By Richard E Frye, M.D., Ph.D., Shannon Rose, Ph.D. and S. Jill James, Ph.D.
The number of children diagnosed with autism spectrum disorder (ASD) is alarmingly high and appears to be continuing to rise. Despite decades of research, the cause of autism is still not clear. The majority of research into the causes of autism has continued to concentrate on genetic disorders, despite that fact that single gene or chromosomal defects only account for a minority of cases of autism (1.) Furthermore, recent research has demonstrated that environmental factors have at least as much and possibility more influence on the risk of developing autism as compared to inherited factors.
Several areas of research have started to become recognized within the last 10 years which implicate abnormalities in the way the body and the cells function in individuals with autism. These include abnormalities of: 1) the energy generation system of the cell known as the mitochondria, 2) the regulation of toxic molecules know as reactive oxygen species and 3) the immune system which protects the body against harmful organisms. What is important about all three of these biological systems is that they all can be negatively influenced by the environment depending on a genetic predisposition. In addition, all of these abnormalities are known to interact with each other such that an abnormality in one can cause an abnormality in the other. For example, dysfunction in immune cell mitochondria can result in an abnormal increase in reactive oxygen species, which, in turn, can further damage the mitochondria resulting in more mitochondrial and immune dysfunction. Thus, these abnormalities can interact with each other to create a vicious spiral which could result in significant damage to the cells in the body.
Until now these potentially detrimental interactions between reactive oxygen species and mitochondria in children with autism have remained primarily theoretical. That is, research has separately demonstrated problems with mitochondrial function and increased levels of oxidative stress in individuals with autism but few studies have demonstrated that there is a link between these two. The few studies which have demonstrated a link between increased levels of reactive oxygen species and mitochondrial dysfunction but these have only been correlative associations, making it impossible to know which came first or whether both abnormalities were initiated by something else like inflammation.
Just last week, researchers from the Arkansas Children’s Hospital Research Institute’s Autism Research Program published a research study which provides insight into the connection between mitochondrial function and oxidative stress (2.) These researchers measured mitochondrial function in cultures of immune cells derived from children and adolescents with autistic disorder as well as age and gender matched control cells before and after adding a chemical that increased reactive oxygen species. It was found that a subset of cells in the group of individuals with autistic disorder were highly sensitive to the increase in reactive oxygen species such that only a low level of reactive oxygen species was needed to make the mitochondria fail. This sensitivity of reactive oxygen species was found in approximately one-third of the cell cultures derived from children with autism. What is also interesting is that even without the added increased levels of reactive oxygen species mitochondrial function of this subgroup of cells appears to be different, demonstrating marked mitochondrial overactivity. These researchers also identified a molecular target in the mitochondria that might be abnormal in this subgroup of individuals with autism. A protein called uncoupling protein 2 which regulates reactive oxygen species at the site of the electron transport chain was found to be increased in this subgroup of cells.
This study helps clarify the connection between oxidative stress and mitochondrial dysfunction. It suggests that mitochondrial function can be particularly sensitive to reactive oxygen species in individuals that have a particular predisposition. The study also suggests that this sensitivity is found in a subgroup of individuals with autism. Interestingly, reports have demonstrated that some children with autism may have a different type of mitochondrial disorder than is commonly recognized as mitochondrial disease. Indeed, children with autism and mitochondrial disease have been shown to have over activity of the mitochondria, rather than the under activity that is typically associated with mitochondrial disease in non-autistic individuals. In addition, recent meta-analyses have suggested that approximately one-third of patients with autism have blood biomarkers of mitochondrial disease.
Altogether, this study, along with previous research, suggests that a significant number of children with autism may have a novel type of mitochondrial dysfunction. Furthermore, this type of mitochondrial dysfunction appears to result from a predisposition (potentially inherited) combined with metabolic stressors (increased levels of reactive oxygen species). As an increase in reactive oxygen species causing metabolic stress is ubiquitous, resulting from a wide variety of environmental exposures, this is potentially a very important connection between environmental factors and cellular dysfunction. This study demonstrates one potential way in which the environment can influence an individual with a predisposition to cause mitochondrial dysfunction. Most importantly, this suggests that it might be possible to identify individuals with this predisposition early and provide treatment that can protect them from the influences of potentially detrimental environmental factors.
Editors note: I have enormous gratitude for this study and the researchers work. Many TACA families have reported back abnormal labs regarding mitochondrial function. Following American Academy of Pediatric treatments for these abnormalities children and their autistic symptoms greatly improve. For families looking into more information on the tests, potential treatments and what to do next please see the work of TACA Physician Advisory Dr. Dan Rossignol: http://www.rossignolmedicalcenter.com/simple-approach/ – Simplified Approach to Mitochondrial Dysfunction in Autism ~ Lisa