The drug, dubbed STX209, is further along than any other treatment for an autism-related disorder. If it passes the next, more rigorous testing phase, it could be in clinics within a few years.

At a meeting on Saturday of the National Fragile X Foundation, Seaside Therapeutics, a small biotech in Cambridge, Massachusetts, announced that in 15 children who had both fragile X syndrome and severe social impairments, STX209 significantly improved scores on several tests of social behaviors.

The drug didn’t work on everyone in the trial, but for some, it was remarkable. According to the lead investigators, some participants improved so much that they stopped taking other medications, such as antidepressants and antipsychotics, which can have nasty side effects. The researchers are indefinitely continuing an ‘open-label’ extension study, in which the participants knowingly take the drug while the company collects data on safety and long-term effects.

In 2002, Mark Bear, one of Seaside’s founders, famously showed that mouse models of fragile X syndrome have excessive activity of the chemical messenger glutamate. Accordingly, STX209 stimulates gamma-amino butyric acid type B receptors, which effectively dampen glutamate signaling. Most of the other drugs in development for fragile X either also stimulate pathways that inhibit glutamate, or directly block glutamate receptors.

Although STX209 showed a trend of improving irritability and social problems in the wider group of 54 children and adults with the syndrome, the results were not statistically significant.

Seaside is also running a preliminary open-label study to test whether STX209 improves irritability in 30 children with autism. About one in three of individuals with fragile X syndrome also have autism.

It’s unlikely that drugs developed for fragile X will improve the full range of symptoms on the autism spectrum, but given the current dearth of treatments, even small gains are reason enough for good cheer.

No one has pinpointed genes or pathways that cause the condition and, partly because it can be triggered by ordinary stressors, it’s difficult to diagnose. Its biology now becomes even more baffling with the release of two new mouse models of compulsive behaviors, each implicating a different type of brain cell.

Three years ago, Guoping Feng‘s team created mice that compulsively groom themselves by deleting the SAPAP3 gene. SAPAP3 makes a protein expressed exclusively at neuron connections in the striatum, a deep region that’s important for planning movements.

Circuits in the striatum are also highlighted in one of the new studies, which appeared in May in Nature Medicine. By knocking out part of SLITRK5, which encodes a synaptic protein found in the striatum, researchers created mice whose intense self-grooming leads to severe facial lesions.

The second new report looked at mice carrying mutations in the HOXB8 gene. Scientists first noticed in 2002 that these animals feverishly groom themselves and their littermates, but didn’t know why. In the 28 May issue of Cell, they reported that HOXB8 is expressed only in microglia, immune cells that originate in the bone marrow and then migrate to many regions across the brain.

Although the two studies finger very different systems, they might begin to explain how and why OCD overlaps with other psychiatric illnesses, such as autism. For instance, some people with autism have movement problems, or abnormally big striata.

There are also many genetic and neurobiological links between the immune system and autism. Most relevant, a study presented at a meeting last year found that postmortem brain samples from individuals with autism have large numbers of microglia.

Over the past few years, Pawan Sinha has worked out a provocative theory that might help explain these anecdotes: people with autism have trouble with ‘temporal integration’, or drawing upon information learned in the past to anticipate the future.

The basic idea is that meaningful social interactions — which are difficult for people with autism — hinge on precisely synchronized events. For example, to understand spoken language, you must quickly and seamlessly integrate sounds to form meaningful words: myoo plus zik becomes music, not muse, use or sick. Similarly, imagine how difficult it would be to have a party conversation if you couldn’t monitor, in real time, your companion’s facial expressions or gestures in response to your words.

In between setting world records, carrying out vision experiments on his infant son, and launching a campaign to build a large eye hospital in New Delhi, Sinha has led an effort to test about 40 children with autism on a variety of visual and auditory experiments. Preliminary data from his team at the Massachusetts Institute of Technology (MIT) show that these children do have deficits in temporal integration.

“We know that motion plays a crucial boot-strapping role in vision, and motion processing has been shown to be deficient in autism,” Sinha says. “Our working hypothesis is that autism might, at least in part, be the manifestation of difficulties in processing dynamic information.”

If this timing problem occurs in early development, he says, it could cascade into the myriad of difficulties seen in the disorder, including difficulty in recognizing faces, hypersensitivity to sounds and lights and the insistence on a daily routine.

Sinha’s theory is provocative because scientists have already identified the brain circuits that are responsible for integrating information over time, says Tony Movshon, director of the Center for Neural Science at New York University.

“Autism needs a mediating hypothesis that takes the behavioral descriptions in one hand, and the molecular-circuitry descriptions in the other, and brings them together,” he says. “Pawan’s ideas are efforts to bridge that gap.”

