methylation & genomics clinical applications...i tried it but i didn't feel very good -...

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Methylation & Genomics Clinical Applications

C A R O L Y N L E D O W S K Y

Brought to you by FxMed


What You’ll learn

Why is methylation important

The pathways you need to consider

The importance of Genomics and what a test

can tell you.

Where do we start? How do you put it all

together without overwhelming the patient?

Case study.


WHY IS METHYLATION SO IMPORTANT?

WHAT IS IT WE DO?

www.mthfrsupport.com.au www.mthfrsupport.com.au

MEDICINE TODAY


THE MEDICAL MODEL A C U T E C R I T I C A L M E D I C I N E I S AW E S O M E

• Chronic health issues are badly addressed:

• No diet is discussed – that’s not what we do

• 15 minutes to decide – do I refer or give a drug?

• Often both - no time to do anything else


SO HOW IS NATURAL MEDICINE DIFFERENT?

• We endeavour to peel back the layers

We address gut We address lifestyle We give supplements We often still give labels to conditions But do our patients always get better? Are we seeing patients that are sicker and

sicker? What makes one person get better when

someone else doesn’t?


THE MODEL I WANT YOU TO THINK ABOUT?

• What is the genetic susceptibility to disease and detoxification issues?

• How do I plug the hole before I move forward?

• Epigenetics is what is key: Our environment puts epigenetic marks on

our DNA and affects the way they act The exciting thing is that this is reversible

(mostly)


SO THINK OF IT LIKE THIS • You are driving down a

freeway with pot holes, your car is constantly getting damaged.

• It doesn’t seem to matter how many times you change the tyres or fix the suspension or change the brake fluid the car continues to get damaged.

• But if you plug up the potholes and the conditions are good, mostly we cope pretty well if we look after the car.


That’s why some people respond initially to your

treatment and others don’t


THE CELL DANGER RESPONSE THEORY


WHAT IS CELL DANGER RESPONSE THEORY

C D R I S T H E E V O L U T I O N A R I LY C O N S E R V E D M E TA B O L I C R E S P O N S E T H AT P R O T E C T S C E L L S A N D H O S T S F R O M H A R M

• Triggered threats exceeding homeostasis

Chemical factors

Physical factors

Biological factors

https://www.ncbi.nlm.nih.gov/pubmed/?term=23981537




PROCEDURES OF CELL DANGER RESPONSE

• Involved biological processes: redox, membrane fluidity, lipid dynamics, one-carbon & sulfur, metal homeostasis, indole, and pterin metabolism

• Involved components: ATP & ADP, TCA cycle intermediates, oxygen, reactive oxygen species (ROS), vitamins & nutrients, SAMe, and purinergic signaling


DANGER ELIMINATED

• Metabolism and the gut microbiome are disturbed • Multiple organ systems are impaired • Behaviours are changed • Chronic diseases will result

DANGER PERSISTS



EXAMPLES OF CELL DANGER

RESPONSE

• Chemical: heavy and trace metals, electrophilic aromatic chemicals, brominated diphenyl ethers (BDEs), and pesticides

• Physical: heat, salt, pH shock, UV and ionizing radiation • Microbial: viruses, bacteria, fungi and parasites • Psychological: trauma particularly during childhood

Prolonged CDR causes altered organ functions and behaviours leading to inflammation and chronic diseases • Chronic infection • Neurological diseases • Autoimmune diseases


DANGEROUS THREATS



THE CELL DANGER RESPONSE



www.mthfrsupport.com.au www.mthfrsupport.com.au https://www.ncbi.nlm.nih.gov/pubmed/?term=23981537



CELL DANGER RESPONSES • Folate & B12 is interconnected with mitochondrial functions

• Methylmalonyl CoA mutase uses adenosyl B12 to convert methylmalonyl-CoA to succinyl-CoA and enter TCA cycle

• Methionine uses methyl B12 to synthesize methionine from homocysteine

• Methionine is used as a precursor for SAM (S-adenosyl methionine) synthesis; folate, glutathione, and methionine metabolism are determined by cellular redox functioning

• CDR directs SAM preferentially to polyamine synthesis to assist with ROS (reactive oxygen species); and antiviral and antimicrobial polyamine aldehyde synthesis

• CDR increases the ratio of formyl-tetrahydrofolate to methyl-tetrahydrofolate (fTHF/mTHF) and the ratio of methylene-THF to mTHF




CELL DANGER RESPONSE AND CHRONIC DISEASES

• Sulphur Sulfur metabolism is shifted to glutathione; and cysteine is diverted to

