Another Piece of the Puzzle

UNC clinical researchers begin the largest-ever genetic study of autism to elucidate the complex genetics of the condition.

Illustration of puzzle piece with smaller puzzle pieces inside of itIllustration by Corina Cudebec
June 9th, 2016

If a child has autism, the condition is uniquely their own. The genes involved, how those genes are expressed to give rise to the proteins his or her brain cells need to function, how the neurons are wired to articulate thoughts or navigate social interactions or think through a problem — all of these things are unique to this child.

“No two children with autism are the same,” UNC-Chapel Hill researcher Gabriel Dichter says, “but the way we try to help kids now is with a one-size-fits-all approach. We use a trial-and-error approach and try to help them with the same interventions to see what works and what doesn’t.” It would be better to know more about what intervention would work best for each child as quickly as possible.

That’s why UNC — along with 20 other research institutions — is taking on the largest genetic study of autism ever attempted. Researchers will collect DNA and other information from 50,000 people with autism and their immediate family members. UNC was one of three pilot institutions tasked with making sure such an ambitious project was even possible. “It will be the first opportunity the research community has had to understand autism genetics in a way that will allow us, in the future, to match a person’s specific genetic profile with a specific treatment plan,” Dichter says. “That’s the ultimate goal.”

Dichter, Carolina Institute for Developmental Disabilities (CIDD) Director Joseph Piven, and colleagues across the state are recruiting families with children with autism to be part of this study, called the SPARK initiative (Simons Foundation Powering Autism Research for Knowledge). The UNC team hopes to recruit thousands of families — perhaps even 10,000 — of which they would have access to their full genome sequences.

To date, approximately 50 genes have been identified that almost certainly play a role in autism, and scientists estimate hundreds more are involved. By studying these genes, their biological consequences, and how they interact with environmental factors, researchers could better understand the condition’s causes, and link possible underlying causes to the spectrum of symptoms, skills, and challenges of people affected.

Piven’s team at CIDD, home to the federally funded Intellectual and Developmental Disabilities Research Center, is no stranger to this kind of work. For more than 15 years, his group — together with the UNC TEACCH Autism Program — has been building a research registry of families with at least one child with autism (whom have all consented to being contacted by UNC researchers conducting studies).

These North Carolina families, now more than 6,000 strong, have made it possible for UNC researchers to deepen their understanding of this complex condition and provide numerous intervention strategies, support systems, and diagnostic tools. Piven and Dichter’s team will now tap into that registry to recruit these families, while continually working to add more to the list.

Mark Zylka is a cell biologist and the incoming director of the UNC Neuroscience Center, which is supporting the SPARK initiative with funds for personnel to boost recruitment efforts. “Those of us in the basic sciences want to partner with clinicians in research projects we hope will ultimately benefit people,” he says. Zylka knows better than most what access to genetic information can mean to a researcher and people with the condition.

A previous group of scientists discovered through genetic analysis that nearly 1,000 genes are potentially linked to autism in some way. Of those genes, Zylka researched UBE3A, a protein coding gene associated with Angelman Syndrome — a neurodevelopmental disorder characterized by severe intellectual and developmental disability, sleep disturbance, seizures, jerky movements, and a typically happy demeanor. He observed cells from a child with a mutated UBE3A gene and cells from the child’s parents.

Jason Yi, a postdoctoral fellow in Zylka’s lab, found that a child had a “hyperactive” version of UBE3A. It’s like a broken water faucet — the gene can’t be shut off. In normal brain development, that gene has to be turned on to produce an enzyme that targets proteins to be broken down within cells. It then has to be shut off to avoid too much production of the enzyme. In a child with the UBE3A mutation, the faucet is never turned off. In his parents, the gene works normally.

“We think it may be possible to tamp down UBE3A in some autism patients to restore normal levels of the enzyme in the brain,” Zylka explains. It’s a long way from the clinic, but his and Yi’s work shows it’s possible to affect the basic biology that plays a role in autism.

From one generation to the next

Piven, along with the CIDD, has begun to study the link between autism and Parkinson’s disease. In two small, preliminary clinical studies, he and colleagues found that Parkinson’s disease may occur much more commonly in older adults with autism than in those without autism.

He and his team identified 20 adults with autism who were not taking atypical neuroleptic drugs. Four of them were diagnosed with Parkinson’s disease. This 20 percent rate of diagnosis was 200 fold higher than the normal rate of incidence — one in 1000 or 0.1 percent — among the general population of people ages 45 to 65. There was an even higher rate of Parkinsonian symptoms among participants with autism who were taking neuroleptic drugs, which can cause the neurological problems seen in Parkinson’s disease.

The study needs to be replicated in a larger pool of people with autism. “We think these findings are the tip of the iceberg,” Piven says. “Studying older populations of people with autism is a new frontier, and we think this continued work will uncover very important information all of us need in order to better care for people with autism as they age.”

And that’s a big deal.

“By and large, what autism is like for older adults is still a mystery,” Piven adds. “Many of these people were misdiagnosed years ago, and there’s nearly nothing in the medical literature about these older people with autism.”

As UNC basic science researchers delve into the genetics of autism and the potential environmental triggers, UNC behavioral researchers are focused on developing and disseminating community-based services. UNC TEACCH Autism Program director Laura Klinger is busy documenting the needs of adults with autism.

Research conducted by Julie Daniels at UNC in collaboration with the Centers for Disease Control shows that the prevalence of autism in 8-year-olds has risen from 1 in 150 in 2002 to 1 in 68 in 2012. The first cohort of 8-year-olds is now 22 years of age.

“So, we can look ahead and expect a large increase in the number of adults with autism in the coming decade,” Klinger said. “Yet, we know very little about how to support a good quality of life for adults with the disorder. We’ve learned so much about autism in children in the past decade. We can diagnose autism earlier than ever before, and we have witnessed firsthand how earlier interventions can make a difference in children’s lives. Now, we need to focus on supporting individuals with autism across the entire lifespan.”

There is much work to be done in developing vocational, residential, medical, and mental health services to support adults with autism, Klinger adds. “The longevity of autism services and research at UNC gives us a unique opportunity to lead the world in understanding aging in autism.”

Right now, scientists don’t understand the underlying genetics well enough and don’t have a good enough handle on potential environmental causes, according to Piven. Clinicians are limited in their ability to help some of the more severe cases, though they’ve made strides in the past decade. And the medical community doesn’t have a good concept of what it’s like to live with autism for many decades into old age.

“The good news is that UNC is one of the few places in the world capable of tackling these and other issues facing the autism community,” Piven says. “We have the scientific and clinical expertise, and we’re making progress every day.”

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Gabriel Dichter is an associate professor of psychiatry and psychology, and also the director of the Clinical Affective Neuroscience Lab at UNC-Chapel Hill.

Joseph Piven is the Thomas E. Castelloe Distinguished Professor of Psychiatry, Pediatrics, and Psychology; director of the Carolina Institute for Developmental Disabilities; and director of the Intellectual and Developmental Disabilities Research Center, which is funded through the National Institute of Child Health and Development.

Mark Zylka is the incoming director of the UNC Neuroscience Center. He is also a professor of cell biology and physiology and an adjunct associate professor of pharmacy.

Laura Klinger is an associate professor in the Department of Psychiatry and Neuroscience and the director of the TEACCH Autism Program.