Late-Onset Retinal Degeneration (L-ORD)

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Article initiated by:
Andreas Theocharis, MD, Rehan Choudhury M.D., Romy Bejjani, MD, Agni Kakouri, MD, MBA, Erin Flynn
All contributors:
Andreas Theocharis, MD, Rehan Choudhury M.D., Romy Bejjani, MD, Erin Flynn, Agni Kakouri, MD, MBA
Assigned editor:
Review:
Assigned status Update Pending
.


Late-onset retinal degeneration (L-ORD) is a rare autosomal dominant inherited retinal degeneration caused by heterozygous pathogenic variants in C1QTNF5 (also known as CTRP5). It is characterized by delayed dark adaptation and nyctalopia in midlife, followed by progressive sub-retinal pigment epithelium (sub-RPE) deposits, retinal pigment epithelium (RPE) and chorioretinal atrophy, and, in some patients, choroidal neovascularization (CNV) with central vision loss.[1]

When present, long anteriorly inserted lens zonules, peripupillary iris atrophy or transillumination defects are valuable diagnostic clues and may precede clinically significant retinal changes or visual decline.[2][3][4]

Disease Entity

Disease

L-ORD is a monogenic retinal dystrophy that can closely mimic age-related macular degeneration (AMD), particularly when reticular pseudodrusen or subretinal drusenoid deposits and scalloped areas of atrophy dominate the phenotype.[1][5][6]

Epidemiology

The population prevalence of L-ORD is unknown. C1QTNF5-associated disease is overrepresented in Scottish inherited retinal disease cohorts, consistent with the Scottish founder effect of the p.Ser163Arg variant.[7][8]

Etiology

Heterozygous pathogenic variants in C1QTNF5 cause L-ORD. The most commonly reported variant is p.Ser163Arg (S163R), a founder allele traced to southeastern Scotland.[1][7]

Additional variants, including p.Gly216Cys and p.Pro188Thr, have broadened the recognized genotype-phenotype spectrum. Functional studies of several variants support a dominant-negative mechanism rather than a pure haploinsufficiency.[9][10]

Risk Factors

The main risk indicator is an affected family member. As inheritance is autosomal dominant, each child of an affected individual has a 50% chance of inheriting the familial variant. Age of onset and disease severity can vary within and among families.[1][9][10]

No proven modifiable environmental risk factors have been established for L-ORD.[1]

General Pathology

Classic clinicopathologic studies demonstrate a thick widespread layer of extracellular deposits between the RPE and Bruch's membrane, accompanied by regional photoreceptor loss and progressive RPE and choroidal atrophy.[11][12]

Experimental work also implicates abnormal extracellular-matrix turnover at the RPE-Bruch's membrane interface. In mouse and cell models, C1QTNF5 interacts with HTRA1. The S163R protein binds HTRA1 but resists HTRA1-mediated cleavage, and mutant mice show accumulation of HTRA1 and extracellular-matrix substrates.[13]

Pathophysiology

Current evidence supports the following proposed disease model:

  1. Abnormal C1QTNF5 folding, multimer assembly, and polarized secretion by the RPE
  2. Extracellular deposit formation at the RPE-Bruch's membrane interface with impaired outer-retinal support
  3. Early rod dysfunction followed by broader rod-cone dysfunction, atrophy, and, in some eyes, choroidal neovascularization (CNV)

Cell and structural studies show that disease-associated variants can alter C1QTNF5 folding, higher-order assembly, and secretion. C1QTNF5 is both secreted and membrane associated in the RPE and ciliary body, and structural analyses predict that pathogenic substitutions destabilize normal protein interactions.[9][14][15][16]

Dark adaptation abnormalities are an early functional feature. Prolonged dark adaptation improved rod-mediated electroretinographic responses in a subset of patients, indicating that part of the rod dysfunction can be reversible, although this has not been shown to alter the natural history of the disease.[17]

Primary Prevention

No intervention has been shown to prevent disease onset in a person who carries a pathogenic C1QTNF5 variant. Genetic counseling may address autosomal dominant inheritance, cascade testing, and reproductive options.[1]