H2S, taurine, and sulfate excretion CDR favours cysteine oxidation to cysteine used to transport cysteine to

the brain, and into macrophages for glutathione synthesis

• ROS (reactive oxygen species) CDR activates ROS production by many enzyme systems The balance between ROS generation and elimination is disturbed

leading to ‘oxidative stress” which leads to chronic disease - rheumatoid arthritis, multiple sclerosis, thyroiditis, and type 1 diabetes

• LPS (lipopolysaccharide) Bacterial infection releases LPS and TNFα implicated in the progressive

nature of neurodegenerative diseases, such as Parkinson's disease LPS increases expression of brain pro-inflammatory factors and disturbs

methylation

https://www.ncbi.nlm.nih.gov/pubmed/?term=23981537+20959147 https://www.ncbi.nlm.nih.gov/pubmed/?term=PMC2871685

https://www.ncbi.nlm.nih.gov/pubmed/?term=23981537+20959147

https://www.ncbi.nlm.nih.gov/pubmed/?term=23981537+20959147

https://www.ncbi.nlm.nih.gov/pubmed/?term=PMC2871685

https://www.ncbi.nlm.nih.gov/pubmed/?term=PMC2871685


INFECTION UNDER CELL DANGER RESPONSE

• Microbial pathogens like viruses cause CDR shifting metabolism to trigger innate immunity, inflammation and oxidizing conditions to oppose the pathogens

• CDR causes disturbances in SAMe levels, methylation, and neurological conditions

• Mitochondria react by detecting change in electrons NADH/NADPH to decrease RNA, protein, and DNA synthesis in the viruses

• Changes in the sulphur balance affects: methionine, and thiols like cysteine, homocysteine, and glutathione; and the disassembly of iron–sulfur clusters

• We see an activation of ROS production, which causes changes in many metabolic pathways




WHAT DOES METHYLATION DO? • Turns genes on and off: gene

regulation

• Repairs and builds DNA & RNA: thymine aka 5-methyluracil

• Reduces the ageing process (protects telomeres)

• Detoxifies chemicals & heavy metals: biotransformation

• Processes hormones : oestrogen

• Builds immune cells- T or B cells, NK cells

• Turns the stress response on/off

• Provides us with energy: CoQ10, carnitine & ATP

• Reduces histamine

• Repairs cell membranes and produces myelination of nerves

• Supports neurotransmitters to prevent depression, anxiety, insomnia and help brain function




CONDITIONS ASSOCIATED WITH A LACK OF METHYLATION

• ADD/ADHD • Addictive Behaviour • Allergic conditions • Ageing • Anorexia • Alzheimer’s Disease • Anxiety • Asthma • Autism • Autoimmune disease • Bipolar • Bulimia • Cancer • Chronic degenerative

diseases • Cardiovascular disease

• Chronic fatigue • Cleft palate • Diabetes • Down’s Syndrome • Delusions • Depression • Poor detoxification • Fibromyalgia • Headaches • Infertility • Joint stiffness, pain

swelling • Insomnia • Muscle pains • Low neurotransmitters • Obesity

• Obsessive compulsive disorders

• Oppositional defiant disorder

• Pain • Phobias • PCOS • Psychosis • Schizophrenia • Recurrent pregnancy

loss/ miscarriage • Thyroid dysfunction


THINGS THAT AFFECT METHYLATION

Environmental toxins e.g. pollution & bisphenol

A

Chemicals & heavy metals e.g. lead, mercury

Stress

both mental and physical

Ageing

Excessive exercise Medications e.g. antacids, methotrexate Diet Alcohol Microbes: virus, bacteria, yeast etc

Methylation: The molecule that unlocks the Body's healing Response. Dr Jack Tips .


Methylation


SO THE ENVIRONMENT MATTERS


So take a step back and look at the big picture


OUR APPROACH SHOULD BE: • A thorough case history

Genetic susceptibility gives you a clue- ask what diseases are in the family on both sides, grandparents, parents, siblings

What job did/do they do? Environment is key!

What bloods do you have?

MTHFR Gene mutation results?

Organic Acids – lots to tell us

Genetic Testing


KEY PATHWAYS


Methylation


First question you get asked? So what does the MTHFR gene mean for me?


First question you get asked? So what does the MTHFR gene mutation mean?

• It’s a gene that makes an enzyme that makes an active folate. This active folate is called a methyl group

• This methyl group think of as a master on/off switch for major metabolic processes like:

Hormone (particularly oestrogen) metabolism Liver function & detoxification (GSH production) Protein Synthesis DNA Neurotransmitter function so you can make brain chemicals Phosphatidylcholine production, energy production


Other questions around folate?

• So what’s the best form of folate for me?

• What are the side effects of folate?

• I tried it but I didn't feel very good - Why?

• I tried it but I felt worse - Why?

• Why won’t my Dr test for this?

• Why don’t Dr’s know about this?