These ideas have stirred up much intellectual debate in the autism field because they assert that the disorder’s fundamental deficit is perceptual, rather than social. But Sinha didn’t set out to study autism. Like many of his projects, this one took a circuitous route — beginning with a blind man in India.

In July of 2004, Sinha was sitting with a young man in a sticky, nondescript hotel room in New Delhi.

The man was poor, and born without lenses in his eyes, making him all but blind for 29 years. Two weeks earlier, he had received a pair of glasses, which allowed him to discriminate light levels and motion for the first time.

By carrying out some simple experiments, Sinha hoped that the man, known as S.K., would help answer the question that’s motivated most of his scientific career: how does the brain learn to see?

S.K. watched black outlines of a square, triangle and circle pop up in different combinations on a computer monitor. “How many things are these?” Sinha asked. When a circle and a square were separated, S.K. could easily count them. But when they overlapped, he saw three objects, and pointed to the three regions contained by the intersecting lines. He had no sense of which segments made up the circle, and which ones the square — until the shapes began to move.

“The world seems to be broken up into too many pieces and he can’t quite put it together. But motion brings about a very significant change,” Sinha says as he watches, for the umpteenth time, a grainy video of the scene.

The soft-spoken scientist proudly plays this clip whenever he gives talks about this work, called Project Prakash, named for the Sanskrit word for light. Like Sinha himself, the project’s goals are equal parts humanitarian and scientific: to restore sight in Indian children with curable blindness, and to then observe how they learn to navigate the visual world.

In November, Sinha published the results of his experiments with S.K. and two other Prakash participants. For all of them, the key to visual integration — perceiving objects as coherent wholes, rather than a mish-mash of spaces and lines — is motion.

He suspects that motion is also a key concept for understanding autism.

Five years ago, Sinha didn’t know much about autism beyond the adage that people with the disorder have trouble ‘seeing the forest for the trees’. After delving into the scientific literature, he discovered that not only do people with autism show abnormalities in visual integration — as shown, for example, by their ability to quickly find hidden pictures in a complex scene — but that they have deficits in processing motion. “The connection [with Project Prakash] seemed to be an obvious one,” he says.

…read the rest at SFARI

In fact, Darwin performed what may be the world’s first study of how people interpret and understand the emotions of others, according to a paper published in the April issue of the Journal of the History of the Neurosciences.

The experiment originated from a disagreement between Darwin and French neurologist G.B.A Duchenne. Duchenne believed that every emotion expressed on a person’s face is created by a separate muscle. To support this, he went about the grim task of electrically stimulating participants’ facial muscles and photographing the resulting expression, ultimately producing a set of 65 different plates.

Darwin thought it was much more likely that there were just a core number of emotions expressed by a face, and that these were shared across many cultures and species.

To test this, Darwin and his wife, Emma, set up an experiment in their home: they showed 24 house guests a series of 11 Duchenne plates and simply asked them to describe what emotion they saw in each. Only a handful of the faces received similar descriptions from all participants. Darwin reasoned that these emotions — surprise, fear, disgust, anger, happiness and sadness — are universally understood, and described them in his 1872 book, Expression of the Emotions in Man and Animals. The rest of the plates, he argued, showed unnatural expressions.

What’s amazing to me is that today’s researchers use photographs showing the same six expressions to learn about the cognitive underpinnings of autism, and to evaluate possible treatments for the disorder.

Of course, these modern experiments have some technological upgrades, such as computerized faces, eye-tracking machines or brain scanners but, once again, Darwin it seems was ahead of the curve.

If the method can be validated in a larger and more diverse sample, it may lead to a useful diagnostic test, researchers say.

The current standard for autism diagnosis, a thorough behavioral assessment, has several disadvantages, notes lead investigator Valerie Hu, professor of biochemistry and molecular biology at George Washington University. For instance, children may not show the full extent of their behavioral oddities on the test day, and their behavior may change over time.

“We’re aiming for a more objective, molecular diagnosis, if possible,” Hu says. “This is not it, but it’s a start.”

Last year, Hu compared the expression of some 40,000 bits of DNA in blood cell lines from three subgroups of people with autism — those who have severe language deficits, mild autism or savant skills — and healthy controls. She reported that compared with controls, 4,160 DNA fragments are expressed differently in the language deficit group, 502 in the mild autism group and 127 in the savant group.

Those are far too many genes to analyze in a commercial diagnostic test, Hu says. So in the new work, she used sophisticated software models — called ‘classifier algorithms’ — to identify a much smaller set of genes whose expression pattern would best predict which individuals have autism.

