Posts tagged ASD
Articles and news from the latest research reports.
Combining two genome analysis approaches supports immune system contribution to autism
Researchers using novel approaches and methodologies of identifying genes that contribute to the development of autism have found evidence that disturbances in several immune-system-related pathways contribute to development of autism spectrum disorders. The report published December 4 in the open-access journal PLOS ONE powerfully supports a role for the immune function in autism by integrating analysis of autism-associated DNA sequence variations with that of markers identified in studies of families affected by autism.
"Others have talked about immune function contributions to autism, but in our study immune involvement has been identified through a completely nonbiased approach," says Vishal Saxena, PhD, of the Massachusetts General Hospital (MGH) Department of Neurology, first, corresponding and co-senior author of the PLOS ONE paper. “We let the data tell us what was most important; and most tellingly, viral infection pathways were most important in this immune-related mechanism behind autism.”
Genetic studies of families including individuals with autism have indentified linkages with different locations in the genome. Since traditional interpretation methods implicate the gene closest to a marker site as the cause of a condition, those studies appeared to point to different genes affecting different families. However, Saxena’s team realized that, since autism has typical symptoms and affects the same biological processes, a common molecular physiology must be affecting the different families studied. To search for genetic pathways incorporating these autism-associated sites, they developed a methodology called Linkage-ordered Gene Sets (LoGS) that analyzes all of the genes within a particular distance from marker sites and ranks them according to their distance from the marker.
Biomarker progress offers hope for early autism spectrum disorder detection
Autism spectrum disorders (ASD) are neurodevelopmental disorders typically characterized by difficulties in social interactions and delayed or abnormal language development. Although ASD reportedly affects 1 in 88 people in the United States, to date there have been no distinctive biomarkers to diagnose the disease. In a special themed issue of Disease Markers, investigators report on the current understanding of ASD genetics and the possibilities of translating genetic research toward biomarker development in ASD.
"Although some individuals with ASD are highly functional, many are severely impaired and require permanent care. The significant level of impairment combined with the fact that no specific therapy is yet available for ASD, make ASD a devastating illness for patients and families, and a heavy financial burden for the healthcare system," says guest editor, Irina Voineagu, MD, PhD, RIKEN Omics Science Center, Yokohama, Japan. "The most effective intervention for ASD has proven to be early behavioral therapy. Thus the identification of biological markers for ASD, allowing very early detection, even before the onset of symptoms, would be of tremendous value."
Five articles comprise this comprehensive issue, providing an overview of ASD genetic models, an exploration of several key emerging concepts in understanding ASD’s molecular basis, and discussion of current biomarker development, focusing on genomic data.
Following an introduction by Voineagu, Yuri Bozzi and colleagues review the phenotype characteristics of currently available mouse models of ASD. Carmen Panaitof then discusses the role of the songbird as an experimental model system for investigating the genetic basis of human language and its ASD-related impairments. Michael Bowers and Genevieve Konopka further explore language deficits and provide new evidence for the role of the FOXP gene to regulate language. Alka Saxena, Dave Tang, and Piero Carninci focus on the functional roles of the gene MECP2, which is mutated in most cases of Rett syndrome, one of the ASDs.
A review rounding out the issue is “Subphenotype-Dependent Disease Markers for Diagnosis and Personalized Treatment of Autism Spectrum Disorders,” by Valerie W. Hu, PhD, The George Washington University, School of Medicine and Health Sciences, Washington, DC, PhD, which discusses current progress toward identifying ASD biomarkers based on genome-wide data.
"Without genetic or molecular markers for screening, individuals with ASD are typically not diagnosed before the age of 2, with milder cases diagnosed much later," writes Dr. Hu. "Because early diagnosis is tantamount to early behavioral intervention, which has been shown to improve individual outcomes, an objective biomarker test that can diagnose at-risk children perinatally is a medical imperative."
Hu demonstrates the possibility and importance of developing ASD subtypes to help identify relevant disease markers, which can ultimately aid in developing specific targeted therapies.
Voineagu concludes, “It is exciting times for genetic research and although the phenotypic and genetic heterogeneity of ASD often seem to be a daunting conundrum, well-defined diagnostic criteria, larger cohort sizes for genetic studies and integrative approaches of genomic and epigenomic data already delineate a promising avenue for elucidating the mechanisms of ASD.”
