EFEMP1 p.Arg140Trp variant linked to late-onset peripheral retinal degeneration in 3 families
A case series in JAMA Ophthalmology describes a new EFEMP1 variant causing night blindness and peripheral vision loss; delayed rod dark adaptation is found with a normal fundus.
A multi-institutional case series in JAMA Ophthalmology describes a second EFEMP1 variant, p.Arg140Trp (c.418C>T), associated with retinal degeneration. The work was done at inherited retinal disease clinics in Philadelphia, Basel and Prague between October 1998 and May 2026. It included three unrelated families with p.Arg140Trp and one comparator family with canonical Doyne honeycomb retinal dystrophy / malattia leventinese (DHRD/ML), caused by p.Arg345Trp. jamanetwork.com
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Until now, p.Arg345Trp was the only EFEMP1 variant reported to cause retinal disease. It produces early-onset, nearly confluent, large central drusen. The authors report that p.Arg140Trp segregated with disease in all three families and produced a different picture.
Phenotype of the new variant
In family 1, the index case developed night blindness (nyctalopia) in the sixth decade, with progressive field loss and an abnormal electroretinogram. Of five at-risk relatives aged 50 to 58 years, four were heterozygous carriers. All four had delayed rod-mediated dark adaptation despite best-corrected visual acuity of 20/20 in both eyes and a normal fundus appearance. The one noncarrier had normal imaging and function.
Carriers from family 2 (age 42, symptom onset at 40) and family 3 (age 69, onset at 55) had night blindness and peripheral lobular chorioretinal atrophy. This had initially been labeled gyrate atrophy-like or choroideremia-like. jamanetwork.com
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Rod function and comparison with DHRD/ML
Topographically matched testing in temporal retina without visible atrophy showed severe rod dysfunction and markedly delayed dark adaptation at 15°, 30° and 46°. The severity increased toward the periphery. In the patient with DHRD/ML, light- and dark-adapted function was normal outside the central 10°, and the delay in rod recovery increased toward the fovea.
The authors conclude that p.Arg140Trp is associated with a late-onset, predominantly peripheral degeneration whose features overlap with late-onset retinal degeneration (L-ORD) and differ from DHRD/ML. Relatively central macular structure and function are spared. Rod dysfunction was seen at retinal loci without detectable outer nuclear layer loss.
Study co-author Artur Cideciyan said that the abnormality in rod recovery can be detected while the retina still looks structurally intact. The researchers call the condition EFEMP1-associated L-ORD, though it has not been formally named. They do not yet know how common the variant is, and larger studies are needed to establish prevalence.