• How come I’ve always had this gene but its only affecting me now?


Second question you get asked? What about CBS?


Second question you get asked? What about CBS?

• Should I take B6?

• Is my ammonia high?

• Do I have a problem with sulphur?

• How do I know if my glutathione is low. Should I be taking it now?

• What's the ideal level of homocysteine?

• I’ve read that I shouldn’t take methyl folate until this cycle is sorted. Is that true?


Third question you get asked? How do I know if I have the COMT gene?


Third question you get asked? How do I know if I have the COMT gene?

• What is COMT ++?

• What does it mean?

• Why does it affect how much folate I take?

• Why do I get anxiety?

• Why do I get depression?

• How is pyrroluria connected to MTHFR and is there a connection?


CASE STUDY 1


Let me give you an example?

• 51 year old female

• Acute anxiety

• Fibrocystic breasts

• Food intolerances – puffy eyes constantly

• Thinning hair

• Tinnitus

• Gut issues – feels like she’s not digesting food, burning pain like it was burning a hole in her gut

• Lymphatic's feel full, pressure feeling


Current symptoms

• Anxiety ++++ • Low energy • Gut – nausea, reflux, burning, appetite loss, weight loss,

bowels ok • Sleep – wakes every 3 hours, wakes unrefreshed • Hormones – partial hysterectomy, heavy bleeding,

painful periods, pain, mood issues • Post Natal depression • Headaches, migraines, vision, light sensitivity, dizziness,

eyestrain, light sensitivity, itchy eyes, swollen puffy eyes


Family history

• Mother – depression, reflux, blood pressure, vertigo

• Father – depression, reflux

• Grandmother – fibrocystic breasts, thyroid

• Grandfather – heart issues, stroke

• Siblings – depression, schizophrenia


Let me give you an example?

Can’t take any supplements without a headache • SAMe gave her a headache • Molybdenum 150mcg gave her a headache • Quercetin headache • Homeopathic Ginseng gave her a headache • Feeling of lymphatic stagnation • All started she thinks with a clay product to reduce histamine

which was ok but when she stopped that’s when the puffy eyes, headaches and anxiety started.

• Dandelion tea made her feel acidic and a consistent pain on top right hand of stomach. With this burning came the anxiety and mood issues.


Bloods and tests

• Morning cortisol low, midday high and afternoon low


Bloods and tests • Iodine 59

• Serum B12 439

• Active B12 128

• Folate was 45.2,

• RBC folate 1370

• Vitamin D 73

• eGFR 76

• Anion Gap 13

• ALT 28

• GGT 7

• ALP 54

• MCV 95

• WCC 7.1

• Cholesterol 7.9

• TSH 1.81

• B6 460 (20-190)

• Selenium 1.9 (.7-1.4)

• Gall Bladder Sludge

• Histamine .9

• Homocysteine 9.1

• Copper 13

• Zinc 9.5

• Glucose 4.3

• Iron 21.2

• Saturation 41

• Ferritin 141


Key Genetic SNP's

• CYP 1A2 ++ • CYP 1B1 ++, ++ • CYP 2B6 ++ • CYP 2C19 ++, ++ • CYP 2C9 ++, ++, ++ • CYP3A4 ++ • SOD3 ++ • PON1 +- • ABP/DAO +- All • ADA ++ • AHCY ++

• GSTP1 ++ • HNMT ++ • MTHFD1 ++ • ALDH2 ++ • CBS C699T ++ • CTH +- all • MAT +- all • MTR ++ many • MTRR +- All


Key Genetic SNP's

• NOS 1 ++

• PEMT ++

• TCN1 ++

• PAH ++

• SOD2 ++

• BDNF ++

• TOMM40++

• HLA ++

• BCOM01++

• AANAT ++

• ANK ++

• COMT +-

• DBH, DDC, DRD2 Many

• GCH1 ++

• MTHFR Compound heterozygous


Genetic Testing


The first thing she says to me?

• I’m terrified about what you are going to tell me?

Been told she has heavy metal toxicity (Hair mineral analysis) and needs to detoxify……. She doesn’t want to

She’s been told because she has CBS she needs lots of B6. She doesn’t feel good on lots of B6 and anyway its high

She’s scared of cancer

She’s terrified of everything - absolute nervous wreck

Jumped around many practitioners because she’s scared of what she’s being told


So what’s the first thing we do? • Put the jigsaw pieces together

• Thorough health history; Family health important. Gives good clues to her

susceptibility. Mentally - Brother has schizophrenia, mother has depression. Genes? DMGDH, HNMT, BDNF, DBH, DRD2, DRD3, GCH1, ANKK1++

Autoimmune – mother has psoriasis, she has a history of Asthma

GUT – FUT2/BHMT +-, use of proton pump inhibitors/ affected by all supplements/Gall bladder insufficiency. Gut upset her. Oxalates? Probably

History of allergies/ HNMT/DAO SNP’s all homozygous


What is happening to me? • Gut key issue

It started with the gut

Been on proton pump inhibitors

Can’t break down red meat, food feels like its sitting in the gut?

