! These tests are not 100% accurate! Positive findings indicates predisposition only.! Results should not be interpreted as diagnostic with treatment

INTERPRETATION

! These tests are not 100% accurate! Positive findings indicates predisposition only.! Results should not be interpreted as diagnostic with treatment recommendations.

! Normal gene (-) (-)! Heterozygous Variant (-) (+)! i.e. one gene variant one normal! Homozygous (+) (+)

! COMT primarily responsible for breaking down catecholamine or excitatory neurotransmitters such as dopamine, epinephrine and norepinephrine.! Inactivates 2 & 4-hydroxyestradiols and catecholamine hormones prior to bile excretion in the liver.

! Individuals with a homozygous mutation may be unable to metabolize dopamine, epi and norepi effectively.! May be a risk factor for bipolar, panic, anxiety, obsessive compulsive disorders, eating disorders and ADHD.! Based on clinical observations, Methyl donor supplementation may increase excitatory neurotransmitters leading to hyperactivity, irritability and erratic behavior.! If COMT +/+ individuals have trouble tolerating methyl donors-> consider hydroxy B12, adenosyl B12, and/or cyano B12.! COMT V158M/H62H associated with prefrontal cortex processing, mood and pain tolerance.

! Key vitamin D receptor that binds 1, 25 di-hydroxy vitamin D to activate the key signaling molecule.! Vitamin D has an important role in approximately 30% of the human genome.! Vitamin D plays an essential role in immune activation, xenobiotic detoxification, calcium metabolism and brain development.

! Helps the liver detoxify biological and xenobiotic amines.! Encodes mitochondrial enzymes which catalyze the oxidative deamination of amines, such as dopamine, norepinephrine, and serotonin.! This gene has also been associated with a variety of disorders, including antisocial behavior, depression, aggression, anxiety and OCD behavior.

! Enzyme responsible for the conversion of 5,10- methylenetetrahydrofolate to 5-methyltetrahydrofolate.! Crucial step in the conversion of homocysteine to methionine and uses methyl B12 and methyl folate.

! The effect these have on the methylation cycle and overall health are different should not be conflated.! C677T SNP s are associated with elevated homocysteine levels.! Elevated homocysteine is a major risk factor for heart disease and neurodegenerative diseases like Alzheimer s disease.! A1298C SNP s do not lead to elevated homocysteine but may have an important role in neurotransmitter function.

! Methylation is a process of adding a methyl group to a molecule.! Methylation s roles include:! Turns on and off genes! Processes chemicals and toxins! Builds brain chemicals called neurotransmitters! Processes hormones! Builds immune cells! Synthesizes DNA and RNA! Produces energy! Produces protective coating on nerves

! When the MTHFR genes work properly, you can more efficiently make proteins, use antioxidants, metabolize hormones, enjoy more stable brain chemistry, better eliminate toxins and heavy metals, and manage inflammation.! Polymorphisms may lead to high homocysteine, which raises inflammation in the body and increases the risk of heart disease and dementia.! Synthesis of glutathione, the body s main antioxidant, becomes compromised, as does the synthesis of important brain neurotransmitters, so that depression and other brain-based disorders may arise.! Because the MTHFR gene is involved in such fundamental processes in the body, an MTHFR mutation has been associated with numerous health conditions, including an increased risk of heart attack, stroke, venous thrombosis, cancer, birth defects, inflammatory bowel disease, and mental and mood disorders.

! The effect these have on the methylation cycle and overall health are different should not be conflated.! C677T SNP s are associated with elevated homocysteine levels.! Elevated homocysteine is a major risk factor for heart disease and neurodegenerative diseases like Alzheimer s disease.

! A1298C SNP s do not lead to elevated homocysteine but may have an important role in neurotransmitter function.

! Methionine Synthase & Methionine Synthase Reductase are responsible for the regeneration of methyl B12, which is critical part of converting homocysteine to methionine.! MTRR helps to recycle B12 for use by MTR.! Mutations in this gene grouping leads to methyl group depletion as the morphed enzyme is using up B12 at a faster rate.! According to Dr. Yasko, individuals with a heterozygous variant may benefit from supplemental methyl B12 and those with a homozygous most likely will need high doses of methyl B12.

! Enzyme that transfers a methyl group from betaine to homocysteine which produces methionine which isconsidered part of the short-cut through the methylation cycle.! Found in the liver and kidney and is also involved in the choline oxidation processes.

! AHCY is an enzyme that breaks down methionine by converting S- adenosylhomocysteinase (SAH) into homocysteine.! This is a key reaction that regulates the methylation of other compounds.! Decreased activity of this enzyme may lead to lower homocysteine levels.