By comparing blood cell lines of 87 men with autism with 29 healthy controls, she found that the expression patterns of 88 genes can discriminate which samples came from the autistic group with 94 percent accuracy. What’s more, when the 87 autism samples are divided by subgroup, the algorithm can use fewer genes — about 30 — and achieve accuracy scores of 98 percent.

These are exciting preliminary findings, and Hu says some companies have already contacted her to inquire about developing this method into a diagnostic test. But the test is far from being ready for the clinic.

First, the data must be validated on a larger set of people with autism. Second, they must be repeated using primary blood cells, rather than the cultured cell lines used here. Cell lines are easier to obtain because they can replicate indefinitely in the lab, but their expression patterns may be different from those of whole blood cells.

It’s also important for scientists to take into account the age of the participants, notes Lou Kunkel, director of genomics at Children’s Hospital Boston.

In Hu’s experiment, participants with autism were, on average, 12 years old, but their ages ranged from 5 to 28 years. Gene expression can change dramatically during development, meaning that a blood-based test would have the best accuracy for a defined age group.

For the past two years, Kunkel’s team has been comparing expression patterns in whole blood samples from more than 400 children with autism. The work is unpublished, but Kunkel says his analyses can distinguish autism from controls with 80 percent accuracy.

Kunkel’s participants are between 5 and 7 years old, and he’s also separately looking at a group of toddlers with autism, as well as at healthy siblings and parents.

“We’re hoping this would be an adjunct to other tests — so you do the blood test and the behavioral tests to come up with a true diagnosis,” Kunkel says. If the test is validated on the younger children, he adds, it could be used to screen for autism before symptoms emerge.

Both Hu and Kunkel’s tests are blood-based but it’s not clear that gene expression changes in blood correlate with brain activity in people with autism, others note.

“I definitely think this approach is worth pursuing, though I’m a little cautious of how well it’s going to reflect what’s going on in the brain,” notes Janine LaSalle, professor of medical microbiology and immunology at the University of California, Davis. Researchers should compare these expression patterns with those seen in postmortem brain samples from people with autism, she adds.

Hu is also interested in studying the function of genes expressed differently in people with autism. Many of the genes identified so far, she says, do not code for proteins, and are responsive to androgens — hormones that some controversial studies have linked to autism. “We don’t know what they’re doing yet, but we’re trying to figure it out,” she says.

The findings dispute the theory, first proposed a decade ago, that flaws in the mirror neuron system give rise to the disorder.

“The theory is that if the system is fundamentally busted, then these individuals would follow a dramatically different developmental trajectory, and that could lead to autism — but that’s not what we observed,” says lead investigator David Heeger, professor of psychology and neural science at New York University.

The researchers found no significant difference in the average activity of mirror neurons in participants with autism compared with healthy controls when the groups either looked at a series of hand gestures or performed them.

However, individuals with autism show a wider range of brain responses during the tasks, possibly because of irregularities in neuron signaling, leading to what Heeger calls ‘noisy circuits’.

“That notion of variability in autism is extremely important,” notes Raphael Bernier, assistant professor of psychiatry at the University of Washington.

What looks like a problem that originates in mirror neurons could in fact be a misinterpretation of these noisy circuits, Bernier says. “We can’t rule out that there’s other stuff going on upstream,” he says.

In 2007, Bernier’s group used electroencephalography (EEG) and found evidence that brain regions thought to harbor mirror neurons function improperly in people with autism. When a paper that came out last year failed to confirm his findings, it prompted him to repeat his experiments with a bigger group of participants.

“There’s been so much excitement about this topic in a short amount of time, and the excitement has outpaced empirical research,” Bernier says. In the new study, he says, “They’re doing exactly what needs to be done to parse out this complicated puzzle.”

…read the rest of my latest at SFARI

No one knows what causes the condition, defined by the inability to recognize and interpret sounds. It appears in an estimated two to five percent of children, and is only beginning to get a bit of public attention.

Last week, speech pathologist Lois Kam Heymann published a book about APD called The Sound of Hope. The book has made a splash thanks to comedian Rosie O’Donnell, who wrote about her 10-year-old son’s struggle with the disorder in the book’s foreword.

APD is often misdiagnosed as autism. Children with either disorder share some overt symptoms — such as a sparse vocabulary, poor grades and trouble paying attention — and both conditions are characterized by difficulties in understanding abstract metaphors. The conversation delays in children with APD can sometimes lead to impaired social interactions and isolation reminiscent of autism.

At the same time, some people with autism report extreme sensitivities to sounds, and a growing number of researchers are taking a close look at auditory processing problems in autism.

For example, using brain imaging, Tim Roberts at Children’s Hospital of Philadelphia has found that the brains of children with autism respond to sounds a split second slower than do those of healthy children. And a few groups have identified distinctive sound patterns in the speech of children with autism.