Diagnosis

History

Key history elements include:

  • Difficulty seeing in dim light and unusually slow visual recovery after bright-light exposure, often beginning in the fourth or fifth decade of life[1][6][18]
  • Gradual loss of reading or central vision, or new metamorphopsia and a more rapid decline that may indicate CNV[1][19][20]
  • A family history compatible with autosomal dominant inheritance[1]
  • A previous diagnosis of AMD at an unexpectedly young age or in the presence of atypically widespread deposits[1][5][6]

Physical Examination

Anterior Segment

Look for long anteriorly inserted lens zonules, peripupillary iris atrophy, iris transillumination defects, and poor pupillary dilation. These findings can precede prominent retinal disease, but their presence varies by genotype.[2][3][4][10]

Posterior Segment

Perform a dilated fundus examination with particular attention to the temporal macula and midperipheral retina. Widefield imaging is helpful because deposits, atrophy, and nonexudative neovascular lesions may extend well beyond the macula. Assess for hemorrhage, fluid, fibrosis, or other signs of CNV.[1][5][21][22][23]

Signs

Commonly reported signs across studies and reviews include:

  • Yellow-white punctate deposits; reticular pseudodrusen (subretinal drusenoid deposits) are also common and may extend from the macula into the midperipheral or peripheral retina[5]
  • Scalloped temporal or extrafoveal areas of RPE and chorioretinal atrophy that enlarge toward the fovea and the remainder of the posterior pole, with pigment migration in advanced disease[21][22][24]
  • CNV, which may present as exudative macular disease or as large minimally exudative or nonexudative type 1 lesions in the midperipheral retina[19][20][23]
  • Long anterior zonules and iris atrophy or transillumination defects, which are common with the S163R phenotype but are not universal and were absent in most patients in a p.Pro188Thr cohort[2][3][4][10]

Peripheral outer retinal corrugations were identified on OCT in 13 of 18 eyes in a nine-patient series and were proposed as an additional diagnostic feature. Their specificity has not yet been established.[25]

Symptoms

Symptoms typically include:

  • Nyctalopia and delayed dark adaptation, usually the earliest symptoms and often beginning in the fourth or fifth decade of life[1][6][18]
  • Constriction of peripheral vision and loss of central vision from progressive atrophy, with new distortion or a more rapid decline if exudative CNV develops[1][21][23]

Clinical Diagnosis

The working clinical diagnosis is usually made from the combination of:

  • Midlife onset of nyctalopia or delayed dark adaptation[1][6][18]
  • Characteristic multimodal imaging findings, including widespread deposits and temporal or scalloped atrophy[1][5][21][22]
  • Supportive anterior segment findings when present[2][3][4]
  • A family history suggesting autosomal dominant inheritance[1]

Definitive diagnosis is established with molecular confirmation of a pathogenic or likely pathogenic C1QTNF5 variant in the appropriate phenotypic context.[1][9][10]

Diagnostic Procedures

The principal imaging and functional testing are:

  • Optical coherence tomography (OCT): Demonstrates sub-RPE material separating the RPE from Bruch's membrane, reticular pseudodrusen or subretinal drusenoid deposits, ellipsoid-zone loss, outer-retinal thinning, atrophy, and exudative complications.[1][21][24]
  • Fundus autofluorescence (FAF): Defines the topography of RPE dysfunction and atrophy. Quantified atrophy area is a useful way to monitor progression.[21][24]
  • Fluorescein angiography, indocyanine green angiography, and OCT angiography: Characterize suspected CNV. Multimodal angiography is particularly useful for recognizing large nonexudative type 1 lesions.[19][20][23]
  • Visual fields: Document regional sensitivity loss and functional progression. Central fields and acuity may remain relatively preserved until later decades in some genotypes.[10][21][24]
  • Dark adaptometry: Can detect delayed rod recovery before obvious fundus abnormalities and may help identify early disease in at-risk relatives.[18]
  • Electroretinography (ERG): May be normal or show predominant rod dysfunction early, with rod-cone dysfunction or extinguished responses in advanced disease. A normal ERG does not exclude early L-ORD.[2][17][18]

