Brain-heart link may explain sudden death in Rett syndrome

In a study published in the journal Science Translational Medicine, BCM researchers and colleagues found that heart problems that occur in nearly 20 percent of children with Rett syndrome, a neurological disorder, originate because the Rett gene (MeCP2) is lost in nerve cells -- not in heart muscle cells.

"The finding in mice opens the door to tailoring treatments to prevent heart rhythm problems and even deaths in girls with the disorder," said Dr. Jeffrey Neul, associate professor of pediatrics at BCM, a researcher at the Jan and Dan Duncan Neurological Research Institute at Texas Children's Hospital and the assistant medical director of the Blue Bird Circle Rett Clinic.

Long QT syndrome

"We began by looking at mice whose symptoms closely mimicked that of Rett syndrome. We found that those mice also exhibited electrical malfunctions in the heart, known as long QT syndrome," said BCM collaborator Dr. Xander Wehrens, professor of molecular physiology and biophysics and the Juanita P. Quigley endowed chair in cardiology at BCM. Long QT syndrome describes an interval usually measured on an electrocardiogram or ECG. These electrical malfunctions cause that interval to be too long, which can lead to a dangerous heart beat that can cause sudden death in people.

"Long QT syndrome is found in nearly 20 percent of people with Rett syndrome," said Neul. Sudden death also occurs in a significant percentage of Rett patients, and Neul and his colleagues wondered if the two might be linked.

The gene MECP2 occurs in the genomes of every cell, providing a code for the protein associated with it, MeCP2. It can have different activities in different cells. In this study, researchers created a mouse in which MeCP2 was missing only in the brain and nervous system. Even though MeCP2 functioned normally in the heart, the heart beat abnormally.

Brain sends wrong message to heart

"We showed that the heart problems were actually secondary to nervous system deficits and that cardiac activity can be remolded by abnormalities in brain activity," said Neul. "Basically, the brain is sending the wrong message to the heart leading to the malfunction."

Taking a closer look at the heart cells affected by the nervous system deficits, researchers found an unusual persistent sodium current.

Sodium currents occur naturally in cell function. When there is cell activity, sodium travels in and out of the cell through a channel that acts like a window opening and closing. Unusual persistent sodium current means the "window" doesn't close properly, causing a slow trickle of sodium to flow through the channel for a longer period of time.

Seizure drug improves sodium problem

There are seizure medications that block this process, which also occurs in other neurological disorders. When Neul and his colleagues used an anti-seizure drug to treat these malfunctioning heart muscle cells in the lab, the sodium current problem improved. They then gave the common anti-seizure drug to the abnormal mice which corrected the heart rhythm problem and blocked sudden cardiac death.

The next step is to treat the animals long term, he said. At that same time, they plan to look at what is going on in children with Rett who are already taking these kinds of medicines to treat their seizures.

"Are the people on these drugs less likely to have long QT intervals?" he said, "More research in the lab will help us reassess what we are doing in the clinic and determine if we need to change our treatment methods," Neul said.

Others who contributed to the research include: Mark D McCauley, Tiannan Wang, Elise Mike, Jose Herrera, David L. Beavers, Teng-Wei Huang, Christopher S. Ward, and Daniel G. Glaze, all of BCM; Steven Skinner, Greenwood Genetic Center; and Alan K. Percy, University of Alabama, Birmingham.

This study is supported by the Cynthia and Anthony Petrello Scholar Endowment at the Jan and Dan Neurological Research Institute at TCH, the National Institutes of Health, the International Rett Syndrome Foundation, the Muscular Dystrophy Association, the Blue Bird Circle of Houston, and the Eunice Kennedy Shriver National Institute of Child Health and Human Development.