Pseudoexfoliation syndrome not yet ready for genetic testing

Take home

Although the LOXL1 gene may increase the risk for pseudoexfoliation syndrome, currently available genetic testing does not effectively predict who will develop disease.

By Vanessa Caceres; Reviewed by John H. Fingert, MD, PhD

Iowa City, IA-Pseudoexfoliation (PXF) syndrome does not yet have a reliable genetic test and is actually the result of multiple genetic and environmental factors, said John H. Fingert, MD, PhD.

PXF is heritable, but it has a complex genetic basis.

“No one thing causes the disease on its own,” said Dr. Fingert, associate professor of ophthalmology and visual sciences, University of Iowa Carver College of Medicine, Iowa City.

There is one gene that’s confirmed as a risk factor for PXF, the LOXL1 gene, he explained.

“This gene increases the risk for pseudoexfoliation, but testing cannot reliably predict who will get the disease,” he said.

Understanding PXF

Previous research involving identical twins showed that PXF is heritable, Dr. Fingert said. There are also commonly seen cases of PXF that cluster within families, again demonstrating the familial connection. Even animal studies of inbred laboratory mice show that PXF can be passed from generation to generation.

The disease also appears to be more prominent in certain ethnic groups, such as Scandinavian populations. In contrast, the disease is much more rare in populations, such as Eskimos.

However, none of these findings seem to point to an exact cause of PXF.

“It occurs because of the combined effects of many genetic and environmental factors, and no single factor can determine which of our patients will develop pseudoexfoliation,” Dr. Fingert said.

Progress has been made toward a better understanding of the environmental factors that contribute to PXF, such as latitude and ultraviolet exposure.

A breakthrough in the understanding of PXF came in 2007, with the finding of LOXL1 as the first known genetic factor, Dr. Fingert said.¹ The original studies investigated Icelandic and Swedish populations, but subsequent research has included other patient populations.

“In all cases, LOXL1 is always a big risk factor,” he said. “However, all the risk variants are extremely common.”

This has led to some unusual findings about the gene. For example, the risk allele G153D is found in about 88% of the normal Swedish population without PXF, yet it is also found in 100% of patients with PXF.

This is why genetic testing has been so difficult, he explained.

“Currently, there’s no clinical utility in the diagnosis of PXF in testing for LOXL1 and the value of testing is limited to research purposes,” Dr. Fingert said. “However, large collaborative genetic studies are underway that will likely find more genetic factors.”

Dr. Fingert concluded by explaining what he tells patients with PXF about their condition.

“I tell them it is a heritable condition caused in part by genes, but currently we don’t know most of those genes. So, testing is not very useful now,” he said. “I also tell them the current best way to diagnose is a careful exam in an ophthalmology clinic.”

Dr. Fingert cited recommendations from the American Academy of Ophthalmology on genetic testing, which state that testing should be avoided until studies have demonstrated a benefit to patients who have tested positive.²

“This is clearly a benchmark not yet met for the LOXL1 gene or PXF,” he concluded.

References

1. Thorleifsson G, Magnusson KP, Sulem P, et al. Common sequence variants in the LOXL1 gene confer susceptibility to exfoliation glaucoma. Science. 2007;317:1397-400.

2. Stone EM, Aldave AJ, Drack AV, et al. Recommendations for genetic testing of inherited eye diseases: report of the American Academy of Ophthalmology task force on genetic testing. Ophthalmology. 2012;119:2408-2410.

John H. Fingert, MD, PhD

E: john-fingert@uiowa.edu

This article was adapted from Dr. Fingert’s presentation during Glaucoma Subspecialty Day at the 2014 American Academy of Ophthalmology. He did not indicate any proprietary interest in the subject matter.