Laboratory Test

Routine laboratory tests are not diagnostic. Molecular confirmation generally uses targeted sequencing of C1QTNF5 or an inherited retinal disease panel, with variant interpretation and genetic counseling. Serum vitamin A testing is appropriate when acquired vitamin A deficiency is a plausible alternative diagnosis.[1][9][10][18]

Differential Diagnosis

L-ORD can resemble AMD and several inherited or acquired chorioretinal disorders. Important considerations include:

  • AMD, when reticular pseudodrusen are prominent. AMD typically presents later, remains predominantly macular, and lacks the autosomal dominant pedigree and anterior-segment findings associated with L-ORD.
  • Extensive macular atrophy with pseudodrusen-like appearance (EMAP), characterized by bilateral, rapidly progressive, vertically elongated or polycyclic macular atrophy, early foveal involvement, widespread pseudodrusen-like deposits, and frequent peripheral paving-stone degeneration. An autosomal dominant pedigree, long anterior zonules or iris abnormalities, and a pathogenic C1QTNF5 variant favor L-ORD.
  • Sorsby macular dystrophy (TIMP3). Sorsby macular dystrophy may present earlier, is initially concentrated in the macula, and is frequently complicated by early CNV or disciform scarring. Long anterior zonules and iris abnormalities are not characteristic
  • EFEMP1-associated autosomal dominant drusen, including Doyne honeycomb retinal dystrophy (also known as Malattia Leventinese). These disorders typically produce radiating or honeycomb-pattern drusen involving the macular and peripapillary regions without the characteristic anterior-segment findings of L-ORD
  • PRPH2-associated pattern or macular dystrophy. PRPH2-associated disease may cause adult-onset autosomal dominant pattern or macular dystrophy and, in some patients, more generalized cone-rod degeneration. A predominantly macular pattern without widespread L-ORD-like deposits or characteristic anterior-segment findings favors PRPH2-associated disease.
  • Late-onset ABCA4-associated retinopathy (Stargardt disease). Late-onset disease may produce retinal flecks, macular atrophy, and foveal sparing. Biallelic inheritance, characteristic autofluorescent flecks, and absence of the anterior-segment findings of L-ORD favor ABCA4-associated disease.
  • RDH5-associated fundus albipunctatus. This disorder usually causes earlier-onset nyctalopia, widespread white retinal dots with relative foveal sparing, and marked rod dysfunction that often improves after prolonged dark adaptation. It is usually autosomal recessive and lacks the characteristic anterior-segment findings of L-ORD.
  • Choroideremia. It is X-linked and typically causes childhood-onset nyctalopia in affected males, followed by centripetal chorioretinal atrophy with relative preservation of a central retinal island until advanced disease.
  • Acquired vitamin A deficiency. Vitamin A deficiency can cause nyctalopia, delayed dark adaptation, peripheral white deposits, and marked rod dysfunction. A history of malnutrition, intestinal or pancreatic disease, or bariatric surgery, together with a low serum retinol level and improvement after replacement, distinguishes it from L-ORD. [1][6]

Key features favoring L-ORD include autosomal dominant family history, midlife onset of delayed dark adaptation symptoms, widespread deposits extending beyond the macula, scalloped or temporal chorioretinal atrophy, long anterior zonules or iris atrophy when present, and molecular confirmation of a pathogenic C1QTNF5 variant.[1][2][3][4][5][6][9][10][21][22][23]

Management

General Treatment

There is no established disease-modifying therapy for L-ORD at present. Management is centered around correct disease identification, genetic counseling, monitoring for treatable complications, and visual rehabilitation as needed.[1]

