT V158M mutation, imbalances in neurotransmitters may be more severe. These imbalances can potentially lead to neuropsychiatric conditions and symptoms such as Obsessive Compulsive Disorder (OCD), mood swings, and aggressive and/or violent behavior.

Note: Genetic Genie reports the wild type as the defective variant as doctors have clinically observed that patients with methylation problems (especially those of Autism) often have trouble breaking down neurotransmitters. The high activity version of MAO-A (which is represented as -/-) can contribute to major depressive disorder. The significance of this SNP should be interpreted with caution.


ACAT1-02 (acetyl coenzyme A acetyltransferase) plays a role lipid metabolism and energy generation. It can also deplete B12.


MTRR (Methionine synthase reductase) helps recycle B12. The combination of MTR and MTRR mutations can deplete methyl B12. MTR A2756G, MTRR A66G, MTRR H595Y, MTRR K350A, MTRR R415T, MTRR S257T, and MTRR A664A all work together to convert homocysteine to methionine.

MTR (5-methyltetrahydrofolate-homocysteine methyltransferase) provides instructions for making the enzyme methionine synthase. Methionine synthase helps convert the amino acid homocysteine to methionine. To work properly, methionine synthase requires B12 (specifically in the form of methylcobalamin). An MTR A2756G mutation increases the activity of the MTR gene causing a greater need for B12 since the enzyme causes B12 to deplete since it is using it up at a faster rate. Mutations in MTR have been identified as the underlying cause of methylcobalamin deficiency. Megaloblastic anemia can occur as a consequence of reduce methionine synthase activity.

A homozygous mutation of MTR A2756G is not very common (<1% of CEU population). Some studies have demonstrated that people with a combination of MTHFR C677T and MTR A2756G have persistently high homocysteine levels unless they are treated with both B12 and folate.


BHMT (betaine homocysteine methyltransferase) acts as a shortcut through the methylation cycle helping convert homocysteine to methionine. The activity of the enzyme can be negatively influenced by stress. The Information on this enzyme related to methylation is mostly based on Dr. Amy Yasko's clinical experience and research.

According to Dr. Yasko, a homozygous mutation of BHMT 01, BHMT 02, BHMT 04, can produce results similar to one with a CBS upregulation even if you don't have a CBS upregulation. In her book, Autism: Pathways to Recovery, She also states that a BHMT 08 mutation may "increase MHPG levels relative to dopamine breakdown (HVA)". This can result in attention type symptoms. It is common to see elevated glycine in someone with a homozygous BHMT 08 mutation.


AHCY (S-adenosylhomocysteine hydrolase) is involved in breaking down the amino acid methionine. It controls the step that converts S-adenosylhomocysteine hydrolase to adenosine and homocysteine. Adenosine plays an important role in energy transfer as ATP and ADP. It helps promote sleep and suppress arousal. Dysfunction of this enzyme can affect levels of homocysteine and ammonia. Some physicians claim AHCY mutations may actually take the strain off the CBS enzyme and may even prevent taurine from becoming very elevated.

11 Responses to “All Mutations”

  1. coby miller Says:

    what about the GAD mutation. is there any work around for that mutation, i have a few of the GAD and GAD1 mutations.
    Thanks, geneticgenie, this is an awsome thing you are doing.

  2. George Manlove, DC Says:

    The GAD enzymes convert glutamate (an amino acid which acts as an excitatory neurotransmitter) into GABA which is the main inhibitory neurotransmitter. GABA does not normally cross and intact blood brain barrier. People with a GAD SNP may need help making more GABA. It is possible to get forms of GABA that do cross the blood brain barrier, ie phenyl-GABA, and herbs such as Valerian and Passionflower which help with GABA receptor sensitivity. Many people who are gluten sensitive may also produce antibodies to GAD which can have the same effect. There is a common blood test for GAD antibodies since it is associated with Type I diabetes.

