The Autistic Brain: Thinking Across the Spectrum (9 page)

But even if geneticists do manage to correlate a mutation with autism (regardless of whether the mutation is related to other conditions), they still don’t know if one mutation alone is sufficient to create an autistic-like trait, or whether the emergence of a single trait depends on a combination of mutations. In recent years, opinion has shifted toward this multiple-hit hypothesis, thanks in large part to findings coming out of Eichler’s lab. “The development of the brain is probably very sensitive to dosage imbalances,” he said,
describing his findings. One insult—as geneticists call a mutation with the potential to damage health—may be enough to cause havoc. And two? Good luck.

That conclusion has been reinforced by other labs. For instance, a 2012 analysis
of mutations in the SHANK2 gene—which codes for a synaptic protein, like SHANK3, neurexins, and neuroligins—would have been significant if it had found only further support for a link between autism and mutations in genes related to neural circuitry. But the study, based on 851 subjects diagnosed with ASD and 1,090 controls, also found that all three subjects with the de novo SHANK2 mutation also carried hereditary mutations in a section of chromosome 15 long associated with autism.

“For these patients, it’s like the genome cannot cope with that extra de novo event,” said
lead investigator Thomas Bourgeron, professor of genetics at the University of Paris, Diderot. “It may be like nitro and glycerin. Alone they’re okay. But if you mix the two, you have to be very careful.”

For me, the multiple-hit hypothesis is supported by observations that I’ve made again and again when I’ve met with families over the past twenty years. I’ve noticed that in a lot of cases, a kid with autism has at least one parent who exhibits a mild form of autistic behavior. A kid with severe autism often has two parents who exhibit this behavior. If both parents are contributing copy number variations of a kind that pose a higher risk for autism, then the incidence of autism in the children in those families is naturally going to go up. The more you load the dice on both sides of the family, the likelier you are to have a kid with a problem.

So far I’ve been addressing only hereditary and de novo mutations—those that are present at or near conception. But geneticists also study what happens to genes throughout pregnancy and over the course of a lifetime—a period when environmental factors enter into consideration. Can automobile exhaust contribute to autism? The mother’s diet during pregnancy? Vaccines?

If your genes carry a higher risk for an environmental factor triggering a disease or condition, then we would say you have a genetic
susceptibility
or
predisposition.
If environmental factors interact with your genes in such a way as to cause a genetic change, then we would say you have an
acquired
or
somatic
mutation. Research into environmental influences on autism, however, is much less conclusive, and often much more controversial, than research into genetic factors alone.

“It is widely accepted that autism spectrum disorders are the result of multiple factors, that it would be extremely rare to find someone who had a single cause for this behavioral syndrome,” the environmental epidemiologist Irva Hertz-Picciotto said
in 2011. “Nevertheless, previous work on genes has generally ignored the possibility that genes may act in concert with environmental exposures.”

Hertz-Picciotto has served as the principal investigator of Childhood Autism Risks from Genetics and Environment (CHARGE), a research program at the Medical Investigation of Neurodevelopmental Disorders (MIND) Institute at the University of California, Davis. “We expect to find many, perhaps dozens, of environmental factors over the next few years,” Hertz-Picciotto said,
“with each of them probably contributing to a fraction of autism cases. It is highly likely that most of them operate in conjunction with other exposures and/or with genes.”

What was the organizing principle behind such a massive project? Hertz-Picciotto says
that from the start, the members of the collaboration had decided to divide their investigations into three areas: nutrition, air pollution, and pesticides.

The first CHARGE study
to attract national attention, in the journal
Epidemiology
in 2011, found that the combination of certain unfavorable genes and a mother’s lack of vitamin supplementation in the three months prior to conception and during the first month of pregnancy significantly increased the risk for autism. Another CHARGE study,
published in 2011 in
Environmental Health Perspectives,
found that children born to mothers living less than two blocks from a freeway were more likely to have autism, presumably due to exposure to automotive exhaust. A third CHARGE study,
published in 2012, found that among the mothers of children with ASD or developmental delays, over 20 percent were obese, while among the mothers of typically developing children, 14 percent were obese.