Medical Therapy

  • Exudative CNV: Treat exudative choroidal/macular neovascularization using standard anti-VEGF principles. Published experience in L-ORD only includes case reports. Ranibizumab controlled leakage without improving vision in one case, while aflibercept produced sustained resolution of exudation after one injection in another.[19][20]
  • Nonexudative type 1 CNV: A four-patient series described large bilateral lesions that enlarged over time but remained nonexudative or minimally exudative without treatment. Close multimodal surveillance is appropriate, with treatment guided by development of exudation rather than vascular tissue alone.[23]
  • Vitamin A and prolonged dark adaptation: Small uncontrolled reports found variable short-term improvement in dark-adaptation kinetics during high-dose oral vitamin A, and prolonged dark adaptation improved ERG responses in a subset of patients. These observations do not establish long-term benefit or support routine vitamin A supplementation as disease-modifying therapy. However, if considered at all, this should be done cautiously and collaboratively with attention to systemic risk/contraindications and with clear counseling about uncertain benefit.[1][2][17][18]
  • Investigational gene-based therapy: A variant-specific CRISPR or prime-editing strategy has been proposed for the S163R founder allele, and retinal regions with potential treatment windows have been mapped. The published study did not test therapeutic efficacy, and gene-editing treatment remains investigational.[26]

Medical Follow-up

Follow-up is individualized based on stage and complications, but commonly includes:

  • Dilated examination with interval OCT and, when useful, FAF or widefield imaging to monitor deposits, atrophy, and CNV[1][21][24]
  • Education about new visual distortion, scotoma, or rapid visual change that should prompt examination for exudative CNV[1][19][20]
  • Periodic assessment of visual function and referral for low-vision rehabilitation when limitations develop[1]
  • Surveillance for ocular hypertension/glaucoma in those with prominent anterior segment findings.[2]

Surgery

There is no disease-specific retinal surgery. Long anterior zonules reduce the central zonule-free area and can make capsulorhexis technically challenging. In a small series, phacoemulsification was completed safely without long-term intraocular lens instability. It should be noted that objective visual improvement was greatest when foveal photoreceptor structure was preserved.[27]

Complications

Common clinically significant complications include:

  • Exudative or nonexudative CNV[20][22][23]
  • Progressive RPE, outer-retinal, and chorioretinal atrophy with central and peripheral vision loss[7][11][12][19]
  • Ocular hypertension or glaucoma in selected patients and families, sometimes in association with the anterior segment phenotype[1][2]

Prognosis

Prognosis is variable across variants and even within families, but several cohorts provide practical counseling anchors:

In a 16-patient cohort at Moorfields Eye Hospital, OCT and FAF structural measures remained relatively unchanged until approximately age 50, then ellipsoid-zone width and atrophy progressed rapidly. Best-corrected visual acuity declined more rapidly after approximately age 70 as atrophy encroached on the fovea.[24]

In a 26-patient p.Pro188Thr founder cohort, visual acuity and fields were generally maintained through ages 50 to 55, useful central vision often persisted between ages 55 and 65, and visual function declined more steeply thereafter. Long anterior zonules were absent in 24 of 26 patients, underscoring genotype-phenotype variability.[10]

