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An overdue query in autism science: What, exactly, is autism?

by  /  30 November 2015
Puzzling origins: The single diagnosis of autism can represent a diverse set of symptoms from many different causes.

Illustration by Bobby Lopez

Fragile X syndrome, tuberous sclerosis (TSC) and Williams syndrome are rare conditions with clear genetic causes: Each springs from a mutation in a single gene — and with unusual frequency seems to simultaneously produce a more common condition: autism1.

But is the ‘autism’ in a child with Williams syndrome the same as in a child with fragile X? And how does it compare with autism of unknown causes?

“This is a really difficult question because — is it the same thing as what? We don’t have a model autism case,” says Bonita Klein-Tasman, professor of psychology at the University of Wisconsin-Milwaukee. “We have a pretty broad umbrella of what we consider to be autism right now.”

In terms of genetics, autism research is much more sophisticated than it was just a few years ago. Scientists have identified a few dozen genes that seem to be important players, and are hot on the trail of these genes’ malfeasance. But along with this increasing clarity, an existential crisis is emerging: What, exactly, is autism?

“Certain folks think that autism is a thing,” says Raphael Bernier, associate professor of psychiatry at the University of Washington in Seattle. “I don’t think so. We’re defining it a certain way and there are a lot of different ways to get there.”

Social subtlety:

Some element of this uncertainty has always accompanied autism. Note the common saying: “If you’ve met one child with autism, you’ve met one child with autism” — a testament to the condition’s maddening diversity.

Some children with autism are social but awkward; others are socially withdrawn. Some don’t speak at all; others are hyperverbal. Some tune out all distractions and can focus intensely; others seem hyperactive and easily distracted.

The advances in genetics over the past few years have only confirmed this variability. As researchers identify people with autism who share the same rare genetic mutation, they are finding that each subgroup has its own distinct profile, with differences even among members of the same subgroup.

“If we had good clinical data on 50 patients for each of the 500 or more predicted single-gene causes of autism, they’d probably all have a different profile,” says David Ledbetter, chief scientific officer at Geisinger Health System in Danville, Pennsylvania. “They’ll each have their own social communication and cognitive profile.”

Bernier brings children to his clinic from all over the world who bear rare mutations in any of a set of genes strongly linked to autism. Grouping these children by the mutation they carry, he paints portraits of their common features. For example, children with a mutation in CHD8 tend to have wide-set eyes, large heads and trouble socializing. Many of them have what Bernier describes as “waiting-room autism” — meaning their autism can quickly be identified by sight alone: “I’m seeing a kid who is not engaged with others, who is not using broad facial expressions, not making eye contact.”

By contrast, children who carry a deletion in the 16p11.2 chromosomal region seem interested in socializing, but awkward, Bernier says. “Many of them have social quirks and oddities, but they’re not that waiting-room autism,” he says. “They are socially motivated and engaged but don’t know what to do once they are engaging with someone.”

Unknown origins:

Estimates of the genetic contribution to autism vary widely. One study, published this year, indicates that as much as half of all cases of autism derive from harmful, spontaneous mutations in single genes2. Other estimates suggest a more significant role for combinations of milder mutations present in the general population3. No single autism-linked mutation seems to contribute to more than about 1 percent of autism cases, however.

For years, many researchers considered idiopathic autism — meaning autism arising from unknown causes — to be separate from the condition seen in genetic syndromes such as fragile X or Williams (see graph). That perception is changing.

Contiguous conditions: A meta-analysis of 158 different studies generated prevalence rates of autism across 16 genetic syndromes (11 shown here). The analysis weighted studies based on the number of participants and rigor of diagnostic methods used. Nigel Hawtin

Contiguous conditions: A meta-analysis of 158 different studies generated prevalence rates of autism across 16 genetic syndromes (11 shown here). The analysis weighted studies based on the number of participants and rigor of diagnostic methods used.

Nigel Hawtin

“In the past, people used to segregate syndromic autism from idiopathic, or ‘pure,’ autism. It’s pretty clear that this distinction is getting blurred now,” says Mustafa Sahin, associate professor of neurology at Children’s Hospital Boston. “At the neurological and circuit level, it seems that they are converging.”