B12 has reduced – MTR/MTRR SNP’s

Can’t cope with any supplements

• B6 is the clue - not absorbing

• History of iron issues

• History of low zinc


What is happening to me?

• Gut key issue

She’s in desperate need of digestive enzymes

• HCL

• Pancreatic enzymes

• Ox bile

Referred for Stool test


Biogenic amine production

http://susfood-db-era.net/drupal/sites/default/files/Postings/Toxicological%20effects%20of%20Dietary%20amines.pdf


What is happening to me? • Issues She has bugs that are increasing histamine levels in the gut

She has genetic susceptibility to having histamine issues i.e.: ABP/DAO and HNMT

She has lots of detoxification susceptibility – GSH deletion, CYP’s/ SOD2/PON1/MTHFR/

She’s eating a diet full of histamine – went paleo – nuts, chocolate, chilli, soy, spinach etc

Histamine is a neurotransmitter and can also influence oestrogen. She has all the oestrogen susceptibility genes: CYP1B1, CYP2C19, MTHFR, COMT

Plus the PPI’s reduced B12 essential for methylation



• Genetic susceptibility to histamine issues?

Histamine is a cause of allergies

Histamine causes gut pain/loose stools

Histamine causes period pain

Histamine is a neurotransmitter so will cause sleep disturbances, anxiety and mood disturbances

Gut bacteria are increasing her histamine intolerance

Symptoms of histamines toxic effects: headaches, sweating, facial flushing, dizziness, oedema (eyelids), respiratory distress, bronchospasm, increased cardiac output, tachycardia, blood pressure

http://susfood-db-era.net/drupal/sites/default/files/Postings/Toxicological%20effects%20of%20Dietary%20amines.pdf



• Tyramines main producers are enterococcus and lactobacillus and particularly gram negative bacteria enterobactericea

An excess of tyramine in the GIT (which cannot be quickly detoxified by MAO’s) can lead to its entering the systemic circulation and cause the functional impairment of sympathetic nerve transmission and result in an increase of norepinephrine

Tyramine can also cause the increase in pathogenic E coli

Raised tyramine in the brain have been associated with Schizophrenia, Parkinson's disease, Depression and Reyes syndrome



• Elevated E coli - may be contributing to her symptoms

Gut pain

Pain in abdomen

Inflammation of lung tissue

Inflammation of the brain

Inflammation of joints

Kidney dysfunction at the extreme

http://www.about-ecoli.com/non_o157_STEC#.WKjslBJ95gc, http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(83)91987-6/abstract

http://www.about-ecoli.com/non_o157_STEC





Histamine related SNP functions

SNP ID SNP Name Risk Allele Allele Effect

rs10156191 ABP1/DAO +- Increased risk of migraine in women Increased risk of higher histamine in blood Reduced DAO activities

rs1049793 ABP1/DAO +- Increased hypersensitivity to non-steroidal anti-inflammatory drugs Decreased DAO activity

http://www.ncbi.nlm.nih.gov/pubmed/?term=25612138+23152756+21488903,

http://www.ncbi.nlm.nih.gov/pubmed/?term=22042713+19164089+25828809,

http://www.ncbi.nlm.nih.gov/pubmed/?term=25403981+25848305+25313998+23697560

http://www.ncbi.nlm.nih.gov/pubmed/?term=23152756


Histamine related SNP functions

SNP ID SNP Name Risk Allele Allele Effect

rs1050891 HNMT G Increased risk in aspirin adverse effect, but no differences between Asians and Europeans Not affecting risk of asthma

rs1801105 HNMT T Association with Asthma. 50% reduction in HNMT activity

Rs758252808 HNMT A Mental Retardation (complete loss of function)

rs1799836 MAOB +-

Increased risk of autism in males Increased risk of Parkinson’s disease by meta-analysis Increased risk of schizophrenia in females Increased risk of ADHD in Asians

http://www.ncbi.nlm.nih.gov/pubmed/?term=27143073+21040557 http://www.ncbi.nlm.nih.gov/pubmed/?term=27399132+19773194 http://www.ncbi.nlm.nih.gov/pubmed/?term=27381555+25066260+23738213+17918234+17427196 https://www.ncbi.nlm.nih.gov/pubmed/26206890


Her Susceptibility

• So genetically not so much however the GUT has influenced her DAO and possibly MAO activity

• The Gut has affected her neurological function and increased anxiety and decreased mood

• BDNF activity in the hippocampus and amygdala are affected by gut bacteria. She is BDNF ++

• Low BDNF levels have been found in patients with depression, schizophrenia, anxiety and borderline personality disorder

• BDNF methylation plays critical roles in regulating gene transcription in response to neuronal activity

http://www.nature.com/nrn/journal/v13/n10/full/nrn3346.html, https://www.ncbi.nlm.nih.gov/pubmed/27267954

http://www.nature.com/nrn/journal/v13/n10/full/nrn3346.html




What do my genetics tell me?