Additional Resources

References

  1. ↑ 1.00 1.01 1.02 1.03 1.04 1.05 1.06 1.07 1.08 1.09 1.10 1.11 1.12 1.13 1.14 1.15 1.16 1.17 1.18 1.19 1.20 1.21 1.22 1.23 1.24 1.25 1.26 Lando L, Borooah S. Late-Onset Retinal Degeneration: Clinical Perspectives. Clin Ophthalmol. 2022;16:3225-3246. doi:10.2147/OPTH.S362691
  2. ↑ 2.0 2.1 2.2 2.3 2.4 2.5 2.6 2.7 2.8 Ayyagari R, Mandal MNA, Karoukis AJ, et al. Late-onset macular degeneration and long anterior lens zonules result from a CTRP5 gene mutation. Invest Ophthalmol Vis Sci. 2005;46(9):3363-3371. doi:10.1167/iovs.05-0159
  3. ↑ 3.0 3.1 3.2 3.3 3.4 Subrayan V, Morris B, Armbrecht AM, Wright AF, Dhillon B. Long Anterior Lens Zonules in Late-Onset Retinal Degeneration (L-ORD). Am J Ophthalmol. 2005;140(6):1127-1129. doi:10.1016/j.ajo.2005.06.023
  4. ↑ 4.0 4.1 4.2 4.3 4.4 Soumplis V, Sergouniotis PI, Robson AG, et al. Phenotypic findings in C1QTNF5 retinopathy (late-onset retinal degeneration). Acta Ophthalmol. 2013;91(3):e191-195. doi:10.1111/aos.12010
  5. ↑ 5.0 5.1 5.2 5.3 5.4 5.5 Borooah S, Papastavrou V, Lando L, et al. Reticular Pseudodrusen in Late-Onset Retinal Degeneration. Ophthalmol Retina. 2021;5(10):1043-1051. doi:10.1016/j.oret.2020.12.012
  6. ↑ 6.0 6.1 6.2 6.3 6.4 6.5 6.6 Borooah S, Collins C, Wright A, Dhillon B. Late-onset retinal macular degeneration: clinical insights into an inherited retinal degeneration. Br J Ophthalmol. 2009;93(3):284-289. doi:10.1136/bjo.2008.150151
  7. ↑ 7.0 7.1 7.2 Hayward C, Shu X, Cideciyan AV, et al. Mutation in a short-chain collagen gene, CTRP5, results in extracellular deposit formation in late-onset retinal degeneration: a genetic model for age-related macular degeneration. Hum Mol Genet. 2003;12(20):2657-2667. doi:10.1093/hmg/ddg289
  8. ↑ Hazelwood JE, Sevgi M, Osborne F, et al. Inherited retinal disorders in Scotland: A 5 year assessment. Eye (Lond). 2026;40(4):487-492. doi:10.1038/s41433-025-04216-z
  9. ↑ 9.0 9.1 9.2 9.3 9.4 9.5 Stanton CM, Borooah S, Drake C, et al. Novel pathogenic mutations in C1QTNF5 support a dominant negative disease mechanism in late-onset retinal degeneration. Sci Rep. 2017;7(1):12147. doi:10.1038/s41598-017-11898-3
  10. ↑ 10.0 10.1 10.2 10.3 10.4 10.5 10.6 10.7 10.8 De Zaeytijd J, Coppieters F, De Bruyne M, et al. Longitudinal phenotypic study of late-onset retinal degeneration due to a founder variant c.562C>A p.(Pro188Thr) in the C1QTNF5 gene. Ophthalmic Genet. 2021;42(5):521-532. doi:10.1080/13816810.2021.1923041
  11. ↑ 11.0 11.1 Kuntz CA, Jacobson SG, Cideciyan AV, et al. Sub-retinal pigment epithelial deposits in a dominant late-onset retinal degeneration. Invest Ophthalmol Vis Sci. 1996;37(9):1772-1782.
  12. ↑ 12.0 12.1 Milam AH, Curcio CA, Cideciyan AV, et al. Dominant late-onset retinal degeneration with regional variation of sub-retinal pigment epithelium deposits, retinal function, and photoreceptor degeneration. Ophthalmology. 2000;107(12):2256-2266. doi:10.1016/S0161-6420(00)00419-X
  13. ↑ Chekuri A, Zientara‐Rytter K, Soto‐Hermida A, et al. Late‐onset retinal degeneration pathology due to mutations in CTRP5 is mediated through HTRA1. Aging Cell. 2019;18(6):e13011. doi:10.1111/acel.13011
  14. ↑ Shu X, Tulloch B, Lennon A, et al. Disease mechanisms in late-onset retinal macular degeneration associated with mutation in C1QTNF5. Hum Mol Genet. 2006;15(10):1680-1689. doi:10.1093/hmg/ddl091
