5|25: Celebrating Five Years of Autism Science Day 10: Functional Underconnectivity Theory of Autism
In honor of the anniversary of Autism Speaks’ founding on Feb 25, for the next 25 days we will be sharing stories about the many significant scientific advances that have occurred during our first five years together. Our ninth item, Copy Number Variations, is from Autism Speaks’ Top 10 Autism Research Events of 2007.
Three studies published in 2007 pointed autism researchers toward the importance not only of mutations within the DNA code of specific genes, but also of variations in the number of copies of genes, known as Copy Number Variations (CNV). Created by submicroscopic deletions or duplications of DNA sequences, recent advances have only now allowed CNV to become routinely detectable, establishing an entirely new avenue of genetic research.
Armed with the latest technology and three different collections of patient DNA, including Autism Speaks’ Autism Genetic Resource Exchange (AGRE), researchers at Cold Spring Harbor scanned the genome for the presence of CNV in autism. In February 2007 they reported that not only do individuals with autism have more CNV than individuals without autism, but that CNV in autism occur more often as “de novo” or spontaneous mutations (mutations not found in the DNA of either parent). They also found that these spontaneous CNV appear to be more common in families with only one child with autism (simplex) than those with multiple affected children (multiplex).
With their data suggesting that genetic mechanisms may be different in different types of autism, the researchers then carefully studied the inheritance pattern of autism in the many families in Autism Speaks’ AGRE and IAN databases. In July they published that they could fit the data to a model in which there are at least two distinct ways that genes may play a role in the development of autism: spontaneous CNV might help to explain autism in simplex families, whereas inherited gene mutations may be at the root of autism spectrum disorders in a greater portion of multiplex families. Such a model is significant because although autism has been thought to have a strong genetic component, so far it has not been shown to be as clearly inherited as other simple genetic disorders.
The team from Cold Spring Harbor has provided a new theory of autism risk that stands to influence how future autism genetic research is conceptualized. Although their results require replication, it also now leads to the question of what causes this increase in spontaneous CNV, opening the door to an exploration of the interplay between genetics and environmental factors. Possible risk factors include age of the parents, specific toxicological factors and accumulated exposures, as well as genetic predisposition.
Update since this story was first run: Improvement in DNA technology since the publication of this first major autism CNV study has meant that new insights into the role of CNV are actively being pursued. The largest and most comprehensive autism CNV study to date was published in April 2009 in the top research journal, Nature. The new study focused on inherited rather than spontaneous CNV, with the researchers finding CNV variations in genes important for neural development [for more details, see http://www.autismspeaks.org/science/science_news/top_ten_autism_research_events_2009_cnv.php]. Researchers in autism are continuing to lead geneticists in other fields with an intense focus on CNV and early recognition of their importance as potential disease risk factors.
In honor of the anniversary of Autism Speaks’ founding on Feb 25, for the next 25 days we will be sharing stories about the many significant scientific advances that have occurred during our first five years together. Our eighth item, Creation of Neuroligin-3 Mutant Mouse, is from Autism Speaks’ Top 10 Autism Research Events of 2007.
Animal models have long been employed to replicate some of the behavioral and biochemical characteristics of autism. The models are chosen for study either because they have behaviors reminiscent of autism, or because they have received genetic or environmental manipulations believed to be linked, directly or indirectly, to autism.
Yet, only with the recent progress of detailed genetic studies in developmental disorders have these models been based on the actual genetic differences found in humans with autism. Some of these newer models for autism include mouse models of medical genetic syndromes that show overlap with autism, e.g., Fragile X syndrome, Rett syndrome and Tuberous Sclerosis. However, no model existed that contained the precise genetic defect found in anyone whose autism is not caused by one of these other genetic syndromes. This changed in October 2007, when researchers in Texas reported they had succeeded in replacing the mouse neuroligin-3 gene with a human version containing the exact mutation discovered in 2004 to be the cause of autism in a Swedish family with two affected brothers. Excitingly, the initial exploratory studies have found the “humanized neuroligin-3″ mouse has several unusual behaviors, including deficits in some social behaviors and an increased ability for spatial learning in a swimming test.
This mouse provided the research community with a strong new tool to directly assess the neurobiology, behavioral deficits and, conceivably soon enough, treatment approaches for autism. Such models are a vital part of the drug discovery process because measurement of changes in their behaviors can be used as surrogate markers for preclinical evaluation of new therapeutics.
Since this story was first run: Genetic studies continue to provide new opportunities for the generation of animal models of autism, including many related to the function of the neuroligins. In 2009 the same group of researchers carried out a behavioral characterization of mice lacking the neurexin-1alpha gene, which creates proteins that serve as binding partners for the neuroligins. Published in the Proceedings of the National Academies of Science, the scientists have now discovered that the neurexin-1alpha mice have abnormal brain physiology and increased repetitive behaviors.