• PAH 1522305 increased risk of schizophrenia

https://www.researchgate.net/profile/Ahmet_Korkmaz4/publication/23232363_Biogenic_amines_in_the_reduction_of_oxidative_stress_ Melatonin_and_its_metabolites/links/572c29e908ae057b0a095c11.pdf



• She has a susceptibility to oestrogen metabolism issues

History of very heavy flooding periods

Terrible mood disturbances

Sore breasts

Clotting

Partial hysterectomy

Oestrogen and histamine work in unison.

Previous practitioner referred for Oestrogen metabolism test – good move


Oestrogen Metabolism


Liver function is key

• Key SNPS

CYP’s

GSTP1

SOD2

SOD3

GSS +- all

COMT +-

This is the key reason why you are so chemically sensitive.

Your homocysteine is elevated and you are avoiding all B6 = no cysteine

But should she detoxify? THE ANSWER IS NO!!!!!!!


Liver



• She has a susceptibility to mood disturbances:

Mother has depression

Brother has schizophrenia

Primarily this is an issue with your choline pathway. You can see that betaine hydrochloride is a key supporter of this pathway and zinc and B2 are major cofactors. Your zinc is low and you are not taking any B’s and your HCl is low. Why did the clay cause such issues? Probably bound to too many nutrients and eliminated them.

Inflammation in the brain? Reduced antioxidants due to decreased melatonin

https://www.researchgate.net/profile/Ahmet_Korkmaz4/publication/23232363_Biogenic_amines_in_the_reduction_of_oxidative_stress_ Melatonin_and_its_metabolites/links/572c29e908ae057b0a095c11.pdf

https://www.researchgate.net/profile/Ahmet_Korkmaz4/publication/23232363_Biogenic_amines_in_the_reduction_of_oxidative_stress_

https://www.researchgate.net/profile/Ahmet_Korkmaz4/publication/23232363_Biogenic_amines_in_the_reduction_of_oxidative_stress_


Step 1

So with so many symptoms going on where do you start?


Step 1 – Address the gut

• Reduce dysbiotic bacteria

• Support with probiotics- Lactobacillus Fermentum ME3

• She has CBS C699T so ammonia may be a major issue for her especially with die off. Consider:

Alpha ketoglutarate

Acetyl L carnitine (watch thyroid)

Perhaps Charcoal? She wont go near the clay product

Digestive enzymes – HCL, pancreatic, ox bile. All required


• Vagal nerve exercises to improve communication to the brain

Gargling with water several times per day

Sing loudly – it works the muscles in the back of the throat to activate the vagus

Gag – tongue blades to stimulate their gag reflex throughout the day

Consider coffee enemas

Step 1 – Address the gut


Step 1

• Diet Low histamine – very strict

Watch oxalates

Gluten free absolutely no questions

Dairy free – due to brain involvement


Step 1

• Balance Key Nutrients B6 – Lysine connection?

Zinc/Copper

Supporting B’s

B12


Step 1

• Help sleep/ Stress and Brain inflammation

Melatonin

Magnesium – with someone so acute be careful with glycine. Citrate is probably better. Start with 150mg 3 x day rather than a big dose - perhaps put in a water bottle


Step 2


Step 2

• Try to help reduce brain inflammation:

Definitely don’t do heavy metal chelation if a leaky blood brain barrier

Consider resveratrol, rutin, curcumin, baicalein, green tea, gingko – maybe even drop doses

Definitely support BDNF levels

• Ketogenic diet • Fish oil • Resistant starch like PHGG • Melatonin • Turmeric


Step 2

Liver is an important next step

• Support GSH regeneration, Zinc, Se, NAC

• Glutathione only when the above is addressed

• 16OH oestrogen must be reduced as this is contributing to anxiety


Step 2

• Assess neurotransmitters

Major issues with Dopamine Receptors – check dopamine levels

If low support with dopamine raising nutrients

• Rhodiola • Green tea • Mucuna pruriens • Acetyl L tyrosine • B6/Zinc • SAMe/Folate??


Ongoing

Next steps:

• Keep an eye on iodine. T4 low/ T3 low. So she may need more B2 if she can tolerate. Acetyl L tyrosine may assist.

