Researchers discover a potential cause of autism

Key enzymes are found to have a ‘profound effect’ across dozens of genes linked to autism. The insight could help illuminate environmental factors behind autism spectrum disorder and contribute to a unified theory of how the disorder develops.

Problems with a key group of enzymes called topoisomerases can have profound effects on the genetic machinery behind brain development and potentially lead to autism spectrum disorder (ASD), according to research announced today in the journal Nature. Scientists at the University of North Carolina School of Medicine have described a finding that represents a significant advance in the hunt for environmental factors behind autism and lends new insights into the disorder’s genetic causes.

“Our study shows the magnitude of what can happen if topoisomerases are impaired,” said senior study author Mark Zylka, PhD, associate professor in the Neuroscience Center and the Department of Cell Biology and Physiology at UNC. “Inhibiting these enzymes has the potential to profoundly affect neurodevelopment — perhaps even more so than having a mutation in any one of the genes that have been linked to autism.”

The study could have important implications for ASD detection and prevention.

“This could point to an environmental component to autism,” said Zylka. “A temporary exposure to a topoisomerase inhibitor in utero has the potential to have a long-lasting effect on the brain, by affecting critical periods of brain development. ”

This study could also explain why some people with mutations in topoisomerases develop autism and other neurodevelopmental disorders.

Topiosomerases are enzymes found in all human cells. Their main function is to untangle DNA when it becomes overwound, a common occurrence that can interfere with key biological processes.

Most of the known topoisomerase-inhibiting chemicals are used as chemotherapy drugs. Zylka said his team is searching for other compounds that have similar effects in nerve cells. “If there are additional compounds like this in the environment, then it becomes important to identify them,” said Zylka. “That’s really motivating us to move quickly to identify other drugs or environmental compounds that have similar effects — so that pregnant women can avoid being exposed to these compounds.”

Zylka and his colleagues stumbled upon the discovery quite by accident while studying topotecan, a topoisomerase-inhibiting drug that is used in chemotherapy. Investigating the drug’s effects in mouse and human-derived nerve cells, they noticed that the drug tended to interfere with the proper functioning of genes that were exceptionally long — composed of many DNA base pairs. The group then made the serendipitous connection that many autism-linked genes are extremely long.

“That’s when we had the ‘Eureka moment,’” said Zylka. “We realized that a lot of the genes that were suppressed were incredibly long autism genes.”

Of the more than 300 genes that are linked to autism, nearly 50 were suppressed by topotecan. Suppressing that many genes across the board — even to a small extent — means a person who is exposed to a topoisomerase inhibitor during brain development could experience neurological effects equivalent to those seen in a person who gets ASD because of a single faulty gene.

The study’s findings could also help lead to a unified theory of how autism-linked genes work. About 20 percent of such genes are connected to synapses — the connections between brain cells. Another 20 percent are related to gene transcription — the process of translating genetic information into biological functions. Zylka said this study bridges those two groups, because it shows that having problems transcribing long synapse genes could impair a person’s ability to construct synapses.

“Our discovery has the potential to unite these two classes of genes — synaptic genes and transcriptional regulators,” said Zylka. “It could ultimately explain the biological mechanisms behind a large number of autism cases.”

Autistic kids who best peers at math show different brain organization

Children with autism and average IQs consistently demonstrated superior math skills compared with nonautistic children in the same IQ range, according to a study by researchers at the Stanford University School of Medicine and Lucile Packard Children’s Hospital.

“There appears to be a unique pattern of brain organization that underlies superior problem-solving abilities in children with autism,” said Vinod Menon, PhD, professor of psychiatry and behavioral sciences and a member of the Child Health Research Institute at Packard Children’s.

The autistic children’s enhanced math abilities were tied to patterns of activation in a particular area of their brains — an area normally associated with recognizing faces and visual objects.

Menon is senior author of the study, published online Aug. 17 in Biological Psychiatry. Postdoctoral scholar Teresa luculano, PhD, is the lead author.

