Lifting the Veils of Autism, One by One by One

He is blond and 3 years old, 33 pounds of compressed energy wrapped in OshKosh overalls.

In an evaluation room at Yale's Child Study Center, he ignores Big Bird, pauses to watch the bubbles that a social worker blows through a wand, jumps up and down. But it is the two-way mirror that fascinates him, drawing him back to stare into the glass, to touch it, to lick it with his tongue.

At 17 months, after several ear infections and a bout of the flu, the toddler's budding language skills began to deteriorate, his parents tell the evaluators. In the playroom, he seems intent on his own activities and largely oblivious to the adults in the room. Only when the therapist bends down to tickle him does he give a blinding smile and meet her gaze with startling blue eyes.

Sixty years after it was first identified, autism remains one of the most puzzling of childhood disorders. Its cause or causes are still unknown. But in recent years, investigators have begun to dislodge some of its secrets.

Studies have offered clues to the brain mechanisms that may lie behind some features of autism — the tendency to focus on objects rather than human faces, for example — and geneticists have begun to home in on genes that may be involved. Scanning has provided glimpses of ways autism may affect brain development: the brains of autistic children, studies find, appear to be larger than normal for some time after birth.

In the future, experts say, such research may yield effective medical treatments to augment or even replace the intensive behavioral therapy that is the prescription most autistic children now receive.

In learning more about autism, a disorder that in some form affects at least 425,000 Americans under 18, scientists may also increase knowledge about language development, emotion, even friendship and love.

"Ultimately, research on autism may teach us a lot about what it means to be social," said Dr. Thomas Insel, the director of the National Institute of Mental Health.

Autistic children were once thought to have a form of childhood schizophrenia. Prone to repetitive, sometimes self-destructive behaviors and driven by "a powerful desire for aloneness and sameness," as Dr. Leo Kanner of Johns Hopkins put it in a now classic 1943 paper, they often spent their lives in institutions. Parents watched helplessly as their children disappeared into a world beyond their reach.

But much has changed. The notion that autism was caused by "refrigerator" mothers and absent fathers, promoted by psychoanalysts in the 1950's and 1960's, has yielded to the realization that the disorder is strongly rooted in genetics and abnormalities of brain development and function. Environmental influences early in life may also play a role.

At the same time, a sharp rise over the last decade in the number of autism cases diagnosed in the United States and other countries has raised public awareness and helped secure more government financing for research.

In the 2003 fiscal year, the National Institutes of Health spent an estimated $81.3 million on autism research, compared with $9.6 million in 1993.

The last two decades have brought a sea change in the way scientists view autism and those who suffer from it.

Researchers now recognize, for example, that autism is not synonymous with mental retardation: more than 80 percent of children with autism were once thought to be mentally retarded.

More recent estimates place the number at 70 percent, or lower if related disorders are included.

Dr. Kanner believed autism to be a product of upper-middle-class homes, a conclusion based on the children he examined, who were the progeny of doctors, lawyers and scientists. But it is now clear that autism crosses class boundaries.

Boys are four times as likely as girls to have the disorder. This sex ratio has led one researcher, Dr. Simon Baron-Cohen, director of the autism research center at Cambridge University in England, to speculate that autism is a form of "extreme maleness," but the theory has yet to be supported by research.

More rigorous studies have allowed clinicians to identify autism in children of younger and younger ages. In the past, the disorder often was not diagnosed until children were 4 or 5. But by studying home movies of birthday parties or first baths, investigators have found telltale signs of autism in children of 12 months or younger.

Dr. Geraldine Dawson, director of the University of Washington's autism center, for example, studied infants from 8 to 10 months old who were later identified as autistic. The infants, she said, often failed to respond when parents called their names.

"Even very young babies, when you call their name, will turn and look at you," Dr. Dawson said.

As toddlers, autistic children show other differences. For example, they make eye contact less frequently, and, unlike most 1-year-olds, do not point at objects or people.

Autism's hallmarks are a delay in language development, an inability to relate to other people and stereotyped or rigid behavior. But researchers have found that children vary greatly in the nature and the severity of their disabilities.

"If you put 100 people with autism in a room, the first thing that would strike you is how different they are," said Dr. Fred Volkmar, a professor of child psychiatry at Yale and an expert on autism. "The next thing that would strike you is the similarity."

Some children attend regular schools, others are so disabled they require institutional care. Some children speak fluently, others are mute. Some are completely withdrawn; others successfully navigate a path through the outer world.

In fact, studies show that many children with autism can improve with treatment, and some — from 15 to 20 percent, experts say — recover completely, holding jobs and living independent lives.

