Rett syndrome discovery could lead to better treatments

Scientists investigating the severe developmental disorder known as Rett syndrome have discovered a series of crucial molecular changes that occur long before any symptoms appear. This breakthrough could lead to more effective treatments for this devastating and life-shortening condition.

Understanding Rett syndrome

Rett syndrome predominantly affects girls, with symptoms typically emerging after an initial period of normal development. Children with Rett syndrome often appear healthy in the first 6 to 18 months, but soon begin to regress, losing previously acquired skills. Skills such as crawling may diminish, and language abilities can decline. Other hallmark symptoms include difficulty eating, seizures, ‘floppy’ limbs, and repetitive hand movements. The severity of symptoms can vary, and while life expectancy differs, many individuals with Rett syndrome die in their 40s or 50s.

New insights into the disease

The new insights into the earliest manifestations of the disorder come from Dr Sameer Bajikar, a researcher who recently joined the University of Virginia (UVA) School of Medicine. In his postdoctoral work at Baylor College of Medicine and UVA, Bajikar and his team began studying how mutations in a gene called MECP2 contribute to the development of Rett syndrome.

Their investigation revealed a cascade of molecular changes that fundamentally alter the way genes operate in brain cells. Particularly, the researchers found that these changes caused significant problems in the hippocampus, a region of the brain critical for memory and learning. These alterations trigger the malfunction of brain cells known as neurons, leading to widespread disruptions in brain function.

“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,” said Bajikar, who works at UVA’s Department of Cell Biology and Department of Biomedical Engineering. “These genes might be drivers of Rett syndrome symptoms downstream of MECP2, whose expression levels could be important for normal brain function as well.”

Potential for better treatments

This discovery of molecular changes is crucial in improving the understanding of Rett syndrome’s development. It opens the door to better treatment possibilities, especially gene therapy, which has generated considerable excitement. The idea is to restore the function of the MECP2 gene in children with Rett syndrome. However, boosting the gene’s activity too much could harm brain cells, presenting a challenge for researchers.

To overcome this, doctors need ways to monitor the gene’s activity carefully. Bajikar’s research could hold the key to developing such methods. He and his team have identified specific biomarkers that could help monitor MECP2 activity and ensure it remains at an optimal level.

While much more research is required before these findings can be translated into clinical treatments, Bajikar is optimistic about their potential.

“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 cataloguing and understanding the earliest biological events that occur during symptom onset in neurodevelopmental disorders.”

Future directions

The findings have been published in the scientific journal Neuron.