Observational study identifies p.Arg140Trp variant linked to night vision loss — Evidence Review
Published in JAMA Ophthalmology, by researchers from Scheie Eye Institute of the Perelman School of Medicine at the University of Pennsylvania, University of Edinburgh, University of Basel, Charles University, University of Bonn
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Table of Contents
A newly identified genetic eye disease linked to the EFEMP1 gene, known as L-ORD, causes gradual night and peripheral vision loss while sparing central vision in early stages. Findings from the University of Pennsylvania study broadly align with prior research on inherited retinal conditions but highlight a distinct genetic variant and disease pattern.
- While age-related macular degeneration (AMD) and retinitis pigmentosa (RP) are established causes of vision loss, this study identifies a rare EFEMP1 gene variant (p.Arg140Trp) that specifically affects night and peripheral vision, distinguishing it from the central vision loss seen in AMD and other EFEMP1-associated diseases 1 2 5.
- Related studies confirm that night vision and peripheral field deterioration are hallmark features of rod photoreceptor dysfunction in inherited retinal diseases like RP, but the genetic and clinical features described here expand the known spectrum of disease associated with EFEMP1 variants 2 5.
- The study’s identification of slow dark adaptation as an early functional marker parallels evidence that early night vision symptoms often precede central vision loss in retinal degenerations, underscoring the importance of functional testing for early detection 1 4 5.
Study Overview and Key Findings
Late-onset retinal degenerations remain under-recognized due to their slow progression and overlapping symptoms with more common conditions. This study is significant because it uncovers a previously hidden genetic cause of night blindness and peripheral vision loss, linked to a specific variant of the EFEMP1 gene. Unlike other EFEMP1-related diseases, which primarily cause central vision (macular) loss, this variant (p.Arg140Trp) presents with a different clinical pattern, beginning with peripheral and night vision difficulties and progressing slowly over years. The research also highlights the potential for functional tests—specifically, measuring night vision recovery—to detect disease before significant cell loss occurs.
| Property | Value |
|---|---|
| Study Year | 2026 |
| Organization | Scheie Eye Institute of the Perelman School of Medicine at the University of Pennsylvania, University of Edinburgh, University of Basel, Charles University, University of Bonn |
| Journal Name | JAMA Ophthalmology |
| Authors | Chloe M. Stanton, Georg Ansari, Kristina Pfau, Theresa Lipsky, Mihail Halachev, Lukas Gerasimavicius, Camilla Drake, Joseph A. Marsh, Caroline Hayward, Alexander Sumaroka, Bohdan Kousal, Petra Lišková, Mathieu Quinodoz, Carlo Rivolta, Tomas S. Aleman, Artur V. Cideciyan, Maximilian Pfau |
| Population | Families with genetic eye disease variants |
| Methods | Observational Study |
| Outcome | Vision recovery in darkness, genetic variants |
| Results | Identified p.Arg140Trp variant linked to L-ORD disease. |
Literature Review: Related Studies
To contextualize these findings, we searched the Consensus research paper database, encompassing over 200 million papers. The following queries were used to identify relevant literature:
- p.Arg140Trp variant L-ORD disease
- night vision loss eye diseases
- genetic factors hidden eye conditions
Below, we synthesize the main topics and findings from related studies:
| Topic | Key Findings |
|---|---|
| What genetic factors underlie inherited retinal diseases and night vision loss? | - Many inherited retinal diseases, including RP and AMD, involve distinct genetic variants and patterns of vision loss, with rod dysfunction leading to night blindness and peripheral field loss 1 2 5. - Recent research has identified hundreds of loci for myopia and refractive errors, showing the genetic complexity of eye diseases 6 7 8. |
| How do clinical features and progression patterns differ among retinal diseases? | - RP and L-ORD both typically begin with night blindness and constriction of visual fields, but the genetic mutations and age of onset differ 2 5. - AMD usually affects central vision first, while RP and L-ORD initially impact peripheral and night vision 1 4 5. |
| What is the role of genetic testing and early detection in managing eye diseases? | - Large-scale genetic testing has revealed numerous causative variants in inherited eye conditions, aiding diagnosis and identifying candidates for gene therapies 9 10. - Functional assessments, such as dark adaptation and night vision testing, can serve as early markers before structural changes are visible 1 4 5. |
What genetic factors underlie inherited retinal diseases and night vision loss?
