Methylation Defects in Autism Spectrum Disorders - The Gene/Environment Interface
Cindy Schneider, MD
It has become increasingly evident that individuals with autism have impairments in their capacity to methylate. Methylation reactions are those reactions in our metabolism that involve the transfer of a methyl group (a carbon with three hydrogens attached) from one compound to another. These reactions are required for many of the most vital pathways in our metabolism. The building or repair of every cell in our bodies requires methylation. The silencing of viral genes involves methylation. We must be able to methylate the dopamine receptor in order for it to bind with dopamine, transform lipid membranes, change the frequency of brain waves, and increase our attention. The coffee addict craves caffeine, a methyl donor, because it causes a burst in focus and attention. An alarmingly large percentage of our pediatric population has been placed on Ritalin (methylphenidate), a methyl donor, for the same reason. Messages are not transmitted along neurons accurately and efficiently unless the nerve is insulated with a substance called myelin, which cannot be produced without methylation. The most commonly known defect in myelination (the protection of nerves with myelin) is multiple sclerosis, a condition in which anti-myelin antibodies are made. Anti-myelin antibodies are frequently found in children with autism as well, and levels of these anti-myelin antibodies correlate with their levels of anti-measles antibodies, raising speculation that a chronic measles infection of the nervous system may be one cause of autism. The success of methylcobalamin (methyl B12) injections in the treatment of multiple sclerosis led Dr. James Neubrander to explore methylcobalamin as a treatment for autism, which has proven to be highly effective.
A person who is less able to methylate may present with inflammatory conditions such as eczema, colitis, asthma, or arthritis, as methylation is also required to produce glutathione, our body’s primary antioxidant. Chronic inflammation and the associated tissue damage can lead to an autoimmune disease, a condition in which a person’s immune system begins to make antibodies again his or her own tissue. Diabetes, Crohn’s disease, lupus, and multiple sclerosis are examples of autoimmune conditions and are commonly seen in the families of individuals with autism. Anxiety and obsessive-compulsive tendencies are also common, as the production of serotonin, our anti-anxiety neurotransmitter, requires properly functioning methylation pathways. Serotonin then goes through a series of reactions including methylation and is converted to melatonin, the compound that allows us to fall asleep. The association between sleep disorders and autism is well known to most parents of these individuals and to even their least enlightened physicians. A person with impairments in methylation is likely to be more susceptible to viral infection and to adverse reactions to live viral vaccines. Chronic viral infections are common and viruses such as measles that attack the gut and nervous system are of most concern.
Although millions of dollars have been spent on genetic research, no autism gene has been identified. There are many genes of interest that are found more frequently in individuals with autism, but none of these genes cause the condition and most people who carry the genes do not have autism. Autism has all the characteristics of a multifactorial disorder, meaning that both environmental and genetic risk factors interact to cause the condition. A person with several genetic weaknesses in his or her ability to methylate, for example, might be perfectly healthy in an ideal environment, but easily become ill in a less than perfect environment. Certain metabolic weaknesses have no impact if exposure to toxins such as mercury or pesticides does not occur, but may lead to rapid deterioration in health and function under conditions of exposure to these and other toxins. Nutritional status is also very important. Many genes have catalysts or cofactors that allow them to operate more efficiently. Without these cofactors, which are often vitamins and minerals, they do not function well. With them, even a weaker enzyme may operate within the normal range. It is for this reason that many functional medicine practitioners utilize higher than average levels of targeted nutritional supplements. Those practitioners that understand the biochemistry behind these supplements can use them to treat the core problem rather than simply reduce the symptom. For example, a serotonin reuptake inhibitor such as Prozac might rapidly increase the amount of time that serotonin remains in the synapse and available to neurons and thereby alleviate some of the symptoms of a serotonin deficiency such as anxiety or depression. A more holistic viewpoint would be that a person with those symptoms might suffer from a methylation defect, making him or her susceptible to a whole range of health problems which result when methylation is impaired. Correcting the serotonin issue with Prozac, even if successful, has only solved one of potentially many related problems, whereas enhancing methylation in general would have widespread beneficial effects.
Rather than thinking in terms of an autism gene, we would be wise to think in terms of autism pathways. Methylation pathways are the best candidates, as permutations in these reactions could led to any of the deficits and symptoms described in autism and the biomedical treatments that have met with success are ultimately impacting these pathways.
Genetic testing is available through various laboratories and in research protocols. The most intriguing genes to date include catecholamine-O-methyltransferase (COMT), methylenetetrahydrofolate reductase (MTHFR), methionine synthase (MS), methionine synthase reductase (MSR), dihydropteridine reductase (DHPR), cystathione beta synthase (CBS), S-adenosylhomocysteine hydroxylase (SAHH), adenosine deaminase (ADA), Paraoxonase (PON1) and reelin. The interplay between these genes determines many aspects of our personality due to their effect on neurotransmitter levels. They also work in concert to allow us to build and repair cells, a process that continues even after growth has ceased. A person undergoing chemotherapy is taking drugs that diminish the capacity for cells to replicate. The most common side effects of chemotherapy are nausea, vomiting, and diarrhea, largely because the cells that line the bowel are unable to replicate. The thin lining of our bowel wall is ordinarily replaced gradually day by day with a complete turnover of cells occurring every three days. Other areas of the body in which cells do not turn over so rapidly are less affected by these drugs and likewise less affected by methylation defects. One could liken a child with autism who has methylation defects to a person on chemotherapy. Such a person would be likely to have gastrointestinal symptoms, be more susceptible to infection, be less able to focus, and may decline cognitively.
