This multi-institutional case series evaluated the clinical and functional phenotype of the *EFEMP1* p.Arg140Trp (c.418C>T) variant in 3 unrelated families with inherited retinal degeneration, compared against a family with canonical Doyne honeycomb retinal dystrophy/malattia leventinese (DHRD/ML) caused by p.Arg345Trp, using multimodal imaging and rod-mediated dark adaptation testing (October 1998–May 2026).
The p.Arg140Trp variant segregated with disease in all 3 families, producing a **late-onset, predominantly peripheral retinal degeneration** distinct from DHRD/ML: 4 of 5 at-risk heterozygous relatives (ages 50–58) showed delayed rod-mediated dark adaptation despite 20/20 visual acuity and normal fundus appearance, while symptomatic carriers from families 2 and 3 had nyctalopia and peripheral chorioretinal atrophy (initially misclassified as gyrate atrophy-like or choroideremia-like); rod dysfunction was most severe toward the periphery (15°, 30°, 46°), with dysfunction present even at retinal loci lacking detectable outer nuclear layer loss.
- Very small sample (3 families, limited number of affected individuals), limiting generalizability. - No longitudinal functional data to characterize disease progression rate. - Rod dysfunction was detected at structurally normal loci, but no histopathologic or molecular mechanistic data are provided to explain the dissociation.
Clinicians should consider *EFEMP1* variants beyond p.Arg345Trp when evaluating late-onset peripheral retinal degeneration with nyctalopia, especially cases resembling gyrate atrophy or choroideremia. Rod-mediated dark adaptation testing may detect early functional loss before structural changes appear on imaging.
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