! CBS converts serine and homocysteine into cystothionine which is the first step of the transsulfuration pathway and it is B6 dependent and a key part of glutathione production.! CBS naturally increases with oxidative stress even without CBS mutations so may produce more sulfur end products from the methylation cycle.

! CBS SNPs lead to increased enzyme activity or upregulation! Is this necessarily harmful?! Medical research has not determined if CBS upregulations are harmful in those with syndromes or disorders leading to impaired methylation.! 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.! Dr. Yasko s caution with upregulation is that harmful byproducts, such as excess ammonia and sulfites may be produced.! In normal populations, studies have shown CBS upregulations to be protective against high homocysteine.

! It s also been claimed that increased urinary taurine and ammonia can help diagnose CBS upregulation.! While it's true that CBS upregulation can cause increased taurine and ammonia production, there s no evidence that this increased production can be detected by measuring their urinary levels.

! The transulfuration pathway begins with the CBS enzyme (which needs homocysteine and B6 to function, and culminates in Cysteine and Hydrogen Sulfide.! The transulfuration pathway is important in the maintenance of the intracellular glutathione pool.! If you have a CBS down regulations (which most are) the CBS enzyme would slow down even further with low B6 levels.! It is upregulated by high B6, high oxidative stress! The most problematic CBS are the ones that down regulate and increase homocysteine and reduce transulfuration.! Most CBS variants do not appear to effect enzyme activity significantly.

! SUOX is a mitochondrial enzyme responsible for oxidizing sulfites to sulfates. Sulfites are produced in the transsulfuration cycle and through ingestion of sulfur compounds.! Assumption: SUOX gene variants may have reduced ability to process sulfur rich foods and sulfites well and should be on lowsulfur diets.! Homozygous individuals could have severe asthma attacks. chest tightness, nausea, hives and difficulty breathing.

! SHMT catalyzes the conversion of glycine to serine which shifts the emphasis of the methylation cycle towards new DNA synthesis and away from processing homocysteine to methionine.! Mutations in this gene can interfere with the balance of the methylation cycle which may lead to elevations in homocysteine.! According to Dr. Yasko, SHMT may have a greater tendency to experience gut dysbiosis and imbalanced flora.

! This gene encodes a mitochondrially localized enzyme that catalyzes the reversible formation of acetoacetyl-coa from two molecules of acetyl-coa.

! According to Dr. Yasko, people with the SHMT and/or ACAT mutations may have a greater tendency to experience gut dysbiosis and imbalanced flora.

! CYP1A1-detoxifies polycyclic hydrocarbons e.g. exhaust fumes, charbroiled meats! CYP1A1 converts estrogens to 2- hydroxyestrogens, which are protective against breast cancer if methylated.

! CYP1B1 is involved in the 4-hydroxylation of estrogen! 4-hydroxyestrogen is a potent estrogen that may, in turn, be oxidized to carcinogenic compounds.! A polymorphism is associated with increased enzyme activity, therefore increased production of these potentially harmful metabolites.

! CYP2C19 detoxifes proton pump inhibitiors (e.g. prilosec) and many anticonvulsants (e.g valium)! CYP2D6 detoxifes ~20% of all prescription drugs including tricyclics, MAOIs, SSRIs opiates, antiarrhythmics, beta-blockers, Cimetidine, etc.

! CYP2E1 detoxifies nitrosamines and ehtanol (acetlyaldehyde).! CYP3A4 detoxifies over 50% of all prescription medications and most steroid hormones.

! Detoxifies nitrosamines and nicotine.! Nitrosamines are chemicals from certain reactions such as making bacon

! N-Acetyl Transferase detoxifes many environmental toxins, including tobacco smoke and exhaust fumes.

Slow metabolizer polymorphisms! NAT1 R64W! NAT1 R187Q! NAT2 I114T! NAT2 R197Q! NAT2 G286E! NAT2 R64QF Fast Metabolizer polymorphisms! NAT2 K266R Slow and Fast acetylators are at increased risk for toxic overload

! GSTp1 I105V! GSTp1 A114V

! Glutathione-S-transferase detoxifies water soluble environmental toxins including many solvents, herbicides, fungicides, lipid peroxides, and heavy mateals (e.g. mercury, cadmium and lead).! The various forms of GST work together to eliminate toxins.! Decreased glutathione conjugation capacity may increase toxic burden and increase oxidative stress.

! SOD is an enzyme that protects cells from increase oxidative stress and free radical damage to cell structure like membranes, mitochondria, DNA, and proteins.

! SOD2 is present in the mitochondria.! Changes in SOD enzymes are associated with changes in risk for neurodegenerateive disease like ALS

THANK YOU! WWW.PALEOBREAKTHROUGH.COM ANNE ANGELONE, MS., L.AC. PALEOBREAKTHROUGH.COM