(Source: eurekalert.org)
Trichuris suis ova (porcine whipworm eggs) as treatment for autism
Autism spectrum disorders are characterized by impairments in three core domains: social interaction, communication and restricted or repetitive behaviors. These impairments are frequently accompanied by disruptive behaviors, such as marked irritability, aggression, self-injury, impulsivity and temper tantrums. There is no treatment for the core symptoms, and only one class of medication — atypical antipsychotics — is approved by the U.S. Food and Drug Administration for treating these disruptive behaviors.
There is evidence for activation of pro-inflammatory processes and a positive family history of autoimmune illness in people with autism spectrum disorders. Therefore, a hygiene hypothesis has emerged for both autoimmune illness and autism, suggesting that in urban hygienic environments where there is a paucity of certain parasites that dampen immune activation, there is an increase in autoimmune processes.
People with autism have also been reported to improve when they have fevers. Given that fever is an immune-inflammatory response, Eric Hollander and his colleagues are investigating the use of immunomodulatory treatments such as Trichuris suis ova (TSO), or porcine whipworm eggs, for treating symptoms of autism. TSO has been shown to be effective in autoimmune disorders such as Crohn’s disease, ulcerative colitis and allergic rhinitis. A case series has also shown it to be effective in reducing symptoms of autism.
The researchers plan to complete a 28-week randomized crossover trial of TSO, including 12 weeks of TSO treatment, 12 weeks of placebo and a 4-week washout period. The investigators plan to compare the effects of TSO versus placebo on repetitive behaviors, aggression and irritability, and global functioning. They also plan to explore the relationship among clinical features, immune mechanisms and treatment response.
Work with immunomodulatory treatments such as TSO may be one way to test both the hygiene hypothesis as well as the fever hypothesis, and to develop alternative treatments for core and associated symptoms of autism spectrum disorders.
(Image credit: Wikimedia Commons)
Researchers Study Cry Acoustics of Infants to Determine Risk for Autism
Autism is a poorly understood family of related conditions. People with autism generally lack normal social interaction skills and engage in a variety of unusual and often characteristic behaviors, such as repetitive movements. While there is no specific medical treatment for autism, some success has been shown with early behavioral intervention.
Understanding the importance of early diagnosis, researchers at Women & Infants’Brown Center for the Study of Children at Riskin collaboration with researchers at University of Pittsburgh have been studying the cry acoustics of six-month-old infants. Their research has recently been published in Autism Research.
“Because we can measure various aspects of babies’ cries from the earliest days of life, it may be possible to use this technique to identify risk for neurological problems such as autism long before we can detect behavioral differences,” said Stephen J. Sheinkopf, PhD, lead researcher, psychologist at the Brown Center for the Study of Children at Risk, and assistant professor (research) in the Department of Psychiatry and Human Behavior at The Warren Alpert Medical School of Brown University.
The study examined ways in which infants at risk for autism produced cries as compared to the cries of low-risk infants. Recordings of babies’ cries were excerpted from vocal and video recordings of six-month-old infants at risk for autism spectrum disorder (ASD) and those with low risk. Infants were considered to be at risk if they had an older sibling with a confirmed ASD diagnosis.
Cries were categorized as either pain related or non-pain related based on observations of the videotapes. At-risk infants produced pain related cries with higher and more variable fundamental frequency (commonly referred to as “pitch”) as compared to low-risk infants. A small number of the at-risk infants were later diagnosed with an ASD at 36 months of age. The cries for these babies had among the highest fundamental frequency values and also differed in other acoustic characteristics.
“These findings demonstrate the potential of this approach for babies as young as six months of age,” said Dr. Sheinkopf.
(Photo: Thinkstock Source: Getty Images)
New hope for understanding autism spectrum disorders
Researchers from McGill University and the University of Montreal have identified a crucial link between protein synthesis and autism spectrum disorders (ASD), which can bolster new therapeutic avenues. Regulation of protein synthesis, also termed mRNA translation, is the process by which cells manufacture proteins.
This mechanism is involved in all aspects of cell and organism function. A new study in mice has found that abnormally high synthesis of a group of neuronal proteins called neuroligins results in symptoms similar to those diagnosed in ASD. The study also reveals that autism-like behaviors can be rectified in adult mice with compounds inhibiting protein synthesis, or with gene-therapy targeting neuroligins. Their results are published in the journal Nature.
Autism spectrum disorders (ASD) encompass a wide array of neurodevelopmental diseases that affect three areas of behaviour: social interactions, communication and repetitive interests or behaviors. According to the U.S.-based Centers for Disease Control and Prevention, 1 in 88 children suffer from ASD, and the disorder is reported to occur in all racial, ethnic, and socioeconomic groups. ASDs are almost five times more common among boys (1 in 54) than among girls (1 in 252).
