New disease found that causes night blindness and loss of peripheral vision

Scientists identified a new vision condition linked to a gene already connected to a different vision-loss disease. While the previously identified disease causes loss of central vision, the new condition affects peripheral and night vision. The two different conditions are caused by two different variants in the same gene, according to an international team of scientists that included researchers from the Scheie Eye Institute of the Perelman School of Medicine at the University of Pennsylvania.

No name has been formally given for the newly discovered condition, but the researchers are referring to it as EFEMP1-associated late-onset retinal degeneration (L-ORD). It occurs due to the p.Arg140Trp variant in the EFEMP1 gene, which causes abnormally thick material to build up between the eye’s cells.

The work began with a clinical description of a United States family in 1998, which then expanded to multiple European families based on the newly discovered genetic information. The work was published in JAMA Ophthalmology.

“The different disease expression in this family was thought to be similar to a condition caused by C1QTNF5 gene variants. However, none of the variants associated with that disease were found,” said Artur V. Cideciyan, PhD, a research of Ophthalmology and co-director of the Center for Hereditary Retinal Degenerations. “Our collaborators then discovered a new variant in the EFEMP1 gene that normally causes a different disease where the macula, which is tied to central vision, is affected first.”

Families reveal a distinct pattern of vision loss

Three unrelated families in different countries that happened to share the p.Arg140Trp variant were studied and compared to a different family with the p.Arg345Trp variant in the EFEMP1 gene, which caused the already-known condition affecting central vision. In addition to Penn Medicine’s team, researchers from the University of Edinburgh, the University of Basel, the Charles University, and the University of Bonn contributed to the research.

They discovered that the newly discovered disease starts slowly in the periphery of the retina, which sits at the back of the eye and converts light into signals for the brain to interpret as sight. People can have good vision for most of their life, but eventually begin to lose peripheral vision and have trouble seeing in low-light conditions, such as dusk or nighttime.

This slow decline and a lack of initial damage to the eye’s rod cells (a variety of “photoreceptors” that specialize in low-light vision) makes L-ORD difficult to catch. But the slow recovery of vision when transitioning from lighted to low-light conditions is a useful clue for pinpointing the condition.

“We can detect a major abnormality in the way rod photoreceptors recover in darkness with retinas that still look structurally intact,” Cideciyan said. “This gives us a functional marker of disease at a stage when photoreceptor cells have not yet been lost.”

Researchers hope to investigate how widely the variant occurs

Currently, the researchers are unsure how widespread the variant is and, thus, how many people might have this form of L-ORD. Though they think it might be relatively rare, larger studies will have to be done to determine that.

But the discovery of the new gene variant for L-ORD will help broaden understanding of sight conditions that come with age.

“Aging is a risk factor for many medical conditions, including retinal diseases such as age-related macular degeneration, the most common retinal condition of aging,” said Tomas S. Aleman, MD, a professor of Ophthalmology and the other co-director of the Center for Hereditary Retinal Degenerations. “Lessons learned from these infrequent, late-onset genetic eye diseases offer glimpses at possible mechanisms of disease for much more frequent retinal problems.”

This study was supported by grants from the University of Edinburgh Chancellor’s Fellowship award, RS Macdonald Charitable Trust Seedcorn Award, the BrightFocus Foundation (M2024009N), the German Research Foundation (532367710), the Medical Research Council (MC_UU_00035/9, MC_UU_00007/10), the Swiss National Science Foundation (204285), the Ministry of Health of the Czech Republic (NW24-06-00083), Charles University in Prague (UNCE/24/MED/022 and SVV 2600631), and the Samuel G. Jacobson, MD, PhD, Memorial Fund.