Recent studies show that inherited retinal diseases are genetically heterogeneous, with numerous gene variants contributing to different clinical phenotypes. The new study’s identification of the EFEMP1 p.Arg140Trp variant adds to a growing list of genes linked to night blindness and peripheral vision loss, expanding the genetic landscape beyond the more common causes such as RP and AMD.
- Retinitis pigmentosa (RP) is associated with over 80 gene variants and typically manifests with night blindness and progressive peripheral vision loss, similar to the newly described L-ORD but with different genetic underpinnings 2 5.
- AMD, while primarily affecting central vision, can also present with early dark adaptation issues, though the underlying mechanisms and genetic risk factors differ from those in the EFEMP1 p.Arg140Trp variant 1 4.
- Recent large-scale studies have identified hundreds of loci for refractive error and myopia, highlighting the complexity and genetic diversity of eye diseases 6 7 8.
- The new study extends the spectrum of EFEMP1-related retinal diseases, demonstrating that variants in the same gene can produce divergent clinical outcomes 1 2 6.
How do clinical features and progression patterns differ among retinal diseases?
Comparing the clinical course of L-ORD with that of RP and AMD reveals important distinctions in symptom onset and disease progression. While RP and L-ORD both begin with night blindness and peripheral vision loss, AMD typically starts with central vision impairment. The identification of slow dark adaptation as an early sign in L-ORD mirrors findings in both RP and early AMD.
- RP is characterized by early onset night blindness, progressive loss of peripheral vision, and later central vision loss, with the rate and pattern influenced by the specific genetic variant 2 5.
- AMD primarily affects central vision through macular degeneration, but early symptoms can include slow adaptation to darkness and reduced scotopic (dim light) vision 1 4.
- L-ORD, associated with the EFEMP1 p.Arg140Trp variant, features a late-onset pattern of night vision and peripheral field impairment, distinguishing it from both typical RP and AMD 1 2 5.
- The progression of visual field loss and functional decline varies among diseases, underscoring the importance of genetic and functional testing for accurate diagnosis 1 2 4 5.
What is the role of genetic testing and early detection in managing eye diseases?
Advances in genetic testing and early functional assessment are transforming the diagnosis and management of inherited retinal diseases. The new study’s use of night vision recovery as a marker for preclinical disease aligns with broader trends toward early detection and precision medicine.
- Large-scale initiatives like eyeGENE have demonstrated the value of genetic testing in diagnosing inherited eye conditions and identifying candidates for gene therapy 9 10.
- Combining detailed phenotypic and genomic analysis can reveal hidden or rare diagnoses that may not be detected through clinical examination alone 9.
- Functional tests such as dark adaptation and night vision questionnaires can highlight early disease even when structural retinal changes are subtle or absent, as seen in both AMD and RP studies 1 4 5.
- The integration of genetic testing with functional and structural assessments may improve early detection and inform potential therapeutic interventions 9 10.
Future Research Questions
Further research is needed to clarify the prevalence of the newly identified L-ORD variant, understand its natural history, and explore targeted therapies. Existing studies highlight the genetic and phenotypic diversity of retinal diseases, but significant knowledge gaps remain, especially regarding rare variants and early detection strategies.
| Research Question | Relevance |
|---|---|
| How prevalent is the EFEMP1 p.Arg140Trp variant in diverse populations? | Determining prevalence will clarify the public health impact of L-ORD and guide screening efforts, especially as most related studies focus on more common variants or populations 1 2 5. |
| What are the early biomarkers for L-ORD and similar retinal diseases? | Identifying sensitive and specific biomarkers could enable earlier intervention and improve outcomes, as functional changes often precede detectable cell loss 1 4 5. |
| How do different EFEMP1 variants lead to distinct patterns of vision loss? | Understanding genotype-phenotype correlations may elucidate disease mechanisms and inform personalized therapy, expanding on findings that the same gene can cause different retinal diseases 1 2 6. |
| Can gene-targeted therapies be developed for rare retinal diseases like L-ORD? | With gene therapies advancing for more common retinal diseases, exploring their potential for rare variants like L-ORD could offer new treatment options 9 10. |
| What environmental or lifestyle factors influence the onset and progression of L-ORD? | Non-genetic risk factors may modulate disease onset and progression, as seen in myopia and AMD, but their role in L-ORD remains unexplored 6 7 8. |
This comprehensive analysis indicates that the discovery of the EFEMP1 p.Arg140Trp variant expands the spectrum of recognized inherited retinal diseases. The study’s emphasis on early functional testing and genetic analysis is consistent with broader trends in precision ophthalmology, although further research is essential to address the remaining gaps in understanding, diagnosis, and treatment.