Category: Autism

People in creative professions are treated more often for mental illness than the general population, there being a particularly salient connection between writing and schizophrenia. This according to researchers at Karolinska Institutet, whose large-scale Swedish registry study is the most comprehensive ever in its field.

Last year, the team showed that artists and scientists were more common amongst families where bipolar disorder and schizophrenia is present, compared to the population at large. They subsequently expanded their study to many more psychiatric diagnoses — such as schizoaffective disorder, depression, anxiety syndrome, alcohol abuse, drug abuse, autism, ADHD, anorexia nervosa and suicide — and to include people in outpatient care rather than exclusively hospital patients.

The present study tracked almost 1.2 million patients and their relatives, identified down to second-cousin level. Since all were matched with healthy controls, the study incorporated much of the Swedish population from the most recent decades. All data was anonymized and cannot be linked to any individuals.

The results confirmed those of their previous study, that certain mental illness — bipolar disorder — is more prevalent in the entire group of people with artistic or scientific professions, such as dancers, researchers, photographers and authors. Authors also specifically were more common among most of the other psychiatric diseases (including schizophrenia, depression, anxiety syndrome and substance abuse) and were almost 50 per cent more likely to commit suicide than the general population.

Further, the researchers observed that creative professions were more common in the relatives of patients with schizophrenia, bipolar disorder, anorexia nervosa and, to some extent, autism. According to Simon Kyaga, Consultant in psychiatry and Doctoral Student at the Department of Medical Epidemiology and Biostatistics, the results give cause to reconsider approaches to mental illness.

"If one takes the view that certain phenomena associated with the patient's illness are beneficial, it opens the way for a new approach to treatment," he says. "In that case, the doctor and patient must come to an agreement on what is to be treated, and at what cost. In psychiatry and medicine generally there has been a tradition to see the disease in black-and-white terms and to endeavour to treat the patient by removing everything regarded as morbid."

The study was financed with grants from the Swedish Research Council, the Swedish Psychiatry Foundation, the Bror Gadelius Foundation, the Stockholm Centre for Psychiatric Research and the Swedish Council for Working Life and Social Research.

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Journal Reference:

1. Simon Kyaga, Mikael Landén, Marcus Boman, Christina M. Hultman, Niklas Långström, Paul Lichtenstein. Mental illness, suicide and creativity: 40-Year prospective total population study. Journal of Psychiatric Research, 2012; DOI: 10.1016/j.jpsychires.2012.09.010

Children with autism have difficulty identifying inappropriate social behavior, and even when successful, they are often unable to justify why the behavior seemed inappropriate. New brain imaging studies show that children with autism may recognize socially inappropriate behavior, but have difficulty using spoken language to explain why the behavior is considered inappropriate, according to research published Oct. 17 in the open access journal PLOS ONE by Elizabeth Carter from Carnegie Mellon University and colleagues.

The authors say the results of their functional MRI studies support previous behavioral studies that reached similar conclusions about language impairment in children with autism. In the current study, the researchers asked children with autism and children with typical development to identify in which of two pictures a boy was being bad (social judgment), or which of two pictures was outdoors (physical judgment). Both groups successfully performed the task, but the children with autism showed activity in fewer brain regions involving social and language networks while performing the task. Even though language was not required for the task, the children with typical development recruited language areas of the brain while making their decisions.

According to the authors, their results support the hypothesis that children with autism may recognize socially inappropriate behavior, but have difficulty using spoken language to explain why the behavior is considered wrong. They suggest that this decreased use of language may also make generalization of the knowledge more difficult.

"These results indicate that it is important to work with these children on translating their knowledge into language," says Carter.

Human and chimp brains look anatomically similar because both evolved from the same ancestor millions of years ago. But where does the chimp brain end and the human brain begin?

A new UCLA study pinpoints uniquely human patterns of gene activity in the brain that could shed light on how we evolved differently than our closest relative. Published Aug. 22 in the advance online edition of Neuron, these genes' identification could improve understanding of human brain diseases like autism and schizophrenia, as well as learning disorders and addictions.

