Research looks for connections in a little-understood disorder

Autism spectrum disorders (ASD) are reported to affect one in 88 children in the United States. Yet despite the growing prevalence, the causes of the disorder are little understood and a cure remains elusive.

Researchers here are studying connections autism may have with other disorders that affect the brain. They are mining genetic and clinical data for common genetic markers. And they are investigating ways to manage symptoms while the hunt for a cure continues.

Exploring genetic clues

Charles Vorhees, PhD, a scientist in the Division of Child Neurology, studies what goes wrong in brain development. One interest is creatine transporter disorder, an X-linked disorder first identified at Cincinnati Children’s by former division Director Ton DeGrauw, MD, PhD. The disorder causes severe intellectual impairment and loss of language. Some children with the disorder have been described as having autistic-like behaviors.

Vorhees and his team engineered a mouse model of the defect that is “remarkably faithful to the human condition,” he says. Further studies using this model will help define the role creatine plays in the brain and may provide insights into autism.

Vorhees also collaborates with Steve Danzer, PhD, in the Division of Anesthesiology, on a study examining PTEN , a tumor suppressor gene that regulates cell growth. Mutations in this gene have been found in some children with autism. Using a genetically modified mouse developed by Danzer that disrupts PTEN in a specific brain region, the team is exploring whether the mice exhibit an autism-like phenotype.

An SSRI connection?

Vorhees also is examining the long-term effects of selective serotonin reuptake inhibitor (SSRI) antidepressants on brain development when taken during pregnancy.

Results from another study in his laboratory sparked his interest.

“We gave one SSRI to rats during hippocampal development – which in humans occurs during the third trimester. As adults, the drug-exposed rats had spatial and egocentric learning and memory problems, which surprised us because these were regarded as ‘safe’ doses that weren’t supposed to cause adverse effects,” Vorhees says. Whether these effects are related to autism is the subject of ongoing studies.

At least 4 percent of US women take antidepressants during pregnancy. It remains to be seen whether an autism connection exists, Vorhees says, but either way, the study would be the first to connect these drugs to learning disabilities after in utero SSRI exposure.

Connecting the genetic and clinical dots

The NIH initiated the e-Merge project in 2007 to expedite research into common diseases. The project links large amounts of genetic data with electronic medical records.

Cincinnati Children’s researcher John Harley, MD, PhD, recently received $2.4 million to lead a portion of the project that involves collecting data on children with obesity, heart disease and ASD.

Imre Solti, MD, PhD, and Keith Marsolo, PhD, in the Division of Biomedical Informatics, are developing the algorithm to identify common phenotypes in children with ASD. Solti and his team are currently creating a computer program that will comb through millions of text notes – progress notes, discharge summaries and the like – written by doctors each year.

“Only 50-70 percent of the information about a patient is found in structured medical entries such as tests and lab work,” Solti says. “The rest is in the notes.” At Cincinnati Children’s alone, Solti says, 5 million text notes are created annually – the equivalent to a nearly two-mile shelf of books.

The study will compare common phenotypes with genetic information to see if they have similar genetic variations. Scientists hope the findings will help to better identify and treat the range of autism spectrum disorders.

“If we know the genetics of the patient, we can individualize the treatment plan – and provide the right medication in the right dose,” Solti says.

Learning from other conditions

Research into other diseases also may improve understanding of autism. With an NIH grant of $12.5 million, Darcy Krueger, MD, PhD, is exploring the connection between tuberous sclerosis complex (TSC) and autism.

TSC is a genetic disorder in which tumors develop throughout the body, including in the brain. Nearly 50 percent of kids with TSC develop autism or autism-like behaviors.

“TSC serves as a model disease to study autism,” Krueger says.

Cincinnati Children’s will lead a five-center study that will enroll 150 children under the age of 3 who have TSC. Using MR I and EEG as well as developmental assessments, doctors will look for signature markers that may predict which children will develop autism.

“This is an opportunity to look at children before they reach age 3 and determine what clues there might be,” says Krueger. “If we can intervene before the onset of autism symptoms, not only with medications but with evidence-based, advanced behavioral interventions, can we perhaps offset future problems?”

Treatment with potential

Psychiatrists Craig Erickson, MD, and Logan Wink, MD, recently joined Cincinnati Children’s from Riley Hospital for Children in Indianapolis, IN. They will continue studies here that explore how specific drugs might help children with behavioral disorders, including Fragile X syndrome and autism.

One drug to be tested will be acamprosate, a medication used to treat alcoholism. In a study funded by the American Academy of Child and Adolescent Psychiatry, Erickson and his team will recruit 5- to 17-yearolds with autism to determine if the drug improves children’s ability to communicate and interact socially.

Another study will evaluate whether the drug D-cycloserine can improve learning in children with autism. The drug, developed to treat tuberculosis, has shown positive effects when combined with behavioral therapy for patients with other psychiatric conditions.

This study will enroll children with autism between the ages of 5 and 11. They will receive a low dose of the drug immediately before group therapy sessions.

“It’s fast-acting and in our experience has shown no significant side effects,” Wink says. “The children love the groups and we see improved social skills in most participants.”