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THE BIOCHEMISTRY OF DOWN SYNDROME:

OPPORTUNITIES FOR INTERVENTION

KENT MACLEOD, B.SC.PHM. NUTRICHEM"

OBJECTIVES •  Review research on supplements & Down

syndrome •  Discuss oxidative stress & the role of

antioxidants •  Describe methylation: what it is & why it’s

relevant to Down syndrome and Autism •  Recognize genetic problems with folic acid

metabolism •  Identify nutritional interventions •  Discuss drug interventions

WHERE ARE WE IN 2013? 4TH GENERATION OF SUPPLEMENTS

•  Lejeune; Dr. Turkel’s “U series” – 1st generation

•  Ruth Harrell; Peeters; Lejeune; Many researchers – 2nd generation

•  MSB Plus - 3rd generation; integrating work of multiple researchers – oxidative stress

•  MSB Plus Methyl Support – 4th generation

4TH GENERATION DOWN SYNDROME INTERVENTIONS

Thyroid

Gastrointestinal Health • Check for Celiac/gluten sensitivity

Antioxidants • Measure individual levels

Insulin •  Assess protein and

carbohydrate intake

Micronutrients •  Vitamin D •  Iron (Ferritin)

Neurotransmitters •  Administer amino acids after

consultation

ATP/Mitochondrial Support • Creatine, Mg2+, CoQ10 • Organic acid assessment

Down Syndrome

Interventions

MethylationàB12 •  Detect MTHRF mutation

WHY ARE WE IN THE 4TH GENERATION?

•  Better understanding of the relationship of oxidative stress

•  Methylation •  Mitochondrial function •  Neurotransmitters •  Serious shortcomings of previous IQ

research •  Relationship of Down Syndrome/Autism

REVIEW OF PREVIOUS GENERATION’S NUTRITIONAL INVESTIGATIONS

•  As of 2013, every single vitamin and mineral has been investigated

•  There are depletions or disturbances in virtually all of them, compared to controls

•  Overwhelming evidence for some e.g. zinc

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DIETARY DEFICIENCIES IN DOWN SYNDROME

•  Vitamins A, C, E •  Thiamine •  Calcium, iron, zinc •  Vitamin D !!J Am Diet Assoc (1996) 96: 1262 J Am Diet Assoc (1976) 69: 152

SERUM ALTERATIONS IN DOWN SYNDROME

•  Vitamins A, B6, E •  Folic acid •  Selenium, zinc, amino acids !!J Ment Def Res (88) 32:169 J Pediatr (89) 114: 781!Internat J Vit Nutr Res (78) 48:188 Nutr Res (89) 9: 709 J Ment Def Res (85) 29: 233 Am J Clin Nutr (83)38: 352 Biol Trace Elem Res (96) 54: 201 Acta Paed Scand(80) 69: 183 S Afr Med J (77) 51: 369 Clin Chim Acta (83) 133: 209 " "

WHY IS SUPPLEMENTATION CONTROVERSIAL IN DOWN SYNDROME?

REASONS FOR CONTROVERSY- VITAMINS ARE “UNPROVEN”

•  Power of the study •  Bias: JAMA “could not find an unbiased

researcher not paid” •  Dosing; selection of nutrients – are anti-

oxidants the answer? •  Objective was global IQ versus specific

affects •  IQ Assessment problems in individuals

with intellectual disabilities

OBJECTIVES AND BIAS PUESCHEL (1990) VITAMIN A STUDY

•  This study essentially “shut down” vitamin A research in Down syndrome

•  Studies had shown vitamin A decreased rates of infections and skin problems

•  This is a significant problem in DS •  Conclusion: “These studies do not support

previous reports of significant decreased vitamin A absorption in individuals with Down syndrome”

VITAMIN A STUDY RESULTS

Dry scaly skin Follicular hyperkeratosis

Xerosis Dry mucous membranes

Photophobia Nightblindness

21 vs 2 14 vs 2 8 vs 1 6 vs 0 2 vs 0 1 vs 0

Symptom of Low Vitamin A Down Syndrome vs Controls

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VITAMIN A ABSORPTION

•  From Pueschel et al. (1990) J Ment Def Res 34: 269-275

PUESCHEL STUDY

•  The proper conclusion was that vitamin A metabolism and distribution is altered in DS