"Scientists usually describe evolution in terms of the human brain growing bigger and adding new regions," explained principal investigator Dr. Daniel Geschwind, Gordon and Virginia MacDonald Distinguished Professor of Human Genetics and a professor of neurology at the David Geffen School of Medicine at UCLA. "Our research suggests that it's not only size, but the rising complexity within brain centers, that led humans to evolve into their own species."

Using post-mortem brain tissue, Geschwind and his colleagues applied next-generation sequencing and other modern methods to study gene activity in humans, chimpanzees and rhesus macaques, a common ancestor for both chimpanzee and humans that allowed the researchers to see where changes emerged between humans and chimpanzees. They zeroed in on three brain regions — the frontal cortex, hippocampus and striatum.

By tracking gene expression, the process by which genes manufacture the amino acids that make up cellular proteins, the scientists were able to search the genomes for regions where the DNA diverged between the species. What they saw surprised them.

"When we looked at gene expression in the frontal lobe, we saw a striking increase in molecular complexity in the human brain," said Geschwind, who is also a professor of psychiatry at the Semel Institute for Neuroscience and Behavior at UCLA.

While the caudate nucleus remained fairly similar across all three species, the frontal lobe changed dramatically in humans.

"Although all three species share a frontal cortex, our analysis shows that how the human brain regulates molecules and switches genes on and off unfolds in a richer, more elaborate fashion," explained first author Genevieve Konopka, a former postdoctoral researcher in Geschwind's lab who is now the Jon Heighten Scholar in Autism Research at University of Texas Southwestern Medical Center. "We believe that the intricate signaling pathways and enhanced cellular function that arose within the frontal lobe created a bridge to human evolution."

The researchers took their hypothesis one step further by evaluating how the modified genes linked to changes in function.

"The biggest differences occurred in the expression of human genes involved in plasticity — the ability of the brain to process information and adapt," said Konopka. "This supports the premise that the human brain evolved to enable higher rates of learning."

One gene in particular, CLOCK, behaved very differently in the human brain. Considered the master regulator of Circadian rhythm, CLOCK is disrupted in mood disorders like depression and bipolar syndrome.

"Groups of genes resemble spokes on a wheel — they circle a hub gene that often acts like a conductor," said Geschwind. "For the first time, we saw CLOCK assuming a starring role that we suspect is unrelated to Circadian rhythm. Its presence offers a potentially interesting clue that it orchestrates another function essential to the human brain."

When comparing the human brain to the non-human primates, the researchers saw more connections among gene networks that featured FOXP1 and FOXP2. Earlier studies have linked these genes to humans' unique ability to produce speech and understand language.

"Connectivity measures how genes interact with other genes, providing a strong indicator of functional changes," said Geschwind. "It makes perfect sense that genes involved in speech and language would be less connected in the non-human primate brains — and highly connected in the human brain."

The UCLA team's next step will be to expand their comparative search to 10 or more regions of the human, chimpanzee and maque brains.

Geschwind and Konopka's coauthors included Tara Friedrich, Jeremy Davis-Turak, Kellen Winden, Fuying Gao, Leslie Chen, Rui Luo, all of UCLA; Michael Oldham of UC San Francisco; Guang-Zhong Wang of the University of Texas Southwestern Medical Center; and Todd Preuss of Emory University.

The research was supported by grants from the National Institute of Mental Health (R37MH060233) and (R00MH090238); a NARSAD Young Investigator Award, the National Center for Research Resources (RR00165) and Office of Research Infrastructure Programs/OD (P51OD11132); and a James S. McDonnell Foundation grant (JSMF 21002093).

