Rett syndrome: Autism Spectrum Disorder Mice improve with synthetic oil

When young mice with the rodent equivalent of a rare autism spectrum disorder (ASD), called Rett syndrome, were fed a diet supplemented with the synthetic oil triheptanoin, they lived longer than mice on regular diets.

Importantly, their physical and behavioral symptoms were also less severe after being on the diet, according to results of new research from The Johns Hopkins University.

Researchers involved in the study think that triheptanoin improved the functioning of mitochondria, energy factories common to all cells.

Since mitochondrial defects are seen in other ASDs, the researchers say, the experimental results offer hope that the oil could help not just people with Rett syndrome, but also patients with other, more common ASDs.

A description of the research will be published on Oct. 9 in the journal PLOS ONE.

ASDs affect an estimated one in 68 children under 8 years of age in the United States. Rett syndrome is a rare ASD caused by mutations in the MECP2 gene, which codes for methyl-CpG-binding-protein 2 (MeCP2).

Rett syndrome includes autism-like signs, such as difficulty communicating, socializing and relating to others.

Other hallmarks are seizures, decreased muscle tone, repetitive involuntary movements, and gastrointestinal and breathing problems.

These other signs are also seen in some patients with other ASDs, suggesting underlying similarities in their causes.

While the causes of most ASDs are unknown and thought to be complex, Rett syndrome is unique, and could be a source of insight for the others, because it is caused by an error in a single gene.

The research team used mice lacking the MeCP2 protein, which left them with severe Rett syndrome.

In examining those mice, what stood out, according to Gabriele Ronnett, M.D., Ph.D., who led the research project at the Johns Hopkins University School of Medicine, was that they weighed the same as healthy mice but had large fat deposits accompanied by lower amounts of nonfat tissue, such as muscle.

This suggested that calories were not being used to support normal tissue function but instead were being stored as fat.

This possibility led Ronnett and her research team to consider the role of mitochondria, which transform the building blocks of nutrients into a high-energy molecule, ATP.

This molecule drives processes such as the building of muscle and the growth of nerve cells.

Mitochondria use a series of biochemical reactions, collectively called the TCA cycle, to make this transformation possible.

According to Susan Aja, Ph.D., a research associate and lead member of the research team, "If the components of the TCA cycle are low, nutrient building blocks are not processed well to create ATP. They are instead stored as fat."

Ronnett suspected, she says, that some of Rett syndrome's neurological symptoms could stem from metabolic deficiencies caused by faulty mitochondria and reduced energy for brain cells.

"Rett syndrome becomes apparent in humans 6 to 18 months old, when the energy needs of the brain are particularly high, because a lot of new neural connections are being made," says Ronnett.

"If the mitochondria are already defective, stressed or damaged, the increased demand would be too much for them."

Previous small clinical trials in people with a different metabolic disorder suggested that dietary intervention with triheptanoin could help.

Triheptanoin is odourless, tasteless and a little thinner than olive oil. It is easily processed to produce one of the components of the TCA cycle.

When Rett syndrome mice were weaned at 4 weeks of age, they were fed a diet in which 30 percent of their calories came from triheptanoin, mixed in with their normal pelleted food.

Though far from a cure, the results of the triheptanoin treatment were impressive, the researchers say.

Treated mice had healthier mitochondria, improved motor function, increased social interest in other mice and lived four weeks, or 30 percent, longer than mice who did not receive the oil. The team also found that the diet normalized their body fat, glucose and fat metabolism.

"You can think of the mitochondria of the Rett syndrome model mice as damaged buckets with holes in them that allow TCA cycle components to leak out," says Aja.

"We haven't figured out how to plug the holes, but we can keep the buckets full by providing triheptanoin to replenish the TCA cycle."

"It is still too early to assume that this oil will work in humans with ASDs, but these results give us hope," says Ronnett.

"It's exciting to think that we might be able to improve many ASDs without having to identify each and every contributing gene."

According to Aja, additional mouse studies are needed to learn if female mice respond to the treatment, to perform a wider range of physiology and behavior tests, and, importantly, to assess the effects of triheptanoin treatment on the brain, which is considered the main driver of many Rett symptoms.

The team would also like to provide triheptanoin at earlier ages, perhaps via the mothers' milk, to mimic developmental ages at which most children are diagnosed with Rett syndrome.

Triheptanoin is currently made for research purposes only and is not available as a medicine or dietary supplement for humans.

More information: PLOS ONE: dx.plos.org/10.1371/journal.pone.0109527

EEG Brainwave test could improve autism diagnosis and classification

A new study by researchers at Albert Einstein College of Medicine of Yeshiva University suggests that measuring how fast the brain responds to sights and sounds could help in objectively classifying people on the autism spectrum and may help diagnose the condition earlier.

The paper was published today in the online edition of the Journal of Autism and Developmental Disabilities.

The U.S. Centers for Disease Control and Prevention estimates that 1 in 68 children has been identified with an autism spectrum disorder (ASD).

The signs and symptoms of ASD vary significantly from person to person, ranging from mild social and communication difficulties to profound cognitive impairments.

"One of the challenges in autism is that we don't know how to classify patients into subgroups or even what those subgroups might be," said study leader Sophie Molholm, Ph.D., associate professor in the Dominick P. Purpura Department of Neuroscience and the Muriel and Harold Block Faculty Scholar in Mental Illness in the department of pediatrics at Einstein.

"This has greatly limited our understanding of the disorder and how to treat it."

Autism is diagnosed based on a patient's behavioural characteristics and symptoms.

"These assessments can be highly subjective and require a tremendous amount of clinical expertise," said Dr. Molholm. "We clearly need a more objective way to diagnose and classify this disorder."

An earlier study by Dr. Molholm and colleagues suggested that brainwave electroencephalogram (EEG) recordings could potentially reveal how severely ASD individuals are affected.

That study found that children with ASD process sensory information, such as sound, touch and vision, less rapidly than typically developing children do.

