By David N. Leff

When an elderly person goes to the eye doctor for a checkup, the ophthalmologist will display a cross-hatched grid of vertical and horizontal lines.

If the patient sees the lines in the middle as curved or blurry, this signifies something wrong with his or her central vision. That's what registers the fine detail on the mid-retina of the eye, which a person needs to read, drive a car, sew or watch TV, for example.

Beginning, say, from about 65 years old, a small oval spot (about 3x5 millimeters) in the center of the retina, the macula (Latin for "spot"), begins to deteriorate, and central vision to fail.

This age-related macular degeneration (AMD), as it's called, afflicts an estimated 30 to 40 percent of people over the age of 75, and the National Eye Institute reckons that 11 million Americans are potentially at risk of the disease. It doesn't cause outright blindness, but impairs the quality of senior-citizen life.

At the other end of the age scale lurks a more distressing, juvenile-onset, form of macular degeneration, Stargardt recessive macular dystrophy, or Stargardt's disease (SD). It attacks the eyes of youngsters around age 10, or adults under 40. Its younger victims are usually blind by 20.

Mercifully, SD is relatively rare, striking one person in 10,000, whereas AMD affects one to two percent of the population. Considering that that population is living longer into its advanced years, AMD represents a serious, and largely untreatable, affliction.

German ophthalmologist Karl Stargardt (1875-1927) described the disease that bears his name in the early years of our century. The retinal disorder has an autosomal, recessive mode of inheritance, which means that both parents must pass on a mutated SD gene to their child, who then has a virtual 100 percent chance of acquiring the disease.

A multicenter group of researchers isolated the SD gene last year, and reported it in the March 1997 issue of Nature Genetics. They tracked the gene to the short arm of human chromosome 1, and named it ABCR (ATP-binding cassette transporter-retina).

Now, as reported in today's Science, most of those same co-authors have linked fully 13 of the ABCR gene's mutations to adult-onset macular degeneration. That paper's corresponding author is molecular geneticist Michael Dean, chief of the human genetics section at the National Cancer Institute's Laboratory of Genetic Diversity, in Frederick, Md.

AMD Shares SD's Genes

"Of the 167 unrelated people with AMD who we screened," Dean told BioWorld Today, "we found 26 — 16 percent — who had mutations in the same ABCR gene that's mutated in SD. But SD patients inherit two defective alleles [gene variants], whereas in the AMD cases, we see them having only one."

He added: "We think that if you inherit only one defective copy of ABCR, you may have a higher likelihood of developing AMD at some time in your life.

"One of the problems with studying this disease in families," Dean went on, "is that the onset is so late in life. If you start getting the disease at age 70, your parents are already dead, so an ophthalmologist can't go back and examine their eyes to see exactly what they had."

He and his co-authors got around that Catch-22 by simply examining the DNA of affected individuals, to see if they had any genetic factors resembling those in SD. "This direct gene analysis," he observed, "is an approach that more and more people are taking with multifactorial, complex diseases."

The ABCR gene descriptor tells a lot about what makes retinal macula degenerate.

"What we observe in these AMD patients," Dean said, "is an accumulation of waste substances in the epithelial cells behind their retinas. The retina," he explained, "is made up of photoreceptor cells, rods and cones, which are fed, and their health maintained, by that epithelial layer behind them."

This buildup of debris is called drusen or lipofuscin. "Nobody knows what it is," Dean observed, "but it damages those retinal epithelial cells."

Normally, those photoreceptor cells collect visible light and translate its photons into visual messages that travel up the optic nerve into the brain.

"There's a very complex recycling of components that make up the whole photoreceptor machinery — all the chemicals that detect light and send the signal, and all the membranes where those proteins sit," Dean pointed out. "The tip of such a photoreceptor cell is actually broken down and turns over at the rate of about 10 percent a day.

"So this," he continued, "involves a huge process of transporting those molecules out of the photoreceptor cells and back in again. We think that those abnormal substances are poisoning those cells, causing the macula in the center of the retina to deteriorate."

Trying to find what protein the normal ABCR gene expresses "was an interesting study," Dean recalled. "That's actually how we got into this.

Pumping Out Trash Harms Retina

"ABCR," he explained, "is a member of the family of transporter proteins that bind ATP [adenosine triphosphate] and use that energy to move specific substances out of cells."

This family includes the cystic fibrosis gene and proteins that enable drug-resistant tumor cells to pump antibiotics and chemotherapeutic compounds back out of their cells.

"We think that probably what's going on in SD," Dean said, "is that ABCR is responsible for pumping out of the retina one of the critical factors needed in phototransduction.

"It's always true in a disease like AMD, which is a mystery," he added, "that finding out the molecular basis of the problem is obviously a critical first step in starting to think about therapies. He and his co-authors at Baylor College of Medicine, in Houston, University of Utah, in Salt Lake City, and Harvard Medical School, in Boston, are now gearing up to expand their gene analysis to much larger, more informative cohorts of AMD patients.

While awaiting prognostic gene screening for AMD, which may someday come about through the ongoing research, Dean made the point that individuals in high-risk age groups can lower their chances of incurring AMD by cutting out smoking, controlling high blood pressure and dieting against cholesterol buildup — all risk factors for AMD.

Baylor's intellectual property company, BCM Inc., has filed for patent protection of the group's ABCR gene, identified as linked to Stargardt's disease.

"I think this project points out," Dean concluded, "probably more for the benefit of the public and the people in Congress, who fund basic research, that a lot of its outcomes are important in ways that you couldn't have predicted to start with." *