Children with autism have difficulty with social interactions, especially interpreting nonverbal cues in face-to-face conversations. They often engage in repetitive behaviors and have a restricted range of interests.

But in addition to such deficits, children with autism sometimes exhibit exceptional skills or talents, known as savant abilities. For example, some can instantly recall the day of the week of any calendar date within a particular range of years — for example, that May 21, 1982, was a Friday. And some display superior mathematical skills.

“Remembering calendar dates is probably not going to help you with academic and professional success,” Menon said. “But being able to solve numerical problems and developing good mathematical skills could make a big difference in the life of a child with autism.”

The idea that people with autism could employ such skills in jobs, and get satisfaction from doing so, has been gaining ground in recent years.

The participants in the study were 36 children, ages 7 to 12. Half had been diagnosed with autism. The other half was the control group. Each group had 14 boys and four girls. (Autism disproportionately affects boys.) All participants had IQs in the normal range and showed normal verbal and reading skills on standardized tests administered as part of the recruitment process for the study. But on the standardized math tests that were administered, the children with autism outperformed children in the control group.

After the math test, researchers interviewed the children to assess which types of problem-solving strategies each had used: Simply remembering an answer they already knew; counting on their fingers or in their heads; or breaking the problem down into components — a comparatively sophisticated method called decomposition. The children with autism displayed greater use of decomposition strategies, suggesting that more analytic strategies, rather than rote memory, were the source of their enhanced abilities.

Then, the children worked on solving math problems while their brain activity was measured in an MRI scanner, in which they had to lie down and remain still. The brain scans of the autistic children revealed an unusual pattern of activity in the ventral temporal occipital cortex, an area specialized for processing visual objects, including faces.

“Our findings suggest that altered patterns of brain organization in areas typically devoted to face processing may underlie the ability of children with autism to develop specialized skills in numerical problem solving,” Iuculano said.

“These findings not only empirically confirm that high-functioning children with autism have especially strong number-problem-solving abilities, but show that this cognitive strength in math is based on different patterns of functional brain organization,” said Carl Feinstein, MD, director of the Center for Autism and Related Disorders at Packard Children’s and professor of psychiatry and behavioral sciences at the School of Medicine. He was not involved in the study.

Menon added that previous research “has focused almost exclusively on weaknesses in children with autism. Our study supports the idea that the atypical brain development in autism can lead, not just to deficits, but also to some remarkable cognitive strengths. We think this can be reassuring to parents.”

The research team is now gathering data from a larger group of children with autism to learn more about individual differences in their mathematical abilities. Menon emphasized that not all children with autism have superior math abilities, and that understanding the neural basis of variations in problem-solving abilities is an important topic for future research.

(Image: Corbis)

Autism affects different parts of the brain in women and men

Autism affects different parts of the brain in females with autism than males with autism, a new study reveals. The research is published today in the journal Brain as an open-access article.

Scientists at the Autism Research Centre at the University of Cambridge used magnetic resonance imaging to examine whether autism affects the brain of males and females in a similar or different way. They found that the anatomy of the brain of someone with autism substantially depends on whether an individual is male or female, with brain areas that were atypical in adult females with autism being similar to areas that differ between typically developing males and females. This was not seen in men with autism.

“One of our new findings is that females with autism show neuroanatomical ‘masculinization’,” said Professor Simon Baron-Cohen, senior author of the paper. “This may implicate physiological mechanisms that drive sexual dimorphism, such as prenatal sex hormones and sex-linked genetic mechanisms.”

Autism affects 1% of the general population and is more prevalent in males. Most studies have therefore focused on male-dominant samples. As a result, our understanding of the neurobiology of autism is male-biased.

“This is one of the largest brain imaging studies of sex/gender differences yet conducted in autism. Females with autism have long been under-recognized and probably misunderstood,” said Dr Meng-Chuan Lai, who led the research project. “The findings suggest that we should not blindly assume that everything found in males with autism applies to females. This is an important example of the diversity within the ‘spectrum’.”