The current study was intended to see whether sensory processing varies along the autism spectrum. Forty-three ASD children aged 6 to 17 were presented with either a simple auditory tone, a visual image (red circle), or a tone combined with an image, and instructed to press a button as soon as possible after hearing the tone, seeing the image or seeing and hearing the two stimuli together.

Continuous EEG recordings were made via 70 scalp electrodes to determine how fast the children's brains were processing the stimuli.

The speed with which the subjects processed auditory signals strongly correlated with the severity of their symptoms: the more time required for an ASD individual to process the auditory signals, the more severe that person's autistic symptoms.

"This finding is in line with studies showing that, in people with ASD, the microarchitecture in the brain's auditory center differs from that of typically developing children," Dr. Molholm said.

The study also found a significant though weaker correlation between the speed of processing combined audio-visual signals and ASD severity. No link was observed between visual processing and ASD severity.

"This is a first step toward developing a biomarker of autism severity, an objective way to assess someone's place on the ASD spectrum," said Dr. Molholm.

"Using EEG recordings in this way might also prove useful for objectively evaluating the effectiveness of ASD therapies."

In addition, EEG recordings might help diagnose ASD earlier. "Early diagnosis allows for earlier treatment, which we know increases the likelihood of a better outcome," said Dr. Molholm.

"But currently, fewer than 15 percent of children with ASD are diagnosed before age 4. We might be able to adapt this technology to allow for early ASD detection and therapy for a much larger percentage of children."

More information: The paper is titled "Neurophysiological Indices of Atypical Auditory Processing and Multisensory Integration are Associated with Symptom Severity in Autism."

Common gene variants account for most genetic risk for autism

The bulk of risk, or liability, for autism spectrum disorders was traced to inherited variations in the genetic code shared by many people. 

These and other (unaccounted) factors dwarfed contributions from rare inherited, non-additive and spontaneous (de novo) genetic factors 

Credit: Population-Based Autism Genetics and Environment Study

Most of the genetic risk for autism comes from versions of genes that are common in the population rather than from rare variants or spontaneous glitches, researchers funded by the National Institutes of Health (NIH) have found.

Heritability also outweighed other risk factors in this largest study of its kind to date. About 52 percent of the risk for autism was traced to common and rare inherited variation, with spontaneous mutations contributing a modest 2.6 percent of the total risk.

"Genetic variation likely accounts for roughly 60 percent of the liability for autism, with common variants comprising the bulk of its genetic architecture," explained Joseph Buxbaum, Ph.D., of the Icahn School of Medicine at Mount Sinai (ISMMS), New York City.

"Although each exerts just a tiny effect individually, these common variations in the genetic code add up to substantial impact, taken together."

Buxbaum, and colleagues of the Population-Based Autism Genetics and Environment Study (PAGES) Consortium, report on their findings in a unique Swedish sample in the journal Nature Genetics, July 20, 2014.

"Thanks to the boost in statistical power that comes with ample sample size, autism geneticists can now detect common as well as rare genetic variation associated with risk," said Thomas R. Insel, M.D., director of the NIH's National Institute of Mental Health (NIMH).

"Knowing the nature of the genetic risk will reveal clues to the molecular roots of the disorder. Common variation may be more important than we thought."

Although autism is thought to be caused by an interplay of genetic and other factors, including environmental, consensus on their relative contributions and the outlines of its genetic architecture has remained elusive.

Recently, evidence has been mounting that genomes of people with autism are prone to harboring rare mutations, often spontaneous, that exert strong effects and can largely account for particular cases of disease.

More challenging is to gauge the collective impact on autism risk of numerous variations in the genetic code shared by most people, which are individually much subtler in effect.

Limitations of sample size and composition made it difficult to detect these effects and to estimate the relative influence of such common, rare inherited, and rare spontaneous variation.

Differences in methods and statistical models also resulted in sometimes wildly discrepant estimates of autism's heritability, ranging from 17 to 50 percent.

Meanwhile, recent genome-wide studies of schizophrenia have achieved large enough sample sizes to reveal involvement of well over 100 common gene variants in that disorder.

These promise improved understanding of the underlying biology, and even development of risk-scores, which could help predict who might benefit from early interventions to nip psychotic episodes in the bud.

With their new study, autism genetics is beginning to catch up, say the researchers. It was made possible by Sweden's universal health registry, which allowed investigators to compare a very large sample of about 3,000 people with autism with matched controls.

Researchers also brought to bear new statistical methods that allowed them to more reliably sort out the heritability of the disorder.

In addition, they were able to compare their results with a parallel study in 1.6 million Swedish families, which took into account data from twins and cousins, and factors like age of the father at birth and parents' psychiatric history.

A best-fit statistical model took form, based mostly on combined effects of multiple genes and non-shared environmental factors.

"This is a different kind of analysis than employed in previous studies," explained Thomas Lehner, Ph.D., chief of NIMH's Genomics Research Branch.

"Data from genome-wide association studies was used to identify a genetic model instead of focusing just on pinpointing genetic risk factors. The researchers were able to pick from all of the cases of illness within a population-based registry."

Now that the genetic architecture is better understood, the researchers are identifying specific genetic risk factors detected in the sample, such as deletions and duplications of genetic material and spontaneous mutations.

Even though such rare spontaneous mutations accounted for only a small fraction of autism risk, the potentially large effects of these glitches makes them important clues to understanding the molecular underpinnings of the disorder, say the researchers.

"Within a given family, the mutations could be a critical determinant that leads to the manifestation of ASD in a particular family member," said Buxbaum.

"The family may have common variation that puts it at risk, but if there is also a de novo [spontaneous} mutation on top of that, it could push an individual over the edge."

"So for many families, the interplay between common and spontaneous genetic factors could be the underlying genetic architecture of the disorder."