Yet the realization that autism takes many forms has also made its diagnosis more complicated. In 1994, psychiatrists added a new diagnostic category — Asperger's syndrome — to the psychiatric nomenclature, to take account of children who displayed some features of autism but did not meet the full diagnostic criteria.

Many researchers view Asperger's as distinct from autism. But the differences become blurred in cases where children have normal or above normal I.Q.'s. In such instances, experts say, whether Asperger's or autism is diagnosed is often arbitrary.

"I don't think anyone's got good evidence for a clear distinction between people with high-functioning autism and Asperger's," said Dr. Tony Charman, a researcher in neurodevelopmental disorders at University College London.

As a child, Donald Jensen lay in bed at night, tracing numbers in the air with his finger. He memorized lottery numbers. He was riveted by the pages of the calendar.

Now 19, his facility with mathematical calculation seems magical. Given any date — Jan. 7, 1988, for example — he can, in an instant, identify the day of the week it fell on. (It was a Thursday.) He virtually never makes mistakes.

Yet even in childhood, there were signs that Donald was exceptional in other ways. He was mesmerized by the washing machine, becoming upset if the laundry was finished before he got up in the morning. He started talking late. Once, when his grandmother slipped on some ice in the yard and fell, he continued to chatter about numbers, seemingly oblivious to her plight.

Problems in school led doctors to diagnose autism when Donald was 6, his uncle, Glen Jensen, said. As an adult, Donald's gifts — he is among the 1 to 10 percent of people with autism known as autistic savants — connect him to the world. "What day were you born?" he asks visitors.

But the things that Donald cannot do also separate him from other people. He rarely makes eye contact. Ask him how he calculates dates or what numbers mean to him and the inquiries are met with silence. His ability to empathize with other people has grown over the years — "John was angry today, and that was upsetting to me," he will say — but unexpected events disturb him, and his conversations sometimes take the form of asking questions over and over.

What lies at autism's core? Over the decades, researchers have come up with a variety of theories. But most were based on what clinicians observed, not on what might be going on in the brain. Only recently have sophisticated technologies allowed researchers to begin bridging the gap between the consulting room and the laboratory.

Dr. Ami Klin, an associate professor of child psychology and psychiatry at Yale, and his colleagues began with the observation that people with autism often have a great deal of intellectual knowledge, but lack "street smarts," and are unable to use what they know in social situations.

"Many of our clients know the currencies of all countries in the world, but they cannot go to McDonald's and buy a burger and count the change," Dr. Klin said. "They know all the bus ramps, but can't take a bus."

In a series of experiments to find out why it is so difficult for someone with autism to function in the world, the Yale team , including Warren Jones, a research associate, developed a device for tracking eye movements that could be mounted on the brim of a baseball cap. Then they had subjects, who either had autism or did not, watch a video clip from the 1967 film "Who's Afraid of Virginia Woolf" and monitored their gaze.

The normal subjects closely tracked the social interactions among the actors in the films, focusing especially on the actors' eyes. In contrast, people with autism focused on objects in the room, on various parts of the actors' bodies and on the actors' mouths.

In one scene, Richard Burton and Elizabeth Taylor kiss. The subjects without autism looked at the actors' embrace; the autistic subjects' eyes went elsewhere: one man stared at a doorknob in the background.

Such research suggests that from birth, the brains of autistic children are wired differently, shaping their perception of the world and other people. "In normal development," he said, "being looked at, being in the presence of another, seeking another — most of what people consider important emerges from this mutually reinforcing choreography between child and adult."

If this duet cannot take place, Dr. Klin said, "development is going to be derailed."

Studies using brain scanning techniques like fast M.R.I. lend weight to the idea that for people with autism, perception molds behavior.

"There is a deep relationship between what we see and what we know," said Dr. Robert Schultz, an associate professor at Yale's Child Study Center.

Researchers have long known, for example, that people with autism have difficulty recognizing faces. In non-autistic subjects, a brain area called the fusiform gyrus is activated in response to the human face. But when pictures of unfamiliar faces are shown to children or adults with autism, studies show, the region is less active.

Dr. Schultz said that autistic people appear to identify faces the way other people identify objects, by piecing features together. While most people are better at recognizing images of faces when they are right-side up, autistic subjects identify them faster when they are upside-down.

A recent study, presented at the annual meeting of the American Association for the Advancement of Science in Seattle this month, illustrates this. Dr. Dawson, of the University of Washington, and a colleague reported that when autistic adolescents and adults were shown pictures of faces, another brain area involved with object recognition was activated, while the fusiform gyrus remained quiet. Yet when the researchers showed photos of the subjects' mothers, the fusiform brain did light up.