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Journal Reference:

1. Genevieve Konopka, Tara Friedrich, Jeremy Davis-Turak, Kellen Winden, Michael C. Oldham, Fuying Gao, Leslie Chen, Guang-Zhong Wang, Rui Luo, Todd M. Preuss, Daniel H. Geschwind. Human-Specific Transcriptional Networks in the Brain. Neuron, 2012; 75 (4): 601 DOI: 10.1016/j.neuron.2012.05.034

According to the Centers for Disease Control and Prevention (CDC), 1 in 88 children in the U.S. has autism spectrum disorder (ASD), a broad group of neurodevelopmental disorders. Children and adolescents with ASD are typically fascinated by screen-based technology such as video games, and these can be used for educational and treatment purposes, as described in an insightful Roundtable Discussion published in Games for Health Journal: Research Development, and Clinical Applications, a peer-reviewed publication from Mary Ann Liebert, Inc.

Individuals with ASD have difficulty with communication and social interaction, but they often have particularly good visual perceptual skills and respond well to visual stimuli. Videogames offer opportunities for successful learning, motivation to improve skills such as planning, organization, and self-monitoring, and reinforcement of desired behaviors without the need for direct human-to-human interaction.

Autism is a growing area of interest for the gamification community, and Games for Health Journal continues to explore various aspects of how videogame technology can be beneficial in treating this complex spectrum of disorders. In a previous issue of the Journal, the article "Comparing Energy Expenditure in Adolescents with and without Autism while Playing Nintendo® Wii™ Games" (http://online.liebertpub.com/doi/full/10.1089/g4h.2011.0019) described how gaming might help individuals with ASD increase their daily physical activity to prevent obesity.

"Children and young adults with ASD have unique opportunities to capitalize on their interest and aptitude in videogames as a resource to develop desired social behaviors and life skills and to increase their physical activity," says Games for Health Journal Editor-in-Chief Bill Ferguson, PhD, who moderated the Roundtable.

Vanderbilt University researchers studying interventions for adolescents and young adults with autism are reporting that there is insufficient evidence to support findings, good or bad, for the therapies currently used.

Although the prevalence of autism is on the rise, much remains to be discovered when it comes to interventions for this population, the researchers concluded.

"Overall, there is very little evidence in all areas of care for adolescents and young adults with autism, and it is urgent that more rigorous studies be developed and conducted," said Melissa McPheeters, Ph.D., M.P.H., director of Vanderbilt's Evidence-Based Practice Center and senior author of the report, a systematic review of therapies published by the Department of Health and Human Services' Agency for Healthcare Research and Quality (AHRQ).

Zachary Warren, Ph.D., director of the Vanderbilt Kennedy Center's Treatment and Research Institute for Autism Spectrum Disorders, said, "There are growing numbers of adolescents and adults with autism in need of substantial support. Without a stronger evidence base, it is very hard to know which interventions will yield the most meaningful outcomes for individuals with autism and their families."

Key findings:

The researchers systematically screened more than 4,500 studies and reviewed the 32 studies published from January 1980 to December 2011 on therapies for people ages 13 to 30 with autism spectrum disorders. They focused on the outcomes, including harms and adverse effects, of interventions, including medical, behavioral, educational and vocational.

• Some evidence revealed that treatments could improve social skills and educational outcomes such as vocabulary or reading, but the studies were generally small and had limited follow-up.

• Limited evidence supports the use of medical interventions in adolescents and young adults with autism. The most consistent findings were identified for the effects of antipsychotic medications on reducing problem behaviors that tend to occur with autism, such as irritability and aggression. Harms associated with medications included sedation and weight gain.

• Only five articles tested vocational interventions, all of which suggested that certain vocational interventions may be effective for certain individuals, but each study had significant flaws that limited the researchers' confidence in their conclusions. The researchers' findings on vocational interventions will be featured in the Aug. 27 issue of Pediatrics.

As recently as the 1970s, autism was believed to affect just one in 2,000 children, but newly released data from the Centers for Disease Control and Prevention (CDC) estimates that one in 88 children has an autism spectrum disorder. Boys with autism outnumber girls 5-to-1, which estimates that one in 54 boys in the United States have autism.

"With more and more youth with autism leaving high school and entering the adult world, there is urgent need for evidence-based interventions that can improve their quality of life and functioning," said Julie Lounds Taylor, Ph.D., assistant professor of Pediatrics and Special Education and lead author of the report.