More information: Gaughler T, Klei L, Sanders SJ, Bodea CA, Goldberg AP, Lee AB, Mahajan M, Manaa D, Pawitan Y, Reichert J, Ripke S, Sandin S, Sklar P, Svantesson O, Reichenberg A, Hultman CH, Devlin B, Roeder K, Buxbaum JD. Most genetic risk for autism resides with common variation. Nature Genetics, July 20, 2014. dx.doi.org/10.1038/ng.3039

Strategies for teaching common core to teens with autism show promise

Credit: High school classroom in Newark, Delaware, public domain image, courtesy of Wikimedia

Scientists at UNC's Frank Porter Graham Child Development Institute (FPG) report that high school students with autism can learn under Common Core State Standards (CCSS), boosting their prospects for college and employment.

Newly published recommendations from FPG's team also provide strategies for educating adolescents with autism under a CCSS curriculum.

Veronica P. Fleury

"The number of students with autism who enter high school settings continues to grow," said Veronica P. Fleury, lead author and postdoctoral research associate with FPG's Center on Secondary Education for Students with Autism Spectrum Disorders (CSESA).

"Many educators may find that they're not prepared to adapt their instruction to meet both state standards and the diverse needs of these students."

In 2010, the National Governors Association Center for Best Practices and the Council of Chief State School Officers released the CCSS for English and mathematics in an effort to better prepare students for college and careers.

According to Fleury, the greater demand for a technologically advanced workforce also makes academic skills now even more essential for high school graduates.

"But the college enrollment of people with autism is among the lowest for all categories of disabilities," Fleury said.

"In addition, less than 40% of the population with autism is employed, and most of those with jobs only work part-time, without benefits."

However, she said that academic performance in high school plays an important role in opportunities for a college education and employment.

Yet, while the CCSS outlines expectations of what educators should teach, it provides no guidance on how to teach these skills to students with or without autism.

Fleury believes the most effective high school instruction requires understanding the complex profile of students with ASD, who possess both strengths and weaknesses.

People with autism have some social deficits and may process language at a slower rate, she said, while many also have enhanced visual processing.

Some may have difficulty learning to make calculations, but others are mathematically gifted.

"It's extremely hard to draw general conclusions about academic performance for these students," Fleury said. "But adolescents with autism often do have difficulties comprehending texts, and many find writing a burdensome task."

Fluery added that work in STEM fields (science, technology, engineering, and math) are replacing manufacturing jobs and may provide viable opportunities for many people with ASD.

She said people with autism often gravitate to these fields in college, highlighting the need to equip them as high school students with skills that will enable them to compete and achieve.

"While the very structure of high school poses challenges for students with autism, being able to anticipate and understand activities, schedules, and expectations can improve their ability to respond to classroom demands," she said. "Establishing routines and creating written schedules also helps."

In a new article in Remedial and Special Education, Fleury and her co-authors recommended several strategies to educate students with ASD effectively, including exposing them to assignments before presenting the work in class.

The researchers also noted a variety of techniques for delivering the highly explicit instruction that teenagers with autism require, such as teaching mnemonic devices for remembering steps in a task.

"High school students with ASD also need ample opportunities to practice skills across settings throughout the school day," she said. "And teaching them to monitor their own behavior can help them to use their skills in a variety of settings."

Fleury added that because there is a strong link between social and academic skills, new research should focus on developing interventions for students with autism that can address both areas of need together.

"We know that when students with autism receive appropriate instruction and support, many of them are capable of learning academic content that is aligned with state standards, AND better academic performance often leads to a more successful outcome after high school." she said.

Autism: Superior visual thinking key to independence for ASD high schoolers

Researchers at UNC's Frank Porter Graham Child Development Institute (FPG) and UNC's School of Education report that teaching independence to adolescents with autism can provide a crucial boost to their chances for success after high school.

"We explored many factors that contribute to the poor outcomes people with autism often experience," said Kara Hume, co-principal investigator of FPG's Center on Secondary Education for Students with Autism Spectrum Disorders (CSESA).

"It's clear that teaching independence to students with autism should be a central focus of their activities in high school."

Kara Hume

According to Hume, independence is the biggest indicator of which students with autism spectrum disorder (ASD) are likely to live on their own, have a job, and participate in their communities after high school.

"However, adolescents with ASD have trouble observing their peers and picking up on skills important for developing independence," she said.

Hume also said students with ASD experience difficulties with communication that inhibit their ability to ask questions and express preferences, and many have trouble dealing with new situations.

This resistance to change can create problems when teachers and caregivers try to reduce their roles.

"When an adolescent with ASD has a pen that runs out of ink, that student may be more likely to wait for prompting from the teacher before asking for a new pen or just finding a new one," she said.

Hume added that it isn't easy to change this default setting from reliance on others to independent action.

Although adolescence is usually a time of increasing autonomy, research shows that the independence of young adults with ASD begins to plateau and then decline.

According to Hume, though, other scientists have demonstrated that many high schoolers with ASD also possess unique skills that teachers and caregivers can emphasize in order to teach independence.

"Brain imaging studies and research on visual tasks show that many people with autism have enhanced mental imagery and superior visual thinking, compared to typically developing people," Hume said.

She added that people with ASD also describe their own reasoning as a series of images.

"For high schoolers with autism, the old adage really is true," she said. "A picture really is worth a thousand words."

Last month, an FPG team released a new report and Fact Sheet for the National Professional Development Center on Autism Spectrum Disorders (NPDC), which screened 29,000 articles to determine the most reliable evidence-based interventions for children and youth with ASD.

Hume served on that team, helping to determine 12 evidence-based practices for high-school-aged students, and some of these interventions have a strong visual emphasis.

"Visual schedules, for instance, allow students with ASD to act independently, because they don't involve verbal prompting from teachers," Hume said.

"Visual information that explains what to do also can be useful in home, school, and employment settings, because it eliminates the need for continual monitoring and support."

Hume also said that video modeling, which the NPDC's report showed to be effective with other age groups, might also prove useful for high school students with ASD.

