How Genetics Affect Head Size and Brain Development in Autism

Research sheds light on development issues

It started with an observation: Children with autism who also have a certain gene mutation tend to have especially large heads.

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That observation led to some of the first research linking the PTEN genetic mutation to developmental issues in a group of children with autism. Researchers Thomas Frazier, PhD, and Charis Eng, MD, PhD, published a study that sheds light on the effect of such a mutation on children.

Dr. Eng originally discovered the PTEN gene in 1997. She has been working with patients with PTEN mutations — and specifically the genetic disorder Cowden syndrome, which highly increases a person’s lifetime risk for cancer — for years. She had observed the head size of children with autism in these families during that time. She also discovered that a small but important subset of individuals with autism and large head size carried PTEN mutations in 2005.

“This whole idea stems from her observations,” says Dr. Frazier, lead author of the study. “In PTEN, we see a consistent pattern: Not only very large brains, but large in a particular way. The inner white matter is much larger and more developed — but imaging shows us that it’s not developed properly.”

Dr. Frazier, Dr. Eng and colleagues studied 17 children who have what they call PTEN autism spectrum disorder (ASD). PTEN-ASD is the type that links to a PTEN mutation, and it may affect as many as 1 to 2 percent of people on the autism spectrum. The children in the PTEN-ASD group also had large heads — specifically, larger than the 97th percentile for their age.

For comparison, the researchers also included groups of 16 children with autism and large heads, 38 with autism only, and a control group of 14 developmentally typical children. The team assessed behavior and memory processing, as well as brain structure using magnetic resonance imaging (MRI).

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The researchers observed that children with PTEN-ASD had significantly more difficulty with brain functions related to working memory (the brain power you use to complete a task) and brain processing speed. And MRI images aligned with those findings, Dr. Frazier says.

“Processing speed is delayed or impaired in these kids,” Dr. Frazier says. “Think of it like an old-fashioned telephone system. If the switchboard isn’t working, you’re not going to get a long-distance call to go through.”

What it means for patients — and future research

When working with children with autism, behavioral therapy can be a painstaking process. It comes with plenty of repetition and reinforcement.

“For these children,” Dr. Frazier says, “the behavioral therapy is similar, but we might need to tailor it a bit for them. Speak slowly. Use shorter sentences. Really think about how they process information and make sure our programs work for them.”

He offers an example. For many children with autism, one might offer a short list of tasks to prepare to go outside: put your shoes on, get your coat, grab your gloves. For children with PTEN-ASD, treating each step as a completely separate item might prove more effective.

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Dr. Eng adds that, because of the connection to the PTEN gene, the same patient communications may apply to lifelong monitoring for cancer risk. “We don’t know for certain yet if PTEN-ASD associates with cancer risk, but we are pushing for surveillance for the sake of safety,” she notes. “When we give that message about monitoring for cancer, we will have to be very smart in how we deliver it.”

Beyond communications, this small-scale research has larger implications. First, Dr. Eng notes, it provides a model for examining the connection between specific genetic mutations and populations of patients with autism. PTEN is but one example among many possibilities.

Second, Dr. Frazier adds, the head size and brain development issue extends beyond children with PTEN-ASD. “In at least 20 percent of autism cases, there is early brain overgrowth,” he says. “This study helps us begin to understand what that overgrowth means in terms of development.”

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