Connecting the Genomic Dots How to incorporate nutritional genomics in treatment modalities in ASD 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. 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) Nutri-Genomics

Focuses on how food constituents impact expression

• How a particular food affects . • How compounds in food can influence molecular pathways • impact disease risk. • What you eat turns on/off Food is information for our genes

• Food sends signals to the genes • Everything we take in food, emotions, • toxins: Affects cells and DNA 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. Epigenetics Etiology of Autism Spectrum Disorders

Genetic Environmental Predisposition Triggers

Altered Biochemical Pathways 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 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) • • Oxidative stress Epigenetics

• Days 20-24 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 Methyl- THFR- WHAT??? Polymorphisms associated with ASD

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

• Methionine Synthase (MTR)

• Methionine Synthase Reductase (MTRR)

• Cystathione Beta Synthase (CBS)

• receptor II (TCN2)

• Folate receptor 1 (FOLR1)

• Betaine Homocysteine S- Methyltransferase (BHMT) 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 • Decreased MET leading to more intense and prolonged immune response to bacteria or viral exposure • Deficiency in IL-10, important cytokine that suppresses pro- inflammatory responses leading to more prolonged inflammatory response. • Van de Water et al. (2011) Transl Psychiatry (online Oct 18) Altered Metabolic Systems in ASD Children

Inflammation

Neurotransmitters Oxidative Stress

Gastrointestinal Neurological Disturbances Abnormalities

Mitochondrial Dysfunction 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 levels • Allergies in 62% of ASD children • Strange skin rashes • Ear infections and coughs 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 Oxidative Stress 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 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 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 GI

Oxidative Stress Biomarkers

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

Biochemical Features of Autism

• Low Glutathione • Under methylation • Elevated Mercury/Lead/Toxins • Copper overload and Ceruloplasmin insufficiency • • Vitamin A deficiency • Low magnesium levels • Low selenium and cysteine • Elevated urine Pyrroles (Autism 38%) • Elevated carboxyethylpyrroles1 • 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), 42027-35. http://doi.org/10.1074/jbcM305460200 Genomic Nutrition Roadmaps

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 Recommendations:

• Address altered metabolic systems: • GI/Inflammation/Oxidative Stress/Neurologic/Mitochondria Dysfunction

• Nutritional support • Antioxidants • Anti-inflammatories • Reliance on organic and whole foods Include nutritional bioactives to support gene cross talk Thank you!

Meryl Brandwein, RD/LDN 954-727-9006

MerylBrandweinNutrition Merylbrand

Merylbrandwein.com