•  Not that vitamin A absorption is the same •  No further research on vitamin A

supplementation since 1990 •  What is used for immune issues? – antibiotics •  Position Statement - Society of Pediatricians

in USA and Canada: do not use antibiotics for URI, bronchitis, colds and ear infections

SUPPLEMENTATION IN DOWN SYNDROME & STUDY SIZE

•  Dr. Henry Turkel; Dr. Ruth Harrell •  Published work showing significant

increase of IQ with supplements in DS in early 80’s

•  Subsequently 3 small controlled studies showed no significant benefit

•  Result: position statements by all National Boards for DS “that there was no benefit of supplements”

POWER OF STUDY AND IMPACT ON MENTAL FUNCTION

•  Cornelius Ani: Require at least 170 individuals to see a 6 point IQ difference

•  Ani et al. (2000) Developmental Medicine and Child Neurology 42: 207-213.

BRITISH MEDICAL JOURNAL (2008) •  No evidence of benefit to IQ in DS •  Antioxidants and folinic acid to children less

than 7 months old for 18 months •  Selenium 10 mcg Vitamin E 100 mg •  Zinc 5mg Vitamin C 50 mg •  Vitamin A 0.9mg or 3000 IU •  Folinic acid 0.1mg

•  Ellis et al. (2008) BMJ 336(7644): 594-7.

BRITISH MEDICAL JOURNAL (2008)

•  Inadequate dose? •  Focus on antioxidants, but incomplete •  Inadequate methylation support •  Insufficient power for IQ changes of 3 points •  Specific benefits not investigated (immune

system, skin, thyroid) •  Or pure anti-oxidants do not work? •  Or standardized IQ assessments in children

with intellectual disabilities are useless?

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VITAMIN-MINERAL SUPPLEMENTS AND INTELLIGENCE

•  13 randomized controlled studies; 11 teams over 4 continents; 1477 participants

•  Independent of race, age, gender, location - average increase in IQ of 3.2 points (p=.000122)

•  If average IQ decreased by 5 points, number of individuals labeled mentally challenged would increase by 50%, gifted decrease by 50%

•  www.igc.org/psr

•  Schoenthaler et al. (1999) Macrolevel analysis of randomized controlled studies. J Altern Comp Med 5(2): 125.

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Flooring effect – when a test cannot assess below a certain score, i.e. the floor."

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“Detecting differences within individuals with DS is important.”

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SERIOUS LIMITATIONS OF IQ STUDIES IN INDIVIDUALS WITH INTELLECTUAL DISABILITIES

•  Floor Effects •  Sam,15 years old, speaks one or two word utterances,

when asked what is a clock he answers time and no other response, full scale IQ is 40 (the floor of the test)

•  Joe, also 15, is verbally fluent and responds to the question with complex phrases or complete sentences however his IQ score is the same as Sam and full scale IQ is 42 . His standardized score is the same as Sam

•  “these problems are common however they are not often recognized or discussed in published studies”

Hessl et al (2009) A solution to limitations of cognitive testing in children with intellectual disabilities J Neurodevelop Disord 1:33-45

DEVELOPMENT & VALIDATION OF THE ARIZONA COGNITIVE TEST BATTERY FOR DS

•  No less than 9 separate areas of improvement based on limitations of previous IQ testing

•  Why is this happening? Why is a test being developed that will specifically determine if an intervention actually helps improve IQ of children with DS

•  “there are a number of promising avenues for pharmacological intervention in DS. Clinical trials are imminent and will require assessments of the cognition that are thorough and validated”

•  In other words, if we are to try drugs on kids with DS we should have a chance that IQ tests are meaningful

•  Obviously since nutrients do not work it was not important to have valid IQ testing in DS