Prompting from teachers can be edited out over time as students become accustomed to behaving independently.

The new issue of Remedial and Special Education published recommendations from Hume and colleagues for promoting independence in adolescents with autism.

She and her co-authors also noted that new technology has the potential to capitalize on the visual strengths of people with ASD.

"IPads and iPhones are everywhere for typically developing teens," Hume said.

"The social acceptability of cell phone or tablet interventions for students with autism could lessen the stigma they face—and contribute to transformative outcomes after high school."

More information: Remedial and Special Education journal rse.sagepub.com/content/35/2/102.full.pdf+html

Helping families cope with autism and aggression

Madeline Rainey

Madeline Rainey holds a portrait of herself with her son when he was a child. 

Rainey hopes a UAlberta study on aggression in kids with autism will spur more research and raise awareness of how families are affected. 

Credit: Richard Siemens

Madeline Rainey admits she compares her son's existence to a life sentence.

"I watched him suffer and be blamed and judged," says Rainey, whose son Eric has autism spectrum disorder with aggression.

"I keep asking, 'When is someone going to do something and recognize the lifelong pain that my kid and I have to live with?'"

Though autism and aggression are not synonymous, many children with autism spectrum disorder (ASD) show aggressive behaviour, which has a significant and lifelong impact on families, according to a University of Alberta study.

"Little has been done to understand families coping with autism and aggression, and if these families don't receive the support they need, things can get bad very quickly," says Sandy Hodgetts, assistant professor of occupational therapy in the Faculty of Rehabilitation Medicine and lead author of the study.

Sandy Hodgetts

"The percentage of children with ASD and aggression is not known because aggression is not a core symptom of autism."

Though the study was small, it was the first to look at families dealing with autism and aggression.

The researchers followed 15 families with male children and young adults with varying levels of autism.

Nine of the 15 families brought up their child's aggression as a barrier to services.

Parents described the impact of the aggression as "constant," "never-ending" and "almost unbearable."

One mother said her son's aggression had become so bad that she was "about ready to be locked up."

Hodgetts says families dealing with aggressive behaviour struggled with social isolation, lack of respite care and limited professional supports.

"The aggressive acts are not malicious. There needs to be better understanding and mechanisms in place to train and support respite care providers and health-care professionals in this area."

Rainey agrees that specialized training could make all the difference. When Eric was in grades 11 and 12, he had a teacher who majored in special education.

She was able to be creative, understand Eric and not be deterred by his aggression.

"I'm grateful for her and we still keep in touch," says Rainey.

Though her son is now 21, Rainey hopes this study can spur more research on autism and aggression. "It raises awareness on the impact on families and can hopefully help remove the social stigma for children and parents."

She hopes that with positive change and awareness, perhaps one day other families don't have to go through what she went through.

"We went from daycare to daycare, from caregiver to caregiver. I was told the reason my son was aggressive was that I was too domineering as a mother and I was told I was too permissive.

I was told to feed my child only organic food so he wouldn't have these behavioural problems. They assumed he was some kind of monster and I was to blame," she says. "It takes a piece of your soul."

More information: Sandra Hodgetts, David Nicholas, and Lonnie Zwaigenbaum. "Home Sweet Home? Families' Experiences With Aggression in Children With Autism Spectrum Disorders." Focus on Autism and Other Developmental Disabilities. September 2013 28: 166-174, first published on January 18, 2013 DOI: 10.1177/1088357612472932

Revised checklist improves detection of autism in toddlers

The Modified Checklist for Autism in Toddlers, Revised with Follow-up (M-CHAT-R/F) is an effective screening tool for autism spectrum disorders (ASDs) in low-risk toddlers, according to research published online Dec. 23 in Pediatrics.

Diana L. Robins, Ph.D., of Georgia State University in Atlanta, and colleagues used the M-CHAT-R/F to screen 16,071 toddlers at 18-month and 24-month well-child care visits.

M-CHAT-R/F uses an algorithm based on three risk levels and is intended to reduce age of diagnosis and hasten early intervention.

The researchers found that the M-CHAT-R/F was reliable and valid.

Children scoring 3 or higher at initial screening and 2 or higher at follow-up had a 47.5 percent risk of being diagnosed with ASD and a 94.6 percent risk of having any developmental delay or concern.

According to the report, compared with the original M-CHAT, the revised tool detects ASD at a higher rate and reduces the number of children who need follow-up.

In the current study, children received a diagnosis of ASD at an age that was two years earlier than the national median age of diagnosis.

"The M-CHAT-R/F detects many cases of ASD in toddlers; physicians using the two-stage screener can be confident that most screen-positive cases warrant evaluation and referral for early intervention," the authors write.

Several study authors disclosed financial interests in the M-CHAT.

More information: 'Validation of the Modified Checklist for Autism in Toddlers, Revised With Follow-up (M-CHAT-R/F)' peds.2013-1813.full.pdf/html 

Clinical histories reveal surprising evidence of multiple, distinct 'autisms'

Simple patterns can emerge from even the most chaotic, complex data.

Analyzing the electronic medical records of thousands of patients diagnosed with autism spectrum disorder, or ASD, a group of researchers at the Harvard Medical School Center for Biomedical Informatics found three distinct kinds of autism, which suggests that "autism" is perhaps an umbrella term comprising several illnesses with different genetic and environmental causes and different potential treatments.

Isaac Kohane

"Rather than there being one 'autism,' these findings show that there are several autisms, each with its own specific course," said Isaac Kohane, the Lawrence J. Henderson Professor of Pediatrics at Boston Children's Hospital, co-director of the Center for Biomedical Informatics and leader of the research team. The results appeared Dec. 9 in Pediatrics.

By separating diagnoses out in six-month segments over the first 15 years of each child's life, the researchers found one group of patients whose autism symptoms were associated with epilepsy and other seizure disorders.

In a second, ASD patients had increased rates of bowel and infectious ear and respiratory symptoms.

