Research stirs hope on Down syndrome

Once, the explanation for Down syndrome was simple: You were born with an extra, third copy of the 21st chromosome, with effects ranging from mental retardation to heart problems. Then science began to delve into trickier questions: How, exactly, did the extra chromosome act? Which of the hundreds of genes on it mattered, and what did they do?

Now researchers have hopes again for a bit of simplicity. New work in mice suggests that one gene on the chromosome is a major contributor to Down syndrome's learning impairment. And if that's so, then perhaps researchers could devise a treatment targeted at that one gene rather than having to counteract the effects of an entire chromosome.

``Some people think, `My God, you'll never figure it out, you have to get rid of the whole chromosome,' " said Dr. William Mobley of Stanford University, senior author of the paper, which was published in last week's issue of Neuron. ``But it's really possible that beginning with a specific abnormality, you can chase it down -- if not to one gene only, then to one gene that plays a major role."

And ``because you can do that, now you can think about therapies, which you couldn't really do before," he said.

Mobley and others cautioned that a cure for Down syndrome lies far beyond the horizon, but still, they said, such advances in research are cause for hope.

Roger Kafker , a cofounder of the Down Syndrome Research and Treatment Foundation, which helped fund Mobley's work, predicts that such progress might eventually lead to the ability to bring children with Down syndrome up to normal intelligence.

It may be wishful thinking, he admits, but he believes that treatment advances could come in time for his 8-year-old son, Michael. ``The possibility exists that though you'll never cure the genetic abnormality, that he could learn at a level close to his peer group," Kafker said.

More than 350,000 Americans have Down syndrome and the moderate or mild retardation that generally goes along with it. They are at higher risk for heart defects and childhood leukemia; they are also overwhelmingly prone to develop an Alzheimer's-like dementia by late middle age.

Indeed, the mice used in the Neuron research are expected to cast light on what causes brain damage in both Down syndrome and Alzheimer's.

They have been genetically engineered to have the kind of triple-chromosome abnormality that Down syndrome causes in humans, including a triple dose of a gene called ``App," which instructs the body to make amyloid precursor protein. A piece of that protein, beta-amyloid, accumulates in an abnormal form in the brains of people who have Alzheimer's disease. It appears that having an extra copy of the App gene means more of the protein is produced.

Researchers found that the extra amyloid protein appeared to block a key communication process from neuron to neuron, a message that tells a neuron to ``be well, stay alive," as Mobley put it. With that message blocked, certain neurons important for learning and memory shrivel up.

The researchers tested the effect of the amyloid gene several ways and found that the more App a mouse had, the more the communication was blocked. In one key experiment, they created a strain of mice with three copies of chromosome 21 but from which the extra copy of the App gene had been deleted. These mice still had some brain damage, but not as much as the mice with three copies of App.

``It's a very significant step, and it's elegantly done," said David Patterson, a professor and Down syndrome researcher at the University of Denver who was not involved in the Neuron paper. ``They have shown that the App gene which is present in an extra copy in these mice does cause part of the problem."

``It's not the only thing that causes trouble," he noted, ``because if you look at mice in which just the App gene is extra, they only have part of the problem. So there must be other genes, and they don't know what those are. But what they have done here is given us some really good ideas" and ``really good targets to pursue."

Carey Goldberg can be reached at goldberg@globe.com