  15. ↑ Mandal MNA, Vasireddy V, Reddy GB, et al. CTRP5 is a membrane-associated and secretory protein in the RPE and ciliary body and the S163R mutation of CTRP5 impairs its secretion. Invest Ophthalmol Vis Sci. 2006;47(12):5505-5513. doi:10.1167/iovs.06-0312
  16. ↑ Tu X, Palczewski K. Crystal structure of the globular domain of C1QTNF5: Implications for late-onset retinal macular degeneration. J Struct Biol. 2012;180(3):439-446. doi:10.1016/j.jsb.2012.07.011
  17. ↑ 17.0 17.1 17.2 Papastavrou VT, Bradshaw KR, Aye KH, Turney C, Browning AC. Improvement of retinal function in L-ORD after prolonged dark adaptation. Can J Ophthalmol. 2015;50(2):112-118. doi:10.1016/j.jcjo.2014.12.001
  18. ↑ 18.0 18.1 18.2 18.3 18.4 18.5 18.6 Jacobson SG, Cideciyan AV, Wright E, Wright AF. Phenotypic marker for early disease detection in dominant late-onset retinal degeneration. Invest Ophthalmol Vis Sci. 2001;42(8):1882-1890.
  19. ↑ 19.0 19.1 19.2 19.3 19.4 19.5 Aye KH, Gupta R, Talks SJ, Browning AC. Treatment of a choroidal neovascular membrane in a patient with late-onset retinal degeneration (L-ORD) with intravitreal Ranibizumab. Eye (Lond). 2010;24(9):1528-1530. doi:10.1038/eye.2010.71
  20. ↑ 20.0 20.1 20.2 20.3 20.4 20.5 Ganesh D, Corradetti G, Sadda SR. MACULAR NEOVASCULARIZATION IN A CASE OF LATE-ONSET RETINAL DEGENERATION TREATED WITH AFLIBERCEPT. Retin Cases Brief Rep. 2024;18(5):633-636. doi:10.1097/ICB.0000000000001439
  21. ↑ 21.0 21.1 21.2 21.3 21.4 21.5 21.6 21.7 21.8 Borooah S, Papastavrou VT, Lando L, et al. CHARACTERIZING THE NATURAL HISTORY OF FOVEAL-SPARING ATROPHIC LATE-ONSET RETINAL DEGENERATION. Retina. 2021;41(6):1329-1337. doi:10.1097/IAE.0000000000003017
  22. ↑ 22.0 22.1 22.2 22.3 22.4 Cukras C, Flamendorf J, Wong WT, Ayyagari R, Cunningham D, Sieving PA. LONGITUDINAL STRUCTURAL CHANGES IN LATE-ONSET RETINAL DEGENERATION. Retina. 2016;36(12):2348-2356. doi:10.1097/IAE.0000000000001113
  23. ↑ 23.0 23.1 23.2 23.3 23.4 23.5 23.6 Keenan TDL, Vanderford EK, de Silva T, Sieving PA, Cukras CA. MASSIVE ADVANCING NONEXUDATIVE TYPE 1 CHOROIDAL NEOVASCULARIZATION IN CTRP5 LATE-ONSET RETINAL DEGENERATION: Longitudinal Findings on Multimodal Imaging and Implications for Age-Related Macular Degeneration. Retina. 2021;41(11):2236-2245. doi:10.1097/IAE.0000000000003205
  24. ↑ 24.0 24.1 24.2 24.3 24.4 24.5 Cheloni R, Venkatesh A, Rodriguez-Martinez AC, Moosajee M. Longitudinal Changes of Retinal Structure in Molecularly Confirmed C1QTNF5 Patients With Late-Onset Retinal Degeneration. Transl Vis Sci Technol. 2023;12(12):14. doi:10.1167/tvst.12.12.14
  25. ↑ Duncan HJ, McNally TW, Ferrara M, Kotagiri A. Outer retinal corrugations in late-onset retinal degeneration: a diagnostic finding demonstrated with multimodal imaging. BMJ Open Ophthalmol. 2023;8(1):e001370. doi:10.1136/bmjophth-2023-001370
  26. ↑ Li RTH, Roman AJ, Sumaroka A, et al. Treatment Strategy With Gene Editing for Late-Onset Retinal Degeneration Caused by a Founder Variant in C1QTNF5. Invest Ophthalmol Vis Sci. 2023;64(15):33. doi:10.1167/iovs.64.15.33
  27. ↑ Papastavrou VT, Borooah S, O’Brien JM, et al. Cataract surgery in patients with late-onset retinal degeneration. J Cataract Refract Surg. 2017;43(8):1036-1043. doi:10.1016/j.jcrs.2017.05.041
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