In a third, children had higher levels of psychiatric disorders, including ADHD, depression and schizophrenia.

NB: A fourth group of patients could not be further characterized due to statistical limitations of the available data.

The patterns of symptoms in the first three groups also correlated with different levels of expressive language disorder, timing of developmental delays and other core diagnostic measures for ASD.

Just as an understanding of the whole suite of symptoms that accompany a fever is crucial for determining whether a patient has strep or flu, Kohane said, it's crucial to understand the entire complex of symptoms associated with the different subsets of ASD in order to advance our understanding of what causes autism.

"Doing a genetic study of 'autism' is like studying fever and looking for a single cause," Kohane said.

Since most primary caregivers might see only a few ASD patients, and since the symptoms manifest differently at various periods of the child's development, having a massive, shareable database of clinical data in searchable electronic medical records was crucial to making sense of the complex picture of autism.

In a previous study, Kohane and colleagues used the Shared Health Research Information Network (SHRINE), a web-based query tool, to analyze 15,000 electronic health records of patients with ASD from HMS-affiliated hospitals.

They found that people with ASD suffer from a higher burden of seizures, psychiatric illness and gastrointestinal disorders than the general population.

While parents of children with autism and other patient advocates had long suggested that this was the case, the smaller population studies conducted without information infrastructure like SHRINE were not able to find evidence that incidences of these illnesses were significantly correlated with ASD.

This current study builds on Kohane's previous findings by showing that the related illnesses are not distributed randomly throughout the ASD population.

"The next step is to look at these subgroups to search for common genetic or environmental factors," Kohane said.

Electronic medical records shared in a flexible, open-source database like SHRINE provide a bird's-eye view of the medical system that offers researchers unique insights into disease and treatment.

"We spend tons of money to construct these databases and open record-sharing systems," Kohane said.

"We should take advantage of all that data not just to bill people for our services, but to better understand and treat disease."

More information: "Comorbidity Clusters in Autism Spectrum Disorders: An Electronic Health Record Time-Series Analysis." Finale Doshi-Velez, PhDa, Yaorong Ge, PhDb, and Isaac Kohane, MD, PhDa. Pediatrics, December 9, 2013. DOI: 10.1542/peds.2013-0819

Children with Autism: New Study questions traditional 'top down' research

The paper describes that rather than a single entity, autism is multiple disorders. Credit: CampASCCA

Information from the families of 1200 children with autism will be collected from next month to begin the largest autism data study in Australia which includes a team of WA researchers.

Telethon Institute of Child Health Research's Andrew Whitehouse says the project involves several prominent research groups across the nation under the umbrella of the Autism Co-operative Research Centre for Living with Autism Spectrum Disorders which received $31 million over eight years from the Federal Government earlier this year.

Professor Whitehouse says the centre will further extensive work by Telethon including its recent "proof of principle" research which advocates a new approach to autism investigation and whose findings have been documented in the Frontiers of Human Science Journal.

Prof Whitehouse says rather than using the traditional "top-down" approach to investigate the causes of autism, it takes the other end of the "causal pathway," starting with the factors that may produce the disorder.

The paper describes that it is now widely accepted that rather than a single entity, autism is multiple disorders. The variability in the nature and severity of behaviours is thought to exceed that of any other.

"What researchers tend to do is look at behaviours, classify people based on that and then look for genetic or biochemical markers that might be associated with those behaviours," Prof Whitehouse says.

"What we're suggesting is going at it the other way; look at genetic or environmental factors that are known to be associated with autism and look at whether they are then associated with behaviours."

He says after 70 years, researchers are frustrated by not being able to find a clear causal pathway but the only way research can proceed is through large collaborations.

"One lab group alone is not going to be able to solve the riddle of autism—that's just not going to happen," he says.

"We need large numbers of participants who can do both the "top-down" and "bottom-up" approach and that's what we're proposing."

The recently published "bottom-up" study selected participants from the WA Autism Biological Registry to analyse two areas previously linked to ASD diagnoses; low birth weight and maternal use of selective serotonin reuptake inhibitors (SRIs) during pregnancy.

These are found in medications used to treat anxiety and major depression.

Prof Whitehouse says the study provides a blueprint for a "bottom-up" approach, which creates smaller homogenous sub-groups with the autism spectrum, compared with a costly top down approach which requires larges sample sizes.

More Information: 'A “bottom-up” approach to aetiological research in autism spectrum disorders' Lisa M. Unwin1, Murray T. Maybery, John A. Wray and Andrew J. O. Whitehouse.

Psychotropic drugs commonly prescribed to children with ASD

Psychotropic medications, singly and in combination, are commonly prescribed for children with autism spectrum disorders (ASD), according to research published online Oct. 21 in Pediatrics.

Donna Spencer, Ph.D., of OptumInsight in Eden Prairie, Minn., and colleagues reviewed claims data from 2001 to 2009 for 33,565 children with ASD to assess rates and predictors of psychotropic use.

The researchers found that 64 percent of children with ASD had filled a prescription for at least one psychotropic medication.

Polypharmacy was evident, with concurrent medication fills across at least two drug classes in 35 percent and across at least three classes in 15 percent.

Factors associated with greater risk of psychotropic use and multiclass polypharmacy included older age; psychiatrist visit; and evidence of comorbid conditions such as seizures, attention-deficit disorders, anxiety, bipolar disorder, or depression.

"Despite minimal evidence of the effectiveness or appropriateness of multidrug treatment of ASD, psychotropic medications are commonly used, singly and in combination, for ASD and its co-occurring conditions," the authors write.

More information: Psychotropic Medication Use and Polypharmacy in Children With Autism

Autism ASD: Researchers discover a potential cause

Topoisomerase inhibitors reduce the expression of long genes in neurons, including a remarkable number of genes implicated in Autism Spectrum Disorders -- 200 kb is four times longer than the average gene. 

Credit: Concept: Mark Zylka. Illustration: Janet Iwasa.

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.