• Previous results manganese low. Will affect SOD

• eGFR 76 – is oxalates an issue?

• Vitamin D 85 – keep an eye on it. Vitamin D supports dopamine synthesis


So what on earth do we tell her?


CASE STUDY 2


• 32 year old male Weight 71kg Height 180cm BMI 21.9

• Family HX: F: 62, pretty good health, slightly overweight, high BP and cholesterol M: 60 Healthy

Case Study 2


• Shingles • Broken arm, football injuries • Stitches in forehead from being punched • Stitches around right eye socket from being

struck by cricket bat • Nasal surgery • Xrays • Brain MRI

Medical History


• Drug Use: Heavy marijuana and recreational drug use between the ages of 15-25

• Major depression, social anxiety

• Presenting symptoms All S/S started around 10 years ago, worse in last 2 years Major depression Social Anxiety Mental Exhaustion, sadness, unable to focus/complete tasks/read Brain fog Physical and Mental Exhaustion Poor Memory Lack of will power/drive and determination

Medical History/ Current Symptoms


• Presenting symptoms Negative thoughts and emotions Confusion, loneliness/social isolation/self loathing, over sleeping –

especially when depressed

• Energy – worst first thing in the morning

• Diet Breakfast – muesli, almond milk, coconut oil, honey and fruit Lunch – sandwich or roll with ham and salad Dinner – meat and vegetables Snacks – nuts, fruit, muesli bars and chocolate Drinks – water, coconut water and herbal tea No caffeine or alcohol Craves sugar, chocolate and ice-cream

Current Symptoms / Diet


• Urinary Pyrroles – 35.6

• Bloods: Histamine .8 Serum copper 13 Zinc 10.3 MCV 90 Neutrophils low Anion gap 19 Creatinine 59 DHEAs 5.7 Serum B12 664 - supplemented Folate 39.7 - supplemented Vitamin D 129 TSH 2.13, fT4 19.5, fT3 4.7, no

antibodies

Bloods and tests

sIGE 124 (High) Fasting Insulin 6.9


• High secretory IGA • Low diversity Index • Low butyrate • High beta glucuronidase • High E Coli and bacteroides • High Gamma hemolytic Strep • Low Butyrate producing bacteria

Gut Results


Genetic testing: CYP1A2*1F +/- L432 +/+ N453 +/+ PON1 +/- A1298C +/- C677T -/- but many MTHFR +/- MTHFS +/- MTHFD1 -/- MTR/MTRR +/- PEMT +/+ CBS +/-

B12 MMAB +/+ MUT +/- FUT2 +/+ TCN1 +/+ TCN2 +/- COMT V158 -/- DBH +/+ DRD1 +/+ DRD2 +/+ and +/- MAO + GAD some +/+

Genetics


LETS LOOK AT HIS SUSCEPTIBILITY !!


ALL OCCURS INSIDE THE CELL…


Genetic testing: CYP1A2*1F +/- PON1 +/- A1298C +/- C677T -/- but many MTHFR +/- MTHFS +/- MTHFD1 -/- MTR/MTRR +/- PEMT +/+ CBS +/-

B12 MMAB +/+ MUT +/- FUT2 +/+ TCN1 +/+ TCN2 +/- COMT V158 -/- DBH +/+ DRD1 +/+ DRD2 +/+ and +/- MAO + GAD some +/+

SUSCEPTIBILITY ***


OESTROGEN METABOLISM 1056827 AA= increased enzyme activity

1056836 = increased enzyme activity

10012 = CC =fast

Remember that SULT’s are inhibited by yeasts/phenols/ glyphosate

COMT works with the above in metabolising oestrogens COMT - - higher activity


SLOW DOWN CYP1B1 These decrease CYP1B1: St John’s Wort Apigenin Ginseng Lycopene a red pigment found in tomatoes, carrots, and watermelon Chrysoeriol present in rooibos tea and celery Naringenin found in grapefruit juice Herbs - a polyherbal formulation produced from the extracts of ten common herbs (rosemary, turmeric, ginger, holy basil, green tea, hu zhang, Chinese goldthread, barberry, oregano, and Baikal skullcap) Quercetin

These herbs were shown to reduce PAH upregulation of CYP 1B1

http://dmd.aspetjournals.org/content/30/4/378, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3324618/,

http://dmd.aspetjournals.org/content/30/4/378



https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3324618/




DECREASE OF CYP FURTHER These increase CYP1B1:

Diesel exhaust particles (DEP)

Tetrahydrocannabinol (THC) found in cannabis

UV exposure

Biotin supplementation

PAH’s

https://www.ncbi.nlm.nih.gov/pubmed/15333708


B12

He needs adenosylcobalamin **** without this his energy cycle will be depleted


PEMT AND CHOLINE

PEMT and MTHFD1 support choline for brain function, phospholipid support, cellular membrane health . This will be

worse if low methyl’s because PEMT and BHMT are methyltransferases.


