By David N. Leff

"You can have 20:20 vision and be effectively blind."

So said research ophthalmologist Eliot Berson, of Harvard Medical School. He explained: "People can have 20:20 with retinitis pigmentosa, but in practical terms be blind, because they're looking down a tunnel that's so narrow they can't get out of the room unaided."

An estimated 50,000 to 100,000 people in the U.S. — one in 4,000 — suffer from the progressive vision deterioration of retinitis pigmentosa (RP), Berson said. Worldwide, the number is 1.5 million.

RP results from the deterioration of the retina's light-trapping rods and cones, the photoreceptors, which form the initial relay station for transmitting visual information to the brain. "Some RP patients go blind," Berson explained, "because of biochemical defects in the rods and cones; others from flaws in the underlying retinal pigment epithelium, which nourishes the photoreceptors.

"Most forms of RP are inherited," Berson pointed out. "It starts out usually when a child or young adolescent comes in to the eye clinic with deficiency of night vision and losses of peripheral vision."

One mercifully rare variant of RP is so severe that it's described as a separate entity — Leber congenital amaurosis (LCA), in which infants are born blind. "They have a diffuse abnormality of retinal function from time zero. Although they can sense motion and light," Berson observed, "these children are severely handicapped at birth."

In this dim picture, he pointed out, one bright spot has emerged. "Among kids with early-onset recessive RP we found that 2 percent had defects in their RPE65 gene. In LCA, the rate was 16 percent."

These data derive from research that Berson, together with clinical molecular geneticist Thaddeus Dryja, report in the current issue of the Proceedings of the National Academy of Sciences (PNAS), dated March 17, 1998. Its title: "Mutations in the RPE65 gene in patients with autosomal recessive retinitis pigmentosa or Leber congenital amaurosis."

Berson and Dryja are the PNAS article's co-senior authors. Dryja directs the Ocular Molecular Genetics Institute at the Harvard-affiliated Massachseutts Eye and Ear Infirmary, in Boston. (See BioWorld Today, Nov. 5, 1997, p. 1.)

Berson heads Harvard's Berman-Gund Laboratory for the Study of Retinal Degeneration.

"We asked the question," Berson told BioWorld Today, "whether patients with RP could have an abnormality in this RPE65 gene, which is known to express itself in the retinal pigment epithelium. That gene," he went on, "was an attractive candidate because of its tissue-specific expression."

Of all the patients who come to the Massachusetts Eye and Ear Infirmary, Berson pointed out, "60 percent are from outside New England and are kind enough to donate their blood DNA as part of their eye exams. So it's our good fortune to have a very large database across the U.S. and Canada — over 5,000 DNA specimens on file."

This collection afforded them "a chance to screen for even the few families that may show something anomalous in their RPE gene. And when we completed our study, we got a fairly good estimate of the frequency of the gene defect. So when we talk about the 16 percent of LCA cases and the 2 percent of recessive RP, we feel pretty confident, because we have such a representative sample from separate families.

"We don't have large, multi-generational families to screen," Berson continued. "Rather than try to delineate genes through a single extended pedigree — as was done for the Huntington's gene, for example — we had to come to grips with the fact that we have, particularly with respect to recessive mutations, the chance meeting of two parents with no history of RP."

Dryja, Berson and their co-authors screened the DNA of 147 RP and 45 LCA patients. They found pathogenic base-pair insertions, and some single-base missense mutations. Most of these genomic anomalies occurred in homozygous patients, arising from two parents carrying the same mutation.

Once parents have one RP-affected child, Mendelian inheritance implies that they face a 25 percent probability with each succeeding birth of bearing a child with LCA or early-onset RP.

The co-authors also encountered cases of compound heterozygotes: "This means," Berson pointed out, "that one parent has one mutation in this gene; another parent has a different alteration in the same gene. And the two come together to produce the disease.

"Now," he went on, "we are taking a hard look at whether there are any phenotype-genotype correlations. In other words, are there particular defects in the gene that correlate with severity of clinical presentation?"

Testing Animals Without Eye Charts

"And I suspect," he said, "that before long there'll be an animal model of this disease too. Although we're not directly working on it, once the gene is known, it will provide the opportunity for another RP laboratory animal.

"We've been doing most of our work in transgenic mice and rats with RP," Berson said. "We record the electrical waves from their eyes, the way you record a cardiogram from the heart. We can assess the visual function of an animal without asking him or her any questions. Which of their eyes are degenerating, at what rate, and exploring treatments using electrical recording."

Progressive retinitis pigmentosa is irreversible, Berson pointed out. But it shows signs of being treatable by vitamin A supplementation, to slow the advancing deterioration.

"The National Eye Institute (NEI) has issued a recommendation," he observed, "that most healthy adults with diagnosed RP should go on 15,000 international units a day of vitamin A. That means pure vitamin A, palmitate, not the beta-carotene in carrots."

It's well known that vitamin A deficiency can cause night blindness. Moreover, Berson pointed out, excessive intake of vitamin E "seems to aggravate RP by lowering blood levels of vitamin A."

"We don't really know what the protein product of this particular gene, RPE65, does. It may have something to do with vitamin A metabolism in the retinal epithelium," he speculated.

Berson and his co-authors did a controlled, randomized clinical trial, sponsored by the NEI. In the 1984-to-1991 study, they gave 600 patients vitamins A and E in varying combinations.

"Despite the genetic heterogeneity of this disease," Berson said, "we found a highly significant treatment benefit of vitamin A. So we're particularly interested in its effects on the retina. Some of the 147 RP patients in the present PNAS report," he concluded, "are taking vitamin A, and we are obtaining long-term information on the course of their disease." *