Gene regulation in brain may explain repetitive behaviours in Rett syndrome patients

Three-year-old Naomi slaps her forehead a few times, bites her fingers and toddles across the doctor’s office in her white and pink pyjamas before turning her head into a door with a dull thud. Her mother quickly straps on a helmet and adjusts the rainbow chinstrap, then watches as Naomi puts a hand back in her mouth and continues exploring the room.

“She keeps me busy,” acknowledges her mother, Laura Elguea.

Naomi was diagnosed at age 2 with Rett syndrome, a rare, debilitating disease in which patients progressively lose brain function and the ability to walk. While she laughs, smiles and toddles around like most 3-year-olds, Naomi’s repetitive hand behaviours offer clues to her condition.

Relatively little is known about the neuronal causes of Rett syndrome, but UT Southwestern Medical Center scientists have now identified a process in the brains of mice that might explain the repetitive actions – research that could be a key step in developing treatments to eliminate symptoms that drastically impair the quality of life in Rett patients.

The finding from UT Southwestern’s Peter O’Donnell Jr. Brain Institute could also potentially benefit people with autism spectrum disorder, though more research is needed to evaluate the link to this disease in humans.

“We are exploring the processes that contribute to Rett syndrome in an effort to develop treatments that may prove useful in the disease,” said Dr. Lisa Monteggia, Professor of Neuroscience with the O’Donnell Jr. Brain Institute, who led the research.

The study demonstrated that MeCP2 – the protein that does not work properly in Rett syndrome – is among a group of three proteins that affect the function of a gene previously linked to obsessive compulsive disorder. Researchers were able to induce and then suppress repetitive behaviours in mice by changing the levels of these three proteins at the synapse – the communication junction between nerve cells.

The research is a significant advancement in the understanding of how dysfunction in MeCP2 leads to key symptoms associated with Rett syndrome. Although MeCP2 was identified less than two decades ago as the cause of the postnatal neurological disorder, the link between the protein’s dysfunction and the specific neurological symptoms characteristic of the disease remains elusive.

Rett syndrome affects girls almost exclusively, occurring in 1 of every 10,000 to 15,000 births and usually diagnosed by age 2. It is characterized by developmental regression, autistic traits, slow brain development, lack of speech, repetitive hand movements, seizures, and problems with walking. Many patients live beyond middle age, though not enough data exist to reliably estimate life expectancy beyond age 40.

While current medications and behavioural therapy can sometimes diminish symptoms such as seizures and hand behaviours, no treatment exists to eradicate or reverse the disorder and the repetitive stereotyped behaviours, due in large part to a lack of knowledge about how MeCP2 dysfunction gives rise to these and other symptoms.

UT Southwestern Medical Center www.utsouthwestern.edu/newsroom/news-releases/year-2016/september/rett-syndrome-monteggia.html