Dr Michael Lombardo, who co-led the study, added that although autism manifests itself in many different ways, grouping by gender may help provide a better understanding of this condition.

He said: “Autism as a whole is complex and vastly diverse, or heterogeneous, and this new study indicates that there are ways to subgroup the autism spectrum, such as whether an individual is male or female. Reducing heterogeneity via subgrouping will allow research to make significant progress towards understanding the mechanisms that cause autism.”

Brain chemistry changes in children with autism offer clues to earlier detection and intervention

Between ages three and 10, children with autism spectrum disorder exhibit distinct brain chemical changes that differ from children with developmental delays and those with typical development, according to a new study led by University of Washington researchers.

The finding that early brain chemical alterations tend to normalize during the course of development in children with ASD gives new insight to efforts to improve early detection and intervention. The findings were reported July 31 in the Journal of the American Medical Assocation Psychiatry.

“In autism, we found a pattern of early chemical alterations at the cellular level that over time resolved – a pattern similar to what others have seen with people who have had a closed head injury and then got better,” said Stephen R. Dager, a UW professor of radiology and adjunct professor of bioengineering and associate director of UW’s Center on Human Development and Disability.

Neva Corrigan, a senior research fellow in radiology, was first author and Dager corresponding author of the study, titled “Atypical Developmental Patterns of Brain Chemistry in Children with Autism Spectrum Disorder.”

“The brain developmental abnormalities we observed in the children with autism are dynamic, not static. These early chemical alterations may hold clues as to specific processes at play in the disorder and, even more exciting, these changes may hold clues to reversing these processes,” Dager said.

In the study, scientists compared brain chemistry among three groups of children: those with a diagnosis of ASD, those with a diagnosis of developmental delay, and those considered typically developing. The researchers used magnetic resonance spectroscopic imaging, a type of MRI, to measure tissue-based chemicals in three age groups: 3-4 years, 6-7 years and 9-10 years.

One of the chemicals measured, N-acetylaspartate (NAA), is thought to play an important role in regulating synaptic connections and myelination. Its levels are decreased in people with conditions such as Alzheimer’s, traumatic brain injury or stroke. Other chemicals examined in the study – choline, creatine, glutamine/glutamate and myo-inositol – help characterize brain tissue integrity and bioenergetic status.

A notable finding concerned changes in gray matter NAA concentration: In scans of the 3- to 4-year-olds, NAA concentrations were low in both the ASD and developmentally delayed groups. By 9 to 10 years, NAA levels in the children with ASD had caught up to the levels of the typically developing group, while low levels of NAA persisted in the developmentally delayed group.

“A substantial number of kids with early, severe autism symptoms make tremendous improvements. We’re only measuring part of the iceberg, but this is a glimmer that we might be able to find a more specific period of vulnerability that we can measure and learn how to do something more proactively,” said Annette Estes, a co-author of the study and director of the UW Autism Center. She is an associate professor of speech and hearing sciences.

Study co-author Dennis Shaw, a UW professor of radiology and director of MRI at Seattle Children’s, observed that the findings “parallel some of the early brain structural differences we and others have found on MRI that also appear to normalize over time in children with autism. These chemical findings will help to better establish the timing and mechanisms underlying genetic abnormalities known to be involved in at least some cases of autism.”

Dager and UW colleagues are currently using more advanced MRI methods to study infants at risk for ASD because of an older sibling with autism.

“We’re looking prospectively at these children starting at 6 months to determine if we can detect very early alterations in brain cell signaling or related cellular disruption that may precede early, subtle clinical symptoms of ASD.”

Despite the encouraging finding, science has yet to pinpoint the when, what and why of autism’s inception, an event often likened to the flipping of a switch. Discovering the earliest period that a child’s brain starts to develop a profile of ASD is crucial because, as the study acknowledged, “even a relatively brief period of abnormal signaling between glial cells and neurons during early development would likely have a lasting effect” on how a child’s brain network develops.

