Multiple hereditary exostoses (MHE) is an inherited genetic disease that affects children, who suffer from multiple growths on their bones that cause pain and disfigurement.
But beyond the physical symptoms of this condition, some parents have long observed that their children with MHE also experience autism-like social problems. Buoyed by the support of these parents, researchers at Sanford-Burnham Medical Research Institute (Sanford-Burnham) used a mouse model of MHE to investigate cognitive function. They found that mice with a genetic defect that models human MHE show symptoms that meet the three defining characteristics of autism: social impairment, language deficits, and repetitive behavior. The study, published online the week of March 12 in the Proceedings of the National Academy of Sciences USA, also defines the molecular and physiological basis of this behavior, pinpointing the amygdala as the region of the brain causing autistic symptoms.
"There is growing evidence that many autistic people have related genetic defects, or defects that are exacerbated by this one," said Yu Yamaguchi, M.D., Ph.D., professor in the Sanford Children's Health Research Center at Sanford-Burnham." Yamaguchi led this study, along with colleagues Fumitoshi Irie, Ph.D. and Hedieh Badie-Mahdavi, Ph.D.
In humans, MHE is caused by a mutation in one of two genes, Ext1 or Ext2. Together, these genes encode an enzyme necessary to produce heparan sulfate—a long sugar chain that helps bone cells grow and proliferate. In this study, Yamaguchi and his team used mice that lack the Ext1 gene in just a certain type of neuron to understand the mechanism of social problems in MHE patients.
Then the researchers examined the mice's behavior to test for the three defining characteristics of autism: social impairment, language deficits, and repetitive behavior. Using several different techniques, the team found that the mutant mice were less social than normal mice. They also exhibited language deficiencies, as determined using ultrasound vocalization measurements, a well-characterized substitute for mouse language. Lastly, Yamaguchi's team took at look at repetitive behaviors in these mice. Using a board covered with holes, they observed that normal mice will poke their noses in many holes at random, while the mutant mice poke their noses in the same hole again and again.
These behavioral measurements clearly demonstrate what the parents of children with MHE have always suspected—the disease affects more than just bones. The genetic defect that causes skeletal deformities also causes social and cognitive problems.
Pinpointing the amygdala
With these definitive simulations of autistic behavior in humans in hand, the researchers went on to define the cellular, molecular, and physiological basis for these symptoms. They did this first using a technique called c-Fos immuno-histochemistry, which illuminates the parts of the brain that are activated by certain experiences.
The researchers stimulated either normal or mutant mice with other normal mice for five minutes, then looked at their brains. In normal mice, the c-Fos immuno-histochemical staining lit up in the hippocampus, the amygdala, and other areas of the brain. In the mutant mice, the hippocampus was activated just as it was in normal mice. However, the amygdala of the mutant mice lacking the Ext1 gene wasn't nearly as activated as it was in normal mice. This finding pinpoints the amygdala as the region of the brain that contributes to autistic symptoms in this model.
"These results are consistent with the amygdala theory of autism," Yamaguchi said, referring to the idea that since the amygdala is thought to control a person's social intelligence, autism could be caused by abnormalities in that part of the brain.
What this means for the general autistic population
Obviously, not all autistic children have MHE, nor are all MHE children autistic. But, according to Yamaguchi, there is evidence that some people who are autistic might have similar defects in heparan sulfate. This is the sugar chain that's defective in MHE, where it causes bone deformities and—as this study now shows—social deficits.