Understanding of Deadly Childhood Disease

Basic studies with yeast, together with a new father's shock at the horrors wrought by a devastating childhood disease and a serendipitous guess by researchers, have led to important new findings about the molecular cascade of events involved in Batten disease, a lethal inherited disorder.

The team of scientists at the University of Rochester Medical Center led by David Pearce, Ph.D., has found that the body's immune system, designed to protect us from microbes and other threats, itself plays a central role in the disease, according to findings published in the June 1 issue of Human Molecular Genetics. While scientists have known the genetic defect that ultimately causes the disease since 1995, this is the first time that they've been able to uncover the key molecular steps involved, knowledge that is crucial for better treatment or eventually a cure.

The disease, a rare disorder that affects roughly 1,000 children in the United States, embodies every parent's nightmare. Children are born healthy but begin to have minor vision problems around age 4 or 5. Youngsters go blind by around age 7 or 8, and they gradually lose the ability to speak, swallow, or move; they also have increasingly serious seizures, and they become mentally retarded. Usually patients die in their teens or 20s; currently there is little doctors can do except try to make patients comfortable as their brain cells die off.

Pearce, an assistant professor in the Department of Biochemistry and Biophysics, had become an expert using yeast to study basic biological processes, when he began to consider new research projects in an effort to establish his own laboratory. At about the same time that he first heard of Batten disease, he and his wife had a healthy baby son.

"Like most people, I had no idea there was this sort of terrible disease out there," he says. "Then I was blessed with a beautiful and healthy son, and I decided that I needed to do something about this disease. It so happened that my previous research in yeast provided the skills necessary to make the next step with Batten disease."

First Pearce used yeast to examine the gene, CLN3, that was known to somehow cause the disease in children; yeast is a common testing ground for researchers learning more about how genes work. Then he took that knowledge and began studying mice with the same defect.

What he found has surprised not only researchers who focus on Batten disease, but also doctors who study or treat similar disorders, such as Tay-Sach's disease, Krabbe disease (the disease that affects the son of former Buffalo Bills quarterback Jim Kelly), and Niemann-Pick Type C. He found that an autoimmune response -- an attack by the body's own cells -- plays a key role in the disease. It's the first time that scientists have found an autoimmune link to a pediatric neurodegenerative disorder, Pearce says.

Scientists have known that in patients with Batten disease, brain cells die because of a toxic buildup of waste material in their cells. In the cells of healthy people, tiny organelles known as lysosomes gobble up a cell's waste, slicing and dicing and disposing of or recycling cellular byproducts. In people with Batten disease and other conditions known as lysosomal storage disorders, the lysosomes don't work correctly. Instead of getting dumped, the waste accumulates in the cells, which actually swell up with "gunk" the way a New York City street swells with garbage when refuse workers go on strike.

The team's work points not to this accumulation of gunk, but rather to other molecular events, as the ultimate culprit in causing the disease. Pearce and colleagues discovered auto-antibodies, antibodies that mistakenly target and attack a protein that is naturally part of our bodies. In this case, the antibodies attack and hinder an enzyme known as GAD65, which plays a critical role in keeping our brain cells functioning by converting one brain chemical to another. Without GAD65, a brain chemical or neurotransmitter known as glutamate accumulates. Too much glutamate can cause the brain's circuits to remain "on" too often, essentially causing them to overload and possibly burn out.

The study marks the first time researchers have tied Batten disease to a problem with the GAD65 enzyme. "It was a serendipitous discovery," says Pearce. "Although it wasn't logical to test for an autoimmune component in Batten disease, we acted on a hunch, and it turned out to be very straightforward to find an auto-antibody to GAD65."

After finding the auto-antibodies to GAD65 in mice, the team moved from mice to people and checked the blood of 20 patients with the disease. Every sample contained the protein, whereas no blood samples from people without the disease had it.

"We finally have a mechanism for understanding the disease. We hope this opens the door to treatment some day. It's possibly a little light at the end of the tunnel for these kids and their families," says Pearce, who also is with the Center for Aging and Developmental Biology and with Strong Children's Research Center, part of Golisano Children's Hospital at Strong.

Joining Pearce in the research were Subrata Chattopadhyay, Masumi Ito, Andrew I. Brooks, Timothy M. Curran, and James M. Powers at the University of Rochester, and Jonathan D. Cooper of Kings College in London. The work was funded by the National Institute of Neurological Disease and Stroke as well as the JNCL Research Fund, which supports research into Batten disease; the EJLB Fund; and the Batten's Disease Research and Support Association, for which Pearce is the chief scientific adviser.