Mark Zylka

"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 neuro-developmental 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."

More information: Nature paper dx.doi.org/10.1038/nature12504

Preferred Play for Children With Autism

Pushing the arms of the windmill and watching them spin was among the play options enjoyed by children with autism spectrum disorder. Credit: Buffalo State

Play is critical to children's development, including children with autism spectrum disorders (ASD).

Kathy Ralabate Doody, assistant professor of exceptional education at SUNY Buffalo State, observed different play options to determine those most likely to appeal to children with ASD.

The findings were published in the North American Journal of Medicine and Science.

"Children with ASD chose to engage in play that provided strong sensory feedback, cause-and-effect results, and repetitive motions," said Doody.

One novel aspect of the research, conducted by Doody with Jana Mertz, program coordinator at the Autism Spectrum Disorder Center at the Women & Children's Hospital of Buffalo, was that the children with ASD could freely select their preferred activities.

The research was conducted at a monthly event, "Au-some Evening," at Explore & More, a children's museum with exhibits that are designed to engage children through play. The event is open to children with ASD, their families, and their guests.

Kathy Ralabate Doody

The most popular activity among children with ASD was the exhibit "Climbing Stairs." Children who climbed a short staircase could then drop a ball and watch it descend.

Another popular activity involved a windmill. Children can push its arms, causing it to spin. A table filled with rice completed the top three exhibits among children with ASD.

In addition to the well-known senses of sight, smell, touch, taste, and hearing, Doody described others, including the vestibular and proprioceptive senses.

The vestibular sense helps us keep our balance and know where we are in space; proprioception has to do with the way our joints respond to movement and pressure.

"It's the sense that makes deep-tissue massage pleasurable," she said. Children with ADS preferred activities that involved the vestibular and proprioceptive senses as well as other senses.

"Children with ADS sometimes tend to crave motion, and if they can't be moving, they like to look at moving objects," said Doody, noting that motion engages the vestibular, proprioceptive, and visual senses.

"So just watching the windmill engaged them. When the windmill turned in response to their push, it also provided cause-and-effect play. And the repetition of the spinning movement provided a third level of satisfaction."



Climbing the stairs also satisfied multiple senses. Playing with rice provided both tactile and visual stimulation as children felt and watched the rice pour through their fingers.

By knowing the kind of play that children with ASD prefer, educators and clinicians can use such play as positive reinforcement in educational and treatment settings.

"This information is especially helpful for children with ASD who have difficulty communicating their preferences," said Doody.

Parents can also benefit from the information. "A child who is playing alone is developing a degree of independence," said Doody, "and that can enable the parent or caregiver to engage in other activities, like making dinner or attending to another child. "

"Parents might use a snow globe so the child can observe movement. Aquariums or water sculptures provide movement, too."

Some of the behaviours exhibited by people with autism -- hand-flapping, for example -- may reflect a need for sensory stimulation. "Sometimes just giving a child a string of Mardi Gras beads to swing and watch will help the child sit still," said Doody.

Toys that provide sensory stimulation -- sounds, movement, or lights -- in response to an act such as pushing a button also may be well-received. However, Doody noted, the need for, and tolerance of, sensory stimulation varies by individual.

At Explore & More, children with ADS tended to avoid the exhibits that required pretending, such as imagining oneself as a butterfly or as a cook in a play kitchen.

Doody explained that pretending requires a phenomenon called Theory of Mind, which is the ability to imagine oneself in the place of another.

"That develops much earlier in children with typical development than in children with autism, if they develop it at all," said Doody.

Doody hopes that options for children with ASD will be built into a variety of recreational facilities, after-school programs, and playgrounds. The benefit is not only inclusion.

"It also encourages social interaction between children with ASD and their peers," said Doody. "Some children with ASD are academically successful, but they struggle in social situations. So opportunities to play with their peers are really valuable."

Journal Reference: Kathy Ralabate Doody, Jana Mertz. Preferred Play Activities of Children with Autism Spectrum Disorder in Naturalistic Settings. North American Journal of Medicine and Science, 2013 DOI: 10.7156/najms.2013.0603128

Autism Training program meets 'critical need' for earlier identification

A Vanderbilt research program that trains community pediatricians to diagnose autism within their individual practices may lead to more effective treatment of the disorder that now affects an estimated one in 88 children.

Vanderbilt University Medical Center researchers released today in the journal Autism the results of a three-year study that evaluated the effectiveness of a training program designed to enhance autism spectrum disorder (ASD) identification and assessment within community pediatric settings across Tennessee.

After participating in training to learn strategies for conducting rapid diagnostic assessments following positive ASD screenings, pediatricians reported significant changes in their screening and consultation practices, with 85 percent reporting an increase in numbers of children with autism evaluated within their practice.

The study also found that pediatric providers were nearly as accurate as specialists in their diagnoses, with agreement seen in more than 90 percent of all cases.

"Ideally, definitive early diagnosis of ASD would be rapidly accomplished by a team of developmental specialists, and children at risk for diagnosis would obtain services immediately after screening positive.

Zachary Warren

The reality is that such diagnostic teams, or even individual professionals, are not available in most locations," said corresponding author Zachary Warren, Ph.D., associate professor of Pediatrics, Psychiatry and Special Education and director of the Vanderbilt Kennedy Center's Treatment and Research Institute for Autism Spectrum Disorders (TRIAD) at Vanderbilt University.

"Even when available, the waitlists for diagnostic services are so long that children referred for evaluation wait extended periods of time for diagnosis. As a parent, I cannot fathom how stressful it would be to be told that your child may have autism, and we'll let you know the answer to that question in six to 12 months."

Despite screening initiatives, advocacy efforts and increased public awareness, the most recent Centers for Disease Control and Prevention data regarding autism prevalence suggest that the diagnosis is still not made until 4-5 years of age.

The increased prevalence of autism and documented benefits of early intensive intervention have created a need for flexible systems for obtaining accurate, time-efficient diagnoses, the authors wrote.