•  J Neurodevelop Disord (2010) 2: 149-164

LIES, DARN LIES: STATISTICS AND IQ MEASUREMENTS IN DS

•  Perhaps first generation to use a tool such as the Arizona scale to determine impact of nutrients on IQ

•  Well meaning researchers, but unless you have Ph.D. in psychology measuring IQ, you would not be aware of severe limitations in normal IQ tests in individuals with intellectual disability

•  This would make sense as nutrients have “proven” to improve IQ in children (non – DS) where there are clearly established nutrient deficiencies

•  Observations and anecdotal reports over 25 years

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SUMMARY - WHERE WE ARE

•  Proven depletion/disturbance in nutrients •  Non-IQ studies biased •  IQ studies need power (# participants) •  Proven alterations in key systems regulating

oxidative stress, methylation, mitochondrial function and neurotransmitters

•  A STUDY ABOUT IQ IN DS WITH NUTRIENTS USING A PROPER ASSESSMENT TOOL (e.g. ARIZONA) HAS NEVER BEEN DONE

STEAM TRAINS & OXIDATIVE STRESS

STEAM ENGINES:

MITOCHONDRIA & ANTIOXIDANTS

Oxidative stress •  heat, boiler pressure, smoke, sparks

Antioxidants (MA modifier) •  water, fire extinguisher, cooling system

Antioxidant enzymes •  firemen on the train

Functional antioxidants (MA Enhancement) •  strength of the boiler

OXIDATIVE STRESS IN DS

•  Extensive evidence of oxidative stress in DS •  In vitro - antioxidants normalize neurons

(Nature 1995 378(6559): 776-9)

•  In children with Down syndrome – work done at NutriChem (Free Rad Biol Med 1998 25(9):1044-8)

VIT E DELAYS LOSS OF DAILY ACTIVITIES, DEMENTIA & INSTITUTIONALIZATION

"""""""

NEJM (1997) 336: 1216 "

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ANTIOXIDANTS IMPROVE IMMUNE SYSTEM

•  Double-blind placebo controlled trial •  200 IU of vitamin E improved immune

response by 7 times in seniors Meydani et al. (1997) Vitamin E and in vivo immune

response in healthy elderly subjects. JAMA 277(17): 1380-6.

ANTIOXIDANT CONFUSION

•  Studies showing antioxidants do not work •  Some even show adverse affects •  There is absolutely no question that

deficiency of any antioxidant vitamin has serious consequences

•  Yet excess has no benefits or even adverse effects. How could this be??

BALANCE OF OXIDATION (TRANSSULFURATION) & METHYLATION FIREFIGHTERS OR REPAIRS/MAINTAIN

OXIDATIVE STRESS: BALANCING METHYLATION & TRANSSULFERATION

Methylation" Transsulferation"

Normal Condition à Oxidative Stress"

DOWN SYNDROME

Methylation" Transsulferation"

Oxidative Stress"CBS"

Protein Synthesis"DNA, RNA"Acetylcholine"Creatine"

Normally Glutathione ,"But due to excess O.S."

MITOCHONDRIA ADAPT TO OXIDATIVE STRESS; ANTIOXIDANTS CAN AFFECT THE ADAPTATION (A) Mitochondrial Adaptation Modifiers, •  Straight antioxidants: vitamin E, vitamin C (B) Mitochondrial Adaptation Enhancers •  4th generation •  Coenzyme Q 10 •  Magnesium Glycinate •  Creatine •  Methyl folate

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TESTING FOR ANTIOXIDANT LEVELS MITOCHONDRIAL RESPONSE MODIFIER

Methionine

Homocysteine

SAH

B12

B6

Methyl Acceptor

Methylated Acceptor

Glutathione

THF

MTHFR

Folic Acid

DHFDietary Folate

Unmetabolized Folic Acid

5,10-MTHFFolinic Acid MS

SAM

e.g. DNA Protein Hormones Neurotransmitters Creatine

CBS

METHYLATION CYCLE

Legend:""

