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ABCA4-retinopathy: for professionals


  • 1:8,000 to 10,000[1]
  • Autosomal recessive
Genes involved (OMIM No.)
Clinical phenotype (OMIM phenotype no.)
  • Macular degeneration, age-related, 2 (#153800)
  • Stargardt disease 1, fundus flavimaculatus (#248200)
  • Retinal dystrophy, early-onset severe (#248200)
  • Cone-rod dystrophy 3 (#604116)
  • Retinitis pigmentosa 19 (#601718)
  • Central vision disturbance/loss
  • Abnormal colour vision
  • Central/paracentral scotoma
  • Photophobia
  • Progressive macular atrophy; foveal sparing in milder, later-onset cases
  • Retinal flecks predominantly in the macula with variable peripheral distribution
  • Flecks are resorbed over time initiating chorioretinal atrophy
  • Choroidal neovascularisation (CNV) is a rare complication
Systemic features
  • No extraocular features reported
Key investigations
  • Pattern ERG: Reduced amplitude
  • Full-field ERG: may be normal/isolated cone involvement/ cone and rod involvement (prognostic indicator)
  • FAF: Speckled pattern of hyper- and hypo-AF corresponding to retinal flecks; loss of AF centrally demarcates area of macular atrophy
  • OCT: Progressive loss of outer retinal layers, RPE and choriocapillaris of the central macula; flecks appear as hyper-reflective deposits above the RPE
Molecular diagnosisNext generation sequencing
  • Targeted gene panels (retinal)
  • Whole exome sequencing
  • Whole genome sequencing
  • Supportive management
  • Avoid Vitamin A supplementation
  • Monitor for CNV—response to intravitreal anti-VEGF injections is variable
Therapies under research
  • Pharmacotherapy (phase 3 for Emixustat)
  • Cell-based therapy (phase 1/2)
  • Gene therapy (phase 1/2)

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Clinical phenotype

Presenting features

Homozygous or compound heterozygous mutations in ABCA4 can lead to a spectrum of phenotypes characterised by early and progressive maculopathy with variable retinal dysfunction:

With more than 1000 pathogenic variants identified in the ABCA4 gene along with the presence of genetic and/or environmental modifiers, there are significant intra- and interfamilial variability in terms of age of onset, severity of visual dysfunction and rate of progression. Although disease onset can occur at any age, patients typically present during adolescence to young adulthood with the following symptoms:

  • Bilateral central vision disturbance (VA reduction)
  • Abnormal colour vision
  • Central/paracentral scotoma
  • Photophobia

Central vision gradually declines as the disease progresses. This may be accompanied by peripheral visual field loss if there is pan-retinal involvement, as in the case of cone-rod dystrophy. However, the far peripheral vision tends to be preserved even in advanced ABCA4-retinopathy cases, which allows clinical discrimination from other cone-rod dystrophies such as those caused by CERKL.

In general, the disease severity and rate of visual deterioration correlate with age of onset, where childhood-onset disease is often associated with a more severe phenotype involving the whole retina while later-onset disease usually have a slower disease course and higher frequency of foveal-sparing macular atrophy.[2-6]

Some degree of genotype-phenotype correlation has been established depending on the residual ABCA4 protein function:

  • The hypomorphic allele p.Asn1868Ile, when in trans with another deleterious allele, is usually associated with a later onset (4th decade of life), localised, unifocal macular atrophy which tends to be foveal-sparing[7]
  • The highly common p.Gly1961Glu allele[8] is associated with a later than usual onset (3rd decade of life) and predominantly central macular disease with long term preservation of rod and cone responses but more severe cases have been reported as well[9-11]
  • Biallelic null mutations are usually associated with an early-onset (within the 1st decade), severe and rapidly progressive phenotype involving the whole retina (cone-rod dystrophy and retinitis pigmentosa)[12]