  3. anonymous Says:

    So what does a person like myself do, having a single copy of the A1298C being identified, yet I do not have elevated levels of homocysteine, nor do I have an abnormality with B12 levels, and yet also have ‘high’ levels of Folate? (i.e….too much in the body simply not being properly utilized)

    Since BH4, at least IMHO, appears to be a rate limiting factor for me (i.e. metanephrines & normetanephrines for instance), what else besides checking for any ammonia by-product metabolites might I possibly need investigated?

    My treating PCP would like be as appreciative of this info, as myself. Thank you.

  4. Jill Says:


    Could this be a typo in your methylation analysis of COMT:

    “The high activity version of MAO-A (which is represented as -/-) can contribute to major depressive disorder.”

    Shouldn’t it say “which is represented as +/+”?

    Thank you for the clarification.

  5. Anonymous Says:


    On average how many people have mutations? I have one +/+ (VDR Tag) and 6 +/- (MAO AR297R, ACAT1-02, MTHFRA1298C, MTRRA66G, BHMT-08, and CBSC699T). I also have which isn’t reported, but was reported in a different genetic test-(before I was born) 47 chromosomes, the extra being labeled as a “marker” gene. I can’t find much information on marker genes-or what they mean. I have an autism clinic and I’m hesitant to have children myself, especially with all these mutations/extra chromosome. How do I find a physician that understands what these tests mean? I feel like my rheumatologist wouldn’t be much help. I have extreme fatigue and can’t figure out why, but maybe these mutations could have something to do with it…

  6. Carol Womick Says:

    Hi anonymous,

    It sounds as if you may have unmetabolized folate floating around. Do you take folic acid supplements(not a good option) or methyfolate supplements(optimal, but build up dosages slowly)? Unfortunately, if you have MTHFR mutations, an “ok” serum b12 may not actually be indicative of your b12 status, for example, how are your CBC numbers that are indicative of b12 levels, ie, MCV? I would recommend that your Doctor run a serum MMA. This will give you more of an idea where your b12 levels are. Since you have A1298C hetero, join the relevant facebook group and the “MTHFR Gene Mutation” group. You will learn a lot there. I would suggest doing some reading about the transsulfuration pathway. I think that might help shore up BH4 levels. Also research low dose lithium orotate.

  7. Carol Womick Says:

    I would suggest talking to a geneticist or even a knowledgeable developmental pediatrician. They can run a chromosomal microarray test which may give you some answers.

  8. Amal Says:

    So i have a mutation in the mthfr C677T (heterozygous) and a mutation for mtrr A66G (heterozygous) , should i take some kind of a supplement or is it not that severe of a case ? Plzzzzz reply i seriously need to know !

  9. Chris Says:

    What about CBS downregulations? I have the I278T mutation, carrier for B6-responsive CBS homocystinuria. Taken a few years, but have found that hyperhomocysteinemia has caused multliple problems, including retinopathy, bladder cancer, spontaneous tonsillar hemhorrage. Heterozygous carriers have been found to have lower than 25% CBS enzyme than wild, which under any kind of folate or B6 deficiency or comorbidity.. i.e hypothyroidism, could basically turn on homocystinuria. They are fairly common carrier mutations..why is everyone focusing on the non-pathogenic CBS mutations?

  10. Kingston Says:

    What, specifically, are the variant codes for CBS?

    CBS is a gene, yes? It is certain configurations that alter its function, yes?

    With MTHFR we have C677T or rs1801133 and A1298C or rs1801131 which can be problematic, so what are the worrisome SNP codes for CBS, COMT, MAO, and the other variants mentioned in this post?

    If you can tell by my questions that I am using faulty thinking or missing a pertinent definable piece of the puzzle (naturally, since this is all above almost everybody’s heads, I am putting the puzzle together slowly according to my aptitude & education) I welcome corrections as I am trying to get this whole gene/nutrition/health biz into a manageable applicable set of ideas.

    Thanks you so much!

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