Although scientists diligently seek the genetic underpinnings of autism, the spectral nature of the disorder has made it difficult to find a “smoking gun” gene. Some researchers hope that their research into the role of environmental risk factors will help explain the disorder’s causes.
The challenges of a spectrum
Autism spectrum disorders are complex and pervasive developmental conditions that affect brain development in the areas of communication, cognition and social interaction. The disorders, which usually manifest themselves during the toddler years, show a great deal of variability from child to child.
“Not all children with autism have the exact same set of characteristics,” says Karl Kuban, a professor of pediatrics and neurology at Boston University. “Some have better-developed language skills, some have profound cognitive disabilities and some are very high functioning with just a few behavioral quirks. What we’ve learned is there is a wide range of phenotype [observable characteristic] in how autism presents itself, but it’s all variations on the same theme.”
But do these variations stem from specific genetic differences? During the past decade, many geneticists have been trying to answer that question.
“We suspect, but don’t know, that different genes are involved at different levels across the spectrum,” says Jonathan Haines, a geneticist at Vanderbilt University. “Trying to identify specific genes requires us to look at the spectrum in a lot of detail and sort out which subtypes or subtyped behaviors might be correlated to specific genes.”
Haines argues that although autism does not follow a typical Mendelian pattern of inheritance, via dominant and recessive genes, researchers have uncovered some common genetic variants that may be important. One of these is copy number variation, the seemingly random deletions and duplications of genetic material that affect how often certain DNA sequences repeat. “The copy number variations do seem to be showing up more frequently in people with autism than in the normal population,” Haines says. “But there is still a lot that we just don’t know.” (Insights into copy number variation were one of Nobel Prize–winning researcher Eric Kandel’s 2008 neuroscience developments of the year.)
What may be causing some of these genetic anomalies? And how might the environment be involved?
Environmental risk factors
“One possible story is that there is a strong genetic effect, but the environment is changing some kind of gene-environment interaction that tips individuals onto the spectrum,” says Steven Buyske, a statistician at Rutgers University who works on autism genetics studies. Anecdotal evidence has pointed at such environmental factors as pre-term birth, age of parents and pesticides as potential risks for autism. Epidemiological researchers across the country are attempting to verify some of these claims.
In the Jan. 28 issue of the Journal of Pediatrics, preliminary findings from the Extremely Low Gestational Age Newborns (ELGAN) study, a large-scale epidemiological study, suggest that children who are born more than three months prematurely are more likely to show autistic symptoms at 16–30 months of age.
“What we found was a rather eye-popping 21 percent of kids screening positive for autism,” Kuban says. But since extremely early birth is also associated with myriad other substantial cognitive impairments, the researchers filtered the sample to remove children diagnosed with common motor, visual and aural handicaps and ran the numbers again.
“We still identified 16 percent that screened positive,” he says. “And then we went to an extreme and removed children that showed a strong cognitive impairment, and we still had positive screens at around 7 percent.”
Kuban concedes that these findings are preliminary but argues that the work presents some interesting questions. “It seems that pre-term birth does play some kind of role,” he says. “But it’s not fair to think that early birth causes autism. Instead, it’s more likely that pre-term birth and autism share some common risks. Or, the things that cause a child to be born early may also put that child at risk for altered brain development.”
Environment and prenatal development
Irva Hertz-Picciotto, an epidemiologist and director of the Childhood Autism Risk from Genetics and the Environment (CHARGE) study at the University of California, Davis, focuses on the effects of different in utero environmental exposures (such as pesticides, medications, flame retardants and fertility treatments) on birth and later development. Hertz argues that studying this prenatal period is critical to a better understanding of autism’s origins.
“There’s no single area of the brain that we can point to and say, ‘Look, there’s the lesion that causes autism,’ ” she says. “This disorder has a fairly diffuse manifestation that you can see across the brain. There is some early insult that is affecting the brain in its very early stages that we just don’t understand yet.”
But one of the most interesting findings from the CHARGE study involves not such brain insults but rather the immune system. “The findings have repeatedly pointed to immune-system alterations in children with autism,” Hertz-Picciotto says. “There’s just something different about how these kids’ immune systems respond compared to typically developing children.”
These differences may provide a key to understanding how brain development veers off course in autism. “The immune and nervous system communicate a lot,” she says. “Neurotransmitters don’t only play a role in the central nervous system; they have receptors on immune cells. Similarly, immune messengers like cytokines have receptors on brain tissue.”
Just crossing the starting line
Hertz-Picciotto says that researchers don’t yet understand if the immune system is influencing the brain, the brain is influencing the immune system or some combination of the two. But it is unlikely that autism’s secrets will be unlocked without examining both genes and the environment.
“We know that genetics play an important role in autism. But we also know that autism has some linkage to just about every human chromosome,” says Hertz-Picciotto. “That really points the finger back at the environment side.” She believes that both genes and the environment need to be examined simultaneously to move our understanding of autism and its effects on the brain and immune system forward.
Buyske agrees but cautions that autism studies are in their infancy. “Autism research in general has gone from very little, say 10 to 12 years ago, to a lot of interest in it today,” he says. “It is very complicated, and that is frustrating, but we’re learning a lot of stuff in a lot of ways all at once. My hope is that we’ll soon start seeing some happy coincidences and the picture will get a lot clearer.”