Additional investigators on this report include Jeremy Veenstra-VanderWeele, M.D., assistant professor of Psychiatry, Pediatrics and Pharmacology and Kennedy Center investigator; Dwayne Dove, M.D., Ph.D., fellow in Developmental-Behavioral Pediatrics; Nila Sathe, M.S., M.L.I.S., program manager, Institute for Medicine and Public Health; and Rebecca Jerome, M.L.I.S., M.P.H., assistant director, Eskind Biomedical Library.

Their research, published in the report, Interventions for Adolescents and Young Adults with Autism Spectrum Disorders, was funded by the Agency for Healthcare Research and Quality's Effective Health Care Program and conducted through Vanderbilt's Evidence-Based Practice Center.

A study based on information collected from 920 parents suggests an estimated 46.3 percent of adolescents with an autism spectrum disorder were the victims of bullying, according to a report published Online First by Archives of Pediatrics & Adolescent Medicine, a JAMA Network publication.

Bullying involves negative actions toward a peer and is characterized by a power imbalance — physical, social or cognitive — between the victim and the perpetrator. Relatively little research has examined bullying involvement among adolescents with an autism spectrum disorder (ASD), according to the study background.

Paul R. Sterzing, Ph.D., M.S.S.W., previously of Washington University, St. Louis but now affiliated with the University of California, Berkeley, and colleagues used nationally representative surveys to identify the prevalence of bullying involvement, compare prevalence rates of bullying involvement with adolescents with developmental disabilities that overlap with the core deficits of an ASD, and identify the social ecological correlates of bullying involvement.

The prevalence of bullying involvement for adolescents with an ASD was 46.3 percent for victimization and was "substantially higher" than the national prevalence estimates for the general adolescent population (10.6 percent). The rates of perpetration of bullying (14.8 percent) and victimization/perpetration (8.9 percent, i.e. those who perpetrate and are victimized), were about equivalent to national estimates found among typically developing adolescents, according to the study results.

Victimization was related to having a non-Hispanic ethnicity, attention-deficit/hyperactivity disorder, lower social skills, some form of conversational ability, and more classes in general education. Perpetration was correlated with being white, having attention-deficit hyperactivity disorder, and getting together with friends at least once a week. Victimization/perpetration was associated with being white non-Hispanic, having attention-deficit/hyperactivity disorder and getting together with friends at least once a week, the results indicate.

"Future interventions should incorporate content that addresses the core deficits of adolescents with an ASD, which limits their verbal ability to report bullying incidents," the authors comment. "Schools should incorporate strategies that address conversational difficulties and the unique challenges of those with comorbid conditions."

The authors also concluded: "Inclusive classrooms need to increase the social integration of adolescents with an ASD into protective peer groups while also enhancing the empathy and social skills of typically developing students toward their peers with an ASD and other developmental disabilities."

Eighty-five percent of children's learning is related to vision. Yet in the U.S., 80 percent of children have never had an eye exam or any vision screening before kindergarten, statistics say. When they do, the vision screenings they typically receive can detect only one or two conditions.

Three researchers at the University of Tennessee Space Institute in Tullahoma are working to change that with an invention that makes children eye exams inexpensive, comprehensive, and simple to administer.

"Eye exams can do so much more than just test vision," said Ying-Ling Ann Chen, device inventor and research assistant professor in physics. "They can detect learning disabilities, such as dyslexia, or neural disorders such as autism. By not testing our youth, we are potentially missing the window for effective treatment for a lot of conditions."

Called the Dynamic Ocular Evaluation System (DOES), the device was developed by Chen; Lei Shi, post-doctoral research associate in laser application; and Jim Lewis, professor emeritus in physics. The researchers hope the device will someday be used in pediatricians' offices across the country, and then expanded to other groups within population.

DOES is low-cost, high-quality and operator- and child-friendly. It takes about a minute to train someone to use it. The test is done as the child watches a three-minute cartoon or plays a computer game. Infrared light is used to analyze the binocular condition and the assessment is reported on-site within a minute. Neither eye dilation nor verbal response is required.