One reason why disorders such as fragile X syndrome seem only peripherally related to autism is that not everyone with a mutation in the fragile X gene has autism. But as researchers identify more autism mutations, it is becoming clear that this variability in symptoms may be the rule rather than the exception.

For example, only about 25 percent of people with a deletion in the 16p11.2 chromosomal region have autism. But a closer look reveals that all of them have social deficits when compared with their parents, says Ledbetter4.

Klein-Tasman works with children who have both autism and Williams syndrome, a disorder characterized by excessive sociability and intellectual disability. Some of these children display autism traits — social communication challenges and repetitive behaviors — well in excess of most children with Williams syndrome, says Klein-Tasman. This is often the case with other syndromes as well: The children who meet the bar for an autism diagnosis have more severe social deficits or repetitive behaviors than those who have only the related syndrome.

In these cases, Klein-Tasman says, more than one gene may be at play. “My hypothesis would be that these [more severely affected] kids have a double hit,” Klein-Tasman says. “They have Williams syndrome and probably some other vulnerability for an autism spectrum disorder.”

Clinicians often stop looking for mutations once a child has tested positive for a known genetic syndrome. But a few researchers are taking a second look at these cases. For example, Thomas Bourgeron at the Institut Pasteur in Paris is sequencing the entire genomes of people known to have one strong autism mutation, with the goal of uncovering additional mutations.

Predictive patterns:

Adding to the complexity in studying autism’s shape is the fact that its symptoms may change as children grow up.

In a 2009 study, Klein-Tasman and her colleagues found that more than half of 30 children with Williams syndrome have autism diagnoses at ages 2 to 55. But an unpublished study from the same team shows that once children can speak in phrases, the proportion of autism diagnoses drops to around 25 percent. This may be because as children begin talking, their interest in socializing becomes more apparent.

To get a better picture of autism, researchers should focus on how it evolves over time, Klein-Tasman says. “We tend to get these snapshots of a single point in development. Maybe what we’re going to find is there’s a prototypical autism in the developmental trajectory.”

Following children during development may also help reveal how autism emerges in the brain. Sahin is exploring this question in children with TSC, a condition marked by benign tumors throughout the brain and body.

Roughly 50 percent of children with TSC develop a characteristic form of autism, says Sahin. Studies suggest that brain patterns in children who have both TSC and autism are more typical of children with autism alone than they are of children with TSC alone6.

Sahin and his colleagues are scanning the brains of 120 children with TSC from infancy to 3 years of age, when they can be reliably assessed for autism. It may be that disparate ways of arriving at autism lead to a similar set of changes in the brain, Sahin says.

This study, along with many others, aims to uncover a biological indicator of autism. The researchers hope to pin the condition down with more than just the behavioral assessments currently used.

“We’re defining autism as impairments in social communication interactions or repetitive behaviors that someone deems to be problematic,” says Bernier. “It’s so tricky, because when you define things behaviorally like that, it makes it difficult to say what something really is.”

  1. Richards C. et al. Lancet Psychiatry 2, 909-916 (2015) PubMed
  2. Iossifov I. et al. Proc. Natl. Acad. Sci. USA 112, e5600-5607 (2015) PubMed
  3. Gaugler et al. Nat. Genet. 46, 881-885 (2014) PubMed
  4. Moreno-De-Luca A. et al. JAMA Psychiatry 72, 119-126 (2015) PubMed
  5. Klein-Tasman B.P. et al. J. Dev. Behav. Pediatr. 30, 289-299 (2009) PubMed
  6. Peters J.M. et al. BMC Med. 11, 54 (2013) PubMed

7 responses to “An overdue query in autism science: What, exactly, is autism?”

  1. Ethyl says:

    I’m not criticizing, because I’m that way myself, but it seems like it is so hard to focus on any one thing. Each different branch of medicine describes from their vantage point. I get whiplash trying to follow it. To a common person, it just seems like the blind men describing the elephant. In the past, it has often been someone familially tied to an autistic individual who changes the trajectory of science or thought, like Bernie Rimland, or Lorna Wing. Maybe it will come from the Markhams, I don’t know.

