Multiple hereditary exostoses (MHE) is an inherited genetic disease which results in multiple bone growths that cause pain and disfigurement. Parents of children with MHE have long observed autism-like social problems in their children. A new study has found that mice with a genetic defect that models human MHE show symptoms of the three defining characteristics of autism: social impairment, language deficits, and repetitive behavior.
The study, by Sanford-Burnham Medical Research Institute (Sanford-Burnham) used a mouse model of MHE to investigate cognitive function and points to the amygdala as the region of the brain causing symptoms of autism.
“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.
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 thrive. In this study, Yamaguchi and his team used mice that lack the Ext1 gene in just a certain type of neuron to investigate the system of social issues in MHE patients.
Using several different techniques, the team found that the mice lacking the Ext1 gene were less social than the control mice. They also demonstrated 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 are not surprising to the parents of children with MHE – it is clear the disease affects more than just bones. The genetic defect that causes skeletal deformities also causes social and cognitive problems.
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. This technique pointed to the amygdala being the source of symptoms of autism.
“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.
While not all children with autism have MHE, or vice versa, Yamaguchi believes there is evidence that some people who have autism might have similar defects in heparan sulfate. This is the sugar chain that’s defective in MHE, where it causes bone deformities and – as is now shown – social deficits.
Yamaguchi’s team is now comparing DNA from volunteers with autism and volunteers without autism to look for mutations in heparan sulfate genes. The initial results have been encouraging.
“I can’t emphasize enough how much it helped that the parents of kids with MHE got involved and supported this research,” Yamaguchi said. “As parents, they noticed their kids had social problems that gave them challenges at school. School officials and other people didn’t take these observations seriously – they usually just waved off the problems, assuming that the kids’ bone deformities just make them shy. This latest research doesn’t solve any bone issues for MHE patients, but it does help support what the parents always knew – these children need special care.”