FOLATE AND MOOD


MOOD

FOLR2 is responsible for bringing folate into the cell. Folic Acid preferentially binds to this receptor. MTHFD1 is key in folate

regeneration and THF , 5, 10 methyleneTHF levels


MOOD


MOOD

NEUROTRANSMITTERS ALL HAVE THE POTENTIAL TO BE LOW! ! !

COMT associated with failure to experience pleasure, major depressive disorder, all about the sensation of reward.

Important in the choline pathway. B2 Dependent.

X linked so only 1 copy for Males. G allele of the 6323 is 75% faster than the normal.


MAO A is fast. So is he losing serotonin? is ALDH2 slow and that’s causing a build up of serotonin?


MAO A is fast. So is he losing serotonin?, is ALDH2 slow and that’s causing a build up of serotonin?.

Ben Lynch StrateGene


GUT

FUT2 INFLUENCES WHAT LIVES IN YOUR GUT.

1. SECRETOR VS NON SECRETOR – influences 2’FL which affects how the bacteria attach to the gut wall. (2’fucosyllactose)

2. ++ = non secretor. Research tells us they are more likely to have Crohns and leaky gut but less likely to have H.Pylori.

3. ++ more likely to be deficient in 2’FL prebiotic. Which means that they can’t produce this on the lining of the gut.

4. Often lacking in Bifidobacterial species.

5. FUT2 feeds the bacterial in our gut that produce amino acids like tyrosine, tryptophan and lysine. ***********

6. Further affected by Glyphosate

7. FUT2 genes help us have lysine and lysine is required for the absorption of B6.


GUT

AGT/AGXT – CRUCIAL IN OXALATE BREAKDOWN


GUT

CHOLINE PATHWAY – NEEDS BETAINE HYDROCHLORIDE


DETOX


SO WHAT’S HAPPENING NOW? THE BIOCHEMISTRY!


Blood tests


• WCC 4.2 – low Ideal 5-7- Inflammation? Adrenals? Intestinal Parasites?

multiple food allergies?

• Neutrophils 1.3 – low Ideal 4-6 – chronic viral infection? He did have shingles Perhaps low Vitamin B12, B6 and or folate? Adrenals? Anterior Pituitary? Food allergies? Intestinal

Parasites?

• MCV – 90 ok but I would like it lower than 89. May indicate B12/folate deficiency

• Anion GAP 19.1 – very high. Perhaps low B1 and/or acidosis (yeast reduces B1)

Blood tests – our case


• Liver enzymes ok – GGT 17, ALT 18, AST 23

• ALP – 45. Low (zinc dependent)

• Protein ok

• Albumin ok

• Globulin – 30 (Ideal 24-28) Elevated Globulin may mean:

Low HCL Oxidative stress, Inflammation Heavy metals Immune activation (he has elevated sIGA) Viral/Bacterial infections



• Iron ok

• Hormones ok

• Folate 39.7 good but is supplemented

• B12 664 from 1205 supplemented and was 395 in 2013

• Vitamin D 129

• CRP .3

• TSH is improving

• Homocysteine 6 – low end (ideal 7-8)

• Pyrroles 35.6 (B6, lysine, shingles connection / Oxalates?



A WORD ON B1 - THIAMINE • Sulphur dioxide and sulphite destroy B1

• Functions increasing demand: Diabetes, diarrhoea, eating disorders, excessive coffee, tea,

alcohol, raw fish and sugar intake. Excessive intake of refined food, smoking

Folate deficiency Formaldehyde exposure- YEAST and alcholol?? GIT surgery, gastritis Hyperemesis gravidarum Infections with Bacillus thiaminolyticus Lead poisoning Hyperthyroid disease

The Nutrient Bible, 9th Edition. Henry Osiecki, AG Publishing



• Thiamine is required for: Acetyl choline synthesis –HE HAS A SUSCEPTIBILITY HERE

Appetite, sugar metabolism

Facilitates that conversion of pyruvate to acetyl CoA within the mitochondria

Converts alpha keto acids to acyl ions, aldehydes and carboxylic acid

Cofactor of the hexose mono phosphate shunt – use by adrenals, leucocytes, RBC’S and breast tissue

Central and peripheral nerve cell function

Digestion

Energy production

Gastrointestinal tone

Myocardial function, neurotransmission

Neutrophil motility


A WORD ON B1 - THIAMINE • Its active form:

Modulates the activity of Nitric oxide synthase

Decreases LPS in the microglia

It remodels activated microglia to acquire the shape it needs to stop stimulation of glial cells