Work by Dr. Isabel Gauthier, an assistant professor of psychology at Vanderbilt University, suggests that, in fact, the fusiform gyrus is not programmed to react to faces per se but to things that people care about and learn to distinguish in detail.

Dr. Gauthier trained people to become experts on "greebles," a class of simply-drawn imaginary beings. When the subjects became adept at telling one greeble from another, she found, the fusiform gyrus lighted up in response to pictures of the creatures. Similarly, when car experts were asked to identify different car models, the region was activated, Dr. Gauthier reported last year in the journal Nature.

The research suggests that children with autism can be trained to become better at face recognition — something that scientists at Yale and other universities are trying. But the seeming indifference to the human face that often accompanies autism has led the Yale resarchers to propose that the fusiform gyrus may be a component of the social brain, intimately tied up with basic emotional responses like fear, anxiety and love.

In fact, some studies have found abnormalities in the amygdala, a brain region involved with emotion and social awareness. But the findings are inconclusive, and differences in autistic brains have been found in structure, including the temporal lobes and the cerebellum.

In his early description of autism, Dr. Kanner noted that heads of the children were larger than normal. Modern researchers have confirmed this observation, finding that for some period of time during childhood, autistic children have bigger brains than their non-autistic counterparts. In 2001, Dr. Eric Courchesne, a professor of neuroscience at the University of California at San Diego, and his colleagues found that 4-year-olds with autism showed increases in the volume of the brain's gray matter, where the cell bodies of neurons are located, and white matter, which contains nerve fibers sheathed with an insulating substance called myelin.

In a 2003 study in The Journal of the American Medical Association, Dr. Courchesne reported that at birth, the heads of infants with autism were smaller than normal, but then showed "sudden and excessive" growth in size from 1 to 2 months and from 6 to 14 months. By adolescence, however, the children's brains were the same size as those of other children or slightly smaller.

Dr. Martha Herbert, an instructor in pediatric neurology at Harvard, has begun to zero in on precisely where this growth spurt occurs. At the annual meeting of the Society for Neuroscience in October, she reported that in autistic children, the outer zones of white matter became enlarged compared with normal brains beginning after age 6 months and continuing into the second year of life. Those outer zones, Dr. Herbert said, are insulated later in development than the areas of white matter deeper in the brain.

In another study, Dr. Manuel Casanova, a professor of neurology and neuropathology at the University of Louisville, found an increase in autistic brains in the stacks of neurons known as mini-columns that extend through the layers of the neocortex. The brains of people with autism not only had more mini-columns, Dr. Casanova found, but the neurons that made up the columns were less variable in size than in normal brains.

One possibility is that the enlargement in white matter reflects an overabundance of myelin, which could disrupt the timing of communication signals throughout the brain. But this growth in volume, Dr. Herbert said, could also represent an increase in nerve fibers, the migration of other types of cells or some type of inflammation.

Dr. Casanova, for his part, theorizes that the proliferation of mini-columns might result in a deluge of stimulation, or as he puts it, "way too much information."

"The sound of rain on a roof might seem like driving nails into a tin roof, a fluorescent light might become extremely perturbing," Dr. Casanova said.

Dr. Nancy Minshew, a professor of psychiatry and neurology at the University of Pittsburgh, argues that autism's core lies in higher brain areas, rather than in deeper structures that govern emotion.

"When I started about 20 years ago, I looked at autism and said this disorder is in the cortex of the brain," Dr. Minshew said. "It's the classical disorder of cognition."

In 1964, Bernard Rimland, a British psychologist with an autistic son, put forward the view, then controversial, that genes, not faulty child rearing, lay behind the disorder.

Most experts now agree that autism is strongly determined by heredity. Studies indicate, for example, that if parents have one child with autism, the chance that they will have a second autistic child is 2 to 6 percent — about 100 times the general risk.

Twin studies also argue for a large genetic component. Identical twins, the studies suggest, run a 60 to 85 percent chance of having autism or a similar disorder if their twins have it. For fraternal twins, the chances are 10 percent.

Two very rare forms of autism — one associated with the congenital disease known as tuberous sclerosis and the other with fragile X syndrome — are known to be caused by chromosomal defects.

But in most cases, autism is thought to have a more complex genetic origin, involving multiple genes acting together.

"The bulk of people with autism develop it because they have inherited a particular genetic predisposition," said Dr. Anthony Bailey, a professor of psychiatry at Cambridge.

Finding those genes, however, is a difficult task. The disorder is relatively uncommon, and most people with autism do not have children, making it difficult to track successive generations of a family.

To get around these obstacles, some researchers are studying families having two or more members with autism and searching for similarities in the genome that could provide the crucial link to the disorder.

Cure Autism Now, an advocacy group based in Los Angeles, has started a program to collect DNA samples from such families and use them for research.

