Using Nutrigenomics to Optimize Supplement Choices Dr. Amy Yasko

I believe that autism is a multifactorial condition, meaning that a number of

circumstances need to go awry simultaneously for autism to manifest. I often refer to my Princess Diana example…if the car wasn’t speeding, if the paparazzi weren’t chasing her, if they weren’t in a narrow tunnel, if she had been wearing a seat belt…if you could eliminate any one of those factors then perhaps the end result would have been different. So too, I believe is the case with autism. I see and address autism as a multifactorial condition that stems from underlying genetic susceptibility combined with assaults from environmental toxins and infectious diseases. It has been shown in other instances that multifactorial diseases are caused by infections and environmental events occurring in genetically susceptible individuals. Basic parameters like age and gender, along with other genetic and environmental factors play a role in the onset of these diseases. Infections combined with excessive environmental burdens only lead to disease if they occur in individuals with the appropriate genetic susceptibility. I believe this is the case in autism, and using this theory to approach autism has resulted in positive improvements. Personalized genetic screening

One clear, definitive way to evaluate the genetic contribution of multifactorial conditions is to take advantage of new methodologies that allow for personalized genetic screening. Currently, tests are available to identify a number of underlying genetic changes in an individuals’ DNA.

The field of nutrigenomics is the study of how natural products and supplements can interact with particular genes to decrease the risk of diseases. By looking at changes in the DNA in these nutritional pathways it enables one to make supplement choices based on their particular genetics, rather than using the same support for every individual regardless of their unique needs. With a knowledge of imbalances in nutritional genetic pathways it is possible to utilize combinations of nutrients, foods and natural ribonucleic acids to bypass mutations and restore proper pathway function. The methionine/folate pathway is a central pathway in the body that is particularly amenable to nutrigenomic screening for genetic weaknesses. The result of decreased activity in this pathway causes a shortage of critical functional groups in the body called methyl groups that serve a variety of important functions.

Your body’s editing function

While the term may seem intimidating, a methyl group is actually just a group of small molecules, similar in size to the water molecule (H2O). Water is a key to life as are methyl groups critical for health and well being. Methyl groups are simply “CH3" groups; they contain ‘H’ like in water and a ‘C’ like in carbon or diamonds. However, these very basic molecules serve integral functions; they are moved around in the body to turn on or off genes.

One way to look at the function of methyl groups is that it is analogous to the editing function on your computer. If we think about your body like a computer then you have just one computer that you need to maintain over the course of your life. The longer you have that computer the more outdated it will become. Over the course of a lifetime many of the keys may become stuck or broken. You may drop the computer and damage its function or spill your coffee on it. However, the editing function of the computer remains intact and compensates for these broken keys, misspelled words, and sticky space bars due to accidents of wear and tear. In the absence of this editing function, assume that these ‘misspells’ are accumulated in your body over the course of your life. If the editing function is impaired then you have no way to get around these misspelled words and other issues that affect your ability to function. Over your lifetime you will accumulate so many misspelled words, missed keys, etc. that at a certain point it would be impossible to read a ‘document’ amidst all of these mistakes. You can start to see why the proper functioning of the pathway that serves to edit your genes is so important. In addition to the editing of genes, this pathway also serves more direct roles in your body and is thus critical for proper function. While there are several particular sites in this pathway where blocks can occur as a result of genetic weaknesses, thankfully supplementation with appropriate foods and nutrients can help to bypass these mutations to allow for restored function of this pathway. The role of the methylation cycle in your body

The methylation cycle is the ideal pathway to focus on for nutritional genetic analysis because the places where mutations occur is well defined and it is clear where supplements can be added to bypass these mutations. In addition to its editing role, the function of this pathway is essential for a number of critical reactions in the body. One very simplistic way to view methylation, is that methyl groups serve as ‘traffic lights’ for the genetic roadways in your body. Lack of proper traffic signaling can lead to a multitude of health problems. One consequence of genetic weaknesses (mutations) in this pathway that generates these ‘traffic lights’ is an increased risk for a number of serious health conditions. Defects in methylation lay the appropriate groundwork for the further assault of environmental and infectious agents resulting in a wide range of conditions including diabetes, cardiovascular disease, thyroid dysfunction, neurological inflammation, diabetes, chronic viral infection, neurotransmitter imbalances, atherosclerosis, cancer, aging, schizophrenia,

decreased repair of tissue damage, improper immune function, neural tube defects, Down’s syndrome, Multiple Sclerosis, Huntington’s disease, Parkinson’s disease, Alzheimer’s disease, and autism.