"Although the field has made great advances in early screening for autism, the steps taken after a positive ASD screening in community settings are much less clear and often problematic for clinicians, families and systems of care alike," Warren said.

"Essentially, more children are being referred for a very limited number of expert diagnostic assessment resources. Because of this, wide-scale screening for ASD at young ages may in fact increase wait times for diagnostic assessment. Given this context, it is critical to develop enhanced ASD-specific diagnostic training programs if we hope to shift the age of diagnosis and promote earlier access to early intervention."

Amy Swanson

The training was designed to teach enhanced diagnostic consultation and interactive screening procedures to community pediatricians so that they could offer families the opportunity to be rapidly evaluated within practice rather than being referred to a specialty clinic, where they would likely have to wait many months before being seen.

"The findings provide initial evidence suggesting early accurate diagnosis of autism may be possible and appropriate within many community pediatric practices," said Amy Swanson, M.A., TRIAD Research and Training Coordinator and lead author of the study.

"Given the potentially harmful consequences of lengthy waits for comprehensive diagnostic evaluations, the potential impact of such training programs for advanced autism diagnosis within community practice settings could be quite powerful."

Key findings:

• Community pediatric providers were more likely to conduct independent autism assessments within their practice, rather than referring the child for outside evaluation.
• Community pediatric providers showed high agreement in ASD classification with expert clinicians.
• A dramatic shift was seen in pediatric providers' sense of the appropriateness for a child to receive a diagnosis from his or her primary care provider, without or before a comprehensive evaluation.
• A dramatic shift in the comfort level of discussing ASD diagnoses with caregivers was seen.
• There was a significant increase in the number of diagnoses made within respective provider practices.

This study builds on pilot findings from 2009 by presenting a more comprehensive evaluation of the training model and utilizing a broader sample of pediatric providers.

Although this training program targeted the state of Tennessee, Vanderbilt's research team has also provided this training in several other states and presented the model to the Society for Developmental and Behavioural Pediatrics.

Autism: Researchers shed light on role of genes

Research carried out by Medical Research Council (MRC) researchers at the University of Oxford (UK) has uncovered a chain of genetic events that are common in individuals with autism, and have examined for the first time how this chain may influence how messages are sent between nerve cells in the brain.

This knowledge will help researchers better understand the role that genetics plays in autism.

Autism Spectrum Disorders (ASD) affects around 1 per cent of the population and typically cause difficulties in social interaction, communication and repetitive behaviour.

While it's known that genes can play a strong role in the development of ASD, doctors are currently only able to identify the exact genetic cause in around one in five cases.

The team, based at the MRC Functional Genomics Unit (FGU), looked at 181 autism patients who had either additional copies of some genes, or fewer copies of other genes, than people without autism.

In around half of these patients, the genes whose copy count had changed were found to work together in a large biological network that plays a key role in the way in which information is passed between cells in the brain.

By changing the number of copies of genes within this network, the study highlighted disturbances in those with autism in the way the information was carried across synapses in the brain.

Notably, the study also found that while some genes had gained more copies while other genes had lost copies, the final effect was predicted to be the same.

Notably, the study also found that while some genes had gained more copies while other genes had lost copies, the final effect was predicted to be the same.

Dr Caleb Webber, lead author on the study at the MRC FGU at the University of Oxford, says: "Think of a pipe that carries water. At some points along the pipe there are genes that act as taps to let more water into the pipe. At other points genes act as holes to let some of the water out. We found that in individuals with autism the mutations in all these different types of genes act in the same way to affect waterflow. This indicates the 'tap' genes are duplicated in some individuals with autism which increases flow into the pipe, while in other individuals with autism the 'hole' genes are deleted which decreases the amount of water leaving the pipe. Both of these events cause the same thing; too much water flowing through the pipe."

"Knowing not just which 'pipes' in the cell are affected in autism but also in what way they are affected helps us to know in which way we have to change the flow to restore the balance."

Professor Hugh Perry, chair of the MRC's Neurosciences and Mental Health Board, says: "Autism Spectrum Disorders are extremely complex in the way they can influence a person's ability to communicate or interact with their environment. Tracking down and understanding the functions of genes that regulate how information is passed around the brain is a crucial part of the story and will help to underpin the evidence with which diagnoses and treatments are given. This study is a clear example of how MRC-funding can use genetic studies to improve our understanding of the brain and its networks."

The research team's findings are published in Plos Genetics

Serotonin Levels: Protein in overdrive links to Autism (ASD)

Early disruptions in serotonin signaling in the brain may contribute to Autism Spectrum Disorder (ASD) and other “enduring effects on behavior,” researchers report.

Serotonin is a brain chemical that carries signals across the synapse, or gap between nerve cells. The supply of serotonin is regulated by the serotonin transporter (SERT).

In 2005, a team of researchers from Vanderbilt University led by Randy Blakely and James Sutcliffe identified rare genetic variations in children with ASD that disrupt SERT function.

In a new study published this week in the Proceedings of the National Academy of Sciences (PNAS), the researchers report the creation of a mouse model that expressed the most common of these variations.

The change is a very small one in biochemical terms, yet it appears to cause SERT in the brain to go into “overdrive” and restrict the availability of serotonin at synapses.

“The SERT protein in the brain of our mice appears to exhibit the exaggerated function and lack of regulation we saw using cell models,” says Blakely, director of the Vanderbilt Silvio O. Conte Center for Neuroscience Research.

“Remarkably, these mice show changes in social behavior and communication from early life that may parallel aspects of ASD,” notes first author Jeremy Veenstra-VanderWeele, assistant professor of psychiatry, pediatrics and pharmacology.

The researchers conclude that a lack of serotonin during development may lead to long-standing changes in the way the brain is “wired.”

In 1961, investigators at Yale University discovered that as many as 30 percent of children with autism have elevated blood levels of serotonin, a finding described as “hyperserotonemia.”