    The table of contiguous conditions was interesting, very much so. Not what I would have guessed. I think it might be a good idea to do genetic testing along with the EEG’s, X-rays and MRI to distinguish possible etiologies immediately upon PDD diagnosis, I think back to how forward thinking my son’s pediatrician was at the time.. This testing should be mandated to be paid by insurance, as much or more than ABA. How many kids are possibly undiagnosed of a genetic disease because of poverty? I wonder if this is commonly done.

    Is there such a thing as an autism workup?

  2. Frank Kelly says:

    Autistic behavior is a symptom of synaptic dysfunction. Back in the 1700s we treated “fever” as one thing. Today we treat “autism” as one thing but we’re slowly learning that it is *many* different disorders that just have a similar behavioral profile but different etiologies e.g. genetic, epigenetic, auto-immune etc.

  3. Seth Bittker says:

    This is an excellent question. Traditionally autism has been defined as severe impairments of, “social interaction and restricted interests and repetitive behaviors.” Unfortunately this behavioral definition is getting needlessly complex with DSM 5’s severity levels.

    Most of those mentioned in the article above seem to be thinking about how one could define autism to incorporate certain genetics, but as highlighted not everyone with a particular gene defect even if it is severe will develop autism.

    Why is this? It probably comes down to gene interactions with other genes, epigenetics, and the environment. The result of these inputs is a specific biochemistry which determines neurology. As biochemistry is closer to the end point of dysfunctional behavior and it can also be manipulated pharmacologically if we can get a definition in terms of biochemistry rather than genetics, I think we will be better off. In addition as the effectiveness of pharmacological approaches are likely predicated on biochemistry, having a biochemical definition has advantages in terms of identifying therapeutics.

    I propose that the following two metabolic markers be used in defining a “typical biochemical definition of autism”: 1) High oxidative stress as demonstrated by nitrotyrosine in blood and 2) Low free sulfate in blood. These appear in the following reference:

  4. Autism Mom says:

    These are obviously brilliant scientists- but, please forgive me, I think they are wrong

    I spend ALL my time with people on the spectrum and syndromic autism is very different from non syndromic autism. So many of kids with syndromic autism come to my son’s school for ASD people and almost none stay more than a year because they are too HF or theier very different needs cannot be met at an ASD school. More and more research has found that most people w Fragile x and TS are inaccurately diagnosed w ASD and almost all people with 22q and Retts do not classify as autism at all. Having spent a fair amount of time w Angelmans kids I can say none even resemble ASD! They are so outgoing, social and affectionate- with new people! Of course Angelmans, FX and 22q kids all have cognitive challenges but those witH Downs syndrome also have cognitive challenges but we don’t assume they are all on the spectrum. Recently someone a MIND got curious why all the genetic autism variant studies are failing and not replicating. MIND then released a study in which the they found NONE of the kids with the 22q variant classified as autism meet the ASD criteria- it wasn’t even close for most. Doctors and pediatricians just assume ASD right away when they see these syndromes.

    These amazing scientists have dedicated so much of their lives to the hypothesis that genetic autism serves as a viable model for non syndromic autism but after lots of time and lots of money we have just not found that to be true. Environmental exposures, immune profiles, metabolics are all yielding more useful information than studies on syndromic autism now.

  5. Me says:

    Maybe the extinction of the extroverts, chatters, dominant bullies, vapid empty-headed people and the like is beggining to happen, making way for those who aren’t so keen to be “popular”, “bubbly” and “social”, but who instead like to use their heads for solving problems, puzzles and conundrums without having to constantly show off by “sharing” stuff in social media sites. Maybe autism is the next step in human evolution, using the mind instead of fists.

    • Me says:

      …because, you know, not all autism implies cognitive disabilities. I mean the people with so-called ASD are usually more intelligent than average, just not as sociable or talkative. They simply like to be left alone and think about things.

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