• Inflammation, bacterial and viral infection

When you have bacterial or viral infections in your system it increases the level of inflammation in your body. This too relates back to this same methylation cycle. Increases in certain inflammatory mediators of the immune system due to infection such as IL6 and TNF alpha lead to decreases in methylation. Chronic inflammation would therefore exacerbate existing genetic mutations in this same pathway. The inability to progress normally through the methylation pathway as a result of methylation cycle mutations combined with the impact of viral and bacterial infections further compromises the function of this critical system in the body. • New cells and the immune system

The building blocks for DNA and RNA require the methylation pathway. Without adequate DNA and RNA it is difficult for the body to synthesize new cells. New cell synthesis is needed to repair damaged cells, to maintain the lining of the gut, to make new blood cells as well as for your immune system that defends you against infection. T cells are a key aspect of your immune system and they require new DNA in order to respond to foreign invaders. T cell synthesis is necessary to respond to bacterial, parasitic and viral infection, as well as for other aspects of the proper functioning of the immune system. T cells are necessary for antibody producing cells in the body (B cells) as both T helpers and T suppressors are needed to appropriately regulate the antibody response. • Herpes, hepatitis and other viruses

In addition, decreased levels of methylation can result in improper DNA regulation. DNA methylation is necessary to prevent the expression of viral genes that have been inserted into the body’s DNA. Loss of methylation can lead to the expression of inserted viral genes such as herpes and hepatitis among other viruses. • Sensory overload

Proper levels of methylation are also directly related to the body’s ability to both myelinate nerves and to prune nerves. Myelin is a sheath that wraps around the nerve to insulate and facilitate proper nerve reaction. Without adequate methylation, the nerves cannot myelinate in the first place, or cannot remyelinate after insults such as viral infection or heavy metal toxicity. A secondary effect of a lack of methylation and hence decreased myelination is

inadequate pruning of nerves. Pruning helps to prevent excessive wiring of unused neural connections and reduces the synaptic density. Without adequate pruning the brain cell connections are misdirected and proliferate into dense, bunched thickets. When nerves grow in this unregulated fashion it can cause confusion processing signals. Synesthesia occurs when the stimulation of one sense causes the involuntary reaction of other senses, basically sensory overload.

• Serotonin, dopamine and ADD/ADHD

Methylation is also directly related to substances in your body that affect your mood and neurotransmitter levels of both serotonin and dopamine. Methylation of intermediates in tryptophan metabolism can affect the levels of serotonin. Intermediates of the methylation pathway are also shared with the pathway involved in the actual synthesis of serotonin and dopamine. In addition to its direct role as a neurotransmitter, dopamine is involved in assuring your cell membranes are fluid and have mobility. This methylation of phospholipids in the cell membranes has been related to ADD/ADHD. Membrane fluidity is also important for a variety of functions including proper signaling of the immune system as well as protecting nerves from damage. A number of serious neurological conditions cite reduced membrane fluidity as part of the disease process including MS, ALS, and Alzheimer’s disease. In addition, phospholipid methylation may be involved in modulation of NMDA (glutamate) receptors, acting to control excitotoxin damage.

Methylation as one piece of a more complex puzzle

In general, single mutations or biomarkers are generally perceived as indicators for specific disease states. However, it is possible that for a number of health conditions, including autism, it may be necessary to look at the entire methylation pathway as a biomarker for underlying genetic susceptibility for a disease state. It may require expanding the view of a biomarker beyond the restriction of a mutation in a single gene to a mutation somewhere in an entire pathway of interconnected function.

This does not mean that every individual with mutations in this pathway will be autistic or will have one of the health conditions listed above. It may be a necessary but not a sufficient condition. Most health conditions in society today are multifactorial in nature. There are genetic components, infectious components and environmental components. A certain threshold or body burden needs to be met for each of these factors in order for multifactorial disease to occur. However, part of what makes the methylation cycle so unique and so critical for our health is that mutations in this pathway have the capability to impair all three of these factors. This would suggest that if an individual has enough mutations or weaknesses in this pathway, it may be sufficient to cause multifactorial disease. Methylation cycle mutations can lead to

chronic infectious diseases, increased environmental toxin burdens and have secondary effects on genetic expression.