In honor of the anniversary of Autism Speaks’ founding on Feb 25, for the next 25 days we will be sharing stories about the many significant scientific advances that have occurred during our first five years together. Our seventh item, AGRE Reaches Milestones, is from Autism Speaks’ Top 10 Autism Research Events of 2007.
Created in 1997 by Cure Autism Now/Autism Speaks, the Autism Genetic Resource Exchange (AGRE) remains one of the most powerful resources for autism research. AGRE is a nation-wide family registry and biomaterials repository that recruits families with at least two members with an autism spectrum disorder. Biological samples (blood, plasma and DNA) are collected along with the accompanying clinical data and made available to AGRE-approved researchers all over the globe. As of December 2007, this open-access, collaborative resource contained information on over 1600 families with autism, making it the largest privately maintained autism repository in the world.As parents know, the research process can be frustratingly slow. AGRE significantly speeds up the process by providing researchers with the necessary materials and information to test a diversity of hypotheses without having to recruit families or collect their own data. Furthermore, having such a large database of sample data provides researchers with more meaningful insight into the disorder. The impact has been enormous. This summer AGRE reached a publication milestone, when the 100th paper citing use of the resource was released. As recognition of this remarkable contribution and the pivotal role of AGRE in advancing autism research, in September 2007 the National Institute of Mental Health awarded an $8.4 million grant to the University of Southern California that will provide funding to support AGRE with the next five years of data collection.
The AGRE program provides families with a means to get involved and positively contribute to autism research. A better understanding of autism will require different scientific approaches and even greater numbers of families. This year scientists studying other complex disorders such as diabetes and heart disease found that sample sizes on the order of tens of thousands of affected individuals were required before common disease genes could be detected. Continued expansion of AGRE and other collections like it will be necessary to reach these goals as fast as possible.
Did you know?: The AGRE collection continues to be the largest private source of genetic and clinical information for autism research available to scientists worldwide, containing information on over 2100 families with autism as of January 2010. AGRE is now responsible for 162 peer-reviewed publications and has been used in most of the major autism genetic discoveries to date. It is currently facilitating 11 collaborations with outside researchers and supports six federal grants. One of these grants was awarded to Autism Speaks by the NIH as part of the 2009 stimulus funding. This new grant will allow AGRE and the NIH to enter a partnership to help build a larger and more flexible national database for autism research.
In honor of the anniversary of Autism Speaks’ founding on Feb 25, for the next 25 days we will be sharing stories about the many significant scientific advances that have occurred during our first five years together. Our sixth item, FDA Approval of Risperidone, is from Autism Speaks’ Top 10 Autism Research Events of 2007.
In late 2006 the U.S. Food and Drug Administration (FDA) approved the first medication indicated to treat certain symptoms associated with autism, making 2007 the first year an approved drug for autism was available. The drug, risperidone sold under the brand name Risperdal, is manufactured and marketed by Janssen, L.P., a subsidiary of Johnson & Johnson.
First introduced in 1993 as an atypical antipsychotic to treat schizophrenia, Risperdal can now be marketed as a treatment of irritability associated with autistic disorder in children and adolescents aged 5-16 years. This includes symptoms of aggression towards others, deliberate self-injuriousness, temper tantrums and quickly changing moods. Importantly, Risperdal does not treat the core symptoms of autism such as communication problems and trouble with social interactions. However, J&J used two clinical trials to demonstrate the benefits of the drug in treating the associated behavioral disturbances that can interfere with school, learning and family life.
This event not only sets precedence for gaining FDA approval for medications that treat autistic symptoms, it also shows that autism is considered a viable market for the pharmaceutical industry which will hopefully lead to the development of new compounds that will benefit the quality of life for those living with autism.
Update since this story was first run: On November 20, 2009 the FDA approved Abilify (aripiprazole) for the treatment of irritability associated with autism, making it the second medication to receive an autism indication. Specifically, the drug is approved for children 6-17 to help alleviate symptoms of “aggression towards others, deliberate self-injuriousness, temper tantrums, and quickly changing moods.” Aripiprazole, which is manufactured and marketed as Abilify by Bristol-Myers Squibb, is an atypical antipsychotic medication used to treat schizophrenia, bipolar disorder and depression. Although an FDA approval for a medication addressing the core symptoms of autism is still lacking, the approval of Abilify will offer additional options for families and clinicians.
In honor of the anniversary of Autism Speaks’ founding on Feb 25, for the next 25 days we will be sharing stories about the many significant scientific advances that have occurred during our first five years together. Our fifth item is Diagnosis at 14 Months.