At the beginning of the cartoon, a three-second comprehensive test screens for binocular refractive risks, high-order aberration, scattering, ocular alignment and significant neural problems. The subsequent dynamic test searches for less significant signs of abnormal ocular alignment, neural responses, amblyopia, and — in the future — mental statuses that include dyslexia, attention deficit hyperactivity disorder, post-traumatic stress disorder and autism. The images and results are digitally recorded and can be electronically transmitted to specialists for referral if necessary.

"Vision screening is important at an early age to detect several different causes of vision disorders," said Chen. "The few children that do get screened today aren't being screened adequately. For instance, many current screening methods do one eye at a time and studies show young eyes will accommodate significantly, and this causes inaccurate results."

According to Chen, children usually do not visit eye doctors unless their eyes hurt. They do not know if their vision is impaired because they do not know what they should be seeing. By having easy-to-administer comprehensive tests as part of the pediatrician's visit, a lot of vision and vision-related diseases could be avoided or treated more effectively — such as lazy eye and cross eyes, which impacts up to 5 percent of the U.S. population.

"During the critical period of childhood up until about age six, if one eye is not as good as the other, the brain will suppress the communication with that eye, and the vision could be lost permanently," said Chen. "This can cause a condition called amblyopia, or lazy eye, which can be prevented through detection."

The researchers are currently performing a clinical test at Tullahoma's Walmart Vision Center to test children's response to the cartoon and to compare their results to doctor's exams. They recently received $15,000 from the UT Research Foundation to assist in further developing the technology to improve positioning for licensing and commercialization. The scientists say they have industry interested in taking their invention to market.

A low dose of the sedative clonazepam alleviated autistic-like behavior in mice with a mutation that causes Dravet syndrome in humans, University of Washington researchers have shown.

Dravet syndrome is an infant seizure disorder accompanied by developmental delays and behavioral symptoms that include autistic features. It usually originates spontaneously from a gene mutation in an affected child not found in either parent.

Studies of mice with a similar gene mutation are revealing the overly excited brain circuits behind the autistic traits and cognitive impairments common in this condition. The research report appears in the Aug. 23 issue of Nature. Dr William Catterall, professor and chair of pharmacology at the UW, is the senior author.

Dravet syndrome mutations cause loss-of-function of the human gene called SCN1A. People or mice with two copies of the mutation do not survive infancy; one copy results in major disability and sometimes early death. The mutation causes malformation in one type of sodium ion channels, the tiny pores in nerve cells that produce electrical signals by gating the flow of sodium ions.

The Catteralll lab is studying these defective ion channels and their repercussion on cell-to-cell signaling in the brain. They also are documenting the behavior of mice with this mutation, compared to their unaffected peers. Their findings may help explain how the sporadic gene mutations that cause Dravet syndrome lead to its symptoms of cognitive deficit and autistic behaviors.

The sodium ion channels in question malfunction in specific nerve cells, called inhibitory neurons, whose job is to send messages to hush the electrical signaling of neighboring cells. If only transmissions that excite nearby cells get through, the balance of cell signals that excite or inhibit the brain is seriously tilted toward excessive excitability.

"Imagine New York City traffic without any red lights, just green lights," said Catterall. This kind of electrical traffic jam might explain the heightened brain state of children with the Dravet mutation. These children suffer from frequent electrical storms, called epileptic seizures, in their brains. They are hyperactive, anxious and have difficulty sleeping. Their problems in learning, remembering and reasoning often follow a downhill course through childhood. The children also show several symptoms of an autistic spectrum disorder, including withdrawing from social interactions, repeated movements, and restricted, intense interests. The brain mechanisms behind this disorder have been poorly understood, Catterall said.

In observing the behavior of mice with the same genetic variation, Catterall and his team saw that they did not display many normal social interactions of mice. Mice are naturally curious about a mouse they haven't met before, and will approach and sniff it. Sometimes they will attack, wrestle and playfully bite the stranger. Usually mice are more interested in mice they haven't met before than those they already know. Mice with the Dravet syndrome were not interested in meeting strangers or acknowledging acquaintances, and did not approach them either aggressively or with mild manners. In fact, they froze when confronted with new mice, the scent of male mouse urine, or new food smells like banana oil, which usually attracts mice unfamiliar with the scent.

