When Adrianna and Jermaine Hannon's second child, Jayden, was 14 months old, the California couple began to worry that something was wrong. The child became preoccupied with toy cars, turning them over and rolling their wheels ceaselessly at an age when most other toddlers flit from one activity to another. Jayden would also line up cars, magazines or blocks on the floor or a table in as straight a line as he could make, never stacking objects as other kids would.
At 16 months, Jayden began to stop blurting the short phrases he had been using for four or five months—“Up, Mom,” “Picky-up” and “Abby,” his big sister's name—and he rarely looked toward family members when they called. One day around that same age, a large pot dropped by accident near to where Jayden was sitting, but the toddler did not respond at all. The pediatrician told Adrianna not to worry about Jayden's behavior, because child development tends to occur in bursts, especially in boys, and speech often develops later than in girls. At the pediatrician's request, Adrianna and Jermaine took their child to an audiologist to test his hearing, which turned out to be normal.
Jayden took another turn for the worse at 18 months when a high fever of 104 required a visit to the emergency room. A complete medical workup failed to locate the source of the fever, and the child returned home with his parents. The temperature eventually subsided, but Jayden never spoke another word. Neither did he respond when his name was called, and he made eye contact only with his mother.
This alarming series of events in Jayden's life still had not tapered off by 22 months. If he wanted something, he would grab Adrianna's or Jermaine's hand and bring them to the object he desired. He continued to be captivated by toy car wheels, rolling them without pause. He also was enthralled with a Mickey Mouse video on his iPad, which he would play over and over until asked to stop. Jayden loved, too, a program featuring the chugging Thomas the Tank Engine, with its crashing sound effects. The parents eventually decided to bring Jayden to a nearby early intervention clinic for children suspected of having autism, or, in clinical terminology, autism spectrum disorder—a condition marked, to varying degrees, by persistent deficits in communicating and interacting with others and a propensity to engage in repetitive behaviors, such as rocking or repeating sounds over and over.
Based on the careful observation of Jayden over the course of a few hours and on the wealth of details furnished by his parents, a psychologist at the clinic gave Adrianna and Jermaine the devastating news that their child did, indeed, have autism. Both parents initially wondered if they could have done something to cause the disorder. And, despite their suspicions, Adrianna recalls, Jermaine, an engineer, took a while to “get his head around” the clinic's confirmation of their fears. Having taught special education classes for 12 years, Adrianna took the diagnosis more in stride. She kept going by repeating to herself silently: “I can't quit,” adding in another inspirational motto: “If I can't give him my all, then what can I expect anyone else to give him?”
Adrianna and Jermaine's experiences with Jayden resemble those of the thousands of parents whose children receive a diagnosis of autism spectrum disorder every year. As in Jayden's case, the condition remains a vexing enigma that taxes a physician's diagnostic powers. In the 70 years since psychiatrist Leo Kanner first coined the term “early infantile autism,” scientists have yet to find any objective measurement—whether a molecule, a gene, electrical activity in a brain circuit or a consistent difference in brain size—to pinpoint how it originates.
Researchers are desperately trying to identify such biological clues in the hope that the information will facilitate diagnosis and the development of better treatments. To date, some drugs have shown that they can manage the irritability, mood swings and tantrums that afflict the child with autism. But nothing approved by the Food and Drug Administration deals with the basic symptoms: the language, social problems and repetitive gesturing.
The need is pressing. In the U.S. alone, about 800,000 people younger than 18 years are on record as having autism spectrum disorder, and the number continues to move upward. Some of the rise stems from increased screening: for nearly six years the American Academy of Pediatrics has recommended examining all children at 18 and 24 months of age for the telltale signs. The trend also results from a broadening of the complex diagnostic criteria for autism spectrum disorder. But even if those changes had not occurred, the numbers of families needing help would be large.
The seemingly bleak outlook is counterbalanced by a few encouraging recent developments. In the past few years medical professionals have begun to spread the important message that a few nonpharmaceutical treatments can profoundly help children like Jayden. Begun early, therapies that ground the child with autism in appropriate forms of social behavior—such as looking at a mother's face as she speaks—may mean the difference between years in a special school or institution versus a normal track for the elementary and secondary years and the eventual hope of an adulthood with a job and family. In coming years, what is more, behavioral therapies may be supplemented by new technologies that will provide a definitive diagnosis before children reach their second birthday and by drugs that may correct biochemical imbalances underlying the disorder.
Early Interventions Bring Hope
Waiting another decade for approval of a new drug is an agonizing prospect for the parents of a recently diagnosed child. Initial despair, however, can be tempered by the knowledge that a few good treatment options already exist. The latest research has shown that the brain of a toddler with autism can learn and change in response to behavioral therapies that enhance the child's social or language skills or that address another common problem: difficulties in engaging in play and other typical toddler activities. The flexibility demonstrated by the young child's brain opens new possibilities for intensive one-on-one therapy with trained professionals and parents to alleviate the difficulties with speech and social interactions that are a hallmark of the disorder.