In a study in the Archives of General Psychiatry, researchers from the Kennedy Krieger Institute in Baltimore, Maryland found that autism can be diagnosed at close to one year of age, which is the earliest the disorder has ever been diagnosed. The study, which evaluated social and communication development in autism spectrum disorders (ASD) from 14 to 36 months of age, revealed that approximately half of all children with autism can be diagnosed around the first birthday. The remaining half will be diagnosed later, and their development may unfold very differently than children whose ASD is diagnosable around the first birthday. Early diagnosis of the disorder allows for early intervention, which can make a major difference in helping children with autism reach their full potential
Researchers examined social and communication development in infants at high and low risk for ASD starting at 14 months of age and ending at 30 or 36 months. Half of the children with a final diagnosis of ASD made at 30 or 36 months of age had been diagnosed with the disorder at 14 months, and the other half were diagnosed after 14 months. Through repeated observation and the use of standardized tests of development, researchers identified, for the first time, disruptions in social, communication and play development that were indicative of ASD in 14-month olds. Multiple signs indicating these developmental disruptions appear simultaneously in children with the disorder.
The current study reveals that autism often involves a progression, with the disorder claiming or presenting itself between 14 and 24 months of age. Some children with only mild delays at 14 months of age could go on to be diagnosed with ASD. The researchers observed distinct differences in the developmental paths, or trajectories, of children with early versus later diagnosis of ASD. While some children developed very slowly and displayed social and communication abnormalities associated with ASD at 14 months of age, others showed only mild delays with a gradual onset of autism symptoms, culminating in the diagnosis of ASD by 36 months.
If parents suspect something is wrong with their child’s development, or that their child is losing skills during their first few years of life, they should talk to their pediatrician or another developmental expert. This and other autism studies suggest that the “wait and see” method, which is often recommended to concerned parents, could lead to missed opportunities for early intervention during this time period.
To read the complete story, including the signs of developmental disruptions for which parents and pediatricians should be watching, please click here http://www.autismspeaks.org/inthenews/landa_study.php.
Update since this story was run: Members of the Baby Siblings Research Consortium, a collaboration between Autism Speaks and the National Institute of Child Health and Human Development, have now published multiple scientific studies demonstrating that early signs of autism can reliably be seen as early as 12-14 months of age. This improved understanding of the early signs and symptoms of autism has permitted development of new measurement tools to both quantify and diagnose autism symptoms earlier than ever before. For example, the Autism Observational Scale for Infants or AOSI was published by Autism Speaks’ grantees in 2008 and is currently a part of many protocols involving early autism diagnosis and intervention. It has been shown to accurately detect autism as early as 12 months of age. In addition, a modification of the ADOS, called the ADOS-t, was released in 2008 to enhance the clinical diagnosis of autism, indicating a range of concern for children as young as 12 months of age. Both tools are huge advances in the field of diagnosis, allowing for reliable early detection and placement in appropriate intervention services.
In honor of the anniversary of Autism Speaks’ founding on Feb 25, for the next 25 days we will be sharing stories about the many significant scientific advances that have occurred during our first five years together. Our fourth item, Convergence on PTEN Signaling Pathway, is from Autism Speaks’ Top 10 Autism Research Events of 2007.
Model systems for studying the complex and fundamentally human challenge of autism will be vitally important to solving autism because they allow researchers to study the underlying biology in a manner that is not possible in humans. Finding an animal model system with similar behavioral tendencies as humans allows researchers to study which biochemical pathways break down in autism and, most importantly, how they can be treated. In 2007, researchers added an important new model system to their arsenal, the “PTEN conditional knockout” mouse.
PTEN is a gene that encodes for a protein involved in several critical signaling pathways inside cells, including metabolism, growth and survival. To carry out its cellular duties, PTEN interacts with several other important proteins in a biochemical signaling cascade. Other proteins in this signaling pathway have previously been tied to developmental disorders such as Tuberous Sclerosis and Neurofibromatosis. In 2005, researchers found that within a small subset of individuals with autism and macrocephaly (large heads) 17% had mutations in the PTEN gene. This raised the possibility that disrupting PTEN activity, and the signaling pathways within which it functions, may result in some forms of autism. This year researchers succeeded in using complex genetic manipulations to shutdown the mouse version of the gene (PTEN) in the brain of young mice. Surprisingly, not only did these animals grow larger brains, the mice also displayed abnormal social behaviors and seizures, both of which can be features of autism.
These results provided important data supporting the emerging relevance of cellular signaling pathways to autistic behaviors, and are now focusing some researchers on specific molecules that could potentially become targets for cell-based therapeutics.
Update since this story was first run: Having discovered that disrupting the PTEN signaling pathway leads to autism-associated signs, in 2009 the researchers went on to further show that manipulation of the PTEN signaling pathway can serve as a successful treatment strategy. Making use of these same mice, they found that treatment with a pharmacological inhibitor of the PTEN pathway improved the autism-like pathology of the animals, including unusual social behaviors and seizures. Published in the Journal of Neuroscience, the newest data strengthen the case for focusing on this signaling pathway as a viable target for novel autism therapeutics.