Some CHARGE studies have been much less conclusive—for instance, this finding from another 2012 paper
: “Certain pesticides may be capable of inducing core features of autism, but little is known about the timing or dose, or which of various mechanisms is sufficient to induce this condition.” In fact, the conclusion of that paper was essentially a plea for further research: “In animal studies, we encourage more research on gene × environment interactions, as well as experimental exposure to mixtures of compounds. Similarly, epidemiologic studies in humans with exceptionally high exposures can identify which pesticide classes are of greatest concern, and studies focused on gene × environment are needed to determine if there are susceptible subpopulations at greater risk from pesticide exposures.” Direction for further research isn’t unusual in scientific papers, but the breadth of the request in this case was notable. In fact, an editorial
in the July 2012 issue of
Environmental Health Perspectives
made a similar plea—and not just regarding pesticides. Instead, it called for the investigation of anything out there that might be hazardous—the “formulation of a systematic strategy for discovery of potentially preventable environmental causes of autism and other NDDs,” or neurodevelopmental disorders.

“I think people had unrealistic expectations,” Hertz-Picciotto says. “People in the genetics field really thought that was going to be
the
story.” Instead of “looking for the rarer and rarer and even rarer mutations,” she says, they might have better luck trying to link environmental factors with
common
genetic variants.

I myself have often wondered if the increase in prescription-drug use over the past few decades has contributed to an increase in the incidence of autism. In June of 2011, the Food and Drug Administration issued a safety alert
cautioning pregnant women about a possible connection between cognitive development and the use of valproate, a mood stabilizer as well as a seizure medication. Later that same year, two studies
showed that children whose mothers had taken valproate during pregnancy had a higher risk for low IQ and other cognitive deficiencies as well as autism and other disorders along the ASD spectrum. “An estimated six to nine percent of babies exposed to valproate
in utero
develop autism,” reported
the website for the Simons Foundation Autism Research Initiative, “a risk several-fold higher than in the general population.”

The first study
to investigate a link between antidepressant use and autism specifically, conducted by the Kaiser Permanente Medical Care Program in northern California, didn’t appear until 2011. The study compared 298 children with ASD, along with their mothers, to more than 1,500 control children, along with their mothers, and it did find evidence for a slightly higher risk among those mothers who used antidepressants during or immediately prior to pregnancy. Okay, I thought, but maybe a mother who needs antidepressants already has more at-risk CNVs, meaning that the trigger for autism might be something related to the depression, not to the antidepressants. But the study took that possibility into account and found that mothers who were depressed but did not take antidepressants showed no increased risk level.

Risk levels, though, are relative. The study concluded that antidepressants are “unlikely to be a major risk factor.” But what about a minor risk factor? The research indicated that mothers who took antidepressants during the year before delivery had a 2.1 percent greater risk of having children with ASDs, and the greatest increase in risk, 2.3 percent, came when the drug was taken during the first trimester.

But here’s the thing. I think Prozac is a fabulous drug. I have friends who would be in really bad shape if they weren’t on Prozac, Lexapro, or some other selective serotonin reuptake inhibitor. I know people who have been
saved
by these drugs. I myself wouldn’t be functional without them. They can transform a life merely being lived into a life worth living. So women who are pregnant or are thinking about becoming pregnant and who take antidepressants should consult a doctor and weigh the risks and benefits.

In any case, we have to be very careful about looking for cause-and-effect relationships between environmental factors and genetics. As every scientist knows, correlation does not imply causation. An observed correlation—two events happening around the same time—might just be coincidence. Let’s use the now infamous vaccination controversy as a way to look at the logical complexity of a causation-versus-coincidence argument. The story goes like this.

