Connecting the Genomic Dots. How to incorporate nutritional genomics in treatment modalities in ASD

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1 Connecting the Genomic Dots How to incorporate nutritional genomics in treatment modalities in ASD

2 Objectives Clarify and define the concepts of Nutritional Genomics. Identify various genetic SNP s and their subsequent impact on health. How to create nutritionally supportive meal plans with the use of the nutritional genomic data.

3 Nutritional Genomics Explores how genetic variations affect the interaction between diet and health. Identifies genetic susceptibility to a disease How people respond to nutrients depending on genetic variation. Not every persons responds the same way (i.e. obesity, diabetes, cancer)

4 Nutri-Genomics Focuses on how food constituents impact gene expression How a particular food affects gene expression. How compounds in food can influence molecular pathways impact disease risk. What you eat turns genes on/off

5 Food is information for our genes Food sends signals to the genes Everything we take in food, emotions, toxins: Affects cells and DNA

6 Epigenetics is Everywhere What you EAT Where you live Who you interact with When you SLEEP How you MOVE Even Aging Can eventually cause chemical modifications that will turn genes on or off over time.

7 Epigenetics

8 Etiology of Autism Spectrum Disorders Genetic Predisposition Environmental Triggers Altered Biochemical Pathways

9 Epigenetics: It s role in ASD What environment is doing to our genes Onset of the disorder is periods of fetal maturation & development Stress of mother Endocrine disruption Pesticide exposure Exposure to drugs Premature birth

10 Possible Environmental Factors Associated with ASD (Post Natal) Childhood vaccines MMR Mercury-containing vaccines 54% of parents believe child s ASD caused by immunization Allergies (good and/or environmental) Inflammation Oxidative stress

11 Epigenetics Days of gestation Establishment of epigenetic bookmarks Permanent- persisting through life Determine expression across multiple genes Exposure to toxic chemicals Permanent physical and mental abnormalities Dominant biochemical factors Methylation and acetylation 95% of ASD children are undermethylated

12 Methyl- THFR- WHAT???

13 Polymorphisms associated with ASD Glutamate Decarboxylase 1 (GAD1) Methylene Tetrahydrofolate Reductase (MTHFR C677T) Catechol-o-methyltransferase (COMT) Monoamine Oxidase (MAO-A)

14 Polymorphisms associated with ASD Methionine Synthase (MTR) Methionine Synthase Reductase (MTRR) Cystathione Beta Synthase (CBS) Transcobalamin receptor II (TCN2) Folate receptor 1 (FOLR1) Betaine Homocysteine S- Methyltransferase (BHMT)

15 MET Gene Variant & Maternal Autoantibodies in Fetal Brain MET gene codes for MET receptor tyrosine kinase MET variant (C allele) present in 9% of mothers of children with ASD compared to controls MET C allele in ASD women: Strongly linked to maternal autoantibodies to fetal brain proteins Decreased MET protein leading to more intense and prolonged immune response to bacteria or viral exposure Deficiency in IL-10, important cytokine that suppresses proinflammatory responses leading to more prolonged inflammatory response. Van de Water et al. (2011) Transl Psychiatry (online Oct 18)

16 Altered Metabolic Systems in ASD Children Inflammation Neurotransmitters Oxidative Stress Gastrointestinal Disturbances Neurological Abnormalities Mitochondrial Dysfunction

17 Inflammation in ASD Children Brain Abnormalities of the microglia Elevated pro-inflammatory cytokines in frontal cortex Peripheral immune system Increased levels of cytokines in brain, CSF, blood and GI tract (upper and lower small intestine) Increased antibody levels Allergies in 62% of ASD children Strange skin rashes Ear infections and coughs

18 Reduced Antioxidant Activity in ASD Children GSHPx activity in plasma and RBC decreased in ASD children compared to controls Decreased catalase and SOD activity in RBCs Reduced levels of total glutathione in plasma Lower redox ratio of GSH and GSSG in plasma

19 Oxidative Stress

20 Mitochondrial Dysfunction in ASD Children Mitochondrial dysfunction in CNS (30 to 40 %) Developmental regression Learning disabilities Behavioral issues Metabolic lactic acidosis seen with ASD maybe associated with pyruvate dehydrogenase deficiency or mitochondrial respiratory chain defects (CoQ10) Carnitine deficiency commonly found with ASD Essential for fatty acid utilization by mitochondria Impairment of ATP production, which can explain fatigue

21 Gastrointestinal Tract Disturbances in ASD Signs and symptoms in 68% of ASD children Reflux Constipation Sensitivity to food Abnormal flora Frequent abdominal pain Inflammatory reaction to gliadin (gluten peptide) Microscopic changes Swollen lymph nodes within submucosa of intestinal wall Mucosal abnormalities Absorptive epithelium disrupted Connective tissue weak Muscularis mucosae

22 Repairing the GUT Prevent undigested proteins from reaching the brain Allows desired nutrients to feed the brain Allows food to be digested Prevents further inflammation of the gut

23 GI

24

25 Oxidative Stress Biomarkers 99% > excessive oxidative stress Pervasive Zinc deficiency Low Copper/Zinc/SOD Copper overload/low Ceruloplasmin Low Glutathione, selenium, or MT proteins Seizures

26

27 Biochemical Features of Autism Low Glutathione Under methylation Elevated Mercury/Lead/Toxins Copper overload and Ceruloplasmin insufficiency Zinc deficiency Vitamin A deficiency Low magnesium levels Low selenium and cysteine Elevated urine Pyrroles (Autism 38%) Elevated carboxyethylpyrroles 1 Depressed metallothianine levels (MT protects cells from free radical exposure) Gu, X., Meer, S.G., Miyagi, M., Rayborn, M.E., Hollyfield, J.G., Crabb, J.W., & Salomaon, R.G. (2003). Carboxyethylpyrrole protein adducts and autoantibodies, biomarkers for age0-related macular degeneration. The Journal of Biochemistry, 278(43),

28 Genomic Nutrition Roadmaps

29

30 Recommendations for ASD Maternal lifestyle choices Very conservative use of pharmaceutical medicines Avoid toxic cleaning products, solvents and pesticides Flexible vaccination schedules Identify ASD subset using appropriate biomarkers Genomic tests help determine predisposition to clinical imbalances

31 Recommendations: Address altered metabolic systems: GI/Inflammation/Oxidative Stress/Neurologic/Mitochondria Dysfunction Nutritional support Antioxidants Anti-inflammatories Reliance on organic and whole foods

32 Include nutritional bioactives to support gene cross talk

33 Thank you! Meryl Brandwein, RD/LDN MerylBrandweinNutrition Merylbrand Merylbrandwein.com

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