This study also suggests that developmental delay and autism spectrum disorder are distinct disorders having different underlying brain mechanisms and treatment considerations, Dager said.

“Autism appears to have a different pathophysiology and different early biological course than idiopathic developmental disorder. There are differences in their underlying biological processes; this supports the notion that ASD is different from developmental delay and challenges the notion that the increasing prevalence of autism merely reflects a re-categorization of symptoms between autism and intellectual disabilities.”

Analysis of 26 networked autism genes suggests functional role in the cerebellum

A team of scientists has obtained intriguing insights into two groups of autism candidate genes in the mammalian brain that new evidence suggests are functionally and spatially related. The newly published analysis identifies two networked groupings from 26 genes associated with autism that are overexpressed in the cerebellar cortex, in areas dominated by neurons called granule cells.

The team, composed of neuroscientists and computational biologists, worked from a database providing expression levels of individual genes throughout the mouse brain, as complied in the open-source Allen Mouse Brain Atlas. To promote reproducibility, the scientists surveyed expression data of over 3000 genes, about three-fourths of all the genes listed in the Atlas for which two independent sets of data have been complied. 

The work was led by Professor Partha Mitra of Cold Spring Harbor Laboratory (CSHL) and scientists from MindSpec, a nonprofit research organization, founded by Dr. Sharmila Banerjee-Basu.

Despite obvious genetic and neuroanatomical differences between mouse and human, the team explains, mouse models are extremely effective in dissecting out the role of specific genes, pathways, neuronal subtypes and brain regions in specific abnormal behaviors manifested in both mice and people.

Based on years of studies in both species, scientists now know of mutations affecting more than 300 genes whose occurrence correlates with autism susceptibility; more are certain to be identified. Some of these candidate genes are more strongly correlated with the illness than others, although correlation is not the same thing as direct evidence of causation. 

Nevertheless, “the key question as yet unanswered,” notes Dr. Mitra, “concerns the way or ways in which particular mutations, singly or in combination, cause pathologies that result in the complex combination of symptoms that characterizes autism in children.” It is assumed that autism pathologies are the result of insults — genetic, environmental, or most likely both — sustained at the time of conception and early in development.

Dr. Idan Menashe, now of Ben-Gurion University of the Negev in Israel, and Dr. Pascal Grange, a postdoctoral researcher in the Mitra lab, demonstrated that co-expression of 26 autism genes was “significantly higher” than would occur by chance. “This suggests that these 26 genes have common neuro-functional properties,” says Dr. Menashe. 

The team found two co-expressed networks or “cliques” of genes that are significantly enriched with autism genes. They then asked where in the mouse brain these cliques are expressed. Notably, genes in both groups showed significant overexpression in the cerebellar cortex, and particularly in regions in which granule cells predominate. “This result supports prior studies pointing to involvement of the cerebellum in autism,” says Dr. Grange. Specifically, a recent neuroimaging study highlighted functional subregions in the cerebellum as playing a role in both motor and cognitive tasks. Other genes associated with autism have been shown in other studies to play a role in the development of this brain region.

“Our study provides insights into co-expression properties of genes associated with autism and suggests specific brain regions implicated in pathology. Complementing these findings with additional genomic and neuroimaging analyses from both mouse and human brains will help in obtaining a broader picture of the autistic brain,” the team concludes.

Novel technology seen as new, more accurate way to diagnose and treat autism

Researchers at Indiana University School of Medicine and Rutgers University have developed a new quantitative screening method for diagnosing and longitudinal tracking of autism in children after age 3. The studies are published as part of a special collection of papers in the open-access journal Frontiers in Neuroscience titled “Autism: The Movement Perspective.”

The technique involves tracking a person’s random movements in real time with a sophisticated computer program that produces 240 images a second and detects systematic signatures unique to each person. The traditional assessment for diagnosing autism involves primarily subjective opinions of a person’s social interaction, deficits in communication, and repetitive and restricted behaviors and interests.