Fundal appearance

The fundal features are highly variable but patients usually have symmetrical ocular findings. ABCA4-retinopathy typically begins as a maculopathy (abnormal/loss of foveal reflex, RPE mottling or bulls-eye maculopathy) which progresses to an enlarging lesion of outer retinal, RPE and choriocapillaris atrophy. This is usually accompanied by characteristic yellow flecks at the RPE level that are situated predominantly in the macula with variable peripheral distribution. It is important to note that up to one-third of childhood-onset cases can present initially without flecks but usually become apparent later on.[2,3] Over time, the flecks become more confluent across the posterior pole and progresses to outer retinal atrophy. In the advanced stages, multiple atrophic lesions coalesce at the posterior pole and spread in a centrifugal direction, leading to chorioretinal atrophy beyond the vascular arcades.[12] Retinal hyperpigmentation might be present during this stage.

Multimodal imaging of a 32 year old female patient with confirmed compound heterozygous ABCA4 mutation (p.Gly1961Glu and p.Arg2030Ter). The wide field colour fundus photograph (A) and FAF imaging (B) showing isolated macular involvement. 55 degree FAF (D) shows a well-circumscribed area of definite hypo-autofluorescence surrounded by flecks. OCT scan of the macula (C) shows outer retinal and RPE atrophy centrally, while the parafoveal outer retinal layers are preserved, correlating with the border of the hypo-autofluorescent lesion.
The various fundal phenotypes of molecularly confirmed ABCA4-retinopathy patients. Patient A has a central dark area of atrophy confined to the posterior pole. Flecks are seen up to the mid-periphery. Patient B has a larger confluent atrophic patch that is extending past the arcades. Flecks are noted up to the mid-periphery. Patient C has one large confluent atrophic patch at the posterior pole with multiple smaller atrophic lesions in the mid-periphery. As the disease progresses, the atrophic lesions coalesce and extend to the periphery in a centrifugal direction (D).
Note: peripapillary sparing in A and B and relative preservation of the far peripheral retina in all patients

Despite the clinical heterogeneity of ABCA4-retinopathy, Cremers and colleagues suggested in a recent review that the presence of the following clinical features together is highly indicative of this condition:  

  • Macular involvement with progressive loss of outer retinal layers, RPE and choriocapillaris
  • Fundus flecks
  • Peripapillary sparing which is most evident on fundus autofluorescence (FAF) imaging (may be lost in advanced stages)

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Gene: ABCA4 (1p22.1)

OMIM: #601691

Protein: ATP-binding cassette transporter (ABCA4) protein

Location of gene expression: Outer segment disc membranes of rod and cone photoreceptors

Function: Facilitates transportation of phototransduction waste material from outer segments of the photoreceptor to the RPE. Pathogenic ABCA4 mutations lead to excessive accumulation of toxic N-retinylidene-N-retinylethanolamine (A2E) in the RPE.

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Key investigations

1) Fundus autofluorescence imaging (FAF)

FAF is a sensitive modality for diagnosis and monitoring disease progression. In the earliest stages, it can detect fundal abnormalities even when retinal flecks are not apparent on fundoscopy. Flecks appear characteristically as “speckled” areas of increased and decreased autofluorescence. Peripapillary sparing is also easily observed on FAF which can aid in making a diagnosis and directing genetic investigations. Furthermore, atrophic areas are clearly demarcated on FAF which can be measured serially to determine progression (areas of definitely decreased autofluorescence).[13]

2) Optical coherence tomography (OCT)

There is usually extensive central macular thinning with progressive loss of outer retinal layers, RPE and choriocapillaris, corresponding to the atrophic areas observed fundoscopically and on FAF. Retinal flecks appear as hyperreflective deposits above the RPE/Bruchs membrane layer.