Decreases production of pro-inflammatory mediators like iNOS and NO, Cox2, heat shock protein, TNFa, IL6

Increases anti-inflammatory IL10 in LPS stimulated microglia

http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0118372




A WORD ON B1 - THIAMINE • Decreased by:

Antibiotics – cephalosporins, fluoroquinolones, quinolones, penicillins , sulfonamides, tetracyclines, trimethoprin containing antibiotics, monobactams, streptogramins, vancomycin etc

Oral contraceptives

Other drugs – phenytoin, caffeic acid, 5 fluorouracil, insulin

Acetylaldehyde



GUT • Pancreatic elastase low

• Faecal secretory IGA 334 – High

• Prevotella elevated (Bacteroidetes Phylum)

• Firmuctes Phyllum Lactobacillus low (no growth in Culture) Pseudoflavonifractor spp elevated Ruminococcus low

• E. Coli elevated – increased by stress (Gram Negative – will increase LPS)

• Has parasite – Blastocystis hominis


NUTREVAL


HE’S SUSCEPTIBLE AND HE MAY HAVE BUGS THAT MAKE THIS WORSE


Elevated level may be B1 deficiency

Elevation due to def’y in B1,2,3,5 and ALA

Especially thiamine.


INHIBITION OF METHYLATION • LPS

MAT1A

eNOS – eNOS uncoupling = increase ADMA, oxidised GSH, decreased 5-MTHF, deceased BH4, decreased arginine

Induces iNOS

• ACETYLALDEHYDE FROM YEAST (MeCHO)

MTR

ALDH

ADH


PRESCRIPTION I N I T I A L P R E S C R I P T I O N :

• Hydroxy B12 injections – one every 10 days x 6

• Then Hydroxy/adenosyl 2000mcg every day in AM

• SAMe 1200mg per day

• Phospholipid complex twice a day

• 5HTP 100mg a day

• Phosphatidylserine to reduce anxiety – 2 BD

• Alkalising powder – 1 scoop BD

• GOS support – once a day

• Betaine Hydrochloride support with meals

• Probiotics with meals


PRESCRIPTION • B Vitamin without B12 or folate

B1,2,3,5,6 formula

Pyrrole formula – Pyridoxine, P5P, Vitamin E, Selenium, Zinc, Ascorbic acid

• Herbs to support Dopamine and mood – 7.5ml bd for 8 weeks.

Rhodiola Saffron St Marys thistle Clove


PRESCRIPTION • Exercise Minimum of 30 minutes per day where he would

break into a sweat Ended up doing F45 3/7, surfing 3/7, yoga 1/7

• Circadian rhythm Had to be up by 7am on his way to exercise Changed bedtime from 1am to 11pm at first visit Banned all smart devices by 9pm. Then brought

bed time down to 10-11pm

A D D I T I O N A L W O R K I N C L U D E D :


PRESCRIPTION • Diet Major component of protocol, GF wholefoods

and high prebiotic diet

Low carb, high protein breakfast with whey based smoothie and mixture of prebiotic foods added

Cut out all bread and flour based products – gradually replaced with beans and lentils and unmilled grains (quinoa, buckwheat, coloured rice)



PRESCRIPTION • Psychological Work Previously been to see many psychologists and

had done many therapies including ECT with no results

During initial consult it was clear that he had childhood issues relating to his father – high achiever, successful businessman with poor communication skills and low levels of emotional intelligence

Referred him to a schema therapy practitioner



PRESCRIPTION S E C O N D P R E S C R I P T I O N

Replaced the phospholipid complex with Liposomal

Phosphatidylcholine 700mg day

CUT OUT 5HTP


PRESCRIPTION T H I R D P R E S C R I P T I O N

NAC and glutathione NOW LOOKING AT REDUCING THE SAMe

RESULTS • Patient experienced complete turnaround within 1 week to 10

days of starting full protocol - Depression lifted completely

• Anxiety lingered another 6 weeks until phos serine was introduced

• He has now regained a fully productive life, both socially and professionally


PRESCRIPTION N E X T S T E P S

Reduce SAMe Incorporate methyl Folate, Tyrosine and slow COMT gene ie: Quercetin, Green

tea, Rhodiola Address GUT if need be


THANK YOU & Questions J O I N O U R P R A C T I T I O N E R

M e m b e r s h i p G R O U P

MTHFR Support Australia

Tel: +61 2 9908 1888 [email protected] www.mthfrsupport.com.au

Copyright MTHFR Support Australia 2108. All rights reserved. This document may not be copied or Distributed without the prior written permission of Carolyn Ledowsky

methylation & genomics clinical applications...i tried it but i didn't feel very good -...

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