The new screening tool is a collaboration between Jorge V. José, Ph.D., vice president of research at Indiana University and the James H. Rudy Distinguished Professor of Physics in the IU Bloomington College of Arts and Sciences; Elizabeth Torres, Ph.D., the principal investigator for the study and an assistant professor in the Department of Psychology in the School of Arts and Sciences at Rutgers University; and Dimitri Metaxas, Ph.D., a Distinguished Professor of computer science at Rutgers. The research was funded by a $670,000 grant from the National Science Foundation.

"This research may open doors for the autistic community by offering the option of a dynamic diagnosis at a much earlier age and possibly enabling the start of therapy sooner in the child’s development," said Dr. José, who also is a professor of cellular and integrative physiology at the Indiana University School of Medicine.

The new technique provides an earlier, more objective and more accurate diagnosis of autism. It factors the importance of changes in movements and movement sensing, thus enabling the identification of inherent capabilities in each child, rather than just highlighting impairments of the child’s movement systems. It measures tiny fluctuations in movement as the individual moves through space and can determine the exact degree to which these patterns of motion differ from more typically developing individuals, and to what degree they can turn into predictive, reliable and anticipatory movements.

Even in nonverbal children and adults with autism, the method can diagnose autism subtypes, identify gender differences and track individual progress in development and treatment. The method may also be applied to infants.

Dr. José said statistical properties of how people move and the speed and random nature of the movements produce a quantitative measurement that can be applied to individuals when the new technology captures their movements.

“We can estimate the cognitive abilities of people just from the variability of how they move,” Dr. José said. “This may lead to a complementary way to develop therapies for autistic children at an early age.”

In a second paper in the collection, the new method can be applied to interventions. The researchers say it could change the way autistic children learn and communicate by helping them develop self-motivation, rather than relying exclusively on external cues and commands, which are the basis of behavioral therapy for children with autism.

Torres and her team created a digital set-up that works much like a Wii. Children with autism were exposed to onscreen media — such as videos of themselves, cartoons, a music video or a favorite TV show — and learned to communicate what they like with a simple motion.

"Every time the children cross a certain region in space, the media they like best goes on," Dr. Torres said. "They start out randomly exploring their surroundings. They seek where in space that interesting spot is which causes the media to play, and then they do so more systematically. Once they see a cause and effect connection, they move deliberately. The action becomes an intentional behavior."

Researchers found that all 25 children in the study, most of whom were nonverbal, spontaneously learned how to choose their favorite media. They also retained this knowledge over time even without practice.

The children independently learned that they could control their bodies to convey and procure what they want. “Children had to search for the magic spot themselves,” Dr. Torres said. “We didn’t instruct them.”

Torres believes that traditional forms of therapy, which place more emphasis on socially acceptable behavior, can actually hinder children with autism by discouraging mechanisms they have developed to cope with their sensory and motor differences, which vary greatly from individual to individual.

It is too early to tell whether the research will translate into publicly available methods for therapy and diagnosis, Dr. Torres said. But she is confident that parents of children with autism would find it easy to adopt her computer-aided technique to help their children.

Novel ‘top-down’ mechanism repatterns developing brain regions

Dennis O’Leary of the Salk Institute was the first scientist to show that the basic functional architecture of the cortex, the largest part of the human brain, was genetically determined during development. But as it so often does in science, answering one question opened up many others. O’Leary wondered what if the layout of the cortex wasn’t fixed? What would happen if it were changed?

In the August issue of Nature Neuroscience, O’Leary, holder of the Vincent J. Coates Chair of Molecular Neurobiology at Salk, and Andreas Zembrzycki, a postdoctoral researcher in his lab, demonstrate that altering the cortical layout is possible, and that this alteration produces significant changes in parts of the brain that connect with the cortex and define its functional properties. These mechanisms may lay at the heart of neural developmental problems, such as autism spectrum disorders (ASD).