DHF "Dihydrofolate"THF "Tetrahydrofolate"5,10-MTHF "5,10-methylenetetrahydrofolate"5-MTHF "5-Methyltetrahydrofolate"SAM "S-Adenosylmethionine"SAH "S-Adenosylhomocysteine""

MTHFR "Methylenetetrahydrofolate Reductase"MS "Methionine Synthase"CBS "Cystathionine-β-Synthase"

Enzymes"

5-MTHF!(Methylfolate)"

FOLATE, METHYLATION & DS

•  5 genes on 21st chromosome affected by methylation

•  Numerous studies show defects in methyl metabolism

•  Sensitivity to anti-folate methotrexate •  Studies have shown benefit of folinic acid in

DS •  Macrocystosis, leukemia, autism, early

dementia, thyroid activation

HOMOCYSTEINE & RELATED GENETIC POLYMORPHISMS IN DS IQ

•  MTHFR 677T/transcobalamin 776G •  Increased risk of lower IQ by 3X

"Gueant et a.l (2005) Homocysteine and related genetic

polymorphisms in Down syndrome IQ. J Neurol Neurosurg Psychiatry 76: 706-709

MTHFR “BOTTLENECK”

•  Evidence in depression & major psychiatric illness

•  MTHFR defect increases risk of leukemia & ADD

•  Increases risk of child with DS

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MTHFR “BOTTLENECK”

•  High association of dementia with MTHFR defect in non-Down population

•  Increased methylfolate decreases macrocystosis (anemia) and increases cognition in presence of normal B12

•  Cognitive decline amplified with UMFA (unmetabolized folic acid)

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4TH GENERATION STRATEGIES TO REPAIR METHYLATION CYCLE IN DS •  Creatine •  Methylfolate •  Methylation co-factors must be present •  Vitamin B12 •  Betaine •  Vitamin B6 •  Vitamin B2 •  Methionine

INTERVENTIONS FOR MTHFR “BOTTLENECK”

•  Folinic acid or methyl-B12 increase methionine & SAM in white blood cells in DS

•  Folinic acid improves developmental age in DS

•  Folic acid improves thyroid function in DS •  Folates have proven to impact mental health •  Folate supplemention prevents methotrexate

toxicity

Methionine

Homocysteine

SAH

B12

B6

Methyl Acceptor

Methylated Acceptor

Glutathione

THF

MTHFR

Folic Acid

DHFDietary Folate

Unmetabolized Folic Acid

5,10-MTHFFolinic Acid MS

SAM

e.g. DNA Protein Hormones Neurotransmitters Creatine

CBS

METHYLATION CYCLE

Legend:""

DHF "Dihydrofolate"THF "Tetrahydrofolate"5,10-MTHF "5,10-methylenetetrahydrofolate"5-MTHF "5-Methyltetrahydrofolate"SAM "S-Adenosylmethionine"SAH "S-Adenosylhomocysteine""

MTHFR "Methylenetetrahydrofolate Reductase"MS "Methionine Synthase"CBS "Cystathionine-β-Synthase"

Enzymes"

5-MTHF!(Methylfolate)"

PROBLEMS WITH FOLIC/FOLINIC

•  Folic acid does not get into brain •  Folinic acid/folic still requires MTHFR •  UMFA = UnMetabolized Folic Acid •  increases cancer in people with existing

cancer •  decreases natural killer cells •  correlates with cognitive decline in seniors

BENEFITS OF L-METHYLFOLATE

•  Only folate that crosses blood brain barrier •  Does not increase UMFA •  Does not require MTHFR •  Identical to folate found in uncooked green

leafy vegetables •  GRAS = Generally Regarded As Safe •  Naturally occurring dominant form of folate •  Suggested to not mask B12 deficiency

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QUATREFOLIC® L-METHYLFOLATE

•  Is the most bioavailable L-methylfolate •  Superior water-solubility and stability •  Dose

BRAIN IS AN ENERGY HOG

•  Highest concentration of mitochondria •  Extensive systems to maintain energy •  Creatine is key •  Recent research in creatine deficiency

showing effects related to serious mental and physical delay

MAJORITY OF METHYLATION (SAM) SUPPORTS BRAIN CREATINE

Majority of SAM is used to produce Creatine

ATP

Regenerates ATP for immediate use. Brain depletes creatine levels rapidly to maintain ATP levels.