Since then, these findings have been replicated many times. Indeed, hyperserotonemia is the most consistently reported biochemical finding in autism, and is a highly inherited trait. Yet, the cause or significance of this biomarker has remained shrouded in mystery.

Until now. In the current study, Veenstra-VanderWeele, Blakely and their colleagues showed that they could produce hyperserotonemia in mice that express a variant of a human SERT gene associated with autism.

Because the genetic change makes the transporter more active, higher levels of serotonin accumulate in platelets and therefore in the bloodstream.

In the brain, overactive transporters should have the opposite effect—lowering serotonin levels at the synapse and producing behavioural changes relevant to autism. That’s exactly what the researchers observed.

Of course, no mouse model can completely explain or reproduce the human condition. Neither does a single genetic variation cause autism. Experts believe the wide spectrum of autistic behaviours represents a complex web of interactions between many genes and environmental factors.

But animal models are critical to exploring more deeply the basis for the developmental changes that are observed in ASD.

The scientists are using these mice to explore how altered brain serotonin levels during development may produce long-lasting changes in behaviour and impact the risk for autism.

Scientists from the National Institute of Mental Health, the Medical University of South Carolina and the University of Texas Health Science Center in San Antonio contributed to the study.

The research was supported by the National Institutes of Health, the advocacy organisation Autism Speaks (UK), and the American Academy of Child and Adolescent Psychiatry.

More news from Vanderbilt University: news.vanderbilt.edu/research

Study of Twins suggests Genetic component of autism spectrum disorders may be more environmental

After evaluating twin pairs in which at least one child has autism or autism spectrum disorder (ASD), researchers suggest that the shared environment may play a more substantial role in development of the condition than shared genes do, according to a report published Online First by Archives of General Psychiatry, one of the JAMA/Archives journals.

Current estimates suggest that 40 of every 10,000 children have autism, and prevalence rates for ASDs are about 1 percent, according to background information in the article. Studies of siblings have found a concordance rate (the likelihood that if one child has the disorder, others will as well) of up to 14 percent.

The authors note that in previous studies of twins, concordance rates for autism were relatively high for identical (monozygotic) twins, but nonexistent for fraternal (dizygotic) twins. Further, studies that depended on differing methods of diagnosis have resulted in a broad range of estimates of autism's heritability.

"However," the authors state, "none of these more recent studies included structured clinical assessments by both parental interview and direct child observation, which is the contemporary standard for establishing the diagnosis of autism or ASD."

In the California Autism Twins Study, Joachim Hallmayer, M.D., from Stanford University School of Medicine, Palo Alto, Calif., and colleagues used data from the California Department of Developmental Services to identify potential participants.

The researchers assessed twin pairs in which at least one child had an ASD diagnosis, using the Autism Diagnostic Interview-Revised, a structured parent interview and the Autism Diagnostic Observation Schedule, as well as other tests to determine verbal and nonverbal cognitive abilities.

Two diagnoses were utilized: strict autism and ASD. Children with autism or ASD that was included in the initial data and confirmed by the researchers were considered "probands."

The final analysis included 54 pairs of identical twins and 138 pairs of fraternal twins (of which 80 were composed of a boy and a girl). Researchers found the likelihood of both children having autism or ASD was higher among identical twins than among fraternal twins.

They also used modeling to estimate how much of the risk could be attributed to genetic factors. This analysis demonstrated that more than half of the variance in risk was probably explained by shared environmental factors, versus less than 40 percent of the risk owing to genetic heritability.

"The results suggest that environmental factors common to twins explain about 55 percent of the liability to autism," the authors write. "Although genetic factors also play an important role, they are of substantially lower magnitude than estimates from prior twin studies of autism. …

The finding of significant influence of the shared environment, experiences that are common to both twin individuals, may be important for future research paradigms."

Read more here

Targetting Core Social Deficits of Autism

Targeting the core social deficits of autism spectrum disorders (ASD) in early intervention programs yielded sustained improvements in social and communication skills even in very young children who have ASD, according to a study funded by the National Institute of Mental Health (NIMH).

The study was published online December 8, 2010, in the Journal of Child Psychology and Psychiatry.

Although some research suggests that ASD may be reliably diagnosed earlier than the current average age of 3 years, few interventions have been tested in children younger than 3.

During the course of typical development, children learn to interact with others in socially meaningful ways. Measures of social communication include:

• Initiation of joint attention -- spontaneously directing others' attention to something of interest, such as by pointing or holding something up to show for social purposes rather than to ask for help
• Affect sharing -- sharing emotions with others through facial expressions paired with eye contact
• Socially engaged imitation -- imitating others' actions while showing social connectedness through eye contact.

Deficits in such measures are hallmark symptoms of ASD and can severely limit a child's ability to engage in and learn from interactions with others or from the world around them.

"This new report is encouraging, as the effects on social behavior appear to provide a scaffold for the development of skills beyond the research setting," said NIMH Director Thomas R. Insel, M.D. "We need better early interventions for the core deficits of autism."


The interventions were designed to encourage children to make frequent and intentional efforts to engage others in communication or play. The single difference between interventions was that the IS group received more opportunities for joint attention, affect sharing, and socially engaged imitation. The toddlers were assessed at the start and end of the intervention and again six months later.

Children in both groups made improvements in social, cognitive and language skills during the six-month intervention period. Children who received IS made greater and more rapid gains than those in the non-IS group.

The researchers also noted that children in the IS group used their newly acquired abilities with different people, locations, and type of activity. This is noteworthy because children with ASD have particular difficulty doing so. They tend to use new skills mostly within familiar routines and situations.

Journal Reference:

1. Rebecca J. Landa, Katherine C. Holman, Allison H. O’Neill, Elizabeth A. Stuart. Intervention targeting development of socially synchronous engagement in toddlers with autism spectrum disorder: a randomized controlled trial. Journal of Child Psychology and Psychiatry, 2010; DOI: 10.1111/j.1469-7610.2010.02288.x