New molecular insights into the early stages of Rett syndrome

Scientists investigating the severe developmental disorder known as Rett syndrome have discovered a series of crucial molecular changes that occur long before symptoms appear. The findings could be used to develop better treatments for the devastating, life-shortening condition, the researchers say.

Rett syndrome strikes girls almost exclusively. Children with Rett initially appear healthy and appear to develop normally for the first six to 18 months before beginning to regress and lose previously acquired skills. For example, children who crawl can become unable to do so, and language skills decline. Other symptoms of Rett include difficulty eating, seizures, “floppy” limbs and the repetitive hand movements that are the disease’s hallmark. These symptoms can range from mild to severe. Life expectancy varies, but many people with Rett die by their 40s or 50s.

The new insights into the earliest manifestations of the disease come from Sameer Bajikar, PhD, who recently joined the University of Virginia School of Medicine. While doing his postdoctoral work (at Baylor College of Medicine and UVA), Bajikar and his collaborators began investigating how mutations in a particular gene, MECP2, trigger the development of Rett.

That investigation has revealed a whole “cascade” of molecular changes that fundamentally alter how genes work in brain cells. In particular, the scientists discovered that the cascade causes far-reaching, “circuit-level” problems in the hippocampus, an area of the brain vital for memory and learning. These sweeping changes cause brain cells called neurons to begin malfunctioning, Bajikar and his colleagues determined. 

We artificially triggered the onset of Rett syndrome symptoms in mice to precisely map the sequence of events that occurs when MECP2 is malfunctioning. Our study uncovered a core set of genes that are disrupted very early on before any overt symptoms have presented. These genes might be drivers of Rett syndrome symptoms downstream of MECP2 whose expression levels could be important for normal brain function as well.” 

Sameer Bajikar, PhD, UVA’s Department of Cell Biology and Department of Biomedical Engineering

Better treatments for Rett syndrome

The discovery of these molecular changes – and the specific mechanisms responsible for the changes – sheds much-needed light on the development of Rett syndrome. It also sets the stage for new and better ways to treat the condition. For example, there is great excitement about the potential of gene therapy to restore the MECP2 gene’s function in children with Rett. The challenge, however, is that augmenting the gene’s activity too much would prove toxic to brain cells. 

Doctors need ways to monitor the activity of the gene, and Bajikar’s research could ultimately provide that. For example, doctors might be able to monitor biological markers, or “biomarkers,” the scientists have identified that reflect whether the MECP2 gene is functioning at an appropriate level. 

While much more research needs to be done before the findings could be translated into treatments, Bajikar is excited about the potential his findings hold.

“We discovered several candidate biomarkers sensitive to MECP2 levels that could be the key to developing safe gene therapies for Rett,” he said. “Our study more broadly demonstrates the importance of cataloging and understanding the earliest biological events that occur during symptom onset in neurodevelopmental disorders.”

Findings published

The researchers have published their findings in the scientific journal Neuron. The research team consisted of Bajikar, Jian Zhou, Ryan O’Hara, Harini P. Tirumala, Mark A. Durham, Alexander J. Trostle, Michelle Dias, Yingyao Shao, Hu Chen, Wei Wang, Hari K. Yalamanchili, Ying-Wooi Wan, Laura A. Banaszynski, Zhandong Liu and Huda Y. Zoghbi. Bajikar has no financial interest in the work; a list of the authors’ disclosures is included in the paper.

The research was supported by the National Institutes of Health’s Eunice Kennedy Shriver National Institute of Child Health and Human Development, grants F32HD100048, R01HD109239 and U54HD083092; the National Institute of Neurological Disorders and Stroke, grants R01NS057819 and K99/R00NS129963; the National Institute of General Medical Sciences, grant R35GM124958; the Welch Foundation, grant I-2025; the American Cancer Society, grant 134230-RSG-20-043-01-DMC; an NRI Zoghbi Scholar Award through Texas Children’s Hospital; the International Rett Syndrome Foundation, grant 4013; and the Howard Hughes Medical Institute.

UVA’s Department of Biomedical Engineering is a joint program of the School of Medicine and UVA’s School of Engineering and Applied Science.