Visionary research on Rett syndrome

Mice with the mutation causing Rett syndrome (middle panel) have an excess of inhibitory connections as compared with normal mice (left panel) and mutated mice reared with no visual stimulation (right panel). Inhibitory connections were also reduced by manipulating the NMDA receptor, restoring a more normal balance of inhibition/excitation.

Research just published in Neuron offers some interesting clues about Rett syndrome, a tragic disease that causes initially healthy girls to lose their ability to speak and to develop motor and respiratory problems. Working with a mouse model, the Boston Children’s Hospital lab of Michela Fagiolini, PhD, explored how the causative mutations, affecting the MECP2 gene, disrupt brain circuitry and function. The team found that the circuit damage can be undone by targeting the NMDA receptor, tipping the brain toward the right balance of inhibition and excitation. They’re now exploring possible pharmaceutical approaches.

The study also suggests that changes in the visual system are a tip-off to what’s going on in the brain as a whole. When MECP2 is mutated in mice, vision initially develops, then regresses—but can be restored by manipulating NMDA at the right time during development. “Looking at the developmental trajectory rather than a snap-shot of the disorder is key to developing proper therapy,” notes Fagiolini.

The mouse findings also raise the question of whether vision could serve as proxy or biomarker for evaluating brain function in girls with Rett syndrome. Fagiolini is now doing a study with the Rett Syndrome Program at Boston Children’s and the Cognitive Neuroscience laboratory of Charles A. Nelson, PhD, using visual evoked potentials (VEPs) to assess visual processing in the brain. (They’re using brain EEG recordings since patients with Rett syndrome cannot communicate what they’re seeing.)

To date, results from a handful of patients indicate that visual evoked potentials on EEG can discriminate mild versus severe disease, but it’s too soon to say whether the findings can predict a child’s course. The technique will be part of an upcoming phase II trial of IGF-1, a drug being evaluated for Rett syndrome.

“In Rett syndrome, we want to intervene early,” says Walter Kaufmann, MD, director of the Rett Syndrome Prgram. “There are still many questions, but to be able to predict regression and know the factors that lead to the loss of a skill would be fantastic.”