By testing to look at mutations in the DNA for this methylation cycle it is possible to draw a personalized map for each individual’s imbalances, which may impact upon their health. Once the precise areas of genetic fragility have been identified, it is then possible to target appropriate nutritional supplementation of these pathways to optimize the functioning of these crucial biochemical processes. As seen in the diagram below there are specific places in the cycle where support can be added. This support helps to bypass mutations in the pathway in a similar manner to the way you might take a detour on a highway. We can look at a mutation in this pathway as analogous to a collision that has totally shut down traffic going in one direction on a highway. Support to bypass mutations in this pathway is like taking an alternate route to avoid the accident on the highway. Thus, the use of key nutrients or foods can aid in helping to bypass methylation cycle mutations and help restore function to this pathway. The newest piece of the puzzle: Genetic susceptibility to Helicobacter pylori

As already discussed, genes can be turned on or off based on their degree of methylation. The ability of the CFTR gene (cystic fibrosis transmembrane conductance regulator) to function optimally appears to be regulated by methylation. Thus, lack of methylation cycle function may impair CFTR function, which can in turn lead to issues with appropriate mucous layer viscosity in the body. It has been observed that the number of individuals with autism testing positive for the bacterium Helicobacter pylori is much higher than would be expected. Helicobacter pylori (H. pylori) is a Gram-negative, spiral-shaped bacterium that lives in the mucous layer of the stomach and duodenum. Changes in the mucous layer environment may be a predisposing factor that accounts for this observed increase in H. pylori. This ulcer-causing gastric pathogen is able to colonize the harsh acidic environment of the human stomach. Although the stomach is protected from its own gastric juice by a thick layer of mucus that covers the stomach lining, H. pylori takes advantage of this protection by living in the mucus lining itself. In the mucus lining, H. pylori survives the stomach’s acidic conditions by producing urease, an enzyme that catalyzes hydrolysis of urea into ammonia and bicarbonate. As strong bases, ammonia and bicarbonate produce a cloud of alkalinity around the bacterium, making it impossible for the body's normal defenses (such as T cells, natural killer cells, and other white blood cells) to get to it in the gastric mucus layer. Because H. pylori burrows into the mucus layer of the stomach and is very persistent there, it is difficult to get a positive test for it even when it is present. In addition, H. pylori can remain for long periods of time and is extremely difficult to eradicate. It appears that H. pylori may play a role in a number of the recognized pieces of the puzzle of autism. Many factors that have been identified as playing a role in autism are related to H. pylori, including problems with gluten and casein, breakdown of glutathione, excess stomach acid, and the high norepinephrine seen in ADD and ADHD. H. pylori affects neurotransmitters and brain neurochemistry. H. pylori infection increases the incidence of food allergy by

facilitating the passage of intact proteins across the gastric epithelial barrier. H. pylori depletes secretin, which had previously been reported to have positive impacts in some cases of speech. Arginine makes urea to neutralize stomach acid or, alternatively, makes intermediates (such as nitric oxide) that relax blood vessels When H. pylori infection is present, it induces arginine to produce urea as opposed to nitric oxide because urea provides the alkalinity necessary for its survival. In this way, H. pylori depletes arginine through its overuse of the enzyme arginase. The depletion of arginine impacts the mitochondria, reducing mitochondrial energy production from glucose. When H. pylori infection is present, it changes the way important phospholipids are positioned in the cell membrane. Phospholipid orientation has been described as playing a role in ADD/ADHD as well as in immune system signaling. H. pylori also decreases levels of B12 in the body; decreases iron levels; increases ammonia and taurine; and can produce glaucoma in young individuals that resolves when the H. pylori is treated. H. pylori infection is not just an immediate acute infection. Rather, it is a long-term chronic problem that may take months or years to eradicate. Chronic H. pylori gastritis alters feeding behaviors, delays gastric emptying, alters gastric neuromuscular function, impairs acetylcholine release; these effects can persist for months after the infection has been eradicated. Taken together, the role of H.pylori in autism may be significant, and its ability to colonize the gut may be closely related to inadequate CFTR function, which in turn may be related to methylation cycle function. The Bottom Line

It has been my experience that viruses, bacteria (including, but not limited to H.pylori ), toxic metals and excitotoxins (like glutamate or MSG) also play a key role in the condition of autism. I do feel it is important to address these issues and to decrease the body’s burden of metals and excitotoxins as well as eliminating bacterial and viral issues in the body. Restoring healthy gut function is another critical area of focus on the path to recovery. However, if we begin with a knowledge of our nutrigenomic weaknesses it makes it easier to address all of these aspects. While autism is a general term there are multiple levels of severity as well as a huge range of clinical presentations. Using nutrigenomic information takes into account that each child is an individual and needs to be seen as unique. This then allows for individualized supplement programs to target areas of weakness that customize support to address specific needs.

Methylation cycle indicating where supplements can be added to bypass mutations at specific points in the pathway. Yasko, A. Pathways to Recovery. Bethel Maine: Neurological Research Institute, 2009. Page 143