By David N. Leff

A baby growing up with extremely large eyes may look cute. In fact, in remote villages of the Third World, enormous orbs enhance a young woman's marriageability.

But unusually oversized eyeballs in small children are a sign of danger.

They may betoken a fairly rare but cruel eye disease in infants called primary congenital glaucoma, (a.k.a. ox eye or buphthalmos). A teleconference for the press Tuesday announced the long-sought discovery of the gene for primary congenital glaucoma (PCG), which makes possible detection of the disease at birth, or even before.

In its April issue, the British journal Human Molecular Genetics reports this feat under the fully explanatory title: "Identification of three different truncating mutations in cytochrome P4501B1 (CYP1B1) as the principal cause of PCG (buphthalmos) in families linked to the GLC3A locus on chromosome 2P21."

The senior author of this article is molecular geneticist Mansoor Sarfarazi, at the University of Connecticut Health Center, in Farmington.

In 30 families having up to four children afflicted with PCG, he and his co-authors were able, by linkage analysis and other molecular genetics techniques, to pinpoint the suspect gene to the short arm of chromosome 2, Sarfarazi told the teleconference.

His work confirms the anecdotal phenomenon that PCG runs in families. Now it's known that its inheritance is homozygous; that is, it requires a mutated gene from both carrier parents.

If detected soon enough after birth, PCG can be corrected surgically by opening the clogged Schlemm's canal (a slender tube encircling the anterior chamber of the eye) and draining acqueous humor back into the bloodstream. In glaucoma, that canal gets shut, with unremitting build-up of the humor, and pressure, which stretches the eyball.

Besides enlarged eyes, PCG symptoms include dripping tears, photophobia (fear of light) and spasms of ocular and facial muscles. But these subtle hallmarks usually escape the notice of pediatricians and parents, while the glaucomatous process progresses relentlessly toward atrophy of the optic nerve and the endpoint of total blindness in early childhood.

In Western societies, PCG occurs once in 2,000 births. In Middle Eastern countries, it's five times as common. Yet they all track back to a single genetic founder.

"We have actually found the same gene mutations in the Middle East, as well as in the PCG-prone French Canadian families we have screened so far," Sarfarazi said.

In hunting down the PCG gene, he deployed the whole bag of molecular genetics tricks — from radiation hybrid and YAC (yeast artificial chromosome) mapping to ESTs (expressed sequence tags) and polymorphic markers.

Intermarriage Enriches Genetic Information

"Our families come mostly from Turkey," Sarfarazi explained, "because of the high degree of consanguinity. Therefore, many affected children are available for study." One Turkish couple they screened "had 14 or 15 children by the same parents, thus providing maximum genetic information."

After two extensive gene searches in 1994 and 1995 came up dry, Sarfarazi and his co-authors finally struck pay dirt last year by randomly typing the entire genomes of their human population. That brought them to a gene-rich locale on the short arm of chromosome 2.

"The linkage showed," Sarfarazi recounted, "that we were in a region of about eight million base pairs." Then they found a very small sub-region in their consanguinous families, and eventually zeroed in on the elusive gene. He thinks it is responsible for 85 percent of PCG cases, with two other genes out there — one hiding on chromosome 1 — causing the other 15 percent.

Now, for the first time, it's possible to test newborns and growing children to see if they carry both mutated genes, and hence have the disease, or one parental allele only, and are carriers.

"In a family with a history of primary congenital glaucoma," Sarfarazi said with emphasis, "every child must be tested. A finger-stick drop of blood is all it takes. Extract the DNA and screen for mutations. If we find any," he added, "obviously, we have to let the pediatrician or ophthalmologist know about it. And they have to keep an eye on that baby. The sooner it's operated, the better the prognosis."

Neonatal Test Makes Timely Surgery Possible

Sarfarazi made the point that "the eyes in children are like elastic. When they are born, the ocular tissues are very soft, so surgery to correct the malformation is more successful, and less costly, than when the eyes harden and the child grows up."

InSite Vision Inc., of Alameda, Calif., has "an executed option to license the test from the University of Connecticut," the company's chairman and CEO, Kumar Chandrasekaran, told the teleconference, "and is now developing a prototype." Sarfarazi told BioWorld Today, "I have been informed that the university's office of technology transfer is willing to work with this company to develop the test commercially."

Not only does this finding now point to early detection of the disease, but to prenatal diagnosis as well. "If parents are interested," Sarfarazi said, "this would be possible. I already have such a request," he added, "which is under discussion with our university."

Eye specialist Maurice Luntz is chief of glaucoma at New York City's Eye, Ear and Throat Hospital. He told the teleconference: "With this breakthrough in detecting primary congenital glaucoma comes the hope that we may be able to identify the genes associated with adult-onset primary open-angle glaucoma, which represents a much larger patient population." (See BioWorld Today, Jan. 31, 1997, p. 1.) *