The human cortex is involved in higher functions such as sensory perception, spatial reasoning, conscious thought and language. All mammals have areas in the cortex that process the senses, but they have them in different proportions. Mice, the favorite laboratory animal, are nocturnal, so they have a large somatosensory area (S1) in the cortex, responsible for somatosensation, or feelings of the body that include touch, pain, temperature and proprioception.

"The area layout of the cortex directly relates to the lifestyle of an animal," says Zembrzycki. "Areas are bigger or smaller according to the functional needs of the animal, not the physical size of the body parts from which they receive input."

Even with relative sizes to other species set in place, areas in the cortex of humans may differ greatly across individuals. Such variations may underlie why some people appear to be naturally better at certain perceptual tasks, such as hitting a baseball or detecting the details of visual illusions. In patients with neurological disorders, there is an even wider range of differences.

The neurons in S1 are arranged in functional groups called body maps according to the density of nerve endings in the skin; thus, there’s a larger group of neurons dedicated to the skin on the face, than the skin on the legs. Neurosurgeon Wilder Penfield famously illustrated this idea as a “sensory homunculus,” a cartoon of disproportionately sized body parts arching over the cortex. Mice have a similar “mouseunculus” in their cortex in which the body map of the facial whiskers is highly enlarged.

These perceptual maps are not set for life. For example, if innervation of a body part is diminished early in life during a critical period, its map may shrink, while other parts of the body map may grow in compensation. This is a version of “bottom-up plasticity,” in which external experience affects body maps in the brain.

In order to study cortical layout, O’Leary’s team altered a regulatory gene, Pax6, in the cortex in mice. In response, S1 became much smaller, demonstrating that Pax6 regulates its development. They found that the shrinkage in S1 subsequently affected other regions of the brain that feed sensory information into the cortex, but more interestingly, it also altered the body maps in these subcortical brain regions, overturning the idea that once established, these brain regions could only be changed by external experience. They dubbed this previously unknown phenomenon “top down plasticity.”

"Top-down plasticity complements in a reverse fashion the well-known bottom-up plasticity induced by sensory deprivation," says O’Leary.

Normally, the body map in S1 cortex mirrors similar body maps in the thalamus, the main switching station for sensory information, which transmits somatosensation from the body periphery to the S1 cortex through outgoing neural “wires” known as axons. In the newly discovered top-down plasticity, when S1 was made smaller, the sensory thalamus that feeds into it is also subsequently reduced in size.

But the story has a more intriguing twist. “According to our present knowledge about the development of sensory circuits, we anticipated that all body representations in S1 would be equally affected when S1 was made smaller,” says O’Leary. “It was a surprise to us that not only was the body map smaller, but some parts of it were completely missing. The specific deletion of parts of the body map is controlled by exaggerated competition for cortical resources dictated by S1 size and played out between the connections from thalamic neurons that form these maps in the cortex.”

"To put it in lay terms, ‘If you snooze, you lose,’" adds Zembrzycki. "Axons that differentiate later are preferentially excluded from the smaller S1 leading to the specific deletion of the body parts that they represent."

"The essential point about top-down plasticity is that altering the size and patterning of sensory cortex results in matching alterations in sensory thalamus through the selective death of thalamic neurons that normally would represent body parts absent from S1," Zembrzycki adds. "Therefore, a downstream part of the brain is repatterned to match the architecture in S1, resulting in aberrant wiring of the brain that has important implications for sensory perception and function. For example, autistics have very robust abnormalities in touching and other features of somatosensation."

O’Leary and Zembrzycki believe that this process provides significant insights into the development of autism and other neural disorders. “One of the hallmarks of the autistic brain early in development is the area profile seems to be abnormal, with for example, the frontal cortex being enlarged, while the overall cortex keeps its normal size,” says O’Leary. “It is implicit then that other cortical areas positioned behind the frontal areas, such as S1, would be reduced in size, and thalamus would exhibit defects that match those in sensory cortex, as has been shown to be the case in autistic patients.”