These altered behaviors suggested that the Dravet mice were unable to have normal social interactions with recently introduced mice and were repelled by new experiences, even new food odors. The Dravet mice also had problems in spatial learning and memory. They were unable to learn and remember the location where fearful events occurred or to learn and remember how to escape a brightly lighted area. In an open field test and maze running comparisons with mice without the mutation, the Dravet mice traveled more, spend less time in the center, and walked in circles. They also groomed themselves and wiped their whiskers excessively.

"Like many children with autism, the mice seemed overwhelmed by changes in their environment and unable to interact socially with other mice," Catterall said. "They also showed stereotypic movements and repetitive behaviors common in autism."

His team went on to explore the cellular and biochemical underpinnings of the autism-related traits and spatial learning deficits in the Dravet mutation mice. They tested the hypothesis that the condition arises from decreased activity of particular sodium ion channels in the brain cells that relay inhibitory information to other nerve cells in the forebrain.

They found that the deep layer of the prefrontal cortex of the brain was the most affected by the mutation. Among the core components linking thinking and emotion circuits of the brain are the interneurons. These cells release a neurotransmitter called GABA, a brain chemical signal that inhibits neighboring cells. On the other hand, excitatory nerve cells release a different neurotransmitter that activates neighboring nerve cells. Normally, these excitatory and inhibitory nerve cells balance each other.

The researchers found that the Dravet mutation mice had the normal number of the GABAergic interneurons, the cells that fire a "turn it down" signal to their neighbors. However, a significant percentage of these cells lacked a specific type (type-1 or Nav1.1) of gated sodium channel. This deficit kept these cells from firing enough electrical signals. As a consequence, excitatory signals dominated circuits in critical areas of the brain.

"We reasoned that the decreased in sodium channel activity in these GABAergic interneurons could be rescued by increasing the strength of the GABAergic transmissions," Catterall said.

His team decided to treat both the normal and the Dravet mutation mice with the benzodiazepine clonazepam. This drug is often given to people suffer from moderate, debilitating anxiety, such as fear of flying. Benzodiazepines also control some forms of epileptic seizures. The researchers lowered the dose to make sure they were not sedating the mice or removing their anxious state.

"The treatment with a single low dose of clonazepam completely alleviated the impaired social interactions of the Dravet mice. It also removed the freezing reaction to novel situations. They were willing to approach mice that were strangers to them and to explore new odors. They behaved just like their peers," Catterall observed. "This dose of the drug had no effect on the behavior of their normal peers." The effects of the drug wore off after it cleared completely from the body, which takes a few days in mice.

"The results showed that a single low dose of clonazepam can reversibly rescue core autistic traits and cognitive deficits in mice with the Dravet mutation," Catterall said. Additional measurements of cell firing in brain tissues from affected mice showed that the behavioral effects were likely based on decreased strength of the inhibitory signals, which caused an overall increase in brain electrical signaling by releasing the restraint on excitatory neurons. Their research also suggested that the cognitive and behavioral impairments in Dravet syndrome are not the result of damage from epileptic seizures, but are due to an innate shortage of a certain type of sodium ion channel and the resulting failure of inhibitory electrical signaling.

Catterall added that the research indicates that low-dose benzodiazepine treatment could be a potential drug intervention for cognitive deficits and autistic symptoms in Dravet syndrome patients, if clinical trials show they are effective in humans, and perhaps more broadly in certain other types of autism spectrum disorders.

"Interestingly, mutations in many other autism spectrum disorders also cause an imbalance of excitatory over inhibitory electrical activity in the brain," the research team noted. Perhaps autistic traits in some other conditions within the realm of autism spectrum disorders might also be caused by a reduction in GABAergic signaling between brain cells.

Dravet syndrome is not the only genetic disorder that has autistic traits accompanying other physical and developmental disabilities. Rett, fragile X, and Timothy syndromes also have autistic features.