Parents routinely have their children vaccinated around age eighteen months. Some parents note that their children begin exhibiting signs of autism around age eighteen months—withdrawing into themselves, reversing the gains they’d made in learning language, engaging in repetitive behaviors. Is the correlation between certain vaccines and the onset of autism an example of coincidence or causation? Along comes a study in the British journal
The Lancet
in 1998
that offers the answer: causation. Parental outrage ensues,
⁴
as does a widespread grassroots movement to persuade parents not to have their children vaccinated. Yet numerous follow-up investigations can’t replicate the results of the 1998 study, and in 2010, following an investigation by the UK General Medical Council that determines the research was misleading and incorrect,
The Lancet
retracts
the study.

End of story? Not quite.

In fact, some children have been known to get incredibly sick and manifest severe symptoms consistent with autism very shortly after receiving the eighteen-month vaccinations. In those rare cases, the correct diagnosis has turned out to be a mitochondrial disease. The nucleus of a cell holds the chromosomes; that’s where our genes are encoded. But outside of the nucleus, in the cytoplasm of the cell, are organelles (the word comes from the idea that organelles are to the cell what organs are to the organism), and some of these organelles are mitochondria. Every cell has hundreds to thousands of mitochondria. Their purpose is to take chemicals in the body and convert them into usable energy. Mitochondria have their own DNA, separate from the DNA in the chromosomes. And just like the DNA in the chromosomes, mitochondrial DNA can suffer mutations. In some cases, the vaccination and the onset of symptoms might indeed be related. Some of the symptoms might be relatively mild, some might be life-threatening, and some might include loss of muscle coordination, visual and hearing problems, learning disabilities, gastrointestinal disorders, neurological problems. All of these symptoms would be part of the mitochondrial disease, and all of them would be consistent with autism.

“There’s intense research going on in this area,” says G. Bradley Schaefer, a neurogeneticist at the Arkansas Children’s Hospital Research Institute as well as the lead author of the guidelines for genetic testing in children for the American College of Medical Genetics in 2008. “But not enough is known to make conclusions.” The 2013 update of the guidelines wasn’t publicly available at the time of this writing, but Schaefer did summarize the recommendations in an interview for this book: “There’s been this question about mitochondrial influence in autism, there’s research going on, there’s clearly anecdotal cases—but right now we don’t recommend routine testing due to the lack of sufficient objective evidence to support it.” (Also, such testing is expensive and difficult, and it usually requires a muscle biopsy.)

A perhaps more compelling example
of a genetic predisposition is in the DRD4 gene, which codes for a receptor that regulates the level of dopamine in the brain. Some people possess a variant of the DRD4 gene called DRD4-7R, the
7R
for “7 repeat allele,” meaning that its nucleotide sequence repeats seven times. The brains of people who possess the 7R version of the DRD4 gene are less sensitive to dopamine—a neurotransmitter
that affects brain processes involving movement, emotional response, and the ability to experience pleasure and pain—putting them at risk for attention and conduct disorders. For this reason, the 7R version of DRD4 has been called the brat gene or the drinking gene.

On a more clinical (and linguistically charitable) level, numerous studies have linked this allele with anxiety, depression, epilepsy, dyslexia, ADHD, migraines, obsessive-compulsive behavior, and autism. For example, a study
published in 2010 reported several associations between autistic children with the 7R variant and their parents.

• Children with the 7R variant who had at least one parent with the 7R variant were significantly more likely to exhibit tic-like behaviors than those whose parents did not have the 7R variant.
  
• If the father had the 7R variant, a child with the 7R variant was more likely to exhibit behavior consistent with obsessive-compulsive disorder and tic severity.
  
• If the mother had the 7R variant, a child with the 7R variant was more likely to exhibit behavior consistent with oppositional defiant disorder and social anxiety disorder.
  

Scientists have known for a while that children with the 7R version of DRD4 (as well as other “risk” genes, like MAOA and SERT) are vulnerable to negative influences from their environment—an abusive or unsupportive parent, for example. Those negative influences can produce more severe versions of whatever behavior the child is already manifesting. For this reason, scientists long considered the 7R version to be the “poster gene” for genes that interact with a negative environment to create negative behavior. Hence its nickname: vulnerability or risk gene.