Guest blogger & TACA Physician Advisory: Dr. Richard Frye
A recent study published in the October 2013 issue of The American Journal of Human Genetics reports to have identified a family of genes that not working as they should in children with autism1. This genetic study examined detailed changes in the genetic code in 811 individuals, 432 cases of children with autism and 379 ancestry-matched controls. Matching on ancestry has been recently recognized as important as some previous studies which claimed to find clear changes in the genetic code related to autism were later heavily criticized because the individuals with autism and the comparison control group had slightly different ancestries, making the genetic changes much more likely to be due to differences in ancestry rather than anything to do with autism. The current study demonstrated that children with autism did indeed have more deletions (missing pieces) in their genetic code than the controls. This is nothing new as several studies have suggested that children with autism have more genetic pieces missing or duplicated. However, these researchers took a very sophisticated and broader view of the significance of the genes that they found missing. These researchers used something called pathway analysis to ask whether many of the genes that were abnormal in the children with autism were connected in some specific way. This type of analysis looks at a large database of known connections between genes to determine if the genes that are disrupted are just randomly disrupted or whether there might be some pattern to these genetic disturbances. Finding that a specific pathway is disrupted would implicate the specific pathway in the disease that is being investigated. This pathway analysis found that the genes disrupted in the children with autism were more likely to be connected in specific pathway whereas the genes that were disrupted in the controls appeared to be randomly disrupted without any specific pattern implicated. The pathway that was implicated in the children with autism was involved in something called autophagy (more on this latter).
The cause of the autism spectrum disorder is not known despite decades of research. A majority of research on autism has concentrated on genetic causes and autism has long believed to be a genetic disease. However, a genetic cause of autism does not explain the exponential rise in the disorder over the past two decades. Indeed, it takes many generations for a genetic disease to spread throughout the population and commonly genetic disease do not spread since there needs to be some advantage for a specific genetic trait to spread. This is one of the reasons that many scientists and public health professionals doubt that the rise in autism is real and suggest that it is due to purely a change in diagnosis – a true rise in autism just does not make sense if it is a genetic disorder. However, more and more research has been demonstrating that the causes of autism are probably a combination of the environmental and genetic influences with the environment have an equal or greater influence as compared to genetic factors.
One of the accepted medical tests for children with autism is genetic testing. This can include specific examination of genes if a child appears to fit a known syndrome or a test called a chromosomal microarray if symptoms of a specific genetic disorder are not obvious. The chromosomal microarray looks for small pieces of the chromosome that are missing or duplications. Such small changes can disrupt the function of the genes in the area of the chromosome where the genetic material is missing or duplicated. The fidelity of this test has increased considerably over the last 5 years, allow the detection of smaller and smaller pieces of the chromosome that are missing or duplicated. Over the last 5 years the ability to examine the details of the genetic code of every gene in the body that provides active instructions to the cell (the so-called exome) has grown. However, over this time period of exponential growth in genetic technology the magic “autism gene” has not been discovered. In fact, this powerful technology has mostly found very rare mutations in gene important for neurodevelopment in a very small number of cases of the large samples of children studied. Furthermore, most of these mutations are what is called de novo, which means that they were not even inherited from their parent’s genes but instead were acquired. So what causes an acquired genetic disease? — you guessed it – environmental factors, including exposures to toxins, nutritional deficiencies, etc.
Most genetic studies search for genes involved in brain function but by taking a broad and careful look at patterns of gene disruption, the researchers in this new study found a disruption in a pathway that was unexpected. So what is the importance of this pathway that was discovered to be disrupted in children with autism? Autophagy is the process by which every cell in the body maintains itself as healthy by several mechanisms. One of the major roles of autophagy is to clean up the waste in the cell. When a part of the cell becomes old or damage, autophagy processes recycle these old and damaged parts of the cell by breaking them down to make building blocks to rebuild the cell. Without autophagy, old and damage parts of the cell build up resulting in cellular dysfunction. This is like never throwing out you garbage and allowing it to fill up your house – your house would be a difficult place to live in after a while. These failures in autophagy have been implicated in aging and cancer.
This could also explain many of the metabolic abnormalities we find in children with autism. Many cellular elements become primarily damaged from reactive oxygen species in the cell which cause oxidative stress. There are many studies which have demonstrated increases in these types of damaged cellular elements in children with autism. If these are not destroyed and recycled, they can result in increased cellular oxidative stress, further challenging the ability of the cell to maintain an adequate redox state and decreasing glutathione. This can make cell more susceptible to environmental toxins and increase the need for specific nutrients – all findings associated with autism. In addition, excess cellular waste can results in that activation of inflammatory processes – another theme associated with autism. In addition, autophagy is also involved in the pruning of synapses that is so important for brain development very early in life and can result in the large brain size we see in some children with autism.
Overall, this genetic study has provided some interesting insights and has demonstrated how disturbances in systematic biological processes of the body (not just biological processes isolated to the brain) might have a role in the development of autism. Since these genetic changes were found to be most inherited from the autistic children’s parents, it is very likely that their parents may have been effected by these same processes, although to a lesser extent as they, on average, probably only had half of the genetic abnormalities each. However, still it is difficult to see how these genetic changes can result in the dramatic rise in autism over the last few decades. Rather, these genetic changes appear to be risk factors which increase the susceptibility of children to detrimental environmental factors during critical times of development. Importantly, understanding studies like these help us better understand that biological abnormalities that are underlying the cause of autism in order to point us in the right direction for determining the best treatments and methods for prevention.
For more information on TACA’s Physician Advisory board or Dr. Richard Frye’s full biography, please see https://www.tacanow.org/about-taca/physician-advisory-board/