One early intervention method derived from developmental psychology and applied behavior analysis (a technique for improving cognitive, language and social skills) is known as the Early Start Denver Model (ESDM). An ESDM therapist tries to deal with the difficulty a child with autism has in heeding social cues—facial expressions, gestures and spoken words. ESDM and other programs—such as Joint Attention, Symbolic Play, Engagement and Regulation—draw the attention of children to faces and voices. Healthy young children react more to a face than to a block, yet the pattern reverses for the child with autism, who typically responds more to an object than to a parent's gaze.
An ESDM therapist tries to encourage the child to focus attention. The professional will present a toy, perhaps name the toy in an inviting way and, when the child looks, will share it and start to play. The therapist tries to keep a child engaged in rounds of play intended to cultivate a nascent liking for social activities, all the while teaching social and communication skills.
ESDM has now begun to receive validation from formal scientific studies. With funding from the National Institutes of Health, Geraldine Dawson of Duke University and Sally J. Rogers of the University of California, Davis, have evaluated the technique and have recently reported the strongest evidence to date of the effectiveness of an early intervention for autism.
After two years of intensive training beginning anywhere from 18 to 30 months of age, children paid attention more to faces than did youngsters with autism in non-ESDM behavioral programs. The children who received ESDM scored higher on cognitive tests: their developmental quotient (an IQ test for very young children) rose in the study by 10.6 points more on average than did that of children in non-ESDM behavioral programs. The severity of social deficits and repetitive behaviors diminished, although some symptoms not directly related to autism lingered.
Imaging shows that the brain undergoes desirable changes as well. Brain areas activated when a child looks at faces lit up more in children with autism who received ESDM relative to those in in non-ESDM programs. In fact, the brain response of the ESDM-trained youngsters was identical to that of typical four-year olds. When charting electrical brain activity with electroencephalography (EEG), the researchers noted an increase in power (the amount of energy in the signal) for certain types of brain waves known as theta oscillations in an area below the brain's surface called the hippocampus, so named from the Greek hippokampos because it resembles the shape of a seahorse. Increases in theta power correlate with more focused attention and short-term memory function.
Researchers also found a reduction in the power of alpha oscillations—which generate EEG recordings that cycle up and down more quickly than theta waves—in several regions, including the hippocampus. A lower level of alpha power hints that the brain was becoming more attuned to people's faces. Increased theta and decreased alpha together reflect higher levels of electrical activity at the surface of the brain, or cerebral cortex, and specifically in the prefrontal and anterior cingulate cortices that are involved in the perception of faces. Observing these changes, the researchers conjecture that ESDM may spur brain changes in the treated children that may explain their higher scores on cognitive tests.
ESDM brought about these changes after more than 2,000 hours of intensive therapy over the course of two years, a labor of two hours twice daily for five days a week. A drug that could replace or hasten this process would make a world of difference to children and their families. The latest research has started to target a range of medications that address symptoms, including impaired social communication, hyperactivity and inattention, as well as repetitive, ritualistic behaviors and sleep disturbances.
A leading prospect for a drug that could mimic the benefits of ESDM is the brain hormone oxytocin, which has made headlines in the popular science press variously as the “cuddle” chemical, the “moral molecule” and the “trust hormone.” Known in the medical textbooks for its role in pregnancy, oxytocin readies a woman's body for childbirth. As levels rise, breasts swell and fill with milk, and later the hormone triggers labor. In the past 25 years researchers have learned that oxytocin, present in men as well, appears to play a role in promoting the bonding of infant to mother and cementing trust between friends. The hormone may even induce a sense of attachment to the baby in fathers-to-be.
Hope that oxytocin might help youngsters with autism comes from the observation that when the compound is administered in single doses either intravenously or within the nasal passages, the child with autism who normally fails to distinguish whether a new acquaintance is being “mean” or “nice” can suddenly detect the difference. Genetic studies add further evidence of oxytocin's role as a chemical that acts as a general social sensitizer and one that does so particularly in individuals with autism. Mice genetically tweaked to shut off the gene CD38, involved in making oxytocin, display less trust and recognition of other animals. Also, patients with autism have fewer oxytocin “receptors”—proteins that bind to oxytocin and convey its messages into specific nerve cells—and therefore lower levels of oxytocin.
These findings pave the way for larger studies. The nih is now providing $12.6 million for five institutions to conduct a trial of intranasal oxytocin in which patients are randomly assigned to a treatment or control group. The Study of Oxytocin in Autism to Improve Reciprocal Social Behaviors (SOARS-B) should determine within a few years whether oxytocin becomes a routine part of treatment. Ascertaining whether the hormone is an effective drug is especially important because a large number of parents already administer oxytocin to their children with autism, using prescriptions from physicians allied with the DAN! (Defeat Autism Now!) faction. Yet the evidence so far is not conclusive enough to justify the practice. If oxytocin receives validation through this study, it might be recommended to facilitate ESDM by readying a child to respond to the ministrations of a therapist.
The long road to a cure—or at least better therapies—will require a more incisive understanding of what lies behind the mental and physical symptoms of autism. The genetic underpinnings, one important factor, remain largely a mystery because identifying the relevant mutations is a daunting task. Some studies suggest that an individual's predisposition is rooted in alterations in as many as 400 to 800 genes. This work finds that the disorder involves what are called copy number variants: the addition or deletion of large swathes of DNA potentially containing several genes.