SAM

Roles of Creatine: 1. Energy Buffer 2. Transport of energy

Diet(Meats)

Creatine Phosphocreatine Creatinine Spontaneously forms 2% per day

ADPSAH

ArginineGlycine

CreatineKinase

(Brain, Muscle, Heart)

Cellular Energy"

DOWN SYNDROME

Methylation" Transsulferation"

Oxidative Stress"CBS"

Protein Synthesis"DNA, RNA"Acetylcholine"Creatine"

Normally Glutathione ,"But due to excess O.S."

Creatine Transporter Defect

•  An individual with CTR will also have autism (100%)

•  X-linked (males) •  5-20% of autistic patients have creatine

defects •  100% have energetic defects

Creatine & Autism / Down Syndrome

•  Creatine/PCr affects neurotransmitters •  Affects cell signalling - sonic hedgehog •  Maintains mitochondrial neuronal gradient

50% of energy in brain •  Prevents apoptosis •  Antioxidant •  Highest percentage in brain areas affected by

autism / Down syndrome

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CREATINE SUPPLEMENTATION

•  Increases cognition in vegetarians •  Reduces consequences from traumatic brain

injury •  Concentrates in brain areas affected in autism

& Down syndrome •  Improves neuromuscular disorders •  Improves focus and attention •  Proven to be safe

Hormones (e.g. thyroid, sex hormones)

Diet & Gastrointestinal Health

Insulin Response

Neurotransmitter Balance (e.g. epinephrine,

norepinephrine)

Micronutrient Status (e.g. Mg2+)

Mitochondrial Function (e.g. CoQ10, carnitine, lipoic acid)

 

 

Creatine Transport and

Metabolism

Oxidative Stress

Methylation

Antioxidant Levels

BENEFITS OF CREATINE There is no magic bullet, but creatine is the closest thing

CREATINE MONOHYDRATE: STABILITY ADVANCES

•  Stabilized creatine – Cognitine •  Dramatic and observed results in DS,

autism, ADD, and creatine transporter deficiency

•  Improved stability and prevention of one way trip to creatinine in presence of stomach acid

4TH GENERATION STRATEGIES TO REPAIR METHYLATION CYCLE IN DS/AUTISM

•  Creatine •  Methylfolate •  Methylation co-factors must be present •  Vitamin B12 •  Betaine •  Vitamin B6 •  Vitamin B2 •  Methionine

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NEW MEDICATIONS ARE THE ANSWER – OR ARE THEY?

NEW DRUG INITIATIVES IN DS WHICH PROMPTED ARIZONA SCALE

•  New and improved mouse models •  Prozac •  Alzheimer’s medication •  Acetylcholine improvement •  Memantine NMDA receptor antagonist •  Xamoterol beta-agonist partial blocker •  GABA blockers, Ginkgo biloba •  Sonic Hedgehog signallers

!" "WHY IS THE ARIZONA IQ TEST CRITICAL?

•  Every single pathway discussed is proven to be improved or affected by key nutrients

•  We obviously need the resources of drug development to have a tool like the Arizona rating scale

•  The first and only tool to measure and understand the impact of nutrients in DS today

4TH GENERATION DOWN SYNDROME INTERVENTIONS

Thyroid

Gastrointestinal Health • Check for Celiac/gluten sensitivity

Antioxidants • Measure individual levels

Insulin •  Assess protein and

carbohydrate intake

Micronutrients •  Vitamin D •  Iron (Ferritin)

Neurotransmitters •  Administer amino acids after

consultation

ATP/Mitochondrial Support • Creatine, Mg2+, CoQ10 • Organic acid assessment

Down Syndrome

Interventions

MethylationàB12 •  Detect MTHRF mutation

MY BIAS •  From $12.00 per month •  Be the first to try the new MSB Methyl Plus •  info@nutrichem.com or call 1-888-384-7855