Major progress has been made in understanding the genetic basis of autism spectrum disorders. Rare or de novo mutations throughout the genome are now known to be important factors. These include copy number variations (CNVs) and point mutations that disrupt the protein-coding sequences of genes.

Several loci, or stretches of chromosomal DNA, have been shown to be defective in individuals with autism. These loci each contain more than one gene, so the next step is to identify the specific genes that are disrupted.

Despite the diversity and the rising prevalence of diagnosed cases of autism, the etiology of the disorder remains an open question. Efforts to understand the pathophysiology of autism have focused on genetic factors. However, considering the tremendous diversity of autism types, it seems likely that the causes of autism spectrum disorders are numerous and perhaps overlapping.

Among the many interesting findings emerging from studies of de novo mutations in the Simons Simplex Collection has been the extreme degree of genetic heterogeneity that underlies autism spectrum disorders. In addition, one mutation may be associated with a wide range of distinct psychiatric and neurodevelopmental outcomes. Many of the genes that contribute to autism also demonstrate considerable pleiotropy, playing diverse biological roles at different points in brain development. These factors present important obstacles to translating the rapidly growing understanding of autism genomics into a deeper understanding of autism pathophysiology.

One of the most common genetic causes of autism is the loss or duplication of a small region on human chromosome 16 known as 16p11.2. These genetic changes account for only about 1 percent of all cases of autism, but when present, they frequently result in the disorder.

Inflammation during pregnancy has been suggested as a possible contributing factor in the development of autism spectrum disorders in children. A replica of this phenomenon, called the maternal immune activation (MIA) model, is used to study inflammation-induced behavioral changes in rodents. Identification of key immune components in the MIA model may lead to a better understanding of underlying causes of autism.

Matthew Goodwin and his colleagues at Northeastern University in Boston and the Georgia Institute of Technology are working to develop a mobile system for recording behavior and physiology in individuals on the autism spectrum, for use in home settings.

Yehezkel Ben-Ari and his colleagues at the Institut de Neurobiologie de la Méditerranée (Inmed) in Marseille, France, showed several years ago that neurons recorded in newly born animals have elevated intracellular chloride, leading to paradoxical excitatory actions of the principal adult inhibitory transmitter gamma-aminobutyric acid (GABA)[ref]Ben-Ari Y. et al. Physiol. Rev. 87, 1215-1284 (2007) PubMed[/ref]. They showed an abrupt and brief decrease in intracellular chloride in central neurons recorded immediately after birth[ref]Tyzio R. et al. Science 314, 1788-1792 (2006) PubMed[/ref]. This shift is associated with an abrupt excitatory-to-inhibitory shift of the actions of GABA that is mediated by the hormone oxytocin, which also triggers labor.

Duplication of a small segment of human chromosome 7 has been found in some children with autism. Lucy Osborne and her colleagues at the University of Toronto aim to understand the effects of duplication of this region, 7q11.23, on the growth and function of the brain. They plan to study this using a mouse model with a similar duplication.

Epilepsy and epileptiform encephalogram (EEG) abnormalities are common comorbidities in autism spectrum disorders. Sarah Spence at Boston Children’s Hospital proposes that these are important biomarkers of cortical dysfunction involved in the pathogenesis of autism spectrum disorders. Although treatment for epilepsy is always indicated, treating epileptiform EEG abnormalities without seizures is controversial. Data suggest, however, that epileptiform discharges — short bursts of brain activity that resemble EEG patterns during seizures — are associated with deficits in attention, language and behavior, indicating that these discharges may represent a novel treatment target in autism.