“My lab is dedicated to elucidating the role of dysregulated protein synthesis in cancer etiology. However, our team was surprised to discover that similar mechanisms may be implicated in the development of ASD”, explained Prof. Nahum Sonenberg, from McGill’s Dept. of Biochemistry, Faculty of Medicine, and the Goodman Cancer Research Centre. “We used a mouse model in which a key gene controlling initiation of protein synthesis was deleted. In these mice, production of neuroligins was increased. Neuroligins are important for the formation and regulation of connections known as synapses between neuronal cells in the brain and essential for the maintenance of the balance in the transmission of information from neuron to neuron.”
“Since the discovery of neuroligin mutations in individuals with ASD in 2003, the precise molecular mechanisms implicated remain unknown,” said Christos Gkogkas, a postdoctoral fellow at McGill and lead author. “Our work is the first to link translational control of neuroligins with altered synaptic function and autism-like behaviors in mice. The key is that we achieved reversal of ASD-like symptoms in adult mice. Firstly, we used compounds, which were previously developed for cancer treatment, to reduce protein synthesis. Secondly, we used non-replicating viruses as vehicles to put a break on exaggerated synthesis of neuroligins.”
Computer modeling played an important role in this research. “By using a new sophisticated computer algorithm that we specially developed to answer Dr. Sonenberg’s questions, we identified the unique structures of mRNAs of the neuroligins that could be responsible for their specific regulation,” explained Prof. François Major, of the University of Montreal’s Institute for Research in Immunology and Cancer and Department of Computer Science.
The researchers found that dysregulated synthesis of neuroligins augments synaptic activity, resulting in an imbalance between excitation and inhibition in single brain cells, opening up exciting new avenues for research that may unlock the secrets of autism.
“The autistic behaviours in mice were prevented by selectively reducing the synthesis of one type of neuroligin and reversing the changes in synaptic excitation in cells,” explained Prof. Jean-Claude Lacaille at the University of Montreal’s Groupe de Recherche sur le Système Nerveux Central and Department of Physiology. “In short, we manipulated mechanisms in brain cells and observed how they influence the behaviour of the animal.” The researchers were also able to reverse changes in inhibition and augment autistic behaviors by manipulating a second neuroligin. “The fact that the balance can be affected suggests that there could be a potential for pharmacological intervention by targeting these mechanisms,” Lacaille concluded.
(Source: nouvelles.umontreal.ca)
Scripps Florida Scientists Uncover Secrets of How Intellect and Behavior Emerge During Childhood
Scientists from the Florida campus of The Scripps Research Institute (TSRI) have shown that a single protein plays an oversized role in intellectual and behavioral development. The scientists found that mutations in a single gene, which is known to cause intellectual disability and increase the risk of developing autism spectrum disorder, severely disrupts the organization of developing brain circuits during early childhood. This study helps explain how genetic mutations can cause profound cognitive and behavioral problems.
The study was published in the November 9, 2012, issue of the journal Cell.
The genetic mutations that cause developmental disorders, such as intellectual disability and autism spectrum disorder, commonly affect synapses, the junctions between two nerve cells that are part of the brain’s complex electro-chemical signaling system. A substantial percentage of children with severe intellectual and behavioral impairments are believed to harbor single mutations in critical neurodevelopmental genes. Until this study, however, it was unclear precisely how pathogenic genetic mutations and synapse function were related to the failure to develop normal intellect.
“In this study, we did something no one else had done before,” said Gavin Rumbaugh, a TSRI associate professor who led the new research. “Using an animal model, we looked at a mutation known to cause intellectual disability and showed for the first time a causative link between abnormal synapse maturation during brain development and life-long cognitive disruptions commonly seen in adults with a neurodevelopmental disorder.”
Research by scientists from the Centre for Brain Research at the University of Auckland has uncovered new information about the mechanisms underlying autism spectrum disorders (ASDs), to be published in the next issue of the prestigious Journal of Neuroscience.
Principal investigator, Dr Johanna Montgomery, says the findings are highly significant: “We’re moving beyond simply what happens in ASDs and starting to understand how it happens.”
The behavioural manifestations of ASDs are well documented and include impaired communication and socialisation, learning difficulties, and repetitive or stereotyped behaviours. These behavioural characteristics are in turn associated with a wide range of gene mutations. Many of these mutated genes are responsible for the production of specific proteins in the neurons of the brain.
