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The Early Origins of Autism by Patricia M. Rodier

A Simpler Symptom of Autism

Scientists at York University and the Hospital for Sick Children in Toronto have recently identified an autism- related behavior that is much simpler than the array of behaviors that have traditionally been used to diagnose the condition. Susan Bryson and her doctoral student Reginald Landry have found that children with autism respond abnormally to a task involving their reactions to visual stimuli. Because this mental activity is probably mediated by a primitive part of the brain -- most likely the brain stem or the cerebellum, or both -- the discovery has important implications for the neurobiology of autism. Bryson and Landry's work could also help clinicians develop a simpler way to test children for the disorder.

In their study Bryson and Landry observed the reactions of two groups of children,those with autism and those without it, as they watched lights flashing on video screens [see illustration above]. The children ranged in age from four to seven. In the first test, each child was placed in front of a three-screen panel, and a flashing light appeared on the middle screen. This stimulus prompted the children to focus their eyes on the flashes (a). Then the middle screen went blank, and a flashing light appeared on the far-right or the far-left screen of the panel. Both groups of children shifted their eyes to that screen (b). In the second test, however, the lights on the the middle screen kept flashing while the lights appeared on the other screen. The children without autism shifted focus on the new stimulus (c), but the children with autism remained "stuck" on the first stimulus and failed to turn their eyes to the new one (d). The two tests were repeated many times for each child.

In 1995 our research team had the opportunity to follow up on the thalidomide study by examining the brain stem of a person with autism. The tissue samples came from the autopsy of a young woman who had suffered from autism of unknown cause; she had died in the 1970s, but fortunately the samples of her brain tissue had been preserved. When we examined the woman's brain stem, we were struck by the near absence of two structures: the facial nucleus, which controls the muscles of facial expression, and the superior olive, which is a relay station for auditory information. Both structures arise from the same segment of the embryo's neural tube, the organ that develops into the central nervous system. Counts of the facial neurons in the woman's brain showed only about 400 cells, whereas counts of facial neurons in a control brain showed 9,000.

Overall, the woman's brain was normal in size; in fact, it was slightly heavier than the average brain. I hypothesized that the brain stem was lacking only the specific neurons already identified -- those in the facial nucleus and the superior olive -- and to test that idea I decided to measure the distances between a number of neuroanatomical landmarks. I was surprised to discover that my hypothesis was absolutely wrong. Although the side-to-side measures were indeed normal, the front-to-back measures were astonishingly reduced in the brain stem of the woman with autism. It was as though a band of tissue had been cut out of the brain stem, and the two remaining pieces had been knit back together with no seam where the tissue was missing.

For the second time in my life, I felt a powerful shock of recognition. I heard a roaring in my ears, my vision dimmed, and I felt as though my head might explode. The shock was not generated by the unexpected result but by the realization that! had seen this pattern of shortening before, in a paper that showed pictures of abnormal mouse brains.

When I retrieved the article from the stacks of papers on my office floor, I found that the correspondence between the brain I had been studying and the mouse brains described in the article was even more striking than I had remembered. Both cases exhibited shortening of the brain stem, a smaller-than-normal facial nucleus and the absence of a superior olive. Additional features of the mice were clearly related to other anomalies associated with autism: they had ear malformations and lacked one of the brain structures controlling eye movement.

What had altered the brains of these mice? It was not exposure to thalidomide or any of the other environmental factors associated with autism but the elimination of the function of a gene. These were transgenic "knockout" mice, engineered to lack the expression of the gene known as Hoxa1 so that researchers could study the gene's role in early development. The obvious question was, "Could this be one of the genes involved in autism?"

The literature supported the idea that Hoxa1 was an excellent candidate for autism research. The studies of knockout mice showed that Hoxa1 plays a central role in development of the brain stem. Groups in Salt Lake City and London had studied different knockout strains with similar results. They found that the gene is active in the brain stem when the first neurons are forming -- the same period that Miller and Stromland had identified as the time when thalidomide caused autism. Hoxa1 produces a type of protein called a transcription factor, which modulates the activity of other genes. What is more, Hoxa1 is not active in any tissue after early embryogenesis. If a gene is active throughout life, as many are, altered function of that gene usually leads to problems that increase with age. A gene active only during development is a better candidate to explain a congenital disability like autism, which seems to be stable after childhood.

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