“We’re beginning to understand that genetics is really about vulnerability,” says neuroscientist Pat Levitt, director of the Vanderbilt Kennedy Center for Research on Human Development. Levitt and his colleagues recently discovered that a common variant of a gene called MET doubles the risk of autism. The finding was widely regarded as a breakthrough because MET modulates the nervous system, gut, and immune system—just the kind of finding that matches up with the emerging new view of autism.
“Everyone was focusing on genes expressed in the brain,” says Levitt, “but this gene is important for repair of the intestine and immune function. And that’s really intriguing because a subset of autistic children have digestive and immune problems.” Equally interesting is that the gene variant occurs in 47 percent of the population—in other words, it is just one contributing factor, and it probably works in concert with other vulnerability genes. And finally, in a twist that intrigues other researchers, the activity of the gene is affected by what is known as oxidative stress—the kind of damage one sees with excessive exposure to toxins. “As we identify other vulnerability genes like this,” says Levitt, who hopes to engineer a mouse model of this gene variant for study, “we may be able to develop effective interventions for children.”
(Click on each map to enlarge)
The Toxic Link to Autism:
The first two maps compare rates of autism in Texas
counties in the
early 1990s (top) and in the late 1990s
(center). The blue map (bottom)
shows pounds of
toxins released in each county in 2001. The darkest
patches in the blue map represent counties where
increases in autism
rates over the past 10 years have
been in the top 20 percent. The
correlation between
toxins and autism is suggestive, though not
definitive.
(Courtesy of Raymond Palmer, University of Texas
Health Science Center, and Stephen Blanchard,
Our Lady of the Lake University)
In other provocative research, Jill James, director of the Autism Metabolic Genomics Laboratory at the Arkansas Children’s Hospital Research Institute (and professor of pediatrics at the University of Arkansas for Medical Sciences) has found that many children with autism do not make as much of a compound called glutathione as neurotypical children do. Glutathione is the cell’s most abundant antioxidant, and it is crucial for removing toxins. If cells lack sufficient antioxidants, they experience oxidative stress, which is often found with chronic inflammation.
In her most recent study, published in the American Journal of Medical Genetics in 2006, James found that common gene variants that support the glutathione pathway may be associated with autism risk. Intriguingly, this pathway is linked metabolically to the methylation pathway. Methylation is a fundamental biochemical process that helps regulate which genes are expressed; abnormal methylation can cause disease. Because the pathway provides the precursors to glutathione, impairments in methylation can also lead to oxidative stress. “It’s very provocative,” James says. “It suggests that some autistic behaviors are a neurologic manifestation of a genetically based systemic, metabolic derangement.” Some of the abnormalities James saw in this study have already been associated with gastrointestinal and immunologic dysfunction.
The good news is that oxidative stress in some autistic children may be treatable with targeted nutritional intervention. James and her colleagues have tracked eight autistic children who were taking supplements of key nutrients in the methylation pathway—folinic acid, trimethylglycine, and methyl-B12—and found a significant increase in important markers of methylation and glutathione synthesis. The next step is to see if the symptoms improve as well.
James and her colleagues just received a $2.4 million grant from the NIH, part of which will be devoted to sorting out the relationship between metabolism, genes, and behavior. ”What would be incredible is if we could correlate individual differences in behavior with specific abnormal metabolites,” James says. They will then look at children between 18 to 24 months old, which is usually before autism is diagnosed. That could help identify the causes of the disease, as well as permit earlier intervention.
“We also plan to look at mitochondrial dysfunction,” she says. “Since mitochondria are the energy powerhouses of the cell, they’re also the place where the most free radicals (which play a role in oxidative stress) are produced. If the electron transport chain in the mitochondria is faulty and you’re not efficiently making ATP, you’ll produce more free radicals and deplete your glutathione. If this hypothesis turns out to be correct, we can give nutrients like coenzyme Q10, magnesium, and acetyl-L-carnitine to help stabilize the mitochondria. Now, this is just a hypothesis, but that’s the risk you take with science. You make your best guess and you carry out your study and you see.”
“It’s interesting to see metabolic abnormalities addressed this way,” says Isaac Pessah, chairman of Molecular Biosciences and director of the Center for Children’s Environmental Health and Disease Prevention at the University of California at Davis. “I think glutathione balance in the kids is potentially very important in terms of toxic environmental exposures.”
There is a growing sense, Pessah adds, that our heavily industrialized, chemical-soaked environment—and the way it acts on vulnerable genes in some individuals—may be a major culprit. In December 2006, Harvard researchers boldly announced in The Lancet that industrial chemicals may be impairing the brain development of children around the entire world. And at a November 2006 conference at the University of California at Davis’s M.I.N.D. Institute, Pessah gathered experts to discuss the clinical implications of environmental toxicology in autism. Says Herbert, “We discussed the enormous number of chemicals in our environment and how little we know about chronic, low-dose, multiple exposures and their effect on diseases like autism. Maybe the many autism cases we are now seeing are a new illness of the current generation.”