Dr Montgomery and her team took a close look at parts of these neurons – the synapses, which are the structures that enable brain cells to communicate with each other. This cell to cell communication is vital for a healthy brain, and underlies how we learn, remember, move and sense.
In a complex cascade of chemical and electrical signalling, information is transmitted from one neuron to another at the synapses. This process is mediated by several families of protein, some of which form the bedrock of the synapse on the ‘listening’ side. Dr Montgomery’s team chose to investigate one of these proteins, known as Shank3, because it has been identified as vital to the communication process between two neurons, and because it is known to be mutated in ASDs.
Early treatment sparks striking brain changes in autism
When given early treatment, children with autism spectrum disorders (ASD) made significant improvements in behavior, communication, and most strikingly, brain function, Yale School of Medicine researchers report in a new study.
The study was published in the current issue of the Journal of Autism and Developmental Disorders by Yale Child Study Center researchers Dr. Fred Volkmar, Kevin A. Pelphrey, and their colleagues.
The results suggest that brain systems supporting social perception respond well to an early intervention behavioral program called pivotal response treatment. This treatment includes parent training, and employs play in its methods.
Brain imaging alone cannot diagnose autism
In a column appearing in the current issue of the journal Nature, McLean Hospital biostatistician Nicholas Lange, ScD, cautions against heralding the use of brain imaging scans to diagnose autism and urges greater focus on conducting large, long-term multicenter studies to identify the biological basis of the disorder.
"Several studies in the past two years have claimed that brain scans can diagnose autism, but this assertion is deeply flawed," said Lange, an associate professor of Psychiatry and Biostatistics at Harvard Medical School. "To diagnose autism reliably, we need to better understand what goes awry in people with the disorder. Until its solid biological basis is found, any attempt to use brain imaging to diagnose autism will be futile."
While cautioning against current use of brain imaging as a diagnostic tool, he is a strong proponent of using this technology to help scientists better understand autism. Through the use of various brain imaging techniques, including functional magnetic resonance imaging (MRI), positron emission tomography (PET), and volumetric MRI, Lange points out that researchers have made important discoveries related to early brain enlargement in the disorder, how those with autism focus during social interaction and the role of serotonin in someone with autism.
"Brain scans have led to these extremely valuable advances, and, with each discovery, we are getting closer to solving the autism pathology puzzle," said Lange. "What individuals with autism and their parents urgently need is for us to carry out large-scale studies that lead us to find reliable, sensitive and specific biological markers of autism with high predictive value that allow clinicians to identify interventions that will improve the lives of people with the disorder."
Autism and autism spectrum disorder (ASD) are terms regularly used to describe a group of complex disorders of brain development. This spectrum characterized, in varying degrees, by difficulties in social interaction, verbal and nonverbal communication, and repetitive behaviors, whose criteria have been revised in the newly proposed Diagnostic and Statistical Manual of Mental Disorders (DSM-5). The prevalence of ASD in the United States has increased 78 percent in the last decade, with the Centers for Disease Control estimating that one in 88 children has ASD.
(Source: eurekalert.org)
Distinct developmental patterns identified in children with autism during their first three years
In the largest prospective study to date of children with early and later manifestation of autism spectrum disorders (ASD) compared to children without ASD, researchers found two distinct patterns of language, social and motor development in the children with ASD. Published in the journal Child Development, the study found that early in development, children who display early signs of ASD show greater initial delay across multiple aspects of development compared to children whose ASD symptoms emerge later. However at 36 months of age, the early differences between these groups are no longer obvious. By the third birthday, the level of impairment between these symptom onset groups of children with ASD is comparable. Additionally, researchers uncovered a preclinical phase of ASD in which the signs of delay are not easily detected with existing clinical tests.
Previous research by Kennedy Krieger Institute researchers found that approximately half of all children with ASD can be diagnosed around the first birthday, while the remaining half do not show diagnostic indicators until later. The current study builds upon these findings by further evaluating motor and language development in a wider age span of children diagnosed with ASD (6 to 36 months), and examining how development unfolds differently in each group.
“Regardless of diagnosis, the development of children with and without ASD appears similar at six months of age on clinical tests,” says Dr. Rebecca Landa, lead author and director of Kennedy Krieger’s Center for Autism and Related Disorders. “However, for those children who went on to develop autism, the earliest signs of atypical development were non-specific to autism, such as general communication or motor delay.”