Why this study matters for the choroideremia community

Choroideremia is an inherited retinal disease marked by progressive degeneration of the retina and underlying tissues, often beginning with night blindness and loss of peripheral vision. Because several inherited disorders can produce similar symptoms and retinal appearances, reaching an accurate genetic diagnosis is essential for individuals and families.

A 2026 JAMA Ophthalmology study expands the range of retinal disease linked to the EFEMP1 gene. The researchers found that a specific EFEMP1 variant, called p.Arg140Trp, causes a late-onset retinal degeneration that can look “choroideremia-like” or resemble gyrate atrophy. The findings are particularly relevant when a person has night blindness, peripheral retinal atrophy, and progressive field loss but does not have a diagnosis explained by the genes more classically associated with these features.

EFEMP1: a gene with a newly expanded disease spectrum

Until now, retinal disease caused by EFEMP1 was strongly associated with one recurring variant, p.Arg345Trp. That variant causes Doyne honeycomb retinal dystrophy, also called malattia leventinese (DHRD/ML), an autosomal dominant condition characterized by prominent central drusen—deposits beneath the retina that can become nearly confluent.

The newly studied p.Arg140Trp variant produced a very different pattern. It was identified in three unrelated families and tracked with disease in each family: people who carried the variant showed evidence of retinal dysfunction or degeneration, while a tested noncarrier did not.

Unlike classical DHRD/ML, the p.Arg140Trp-associated disease was mainly peripheral, rather than centered in the macula. This distinction matters because the macula supports detailed central vision, while the peripheral retina is especially important for vision in dim lighting and for the visual field.

Night blindness can precede visible retinal changes

The study provides an important example of how retinal function testing can reveal disease before clear structural changes are visible on routine examination or imaging.

In one family, the initial patient developed nyctalopia, or difficulty seeing in the dark, during the sixth decade of life. The individual later experienced progressive visual-field loss and had abnormal electroretinography results. However, four relatives who carried p.Arg140Trp—between 50 and 58 years old—had normal-appearing fundus examinations and 20/20 vision in both eyes. Despite this, all four showed delayed rod-mediated dark adaptation.

Dark adaptation is the process through which the eye recovers sensitivity after moving from bright to dim conditions. Rod photoreceptors are central to this process and are particularly important for night vision. In the EFEMP1 p.Arg140Trp families, testing showed that rod dysfunction could be detected in retinal areas where there was not yet visible loss of the outer nuclear layer, a retinal layer containing photoreceptor cell bodies.

This suggests that functional changes may occur before obvious tissue loss. For families, it also highlights why genetic testing and specialized measures of retinal function can add information beyond visual acuity and standard retinal photographs.

A pattern that can resemble choroideremia

Affected carriers in two additional families developed night blindness in their 40s or 50s and had peripheral, lobular areas of chorioretinal atrophy. Their retinal appearances had initially been described as gyrate atrophy-like or choroideremia-like.

Targeted testing found severe rod dysfunction in temporal retinal regions that did not yet show visible atrophy. The abnormalities were present at 15, 30, and 46 degrees from the center of vision and became more severe farther into the periphery. By contrast, the comparator participant with the classic EFEMP1 p.Arg345Trp variant had preserved light- and dark-adapted function outside the central 10 degrees, with rod recovery becoming more delayed closer to the fovea.

Together, these results show that different EFEMP1 variants can affect different retinal regions: p.Arg345Trp primarily affects the central retina, whereas p.Arg140Trp preferentially affects peripheral retina and rod function while relatively sparing central macular structure and function.

Implications for diagnosis and future treatment research

For people with a choroideremia-like clinical picture, this research reinforces the value of comprehensive genetic testing. Similar symptoms or imaging patterns do not necessarily mean that the same gene is responsible. Identifying the causal gene is important for understanding inheritance within a family and for matching patients to gene-specific research and therapeutic programs.

The work also provides potential tools for future studies of EFEMP1-associated disease. Measures such as dark-adaptation kinetics and chromatic perimetry detected substantial rod dysfunction outside visibly atrophic areas. These tests may help researchers follow disease progression and evaluate whether future treatments preserve function before structural degeneration becomes apparent.

Looking ahead

This study widens the recognized spectrum of EFEMP1-related retinal disease beyond the central-drusen pattern of DHRD/ML. It also illustrates a broader lesson in inherited retinal degeneration: genetics, retinal structure, and visual function must be considered together.

As more families undergo detailed genetic and functional evaluation, researchers are likely to identify additional gene variants and disease patterns that refine diagnosis. For the choroideremia community, this growing knowledge can help distinguish look-alike conditions, improve counseling for families, and build a stronger foundation for precisely targeted treatment development.