Parents, practitioners, scientists, and other community members convened at the Fall 2008 DAN! conference held last weekend in San Diego, CA. The conference offered a wide range of talks, workshops and exhibitors on biomedical information and interventions for autism organized into a general and a science session.
One of the major themes of the science session was the influence of a variety of environmental toxins on health. Paul Shattock, B.Pharm. focused on organophosphates found in insecticides and other industrial compounds. Dr. Shattock described their biological impact and highlighted specific instances where genetic susceptibility can influence an individual's sensitivity to environmental toxins. Through a variety of examples, he stressed the importance of taking into account both country of origin and ethnicity of those exposed because these factors can influence how one responds to an environmental toxin. These factors, along with the influence of genetics, make it challenging to determine how environmental factors play a role in autism.
Cindy Schneider, M.D., provided the audience with a detailed survey of the toxicity of different heavy metals (such as lead, cadmium, arsenic and mercury), alcohol, cigarette smoke and organophosphates. Noting the presence of many associated symptoms in autism such as digestive problems, allergies, sleep disorders and hyperactivity, she discussed the way toxins can lead to neurological, immunological, and gastrointestinal problems. Dr. Schneider extended the concept of environmental toxins to include the study of combined toxicities. She discussed the potential synergism among sets of toxins and called for more studies to test both sequential and simultaneous exposures, and at different developmental time windows.
Richard Deth, Ph.D., discussed Autism Speaks-funded research aimed at providing a much more detailed understanding of the body chemistry that can potentially be affected by environmental toxins. Dr. Deth described the folate and vitamin B-12 dependent methionine synthase system, highlighting how environmental stressors such as heavy metals disrupt the biochemical pathways. Dr. Deth hypothesized that disruptions at key points of the methionine synthase system can result in autistic symptoms.
Autism Speaks grantee Judy Van de Water, Ph.D., further extended the discussion of immune abnormalities in autism. Her laboratory has collected data suggesting a variety of different immune deficiencies in some children with autism, including depressed immune responses to specific antigens, the presence of auto-antibodies, and decreases in total amount of immunoglobulin (which are involved in the antibody response). In addition, Dr. Van de Water has discovered antibodies to fetal proteins in the serum of mothers who had previously given birth to children with autism, suggesting that the mother had an atypical immune response during pregnancy to the fetus. These fetal antibodies were more common in mothers whose children with autism had experienced regression. She and her collaborators are currently developing model systems to study whether and how these affect the development of the fetus. Understanding these mechanisms could potentially lead to interventions that could reduce the risk for autism.
A different view point was offered by Derrick MacFabe, M.D. He hypothesized that Proprionic Acid (PPA) produced by bacterial infections in the digestive tract leads to autism. He presented experiments showing how direct application of PPA to the brains of adult rats can lead to temporary changes in the animal that bear some similarity to autism, including atypical social and stereotyped behaviors, neuroinflammation, and seizure activity. Dr. MacFabe, like some other speakers, concluded that diet may be an important link to autism and argued that much more attention should be paid to the role of the digestive tract and metabolism in autism.
Susan Swedo, M.D., a researcher at the National Institute of Mental Health (NIMH) opened the final day of the science session by discussing the current NIH research programs on autism treatment, emphasizing the need to identify symptom phenotypes as a means to better target treatments and provide clues to the etiology of the disorders. Dr. Swedo discussed how their work in characterizing Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptoccocal infections (PANDAS), a subgroup of obsessive compulsive disorder (OCD) triggered by bacterial infection, led to identification of a specific type of OCD for which treatments could be targeted and for which biomarkers could begin to be identified. The NIMH is now applying a similar model to autism. Dr. Swedo and collaborators are looking for clinically meaningful subgroups of patients by examining patterns of symptom onset, specifically characterizing children who have early symptom onset and comparing them with children who have experienced a developmental regression. They are also paying close attention to biomedical issues, including environmental exposures and medical conditions, such as epilepsy and sleep disorders. Dr. Swedo closed her presentation by highlighting several treatment trials currently ongoing at the NIMH which seek to target specific symptoms, such as a study of donepezil (acetylcholinesterase inhibitor) for sleep, minocycline (anti-inflammatory) for maladaptive behavior, and riluzole (a glutamate modulator) for OCD symptoms.
J. Jill James, Ph.D. the Autism Speaks' Autism Treatment Network site director at the University of Arkansas Medical School, provided an update on the findings from several clinical trials of treatments targeted at the folate, methionine and glutathione pathways. An open label study of methyl-B12 and folinic acid supplementation in children with autism resulted in improvements in certain metabolites and improved adaptive behaviors as measured on the Vineland Adaptive Behavior Scales, demonstrating potential for the treatment and the need follow up with a placebo-controlled study. An on-going NIH-funded study on metabolic bio-markers is examining the relationship of metabolic abnormalities with autistic behaviors and gene polymorphisms, and hopes to identify metabolic biomarkers as a predictor of autism risk. Results to date from a study component using Autism Speaks' AGRE cell lines indicate that children with autism may be more vulnerable to environmental exposures promoting oxidative stress. Another study funded by the U.S. Department of Defense will examine the potential of glutathione redox in immune cells as a biomarker for regressive autism, and whether treatment of this pathway can improve immune function. Dr. James also highlighted an on-going treatment trial examining the effect of a nutritional supplement on behavior and metabolic profile.
In summary, the DAN! conference emphasized the complex interplay among a wide range of factors, and their role in both increasing the risk for autism and the health of individuals with ASD. Among the factors that were discussed were genes, ethnicity, environmental toxins, the immune system, infections, and diet. Speakers emphasized the need for future studies to examine the interaction among these different factors, which ultimately will help explain the different causes, symptoms, and health problems related to autism.