ARRA IMPACT REPORT:
Autism Spectrum Disorder – Sub-Groups & Biological Differences Affecting Symptoms
Public Health Burden
Current estimates suggest that autism spectrum disorder (ASD) affects as many as 1 in 88 U.S. children.1 ASD is associated with a wide range of developmental issues, but the core symptoms are problems with social interactions and communication skills, as well as repetitive and stereotyped behaviors. Symptoms usually appear before age three, and can cause delays or problems that develop from infancy to adulthood.
What Happens in Early Development
Research examining the biomedical, neurodevelopmental, and behavioral trajectories of children with ASD, starting in infancy, can help determine the onset of ASD as early as possible, enabling earlier initiation of treatment and thereby improving long-term outcomes. ARRA funding is allowing the following research teams to address key developmental issues related to ASD.
A multidisciplinary team of investigators at Yale University is studying the genetic and cellular differences between children with ASD—which previous research has associated with abnormal patterns of brain growth—versus typically developing children with macrocephaly (enlarged brains). Importantly, this study will produce cell lines from skin samples donated by participants and family members, which can be used to identify altered genes and cellular processes that may cause disease.2
Another group at the University of Pennsylvania is studying a mouse model of reduced sociability that may have genetic and/or neural circuitry changes relevant to ASD.3 So far, the investigators have:
Examined the developmental trajectory of sociability in the mice, demonstrating an important effect of puberty;4
Used a brain imaging technique called diffusion tensor imaging to study connectivity between brain regions involved in sociability;5,6 and
Identified regions of the genome potentially involved in inter-male aggressive behavior.7
A team at Johns Hopkins University has also developed a mouse model with autism-like social behaviors to study biological mechanisms underlying ASD. This model affords insights into the role of genes important for strengthening and maintaining synapses, the connections between individual brain cells.8
Biological Differences Underlying ASD Symptoms
ARRA funds have also been used to advance our understanding of the underlying biology of ASD with respect to symptoms, neuropathology, and cellular activity.
Investigators at the Children’s Hospital of Philadelphia have described a region of the temporal lobes located on each side of the brain that produces electrical current in response to sound and language, referred to as the M100 signal. In individuals who do not have ASD, the M100 signal is larger in the right front side of the brain than in the left front side. The investigators found that children with ASD did not demonstrate this M100 asymmetry, and the degree of reduced asymmetry correlated with reduced language skills. Thus, an identified lack of M100 asymmetry could serve as a diagnostic marker for decreased language abilities in children with ASD.9
Researchers at the University of Texas, Southwest Medical Center are investigating a family of proteins called neuroligins, which are involved in synapse formation and have been linked in humans to autism and mental retardation. The researchers found that mice lacking a gene encoding these proteins displayed spatial learning and memory deficits and a dramatic increase in repetitive, stereotyped grooming behavior. The findings suggest that neuroligins may be a potential target for developing targeted ASD treatments.10
ARRA-funded investigators from the University of California, San Diego have shown that children with ASD have deficits in orienting visual attention to particular items in view. Moreover, the extent of these deficits correlates with the severity of social communication symptoms, suggesting that brain networks that control attention may contribute more broadly to symptoms of ASD.11
Subgroups in ASD Providing Insights into the Mechanisms of ASD
One of the greatest barriers to progress in determining the biological bases of ASD has been the heterogeneity of the spectrum, including regressive and non-regressive forms of the disorder, gender differences, and variations in severity and range of symptoms. These ARRA-funded researchers are studying regressive forms of ASD in particular populations to help decipher the complexity.
Boston Children’s Hospital, Harvard Medical School investigators studied how the connections between neurons within the brain develop and mature in a mouse model with a mutated form of the gene known to cause Rett syndrome, a severe, regressive form of ASD. Although early brain connections formed normally in young mice, the ability of these connections to be strengthened or changed based on the animal’s experience was severely disrupted. The results suggest a mechanism by which disruption of the gene causing Rett syndrome may lead to delayed onset of symptoms in regressive ASD.12
Another group of researchers at the University of California, Davis examined the relationship between accelerated brain growth and the onset of ASD symptoms in a large sample of 2 to 4 year old children with ASD. They found that abnormally large brain growth was more common among boys with regressive ASD than among boys whose ASD emerged early in childhood. They found no evidence of brain enlargement among girls with ASD. Their findings may indicate brain enlargement in early childhood as a possible indicator for boys at higher risk for developing ASD.13
Contributing NIH Institutes & Centers
- Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
- National Institute on Deafness and Other Communication Disorders (NIDCD)
- National Institute of Mental Health (NIMH)
- National Institute of Neurological Disorders and Stroke (NINDS)