There are obvious differences between APD and autism. Autism often includes problems in other sensory systems, including vision, touch and smell. Children with autism often have low intelligence quotients or mental retardation, whereas those with APD usually have normal intelligence.

So far, there’s also one promising overlap: children with either condition can be helped by speech therapy and intensive behavioral intervention.

This begs the question: How many people with autism are also obese?

There’s scant data to address that, but two studies published earlier this year begin to give a rigorous account.

In both, researchers reanalyzed some of the same data from the National Survey of Children’s Health, gathered from phone interviews given in 2003 and 2004 to parents of some 85,000 American children.

The most recent study, published in late February, reports that the rate of obesity in 3- to 17-year-old children with autism is 30.4 percent, significantly higher than the 23.6 percent in healthy controls.

The other report, published in January, only looked in older children, but found roughly the same trend. Looking at data from 47,000 kids aged 10 to 17 years, researchers reported that 23.4 percent of adolescents with autism are obese, compared with 12.2 percent of controls.

Comparing both studies, two important points stand out.

First, the rate of childhood obesity in both groups is much higher in the recent study, which only included children younger than 10. That’s probably a reflection of the growing obesity epidemic.

Second, it seems that the difference between the autism and control groups is more striking in older children and teenagers. This meshes nicely with the genetic study on chromosome 16, which found that the association between obesity and developmental delay is strongest in late adolescence or adulthood.

There are a couple of methodological problems with the studies’ design, however. For instance, they did not define autism using a standardized test, such as ADOS, but rather as something that any ‘health professional’ once diagnosed.

Still, all evidence to date suggests that kids with autism have an increased risk of being overweight, and will probably prompt some labs to figure out a biological explanation. In the meantime, clinicians should counsel patients with autism about healthy food and exercise.

But what if you carry more than one?

A study published last month in Nature Genetics is among the first to focus on the combined risk of having multiple CNVs for psychiatric disease.

Screening more than 20,000 children with intellectual disability, Evan Eichler and an international group of colleagues found a deletion on chromosomal region 16p12.1 in 42 individuals, or about 0.2 percent — about four times the frequency they saw in the healthy control population.

In addition to developmental delay, children who carry the 16p12.1 deletion may also have congenital heart defects, seizures and severe growth abnormalities, the researchers found. The deletion joins three others on the short arm of chromosome 16 that are associated with autism or other neurodevelopmental disorders.

As it turns out, 10 of the children who carry this particular CNV also have a second large CNV on another chromosome. This ‘two-hit’ subgroup tends to have distinct or more severe symptoms than do children who carry the second CNV alone, suggesting that the 16p12.1 hit exacerbates the phenotypes from the second hit.

For instance, the paper describes a 2-year-old with both the 16p12.1 deletion and another deletion on chromosome 22. The child has a small head, brain fiber abnormalities and no autistic features. That’s a remarkably different description than the large head size, undersized jaw, low muscle tone and autism that typically characterize this Chr. 22 deletion on its own.

Another provocative finding: the 16p12.1 deletion is almost always inherited (and usually from the mother), rather than arising spontaneously. From the few clinical descriptions the researchers could collect, they found that most of the carrier parents have some kind of developmental delay or depression, but three are normal. In children with two CNV hits, the second CNV is also mostly inherited, from the parent who does not carry the 16p11.2 deletion.

This paper starts to piece apart why a disease-associated genetic variant may crop up in so many different clinical disorders, and even in healthy people. A CNV may have to interact with another CNV or other environmental factors at specific points of development in order to ultimately produce a complex condition such as autism.

Studies in the past two years have found that people carrying specific genetic variants of the hormone’s receptor are at increased risk of developing autistic traits.

Children with autism have low levels of oxytocin in their blood, and a few small clinical trials have shown that getting extra doses of the hormone can improve some characteristic deficits of the disorder, such as body rocking or interpreting emotion from faces and words. Oxytocin is considered a pretty safe drug, because it doesn’t last long in the body and its effects are short-lived.

On 15 February, French researchers showed for the first time that inhaling small doses — three puffs per nostril — of the hormone can also improve social behaviors, the Holy Grail for autism treatments.

In one experiment, a computer ball-tossing game, participants with autism have more interactions with cooperative virtual partners, and report that they trust them more, after inhaling oxytocin. Similarly, when looking at pictures of faces, oxytocin increases the time participants spend looking at the eyes, which they normally avoid.

The results are based on just 13 adults with high-functioning autism or Asperger’s syndrome, though, so it’s not clear whether they would hold in a larger autism population, or in children with the disorder.

Even so, these are arguably the most exciting results of an autism treatment to date, and should encourage companies to place their trust in oxytocin.