The observation that some individuals with autism show clinical improvement in response to fever suggests that symptoms may be modulated by brain systems or enzymes that become altered at high temperatures or by immune-inflammatory factors. The febrile hypothesis of autism stems from this observation. The effect could be due to the direct effect of temperature on enzymes that are heat-labile (can be changed or activated at high temperatures) or on gene expression in the brain. It could also be due to a resulting change in the immune inflammatory system or an increase in the functionality of a previously dysfunctional system in the locus coeruleus, a brain region that modulates physiological responses.

Stephen Bent’s primary goal in this project was to determine whether a randomized, controlled trial of a treatment for children with autism could be conducted entirely over the phone and Internet. He and his team designed an Internet-based clinical trial platform within the Interactive Autism Network (IAN), an online community and longitudinal study of more than 13,000 families that include a child with autism.

The Simons Foundation has funded five university-based medical centers to identify and study a large number of individuals (~200 families within two years) with a recurrent genetic variation (deletion or duplication of segment 16p11.2) that increases their risk of developing autism spectrum and other neuro­developmental disorders. The immediate goal is to identify medical, cognitive, neural and behavioral profiles shared by this genetically identified group. Families are recruited through web-based networks or referral by clinical genetic centers or testing laboratories. Extensive psychological and neurological testing and neuroimaging with a uniform protocol will take place at the collaborating medical centers.

For individuals with autism, the process of socialization is derailed at a very early age. Typically developing babies are drawn more toward socially relevant aspects of their environment (e.g. people, particularly their eyes) than toward inanimate objects. Ami Klin and Warren Jones at Yale University have found that this is not the case for children with autism, who often possess a great deal of knowledge about their world, but are profoundly lacking in socialization.

Large-scale population studies are valuable for elucidating gene-environment interactions that contribute to the risk of autism. Young Shin Kim and her colleagues at Yale University are assembling a large-scale collection of autism-related data from a group of children in South Korea who show a variety of symptoms across the autism spectrum.

Genetics plays a major role in autism, but the relationships are complex and not well understood. Individuals with autism frequently also have other disorders such as fragile X syndrome, Rett syndrome and tuberous sclerosis. Mutations in specific genes — such as neuroligins, which help relay signals between neurons — have also been linked to autism.

Abba Krieger and Andreas Buja at the University of Pennsylvania (in collaboration with Eric Fombonne, Edwin Cook and Alex Lash) analyzed the relationship between body temperature and cognitive functioning as measured by intelligence quotients (IQ) in individuals with autism.

16p11.2 are the most common chromosomal change seen in individuals with autism. State and his multisite team of investigators also showed that girls with autism carry evidence of more profound genetic risks, suggesting that they are protected from autism when carrying less serious mutations that would lead to autism in boys.

Mirror neurons are nerve cells that are activated when an individual observes an action being performed by someone else. These neurons are believed to be involved in cognitive abilities such as empathy and learning by imitation — skills that are often impaired in people with autism. Raphael Bernier at the University of Washington is exploring a potential link between mirror neuron dysfunction and autism, which could help elucidate how the disorder develops, and might provide a basis for early detection and intervention.

The overarching goal of our work is to delineate the clinical and genetic heterogeneity within the Autism Spectrum Disorder diagnosis so that prognoses, treatments and preventive strategies can be implemented which are specific to each autism subgroup. We start by looking for biologically-based phenotypes which can be used to define discrete subgroups. One autism subgroup has been recognized based on findings generalized through often subtle differences in their physical features, indicating an insult to normal morphogenesis. Based on the premise that they would be genetically different from the rest, our goal has been to learn how to distinguish those children, characterize the ways they differ from children without dysmorphology and translate that information into best clinical practices.