February/March 2017

CHOP Named Rett Syndrome Clinical Research Center of Excellence

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Although they aren’t able to talk, girls with Rett syndrome have 14 Rett Syndrome Clinical Research Centers of Excellence who are speaking up for them by accelerating research through a natural history study and other projects aimed at improving care and finding a cure. One of those Centers of Excellence, which were designated by the nonprofit organization Rettsyndrome.org, is at Children’s Hospital of Philadelphia, under the leadership of Eric Marsh, MD, director of the Neurogenetics Program at CHOP.

“It’s an honor to be chosen, and it shows that we’re doing good work,” said Dr. Marsh a pediatric neurologist with expertise in neurogenetic conditions and genetic epilepsies at CHOP and assistant professor of Neurology at the Perelman School of Medicine at the University of Pennsylvania. “There is a lot of research activity going on that we hope to be a part of into the future to really see a change for the care of these girls and kids with related diseases too.”

In 1999, a research team at Baylor University in Waco, Texas, discovered that mutations on the MECP2 gene, located at the Xq28 site on the X chromosome, cause Rett syndrome. It’s a chance mutation that happens in DNA, and children almost never inherit the faulty gene from their parents. Rett syndrome occurs in an estimated one of every 10,000 female births.

Researchers suggest that MECP2 provides instructions for making a protein called MeCP2, which has an important role in maintaining neurons responsible for cell-to-cell communication and normal brain function. Children with Rett syndrome have a deficiency of MeCP2 protein. While basic scientists have revealed the genetic underpinnings of Rett syndrome, they don’t yet fully understand how mutations in the MECP2 gene disrupt the function of neurons and other cells in the brain and lead to the unique pattern of symptoms seen in the disease. Related disorders are caused by duplications of MECP2 (MECP2 duplication syndrome) and mutations in the CDKL5 or FOXG1 genes.

Girls with Rett syndrome usually seem to be developing normally until symptoms appear between 6 and 19 months of age. Their communication skills regress, and they lose the functional use of their hands because they constantly rub or wring them. They also tend to have trouble walking and have a small head size. Other problems include seizures, disorganized breathing, scoliosis, and sleep disturbances.

Despite having the same MECP2 mutation, girls with Rett syndrome can appear quite differently because the disease has a great deal of clinical variability. For example, when Dr. Marsh sees patients with Rett syndrome in his clinical practice, some girls are able to walk and express themselves with their eyes and use augmentative communication devices, while others are immobile and noncommunicative. Knowing the path someone with Rett syndrome generally follows if they have milder or more severe forms of the disease is one of the goals of the Rett Syndrome, MECP2 Duplication and Rett-Related Disorders Natural History Study that CHOP is participating in.

“By gathering all this natural history data, we hope to have a good baseline from which to compare people to, especially as research gets closer to finding possible treatments,” Dr. Marsh said.

A subproject of the natural history study that Dr. Marsh launched in January with the help of Timothy Roberts, PhD, vice chair of research in the department of Radiology and professor of Radiology at Penn, is taking a close look at evoked potentials in patients with Rett syndrome. Evoked potential tests are harmless and involve electrodes placed on the scalp to measure the electrical activity of the brain in response to stimulation of specific sensory nerve pathways. In this study, the researchers will focus on visual and auditory evoked potentials to analyze the spectrum of brain waves in girls with Rett syndrome and identify biomarkers of the disease.

“We know from some preliminary studies that the way the brain responds in Rett syndrome is different than in healthy, age-matched individuals,” Dr. Marsh said. “We’ll be testing evoked potentials at different time points with children with different severity of illness to see if we can see any changes in the evoked potentials that would predict or demonstrate a change in severity or change over time. Our hypothesis is that the signature will be more different and get worse over time. If that does happen, you can imagine that if you give a patient a particular drug and you see the signature go closer toward the normal response, then it would suggest that your intervention is working.”

CHOP and four other sites have begun to enroll 120 girls with Rett syndrome, and they plan to follow them yearly for at least three years. The study participants, ages 2 to 15, will be grouped into different age brackets. For the visual evoked potentials, the girls will be placed in a comfortable chair and watch a checkerboard on a big screen. The spaces will flash in a repeated pattern, and the researchers will monitor how the girls’ brains respond to that stimuli. Testing the girls’ auditory evoked potentials involves them wearing headphones and listening to a series of tones while they are watching a movie without sound.

So far, the investigators have received an exceptionally favorable response from study participants, according to Dr. Marsh, who gives much of the credit to excellent patient advocacy groups like Rettsyndrome.org for emphasizing the importance of families being at the forefront of research that has the potential to improve their daughters’ quality of life. Moving forward, CHOP also will be involved in a clinical trial of a pharmaceutical agent for Rett syndrome and a blood-based biomarker study.

In an announcement of the Centers of Excellence, Rettsyndrome.org’s Chief Science Officer Steve Kaminsky, PhD, stated, “As a rare disease, the Rett community is fortunate to have these 14 Clinical Research Centers of Excellence. The clinicians, nurses, and the medical team are deeply committed to the care of individuals with Rett syndrome, while being heavily involved in clinical research through the Rett Consortium and Natural History Study. These clinics understand our mission and make it possible to accelerate research and empower families.”

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