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Journal Reference:

1. Sung Han, Chao Tai, Ruth E. Westenbroek, Frank H. Yu, Christine S. Cheah, Gregory B. Potter, John L. Rubenstein, Todd Scheuer, Horacio O. de la Iglesia, William A. Catterall. Autistic-like behaviour in Scn1a /− mice and rescue by enhanced GABA-mediated neurotransmission. Nature, 2012; DOI: 10.1038/nature1135

A team of Australian researchers, led by University of Melbourne has developed a genetic test that is able to predict the risk of developing autism spectrum disorder (ASD).

Lead researcher Professor Stan Skafidas, Director of the Centre for Neural Engineering at the University of Melbourne said the test could be used to assess the risk for developing the disorder. "This test could assist in the early detection of the condition in babies and children and help in the early management of those who become diagnosed," he said. "It would be particularly relevant for families who have a history of autism or related conditions such as Asperger's syndrome," he said.

Autism affects around one in 150 births and is characterized by abnormal social interaction, impaired communication and repetitive behaviours. The test correctly predicted ASD with more than 70 per cent accuracy in people of central European descent. Ongoing validation tests are continuing including the development of accurate testing for other ethnic groups.

Clinical neuropsychologist, Dr Renee Testa from the University of Melbourne and Monash University, said the test would allow clinicians to provide early interventions that may reduce behavioural and cognitive difficulties that children and adults with ASD experience. "Early identification of risk means we can provide interventions to improve overall functioning for those affected, including families," she said.

A genetic cause has been long sought with many genes implicated in the condition, but no single gene has been adequate for determining risk. Using US data from 3,346 individuals with ASD and 4,165 of their relatives from Autism Genetic Resource Exchange (AGRE) and Simons Foundation Autism Research Initiative (SFARI), the researchers identified 237 genetic markers (SNPs) in 146 genes and related cellular pathways that either contribute to or protect an individual from developing ASD.

Senior author Professor Christos Pantelis of the Melbourne Neuropsychiatry Centre at the University of Melbourne and Melbourne Health said the discovery of the combination of contributing and protective gene markers and their interaction had helped to develop a very promising predictive ASD test.

The test is based on measuring both genetic markers of risk and protection for ASD. The risk markers increase the score on the genetic test, while the protective markers decrease the score. The higher the overall score, the higher the individual risk.

"This has been a multidisciplinary team effort with expertise across fields providing new ways of investigating this complex condition," Professor Pantelis said.

The study was undertaken in collaboration with Professor Ian Everall, Cato Chair in Psychiatry and Dr Gursharan Chana from the University of Melbourne and Melbourne Health, and Dr Daniela Zantomio from Austin Health.

The next step is to further assess the accuracy of the test by monitoring children who are not yet diagnosed over an extended study. The study has been published today in the journal Molecular Psychiatry.

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Journal Reference:

1. E Skafidas, R Testa, D Zantomio, G Chana, I P Everall, C Pantelis. Predicting the diagnosis of autism spectrum disorder using gene pathway analysis. Molecular Psychiatry, 2012; DOI: 10.1038/mp.2012.126

 An international team of researchers, led by scientists at the University of California, San Diego and Yale University schools of medicine, have identified a form of autism with epilepsy that may potentially be treatable with a common nutritional supplement.

The findings are published in the Sept. 6, 2012 online issue of Science.

Roughly one-quarter of patients with autism also suffer from epilepsy, a brain disorder characterized by repeated seizures or convulsions over time. The causes of the epilepsy are multiple and largely unknown. Using a technique called exome sequencing, the UC San Diego and Yale scientists found that a gene mutation present in some patients with autism speeds up metabolism of certain amino acids. These patients also suffer from epileptic seizures. The discovery may help physicians diagnose this particular form of autism earlier and treat sooner.

The researchers focused on a specific type of amino acid known as branched chain amino acids or BCAAs. BCAAs are not produced naturally in the human body and must be acquired through diet. During periods of starvation, humans have evolved a means to turn off the metabolism of these amino acids. It is this ability to shut down that metabolic activity that researchers have found to be defective in some autism patients.

