A second EFEMP1 variant causes night blindness from the periphery inwards

Design

multi-institutional case series with chromatic perimetry and rod-mediated dark adaptation kinetics

Population

three unrelated families with EFEMP1 p.Arg140Trp and one comparator family with canonical p.Arg345Trp, 1998-2026

Primary outcome

anatomical and functional topography of retinal degeneration

Effect

variant segregated with disease in all three families; 4 of 5 at-risk relatives aged 50-58 had delayed dark adaptation despite 20/20 acuity and normal fundi; rod dysfunction worsening towards the periphery, opposite to the Doyne dystrophy gradient

EFEMP1 has been a one-variant gene in retinal disease: p.Arg345Trp causes Doyne honeycomb retinal dystrophy, with early-onset confluent central drusen. This multi-institutional series across inherited retinal disease clinics in Philadelphia, Basel and Prague describes three unrelated families carrying a different variant, p.Arg140Trp, alongside a comparator family with the canonical mutation.

The phenotype is close to the opposite. Index cases presented with nyctalopia - in the sixth decade in family 1, at 40 in family 2, at 55 in family 3 - with progressive field loss and peripheral lobular chorioretinal atrophy that had been labelled gyrate-atrophy-like or choroideremia-like. Topographically matched testing in temporal retina without visible atrophy showed severe rod dysfunction and markedly delayed dark adaptation at 15, 30 and 46 degrees, worsening towards the periphery. The comparator patient with Doyne dystrophy showed the reverse gradient, with normal function outside the central 10 degrees.

The detail with the most practical reach is in the at-risk relatives. Of five relatives aged 50 to 58 in family 1, four carriers had delayed rod-mediated dark adaptation despite 20/20 vision in both eyes and normal fundus appearance, and the one non-carrier was normal. Function was abnormal where structure was not. For a clinician seeing an adult with unexplained night blindness and peripheral atrophy, this widens the differential and argues for genetic testing rather than a descriptive label - and for testing relatives, whose disease may be detectable long before it is visible.

• Consider EFEMP1 in adult-onset nyctalopia with peripheral lobular chorioretinal atrophy, alongside gyrate atrophy and choroideremia
• Do not exclude the diagnosis on a normal fundus and 20/20 acuity in an at-risk relative - dark adaptation was already abnormal
• Send genetic testing rather than settling for a descriptive phenotype label
• Note the gradient runs the opposite way to Doyne dystrophy: peripheral first, macula relatively spared
• Offer family testing, since carriers were identifiable before any structural change

Why it matters

It turns a gene associated with one central macular phenotype into a cause of peripheral rod degeneration presenting decades later.

Don't overread it

Three families in a case series - this establishes the phenotype exists, not how common it is or how it progresses on average.

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