Basic research into how autism develops is now trying to disentangle this complex genetic web. One of the most exciting recent findings came this past January. It hinted that the numbingly complex genetics of autism might be less convoluted than originally thought. The project examined the genetics of 55 patients from nine Utah families who collectively turned out to have 153 copy number variants that were not present in children without autism and 185 copy number variants associated with autism from the published literature. The geneticists searched for those same copy number variants in 1,544 children with autism from the Autism Genetic Resource Exchange (AGRE) and Children's Hospital of Philadelphia (CHOP) and in 5,762 control subjects, unrelated to one another or to the children in Utah. A stringent molecular checking procedure eventually narrowed down the total to 15 familial and 31 literature copy number variants that seemed most likely to be implicated in some fashion.
More analysis is needed to clarify how the variants might contribute to autism and to explain the contribution of other nongenetic autism triggers, such as hormonal imbalances in the womb and exposure to chemicals in the environment. But this important study—and its ability to eliminate from consideration many of the originally targeted copy number variants—provides evidence that a large number of genetic factors putatively linked to autism in the scientific literature might be ultimately ruled out.
Even with a winnowing process that reduces dramatically the number of suspect genetic elements, the possibility of finding a single autism gene that unlocks the underlying disease process in everyone will never materialize in the vast majority of cases. Most of the time at least a handful of genes are sure to be involved, each one potentially having a relatively minor role in precipitating symptoms. Many of these genes may contain so-called de novo mutations—ones that are present for the first time in the fertilized egg.
A few autism cases, however, have been shown to derive from a single disrupted gene and are proving vitally important in advancing research. Scientists are studying individuals with very rare single-gene mutations that account for about 5 percent of autism cases. Exploring the psychological and molecular disorders in these children should offer clues to what goes wrong in the more common cases where multiple genes are activated in a manner that induces the symptoms of autism.
Investigators have uncovered several of these disorders that result from single-gene mutations and lead to autism, along with sets of unrelated symptoms. One prominent example is Rett syndrome, which occurs mostly in girls and impairs development of brain circuits. It leaves children with IQs that are difficult to assess and, at times, a severe form of autism that leads to the loss of any rudimentary language and basic motor skills already acquired. Research has focused on compounds that can reverse these symptoms by nourishing stunted brain circuits, among them a hormone called IGF-1, or insulinlike growth factor 1. Investigators have shown that mice with a condition resembling Rett show fewer symptoms after dosing with a compound derived from IGF-1. A small trial of the IGF-1 derivative in as many as 50 children with autism has passed initial safety testing, and work is now beginning to assess its ability to reverse symptoms.
As research progresses, future studies must come to grips with the complexity of a disease with multiple causes, differing degrees of severity, and the involvement of large areas of the brain that regulate basic social behaviors and communication skills. A multipronged approach will be needed to develop ways to accurately detect the initial onset of symptoms in an 18-month-old toddler and to devise treatments that extend ultimately to correct the functioning of defective brain cells. Beyond an analysis of genetics, researchers looking for better diagnostic tools are turning to brain imaging. Studies have begun on techniques that image a few of the 40 percent of autism patients with minimal or no verbal ability in an attempt to find better criteria for diagnosing autism.
Down at the cellular level, researchers are manipulating stem cells in laboratory dishes with the goal of developing new treatments. Stem cells have the ability to turn into any of several cell types. First, investigators convert specialized but easily accessible cells from a patient, usually from the skin, into stem cells known as induced pluripotent stem cells [see “Your Inner Healers,” by Konrad Hochedlinger; Scientific American, May 2010]. Then they treat these cells in ways that convert them into brain cells, such as neurons or supporting cells known as glia. Or they can begin with stem cells from frozen and stored umbilical cord blood of a child with autism. Now the researchers have the equivalent of neurons or glia taken from the brain of a person with autism, replete with genetic anomalies.
An analysis of the particular genetic makeup—and which genes are active in the newly minted neurons—might assist in determining where a young child could be placed on the autism spectrum, whether he or she is afflicted with a mild form of the disorder or has a severe case that will prevent the uttering of even a single word. And if the cells respond well to a particular drug—forming better connections with other cells—researchers would have reason to hope that the person might respond favorably as well. By applying such techniques, doctors may one day be able to determine which medications would best help address particular symptoms.
The longer horizon holds even more far-reaching possibilities that are today only one step removed from the realm of a science-fiction story. Consider the possibility of a cell transformed into a neuron or glial cell in the laboratory that holds genetic material identical to that of the donor but has perhaps been genetically altered to correct some molecular defect involved in autism. In what is today a wholly theoretical scenario, a child with autism could be implanted with these stem cells and then exposed to therapeutic learning experiences, such as those provided by ESDM. This combination of genetic and behavioral therapies could then reshape the nervous system at the cellular and molecular levels and perhaps dramatically improve communication difficulties and repetitive behaviors. If such futuristic scenarios ever materialize, we may one day be able to say that we indeed are nearing a cure for children such as Adrianna and Jermaine's young Jayden.