"It was very surprising to find mutations in a potentially treatable metabolic pathway specific for autism," said senior author Joseph G. Gleeson, MD, professor in the UCSD Department of Neurosciences and Howard Hughes Medical Institute investigator. "What was most exciting was that the potential treatment is obvious and simple: Just give affected patients the naturally occurring amino acids their bodies lack."

Gleeson and colleagues used the emerging technology of exome sequencing to study two closely related families that have children with autism spectrum disorder. These children also had a history of seizures or abnormal electrical brain wave activity, as well as a mutation in the gene that regulates BCAAs. In exome sequencing, researchers analyze all of the elements in the genome involved in making proteins.

In addition, the scientists examined cultured neural stem cells from these patients and found they behaved normally in the presence of BCAAs, suggesting the condition might be treatable with nutritional supplementation. They also studied a line of mice engineered with a mutation in the same gene, which showed the condition was both inducible by lowering the dietary intake of the BCAAs and reversible by raising the dietary intake. Mice treated with BCAA supplementation displayed improved neurobehavioral symptoms, reinforcing the idea that the approach could work in humans as well.

"Studying the animals was key to our discovery," said first author Gaia Novarino, PhD, a staff scientist in Gleeson's lab. "We found that the mice displayed a condition very similar to our patients, and also had spontaneous epileptic seizures, just like our patients. Once we found that we could treat the condition in mice, the pressing question was whether we could effectively treat our patients."

Using a nutritional supplement purchased at a health food store at a specific dose, the scientists reported that they could correct BCAA levels in the study patients with no ill effect. The next step, said Gleeson, is to determine if the supplement helps reduce the symptoms of epilepsy and/or autism in humans.

"We think this work will establish a basis for future screening of all patients with autism and/or epilepsy for this or related genetic mutations, which could be an early predictor of the disease," he said. "What we don't know is how many patients with autism and/or epilepsy have mutations in this gene and could benefit from treatment, but we think it is an extremely rare condition."

Co-authors are Paul El-Fishawy, Child Study Center, Yale University School of Medicine; Hulya Kayserili, Medical Genetics Department, Istanbul University, Turkey; Nagwa A. Meguid, Rehab O. Khalil, Adel F. Hashish and Hebatalla S. Hashem, Department of Research on Children with Special Needs, National Research Centre, Cairo, Egypt; Eric M. Scott, Jana Schroth, Jennifer L. Silhavy, Neurogenetics Laboratory, Howard Hughes Medical Institute, Department of Neurosciences, UC San Diego; Majdi Kara, Pediatric Department, Tripoli Children's Hospital, Libya; Tawfeq Ben-Omran, Clinical and Metabolic Genetics Division, Department of Pediatrics, Hamad Medical Corporation, Doha, Qatar; A. Gulhan Ercan-Sencicek, Stephan J. Sanders and Matthew W. State, Program on Neurogenetics, Child Study Center, Department of Psychiatry and Department of Genetics, Yale University School of Medicine; Abha R. Gupta, Child Study Center, Department of Pediatrics, Yale University School of Medicine; Dietrich Matern, Biochemical Genetics Laboratory, Department of Laboratory Medicine and Pathology, Mayo Clinic; Stacy Gabriel, Broad Institute of Harvard and Massachusetts Institute of Technology; Larry Sweetman, Institute of Metabolic Disease, Baylor Research Institute; Yasmeen Rahimi and Robert A. Harris, Roudebush VA Medical Center and Department of Biochemistry and Molecular Biology, Indiana University School of Medicine.

Funding for this research came, in part, from the National Institutes of Health (grants P1HD070494, R01NS048453, P30NS047101, RC2MH089956, K08MH087639, T32MH018268, U54HG003067), the Center for Inherited Disease Research, the Simons Foundation Research Initiative, Veterans Administration Merit Award, the German Research Foundation, the American Academy of Child and Adolescent Psychiatry Pilot Research Award/Elaine Schlosser Lewis Fund and the American Psychiatric Association/Lilly Research Fellowship.