Study Aims to Establish Key Biomarkers in Rett Syndrome

Like many neurodevelopmental disorders, Rett syndrome has long had a lack of disease-specific treatments. But that landscape is poised to change. The Food and Drug Administration approved the first treatment for Rett, trofinetide, in 2023, and other novel therapies—including a potential gene therapy—are in the pipeline.

Now, a multicenter study at Children’s Hospital Los Angeles is playing a critical role in setting the stage for future clinical trials. Using electroencephalography (EEG), the study aims to identify and validate key biomarkers in Rett syndrome, which could then be used in clinical trials to see if a new treatment is working.

CHLA is one of just six centers in the nation—and the only one on the West Coast—participating in the National Institutes of Health-funded study.

“This is an extremely exciting time because there are quite a few potential therapies being developed for Rett syndrome,” says Payal Gu, MD, who leads the Rett Syndrome Clinic at Children’s Hospital Los Angeles and is a co-investigator for the study. “Establishing biomarkers is an important step because it will provide a more reliable way to measure whether a treatment is effective.”

A focus on precision health

A rare genetic disorder associated with a mutation in the MECP2 gene on the x-chromosome, Rett syndrome disrupts brain development and almost exclusively affects girls. Although most babies with Rett seem healthy at first, between 6 to 18 months of age, their development begins to slow and regress—affecting their ability to walk, talk, eat, sleep, and communicate.

Symptoms and disabilities can vary widely from child to child. But an earlier study identified a characteristic EEG pattern and evoked potentials—the brain’s electrical response to a certain stimulus—in girls with Rett.

The current study is gathering more data on those electrophysiological findings—looking at these measures across time, in more patients, and correlating them with behavioral and clinical features of the condition.

“We want to know: Do these biomarkers correlate with clinical severity? Do they change before a clinical change is seen in the patient?” explains Shafali Spurling Jeste, MD, Chief of Neurology and Las Madrinas Chair at CHLA and principal investigator on the study.

The effort is part of a larger, field-wide focus on precision health. Dr. Jeste is also a site principal investigator in a National Institutes of Health-sponsored consortium evaluating biomarkers in autism spectrum disorder.

“We need to find reliable, objective measures of a child’s response to a treatment, not only for Rett but for other neurodevelopmental disorders, too,” she says. “Without that level of precision, we could end up missing out on effective therapies.”

Following biomarkers over time

The study aims to enroll 132 girls with Rett across all centers. Inclusion criteria include girls 18 and under with a known or likely pathogenic variant in the MECP2 gene. Candidates must either be mid- or post regression and have symptoms consistent with Rett syndrome. Children with a pathogenic mutation who may not have regressed yet are also eligible to participate. The study is also enrolling typically developing females to serve as a control group.

Participants undergo EEG testing at the first visit, again six months later, and then once a year for five years. The younger participants who are pre- or mid-regression are followed more closely.

“Measuring these biomarkers in younger children is particularly important because we want to see how electrophysiological patterns and responses change during this early regression period,” says Dr. Gu.

One of the top-recruiting sites for the study, CHLA has a large, multidisciplinary Rett Syndrome Clinic that features team-based care. That includes a child neurologist; nurse manager; physical, occupational, and speech therapists; and a registered dietitian.

Recently, the team hosted RettEd Day, a special Rett Syndrome education event for families, on May 3. A designated International Rett Syndrome Foundation Center of Excellence, the CHLA clinic attracts patients from around the region.

“We have many families who live two or more hours away, so we coordinate the study visits and clinic visits in one day,” explains Sydney Jacobs, Clinical Research Coordinator for the study. “We make it as convenient as possible.”

CHLA’s diverse patient population also makes the hospital an ideal place for these studies. “Families from under-represented minority groups, especially those that do not speak English as their primary language, often are left out of research,” Dr. Jeste says. “It’s vital that they be included. The hope is that all children can ultimately benefit from new and better treatments for this condition.”