An international team of scientists studying genetic causes of autism spectrum disorders by focusing on families where both parents shared a recent ancestor, found that seemingly diverse genes linked to autism had something in common in that many were triggered by by brain development that is regulated by early childhood experience.

The findings support the emerging and rather exciting notion that autism is caused by disruptions in the formation of new connections in a baby’s brain during early learning experiences, which coincides with autism’s onset during a child’s first twelve months of life. The findings add to the excitement in that they introduce the element of hope: perhaps it is possible to develop therapies to reactivate the disabled genes.

The study is the work of US scientists Dr Christopher Walsh, a Howard Hughes Medical Institute investigator and who also works at Beth Israel Deaconess Medical Center and at Children’s Hospital Boston, and geneticist Dr Eric Morrow of Massachusetts General Hospital, and colleagues in the United States, Turkey, Saudi Arabia, Pakistan, and Kuwait. It is published in the 11th July issue of the journal Science.

Autistic children share three distinctive traits said the researchers: they are slow in language development, they are poor at interacting with others, and they tend to repeat stereotyped behaviour over and over. But that’s where the similarity ends, with some forms of autism appearing to be very subtle while others severely affect every aspect of functioning.

This variation in the spectrum of autistic disorders is evidence of the large number of genes involved said Walsh in a prepared statement. This makes it very difficult to pinpoint genetic causes of autism; it is not a case of looking for a single gene mutation, as has been done with diseases like cystic fibrosis or Huntington’s disease. So, although scientists agree that autism is caused largely by genetic disorders, understanding what they are and how they translate into the observed traits is far from being understood, as Walsh explained:

“At the moment, we understand the genetic causes of 15 to 20 percent of autism; the remaining 80 percent remain unexplained.”

To find inherited causes of autism spectrum disorders, Walsh, Morrow and colleagues included subjects from 88 Middle Eastern families where the parents shared a common ancestor, such as when cousins marry, thus enhancing the role of genetic factors. The vast amount of information available from such families reduced the need for a much larger sample.

Another feature of the families whose parents shared a recent ancestor is that the ratio of females to males with autism was less lopsided (it is normally about one female to four males in the general population). The ratio was even more balanced in those families with more than one member with autism, which suggested to the researchers that the rate of autism doubled due to recessive causes on non-sex linked chromosomes.

The researchers also found that another reason to suspect some of the causes were due to recessive inherited genes because they found much fewer autism-linked spontaneous deletions and duplications of genetic material in the families.

Walsh, Morrow and colleagues found many different genetic causes of autism in different individuals with little overlap between the families in which parents shared ancestry. And in five of the families they found that large segments of a person’s genome was missing whereby family members who had one functional copy of a segment did not have autism, those with both copies missing had the disorder.

Many of the missing segments switched off genes that are involved in learning, said Walsh, explaining that the result would be nerve cells would fail to develop physically, impeding the connection between synapses, the process that underpins learning and the formation of new memories.

Walsh said this was a key finding because:

“There’s lots of evidence to suggest that this process of synaptic learning is key to autism.”

But Walsh Morrow and the rest of the team were also thrilled because they think they discovered the way in which the deletions affected gene activity:

“Only one of these deletions completely removed a gene,” said Walsh. The others removed segments close to where the on/off switches for the genes were located.

This raises the hope that some types of autism may be treatable. If it is caused by a missing gene, then perhaps gene therapy that supplies the missing gene is an option, but if the autism is caused by an inactivate rather than a missing gene, then the more hopeful option is to reactive the gene, and there are more ways to do this. For example, placing autistic children in enriched learning environments has been successful, and this could be activating brain pathways that bypass the “broken on/off switches” in the disabled genes.

“By being able to characterize more about the genetic mutations at work in various forms of autism, we may be able to predict which kids need gene therapy, and which just need some form of training,” said Walsh.

Dr Thomas R Insel, Director of the US National Institutes of Mental Health (NIMH) who part funded the study said:

“The emerging picture of the genetics of autism is quite surprising. There appear to be many separate mutations involved, with each family having a different genetic cause.”

“The one unifying observation from this new report is that all of the relevant mutations could disrupt the formation of vital neural connections during a critical period when experience is shaping the developing brain,” he explained.

“Autism symptoms emerge at an age when the developing brain is refining the connections between neurons in response to a child’s experience,” said Walsh.

“Whether or not certain important genes turn on is thus dependent on experience-triggered neural activity. Disruption of this refinement process may be a common mechanism of autism-associated mutations,” he added.

The study drew two main conclusions. One was that the findings highlighted the usefulness of the method the researchers called “homozygosity mapping”, where they can study a person who has inherited two identical copies of the same gene. The second conclusion was that:

“Defective regulation of gene expression after neural activity may be a mechanism common to seemingly diverse autism mutations.”

“Identifying Autism Loci and Genes by Tracing Recent Shared Ancestry.”
Eric M. Morrow, Seung-Yun Yoo, Steven W. Flavell, Tae-Kyung Kim, Yingxi Lin, Robert Sean Hill, Nahit M. Mukaddes, Soher Balkhy, Generoso Gascon, Asif Hashmi, Samira Al-Saad, Janice Ware, Robert M. Joseph, Rachel Greenblatt, Danielle Gleason, Julia A. Ertelt, Kira A. Apse, Adria Bodell, Jennifer N. Partlow, Brenda Barry, Hui Yao, Kyriacos Markianos, Russell J. Ferland, Michael E. Greenberg, and Christopher A. Walsh.
Science 11 July 2008, Vol. 321. no. 5886, pp. 218 – 223
DOI: 10.1126/science.1157657

Click here for Abstract.

Source: NIMH, Howard Hughes Medical Institute, journal abstract.

Written by: Catharine Paddock, PhD