Much of the focus is on or around the synapse—impaired signaling is thought to be a key factor in the cognitive deficits and behavioral problems seen in patients with these disorders. Studies in knockout mice whose disease phenotype is corrected to normal are also yielding insights into the condition as are whole exome and whole-genome sequence analysis of individuals with autism. Some scientists are beginning to look beyond neurons to elucidate possible roles in autism for other types of brain cells, such as microglia (the brain's macrophages) and astrocytes, although this remains an early-stage effort.
With no diagnostic test and no suitable endpoints for clinical trials, progress has been slow. To complicate matters, the differences between autism and other neurodevelopmental conditions are substantial. “Whatever is effective in fragile X syndrome, tuberous sclerosis complex or Rett syndrome does not necessarily mean it's going to be translated into that black box called idiopathic autism,” says Walter Kaufmann, director of the Rett syndrome program (and co-director of the FXS program) at Boston Children's Hospital, in Boston. Although genetics plays a major role in autism and ASD—concordance rates are up to 90% in identical twins but much lower in fraternal twins—its contribution is highly varied and still largely undefined. “A major outstanding issue is how the hundreds of genetic mutations discovered to be associated with autism lead to essentially the same syndrome,” says Jacqueline Crawley, professor of translational research at the Mind Institute at the University of California (UC), Davis.
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