The question is then how to enhance methylation in those who have methylation defects. A wide range of methyl donors are available and the optimal combination of compounds is a matter of trial and error. In those who can obtain genetic testing, errors are less frequent because more information is available. The most commonly beneficial supplements include methylcobalamin, the active form of folic acid called 5-methyltetrahydrofolate, and coenzyme Q10. Many, but not all individuals tolerate vitamin B6 or its more active form, pyridoxyl-5-phosphate (P5P), magnesium, and zinc with considerable benefit, as these enhance the function of critical enzymes. Some do well with dimethylglycine (DMG) or trimethylglycine (TMG), as they influence the direction of traffic along certain methylation pathways. It is not unusual for irritability, hyperactivity, or insomnia develop if the wrong supplement is given or if the right supplement is given at the wrong time. When side effects occur, the guidance of a qualified health professional should allow identification of the problem. Some adverse effects are simply evidence of detoxification. In these cases, symptoms resolve and areas such as language and attention improve after toxins have cleared. When in doubt, urinary tests for toxic metals should be obtained to investigate the possibility of toxic metal excretion. Some of these same supplements have the capacity to increase ammonia levels, which would cause irritability, lack of focus, and/or an increase in self-stimulatory behaviors. Accurate ammonia measurements are difficult to obtain outside of a hospital setting, but the possibility of ammonia toxicity should be considered when these behaviors are present. Many genetic variants, such as the more active CBS allele, the less active MTHFR allele (A1298C), and weaker variants of nitric oxide synthase (NOS) may predispose an individual to high ammonia levels. When these genes are present, ammonia levels must be managed in a variety of ways. Certain gut bacteria produce high levels of ammonia. Improving bowel health and digestive through various means such as aggressive management of constipation, the administration of probiotics, the reduction of simple carbohydrates in the diet, and the provision of digestive enzymes when tolerated will significantly decrease bacterial ammonia production. Limiting protein intake and dividing this intake between meals rather than allowing a protein load at one meal will place less demand on the pathways that clear ammonia. In those who tolerate it, 5-methyltetrahydrofolate will often decrease ammonia levels by increasing tetrahydrobiopterin (BH4) levels. BH4 may also be given toward this end, although pharmaceutical grade BH4 is difficult to obtain and not yet FDA approved. A less pure source of BH4 is available by the trade name Bio Thyro and has been effective in many cases. Some practitioners advocate the use of activated charcoal to decrease ammonia levels, but frequent use of charcoal is not practical because it interferes with the absorption of nutrients and is highly constipating. The administration of charcoal must be followed by high dose magnesium or other means to induce a bowel movement for this reason.
Paraoxonase (PON1) is an enzyme required for the metabolism of organophosphate pesticides. Many forms of this gene exist, some allowing organophosphate pesticides to be cleared 40 times more rapidly than others. The PON1 gene is located in 7q21.3-22.1, a region showing strong genetic linkage with autism. Persico et al assessed three functional genetic variants called C-108T, L55M, and Q192R in 177 Italian and 107 Caucasian-American families with one or more affected children. Caucasian-Americans displayed a significant association between autism and the PON1 variant marked by L55 and R192 (P<0.025 with patients vs normal controls, transmission/disequilibrium test, family-based association test, and haplotype-based association test). No trend was found in Italian children with autism. This was the predicted finding, as organophosphate pesticide use is much higher in the United States than in Italy and the predominant form of autism in America does not seem to be the same as that most frequently seen in Italy. Caucasian-American children with autism carrying at least one copy of the R192 (weaker) variant had significantly lower serotonin blood levels, but Italian children with this gene did not. This may be explained by the impact of paraoxonase on an enzyme called dipeptidyl peptidase IV (DPPIV). When paraoxonase activity is impaired through either the inheritance of a weaker version of the gene or by pesticide exposure, this in turn affects the activity of an enzyme called adenosine deaminase (ADA). When ADA does not function properly, levels of its substrate adenosine rise. This becomes a roadblock to methylation, potentially leading to any or all of the complications previously described. DPPIV and ADA function may be increased by the avoidance of two of the substrates for DPPIV, gliadomorphin and casomorphin. It is by this and other mechanisms that the avoidance of gluten and casein lead to enhanced cognitive function, decreased inflammation, and improved attention.
We are entering an age of research that will ultimately explain why some individuals become ill with any given environmental exposure while others remain well and how those who are most vulnerable to environmental toxins can best protect their health.