Searching for early signs of autism spectrum disorders
(This article was first printed in the November 2007 issue of the Harvard Mental Health Letter.)
Autism spectrum disorders (ASDs) continue to generate debate in the mental health field. This has been fueled in part by the ongoing controversy about whether childhood vaccines somehow trigger these disorders in some children. Although the Institute of Medicine has issued three comprehensive reports reviewing the scientific literature — the most recent published in 2004 — and each time concluded that vaccines are safe, the issue refuses to go away.
In June 2007, for instance, a federal “vaccine court” began hearing testimony about whether a vaccine triggered autism in a girl who is now 12 years old. Hers was the first of three test cases scheduled to be heard by the U.S. Court of Federal Claims in 2007. (An additional 4,800 petitions concerning vaccine safety have been filed with the same court.) The court has said it will not issue a ruling until after the last of several written briefs are submitted in 2008.
Meanwhile, evidence mounts that ASDs are caused by what happens before vaccination, and probably before birth. Research shows that genetic vulnerability is of fundamental importance. Furthermore, scientists are documenting ever-earlier behavioral clues that a child may be at risk for developing an ASD, with the hope of improving detection and treatment.
Complicated genetic picture
ASDs consist of five pervasive developmental disorders: autistic disorder, Asperger’s disorder, childhood disintegrative disorder, Rett’s disorder, and pervasive developmental disorder not otherwise specified. The consensus is that the five disorders vary in severity, with gradations of symptoms.
For the most part, it’s not clear what causes ASDs, but experts agree that an interaction between genes and environment results in abnormal brain development and symptoms. But the debate continues about which genes and what environmental factors are involved.
Evidence that genes contribute significantly to the development of ASDs, either by increasing susceptibility or causing particular symptoms, comes mainly from studies of identical twins. Various analyses of concordance rates have revealed that if one identical twin develops an ASD, then 82% to 92% of the time the other one will also develop the disorder. The concordance rate drops to 10% or less in fraternal twins, who don’t share as many genes.
Epidemiologic studies from around the world also show that older parents are more likely to have autistic children. Often this reflects the fact that genetic mutations become more likely the more that cells divide. For example, the germ cells that give rise to sperm make copies of themselves throughout life. After several decades, germ cells are copies of copies of copies. This increases the chance of duplication errors.
One Israeli study found that children of men who were 40 or older were almost six times as likely to develop an ASD compared with children of men younger than 30. Likewise, a U.S. study found that children born to mothers who were 35 or older were more than three times as likely to have an ASD compared with those born to younger women, while a European study found the risk of having an autistic child more than doubled for mothers 35 or older.
Scientists identified the gene responsible for most causes of Rett’s disorder in 1999. But finding the responsible genes that cause other, more common ASDs has been difficult. Scientists have evaluated more than 100 candidate genes so far, and while several look promising, none have yet been proven to cause ASDs. Some researchers think that 5 to 10 (or more) genes must somehow interact to create vulnerability.
Complicating the search is the heterogeneity of ASD symptoms, which can involve three types of behaviors: impaired speech, problems in interacting socially, and a tendency toward repetitive behavior and interests. ASDs also differ in terms of symptom onset and degree of severity. It is likely that different genes contribute to the different symptoms and subtypes.
Given the challenges, some researchers are trying to identify ASD endophenotypes — subtle signs of an underlying genetic aberration, such as atypical electrical activity in the brain while looking at a face. Compared to complex behavior, endophenotypes might be easier to trace back to particular genes.
Environmental factors debated
Others are searching for environmental culprits, both because concordance rates in identical twins are not 100%, and because there is enough variation in symptoms, even in twins, to suggest that something besides genes must be involved in ASDs.
A review in 2007 in the Archives of Pediatric and Adolescent Medicine found evidence that prolonged or acute oxygen deprivation during fetal development or delivery plays a role in promoting ASDs. Oxygen deprivation may occur as a result of maternal hypertension, gestational diabetes, or prolonged or complicated labor.
Potentially neurotoxic agents have also been investigated. A review that examined specific drugs and toxins, published in Trends in Neurosciences, found that the strongest evidence exists for prenatal or perinatal exposure to viral infections, two drugs (thalidomide and valproic acid), and organophosphates (chemicals found in pesticides and insecticides). Such agents might be particularly harmful to the developing brain, according to an analysis in the Lancet, which argued that the blood-brain barrier, which protects people from toxins, does not fully develop until an infant is 6 months old, and that young children are more likely than adults to absorb toxic chemicals and are less able to detoxify them.
Advancing earlier detection
Even as researchers try to determine why ASDs develop, others have been documenting ever-earlier signs and symptoms of the disorders to make it easier to identify at-risk children. The issue is important because children are diagnosed with an ASD, on average, at around age 3. Yet diagnosing these disorders earlier might enable earlier intervention with special education and cognitive behavioral techniques. The hope is that early treatment will improve learning, communication, and social skills.
Researchers have reported a number of intriguing findings. Prospective studies of infant siblings of children already diagnosed with an ASD indicate that by their first birthday, babies later diagnosed with an ASD are less likely than other babies to make eye contact, follow objects visually, turn in response to hearing their name, to smile, or to imitate other people. Some abnormalities are evident even earlier. Babies who are passive and inactive at 6 months, but then extremely irritable or lacking in positive emotions at 12 months, are more likely than others to be diagnosed with an ASD.
Several initiatives are underway to advance earlier detection and improve diagnosis. For example, the CDC has partnered with the American Academy of Pediatrics (AAP) and several advocacy and research organizations to launch a national public awareness effort, the “Learn the Signs. Act Early.” campaign, to educate parents and others about the earliest signs of a developmental problem such as ASDs. (For more information, visit www.cdc.gov/ncbddd/autism/actearly.)
Both the American Academy of Neurology and the AAP have issued developmental screening guidelines. The AAP recommends that pediatricians start evaluating children for ASDs and other developmental disorders in infancy, during regularly scheduled visits, and conduct developmental screening tests at 9, 18, and 30 months.
At the state level, a particularly innovative program is the Massachusetts Child Psychiatry Access Program (MCPAP), launched in July 2004 with the goal of making child psychiatry services more accessible to pediatricians, who are in the best position to spot mental disorders in children. MCPAP is operating in six locations around the state. Pediatricians enrolled in MCPAP call the program located nearest them and, within 30 minutes, are able to speak with a child psychiatrist, social worker, or care coordinator, who answers questions about screening, diagnosis, or treatment of psychiatric disorders, including ASDs. The program, which is funded by the state department of mental health, is offered at no cost to pediatricians.
Of course, the long-term goal is to find a combination of biomarkers and behaviors that will enable doctors to identify children at risk for ASDs even earlier than is now possible. Given the brain’s marvelous plasticity, the hope is that it may be possible in the future to intervene and help the brain “rewire” to either avoid an ASD or minimize the consequences.
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