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Making Strides in Childhood Intellectual Disabilities and Autism

By Eric Butterman

When Maria Chiara Manzini, Ph.D., was a first-year student at the University of Pavia in Italy, she had her choice of careers. Ultimately, she focused on studying the brain and behavior, but she couldn’t shake one thought. “I was always struck by how, in many cases, psychiatric disorders are chemical imbalances, but they completely change your personality,” says Manzini, assistant professor of pharmacology and physiology at GW’s School of Medicine and Health Sciences. “When you have high blood pressure, it’s treated with a drug, and you’re reset to normal levels. But with psychiatric problems, it overtakes so much of your life. I realized how unfair and how misunderstood it was.”


That combination of compassion and curiosity has helped guide Manzini on a nearly decade-long journey to help improve the lives of children with intellectual challenges and autism. An award presented by the Eunice Kennedy Shriver National Institute of Child Health and Human Development, which started as a career-development grant during Manzini’s postdoctoral career, grew on her promise as an investigator to become $740,000 to be applied to her independent research into severe intellectual disability and autism caused by loss of function of the CC2D1A gene.

Manzini’s project, titled “Intracellular signaling in the development of human cognitive function,” explores the function of the gene and of the mutations that cause disease by both using cell-based systems — analyses of neurons generated from animal models — and studying the behavior in mouse models to better understand the pathogenesis of the disease.

Autism does not fit a simple definition, according to Manzini, who earned her doctorate in neurobiology and behavior from Columbia University. “That’s why it’s called autism spectrum disorder. We now know that it can have multiple different causes,” she says. “We also know it’s a developmental disorder and most likely starts in the fetus, but it is often diagnosed when a child is 2 or 3.”

She categorizes the intellectual disabilities at the center of her research as severe. “An example would be someone who grows up to be a 30-year-old who functions at about the level of a 3-year-old and is able to say around three words,” she says. “They never adapt and continue to have the capacity of a very small child.

“For example, they probably don’t know what money is, and they might have issues with expressing themselves,” she explains. “With autism, it’s also issues in social interaction and repetitive behaviors.” One thing they all have in common is that they have no other physical or neurological conditions, and their only difficulties are in brain functions controlling cognition and behavior.

Detective Work

Manzini still remembers the excitement of discovering the CC2D1A gene mutation in 2006 at the Boston Children’s Hospital lab that led to so much of her work. “We found it in the DNA sequence, but we didn’t know anything about what losing that gene did to the brain” she says. “You needed to generate a model to look at the brain to see if it’s normal — asking questions like: Does the animal model have a learning deficit or a social deficit? We could find the source of the problem in the genetics, but you can find the gene and still not know what that gene does. It’s truly detective work.”

She knew early on that she wanted to get beyond identifying the genes, to figure out how the gene regulates multiple signaling mechanisms inside the cells, as well as how it responds to the outside. Only then can Manzini establish ways to modulate the gene and have a positive effect on the disease. “You see the neuron is not quite able to respond to stimuli from the outside, and we’re trying to figure out from a molecular point of view why there is the misinterpretation,” she explains. “You also want to look into whether there are applicable drugs available or hopefully create ones that will help restore normal responses in the neurons.”

Presently, Manzini is focused on behavioral tests through animal modeling, looking at learning capacity, social interaction, and whether the subject’s behaviors are repetitive. Examples of tests include having a mouse subject in a cage with a sibling and an unknown mouse and looking at how often the subjects choose to interact with each other. “A lot of the time the ones with social deficit won’t even care,” she explains. “If they don’t have a social deficit, they’ll tend to go to the mouse they don’t know because it’s someone new — they are checking out if they’re friend or foe.” Or, to study anxiety, researchers might put the mice in an open box and see how often they’re willing to leave the sides and go into the open space in the center.

“We’re also looking at animals with self-injury and other issues,” she says. “The final overarching goal is to understand the molecular deficits caused by loss of this gene and see if we can cure behavior in the animal model and extend that to other autism research.” The problem, explains Manzini, is that literally hundreds of genes are affected. “We have to try to figure out whether we can group patients based on genes with similar functions, or do more when it comes to understanding how the different genes work together.”

Manzini says her work is still in the early phase, and she is working to understand why these mutations cause these effects on brain function and development. “Specific electric signals when you develop a memory become stronger,” she says. “You can measure the strength of these electrical signals and see whether the cell is able to increase its strength. But, in our case, in our models, that doesn’t happen. … Where we’re at now, we have cellular deficits and some other deficits, but what we want to do is to get the molecular deficit. So, we go inside the cell and figure out what is wrong and what is the cause.”

Family Matters

Manzini’s passion grew partly out of meeting families affected by autism, believing it was important to get beyond the microscope in this kind of work. “We have families in genetic labs trying to get more information, and we have to try to help them make sense of this genetic disorder,” she says. “It’s also very helpful to see the positive [side] and the love of the parents for these kids — it’s been really inspiring. I recommend that even if you always work with DNA and just see the samples, you want to understand what people are going through. By understanding the community and seeing what effect [a disease] has on the quality of life, you can focus on those aspects of the disease, and it can inform your work.”

One family visit led Manzini and her medical team as far as a mountain peak at the tip of the Arabian Peninsula in Oman. “You go through the desert, climb a dirt road, and they were in a mud building on the top of a mountain,” she recalls. “They were really excited to see us — I believe the two brothers and their wives had seven children who were affected. You could see how driven they were to find out what had happened to their children and how much they wanted to help them.”

But the families go beyond offering inspiration — they’ve provided vital clues. “When we first identified mutations in CC2D1A, it was in a family who had severe cognitive deficits,” she says. “Then another family with the same mutation had intellectual disability, but also had autism. A third [who] had a different mutation also had both intellectual disability and autism.” Confusing, yes, but also challenging, says Manzini.

As Manzini trudges on, she is strongly encouraged by improvements in the positivity of the medical community. “In the past five to 10 years, we have gained a better understanding of what causes these disorders,” she says. “And right now there is a lot of focus on trying to develop therapies. It’s hard to believe that just five years ago there weren’t really any clinical trials! You want to know the difference? I was at a conference recently, and it’s so great to see clinicians, scientists, and pharmaceutical companies talking about a variety of disorders and assessing improvements in learning. Advocacy groups should be very proud of the role they’ve taken.”

And it’s extra incentive for her to also see the way society has changed its view. “Young children are receiving early diagnosis and extra help at home and in school,” she says. “Therapists are playing a very important role. We can make their lives better in many ways … and I think it will only improve.”