A gene previously known to cause one inherited eye condition has also been found to cause a different form of retinal degeneration, triggered by a separate genetic mutation. The new eye condition, called EFEMP1-associated late-onset retinal degeneration (L-ORD) leaves patients finding it difficult to see at night, or adapt to changes in light. Retinal diseases become more common with age and can cause sight loss when the retina (the light-sensitive tissue at the back of the eye) becomes damaged. Some of these conditions are inherited and caused by changes, or mutations, in specific genes.One gene, two different conditionsMalattia Leventinese is a rare inherited retinal condition caused by a mutation in the EFEMP1 gene known as p.Arg345Trp. It primarily affects the central retina, including the macula, leading to progressive loss of central vision.However, researchers have identified families in which the pattern of retinal damage is very different. In these individuals, central vision remains relatively well preserved while the peripheral retina becomes damaged, affecting peripheral and night vision. Until now, it was unclear what was causing this distinct pattern of disease.IRR Group Leader Dr Chloe Stanton co-led an international study, with collaborators from the University of Basel, the Charles University, Penn Medicine and the University of Bonn. They investigated three unrelated families with peripheral vision loss in different countries and compared these families with a family carrying the p.Arg345Trp EFEMP1 variant associated with Malattia Leventinese.The study found that the families with peripheral vision loss carried a different EFEMP1 variant, known as p.Arg140Trp.This variant causes a pattern of retinal degeneration that is almost the inverse of Malattia Leventinese: the peripheral retina is affected while the macula remains relatively preserved. Our international team brought together observations that, in isolation, could easily have been interpreted as coincidental genetic variation. By combining genetic information across families with detailed clinical and experimental data, we were able to connect them to a single genetic cause and define distinctive markers of the disease that had not previously been recognised as such. Chloe Stanton IRR Group Leader The researchers have not formally named the newly defined condition but are referring to it as EFEMP1-associated late-onset retinal degeneration (L-ORD). L-ORD was previously associated with mutations in a different gene, C1QTNF5.Detecting disease before visible damageThe condition primarily affects the peripheral retina and the rod photoreceptors responsible for vision in dim light and darkness.One of the challenges in identifying the condition is that rod function can be severely impaired before obvious structural changes are seen in the retina. This means that someone may have difficulty seeing in low light even when their vision is normal and their retina appears largely healthy during a clinical examination.In patients carrying the p.Arg140Trp variant, the researchers found that rod-mediated vision recovered much more slowly after exposure to bright light. Some had 20/20 vision and no obvious structural abnormalities in the retina.This difficulty adapting from light to dark could therefore provide an important early clue to the condition.How the mutation affects cellsThe researchers also investigated what the p.Arg140Trp mutation does inside cells.They found that the altered form of the EFEMP1 protein accumulated abnormally inside cells and was less efficiently secreted. This provides a potential explanation for how the variant contributes to retinal degeneration.Together, the genetic, clinical and laboratory findings allowed the researchers to distinguish this condition from Malattia Leventinese and C1QTNF5-related L-ORD and establish p.Arg140Trp as its underlying genetic cause.Why is this important?The findings could help clinicians recognise the condition earlier. Identifying the underlying genetic cause can allow patients and their families to access genetic counselling, specialist monitoring and support services sooner. Although these inherited, late-onset retinal conditions are rare, studying them can reveal mechanisms that may also be relevant to more common retinal diseases associated with ageing.What’s next?It is not yet known how widespread the p.Arg140Trp variant is or how many people may have this form of L-ORD. The researchers believe it may be relatively rare, but larger studies will be needed to establish its frequency and determine the full range of symptoms and retinal changes associated with the condition.Further research will also be needed to understand how the disease develops over time and to investigate potential therapeutic approaches.This study was funded by the University of Edinburgh Chancellor’s Fellowship award, RS Macdonald Charitable Trust Seedcorn Award, the BrightFocus Foundation, the German Research Foundation, the Medical Research Council, the Swiss National Science Foundation, the Ministry of Health of the Czech Republic, Charles University in Prague, and the Samuel G. Jacobson, MD, PhD, Memorial Fund.Related linksStanton research groupRead the full paper in JAMA Ophthalmology Tags CIR This article was published on Wednesday 9 September 2026