Large-scale studies are in progress at a variety of institutions in the United States and other countries. DeCode Genetics, an Icelandic company that last year identified a gene that may contribute to schizophrenia, announced in January that it would use the Icelandic population to search for genes underlying autism and similar disorders like Asperger's.

Some researchers are also hunting for genes that may underlie specific aspects of autism.

Dr. Daniel Geschwind, director of the neurogenetics program at the University of California, Los Angeles is hoping, in a study of autistic children and their families, to find genes that contribute to the delayed development of language.

No specific gene for autism has yet been pinpointed. But promising areas have been identified on a variety of chromosomes, including the 2, 3, 7, 13, 15 and the X chromosome.

"My sense is that we are close to the tipping point in this illness," said Dr. Insel of the National Institute of Mental Health, "and that over the next couple of years we will have, not all of the genes, but many of the genes that contribute."

At the same time, the disorder is not entirely genetic, indicating that some environmental influences, either during a mother's pregnancy or in the first years of life, have roles in setting off the disorder, perhaps by changing the way genes function without actually altering DNA.

Over the years, many candidates have been proposed, including German measles during pregnancy; yeast infections; the sedative drug thalidomide; childhood vaccines; viruses; the labor-inducing drug Pitocin; and dietary, hormonal or immune system changes during pregnancy.

But so far, researchers say, solid evidence for any single factor has not emerged. Still, several research groups are trying to address the issue of environmental triggers. A study based at Columbia University, for example, will follow 100,000 pregnancies in Norway, examining a variety of environmental influences, including infections, vaccinations, mercury exposure and prenatal stresses.

Experts disagree about the importance of environmental influences. But there is a consensus that autism probably has more than one cause, its symptoms the common end point of different biological pathways.

Yet it may be some years, experts say, before scientists are able to link the findings from genetic studies and brain research with the outer signs of the perplexing world that people with autism inhabit.

When it comes to autism, said Dr. David Amaral, a professor of psychiatry at the University of California at Davis,"In many respects, we're still in the dark ages."

Some children speak fluently, others are mute.

Past (1970')studies have shown that giving a mute child some B-6 supplementation will get them talking.

It looks like quite a nice summary of what has turned up in the papers in the last year or so.

Whatever is found will be far too late to help my older son, but I worry about my younger son having children, and what he might pass on.

Thanks for this excellent article! I'll be forwarding it to my son and daughter-in-law. Our 4 year old grandson has autism, and our 16 year old son has a mild form of it.I can't begin to tell you how it impacts families! I'm glad people are becoming more educated about it, and I'm glad that there are continuing studies going on, to try to figure out this condition.

Two very rare forms of autism — one associated with the congenital disease known as tuberous sclerosis and the other with fragile X syndrome — are known to be caused by chromosomal defects. -Erica Goode, New York Times

My son has fragile X syndrome, which is absolutely genetic. He also has a diagnosis of autism which is directly due to the fragile X. The article deals mostly with regular autism, which usually does not have with it the mental retardation that my son has.

It is true that these disabilities have an incredible impact on families. Rain Man with Dustin Hoffman was a good exploration of autism. We've watched it twice with my daughter to give her some perspective on her brother's disability.

I really hope they find a cause, and hopefully a cure.
I have a friend with autistic twins, and they have all worked so very hard as a family to deal with autism.
They do better than a lot of other families with no dysfunction to blame for their problems.
I know it would not really change anything for them, but if they just knew how or why, it would bring some level of peace to them.

Interesting article. My nephew has Asperger's autism. My brother and his wife were told that many people exhibit mild symptoms without ever being clinically diagnosed, and chances are there is a recessive tendency towards autism in both families (I have a cousin who is in her 50's who, had she been child today would probably have this diagnosis).

I also see some of my nephew's traits in one of my twins, albeit slight. I know when and if she ever has children this will be on my mind.

The truth is they really don't know the cause of autism.Sure it's hard to raise an autistic child, but what rewards you get ! My son is a gift from God, so brilliant, so funny with the way he phrases things. His shrink is the "talk doctor", he fires me as Dad once a week, and he told me last week a girl at his high school made his heart go "pitter patter". He taught himself to read when he was three years old, and is a whiz at math like you've never seen. He bugs me incessantly at Christmas time about Santa, and gifts- he always wants to open his gifts. He will fight me tooth and nail about everything , then turn around and ask permission to go to sleep. Life with Josh is never dull...

Have any of you all tried the Epson Salts baths? For the physical overactivity and agitation,,just wondering. I think this is so much more common, the spectrum disorders that is, than we know. It seems I keep hearing of someone who has a child or relative with this.

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