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Genetic markers for brain cells found lacking

Autism begins in the womb: study

Bloomberg

Autism may begin when certain brain cells fail to properly mature within the womb, according to new research by U.S. scientists.

The scientists, studying postmortem brain tissue taken from children, found that those diagnosed with autism lacked key genetic markers for brain cells that are supposed to develop prior to birth.

The phenomenon occurred in regions of the brain that control emotion, communication, language and social comprehension — all functions impaired in autism — the researchers reported Thursday in the New England Journal of Medicine.

The finding may one day offer a way to diagnose the condition earlier, when the potential for treatment is greatest. The cause of autism and its related disorders is unknown. Affecting 1 in 50 American children, it is mostly diagnosed from the ages of 3 to 5, based on behavioral changes.

There is no cure for autism, and treatments for children with autism involve behavioral therapies designed to improve learning, communication and social skills, as well as medications, or a combination of the two.

“We found a novel aspect of cortical development never seen before that provides clues to the potential cause of autism and when it began. The type of defect we found points directly and clearly to autism beginning during pregnancy,” said Eric Courchesne, director of the Autism Center of Excellence at the University of California, San Diego.

What triggers the brain-cell disruptions remains a mystery, Courchesne acknowledged in an interview. The cause could be genetic, environmental or a combination.

The study, by scientists at UCSD’s School of Medicine and the Allen Institute for Brain Science in Seattle, examined samples from 22 children, ages 2 to 15, half of whom were diagnosed with autism before they died. Samples from the 11 children who didn’t have autism were used as a control group.

The findings further suggested that the disruption of cell development in the brain probably occurs in the second and third trimesters, Courchesne said.

“These patches of disorganized cortex are patches where cell types have failed to develop,” he said. “This indicates this must have happened in fetal life when the brain is setting up neural cell types, neural connections and neural layers.”

By the second trimester, fetal brain cells are making complex connections, the scientists said.

At this point, the cortex develops into six layers, each with its own specific types of cells, assembly patterns and connections, that perform unique roles in processing information. As each cell develops, it leaves behind an observable genetic marker that the researchers used to find differences in the brains of children with autism.

The undeveloped cells that they found, meanwhile, occurred in disorganized patches, possibly showing why the condition can take on so many forms. The scientists found the disorganized patches of abnormal cells in brain tissue in 10 of the 11 children tested with autism but in only one of the control group of children.

“The next step is to investigate the cause of these abnormalities and if anything can be done about it,” said Ed Lein, a member of the study from the Allen Institute for Brain Science.

While most autism studies have been conducted using imaging technology, such as MRI scans, a handful have been based on analyses of brain tissue, mostly taken from adults.

Even with the small sample, the study, involving painstaking analysis of more than 12,000 slides, was as large or larger than previous postmortem studies, the researchers said. To visualize the work, the study’s lead author, Rich Stoner of UCSD’s Autism Center of Excellence, created the first 3-D model of its kind showing brain locations where patches of cortex failed to develop normally.

Because the abnormalities weren’t uniform, the findings may show why autism has such a wide range of symptoms and can occur with varying severity, Courchesne said. Some children diagnosed with autism also improve over time, which may have to do with brain cells rewiring themselves to compensate for abnormalities.

“The broader implication is now we have more evidence that brain changes early in life are very important for understanding autism, and it helps make the case that we have to start earlier to understand causative factors,” said Dan Smith, senior director for discovery and research at Autism Speaks, a New York-based advocacy group. “We need to expand on findings like this study to understand whether there are biological markers that we can detect before we detect behavioral changes.”

Broader studies that include more subjects and genetic markers, as well as more extensive brain mapping, will be needed to confirm the findings or to identify potential triggers that cause the brain differences, Courchesne said.

“Our panel had only 25 (gene markers), the largest panel ever used, but it’s not enough,” he said. “Even though we had 12,000 slides, that still isn’t sufficient.”