Researchers can spot signs of a newly identified genetic eye disease before light-sensing cells are lost by measuring how vision recovers in darkness.
People with a newly identified genetic eye condition can see well for most of their lives before gradually losing peripheral vision and struggling to see at dusk or at night. The condition is linked to a gene already associated with a different eye disease, one that affects central vision first.
The two conditions arise from different variants, or versions, of the EFEMP1 gene. The newly identified variant, p.Arg140Trp, causes abnormally thick material to build up between cells in the eye. Researchers are calling the condition EFEMP1-associated late-onset retinal degeneration, or L-ORD, although it has not been formally named.
Slow adjustment to darkness offers a clue
L-ORD begins slowly at the periphery of the retina, the tissue at the back of the eye that converts light into signals the brain interprets as sight. Its gradual progression makes it difficult to detect. One useful clue is unusually slow recovery of vision when a person moves from a lighted setting into low light. This adjustment involves rod photoreceptors, the retinal cells specialized for seeing in dim conditions.
“We can detect a major abnormality in the way rod photoreceptors recover in darkness with retinas that still look structurally intact,” said Artur V. Cideciyan, PhD, an ophthalmology researcher and co-director of the Center for Hereditary Retinal Degenerations. “This gives us a functional marker of disease at a stage when photoreceptor cells have not yet been lost.”
One gene, two patterns of vision loss
The investigation began with a clinical description of a family in the United States in 1998.
“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,” Cideciyan said. “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.”
The genetic finding allowed researchers to expand the investigation to multiple European families. They studied three unrelated families in different countries that shared the p.Arg140Trp variant and compared them with a separate family carrying p.Arg345Trp, the EFEMP1 variant responsible for the already-known condition affecting central vision.
Published in JAMA Ophthalmology, the research involved an international team that included scientists from the Scheie Eye Institute of the Perelman School of Medicine at the University of Pennsylvania. Researchers from the University of Edinburgh, the University of Basel, Charles University, and the University of Bonn also contributed.
Possible clues to common retinal diseases
The researchers do not yet know how widespread p.Arg140Trp is or how many people have this form of L-ORD. They suspect it may be relatively rare, but larger studies are needed to establish its prevalence.
“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.”
Reference: “Widening the Spectrum of Disease Expression due to Heterozygous Variants in EFEMP1” by Chloe M. Stanton, Georg Ansari, Kristina Pfau, Theresa Lipsky, Mihail Halachev, Lukas Gerasimavicius, Camilla Drake, Joseph A. Marsh, Caroline Hayward, Alexander Sumaroka, Bohdan Kousal, Petra Lišková, Mathieu Quinodoz, Carlo Rivolta, Tomas S. Aleman, Artur V. Cideciyan and Maximilian Pfau, 10 September 2026, JAMA Ophthalmology.
DOI: 10.1001/jamaophthalmol.2026.3828
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.
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