Another OCT phenotype that has been described in ABCA4-retinopathy is a sharply demarcated focal loss of reflectance in the foveal ellipsoid zone with intact external limiting membrane and RPE layers (also known as foveal cavitation).[14,15] However, this is not pathognomonic of ABCA4 disease, rather it appears to be a generic sign associated with cone dysfunction.[15]

OCT scan of a patient with ABCA4-retinopathy showing a retinal fleck appearing as a hyper-reflective deposit above the RPE/Bruchs layer

3) Fundus fluorescein angiography (FFA)

A characteristic “dark choroid” sign can be observed due to the obstruction of choroidal hyperfluorescence by lipofuscin accumulation. This may be absent in patients with less extensive disease.

4) Electrophysiology

Pattern electroretinogram (ERG) is usually abnormal. Patients can be divided into three groups based on the initial full-field ERG findings:

  • Group 1: normal cone and rod responses (isolated macular dysfunction)
  • Group 2: Abnormal cone but normal rod responses (generalised cone dysfunction)
  • Group 3: Abnormal cone and rod responses (generalised retinal dysfunction)

This classification can serve as a prognostic indicator for the rate of disease progression. All group 3 patients will have significant ERG deterioration in 10 years while only 22% of group 1 patients have similar progression.[16]

5) Static perimetry

To establish baseline visual field. Monitoring of visual field is usually not necessary for clinical management but it is an instructive metric for clinical trials.[17]

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With such heterogeneous clinical presentations, the diagnosis of ABCA4-retinoapthy can only be confirmed through genetic testing.

This can be achieved through a variety of next generation sequencing (NGS) methods:

  • Targeted gene panels (retinal)
  • Whole exome sequencing
  • Whole genome sequencing

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1) Supportive ocular management

  • Correcting any refractive errors
  • Referral to low vision services
  • Regular monitoring of visual development in children and commence treatment for amblyopia promptly if detected
  • Directing patients to supporting organisations 
  • Avoid Vitamin A supplementation
  • Encourage UV protected sunglasses wear 
  • Blue light screen protectors on mobile devices or computer screens*
  • Monitoring for CNV (rare complication)—anti-VEGF treatment have variable efficacy[18-20]

*Current available evidence shows that blue light emitted from screens do not damage the retina but it can disrupt our sleep cycle. The screen protectors are used as a precautionary measure.

Optimisation of development

As vision is important in normal childhood development and education, children with visual impairment due to ABCA4-retinopathy should be referred to developmental paediatricians and advisory teaching services for children/adolescents with visual impairment (e.g. sensory support services within local authority). This will enable provisions to be made within the educational and home settings so that the child can reach his/her developmental potential and develop skills to achieve independence.

Family management and counselling

ABCA4-retinopathies are inherited in an autosomal recessive manner. Patients and families require genetic counselling and can seek advice for family planning including prenatal testing and preimplantation genetic diagnosis.

Emotional and social support

Eye Clinic Liaison Officers (ECLOs) act as an initial point of contact for newly diagnosed patients and their parents in clinic. They provide emotional and practical support to help patients and parents deal with the diagnosis and maintain independence. They work closely with the local council’s sensory support team and are able to advise on the broad range of services provided, such as visual rehabilitation, home assessment, work and access to qualified teachers for children with visual impairment (QTVI) among other services.

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Referral to a specialist service

In the UK, patients should be referred to their local genomic ophthalmology (if available) or clinical genetics services to receive a more comprehensive genetic management of their conditions (genetic testing and genetic counselling) and having the opportunity to participate in clinical research.

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Current research in ABCA4-retinopathy

1) Pharmacotherapy

Pharmacological interventions focus on screening compounds that can reduce toxic metabolite accumulation in the retina, a hallmark of Stargardt disease. These drugs aim to preserve retinal function and slow degeneration. Clinical trials assess the effectiveness of these drug candidates, offering potential therapeutic options.

Various pharmacological compounds are currently being investigated with the aim of reducing A2E/lipofuscin accumulation. These include:

Recently completed clinical trials are:

(a) Tinlarebant

Tinlarebant is a novel oral therapy intended as an early intervention to prevent the accumulation of vitamin A-based toxins (bisretinoids) that cause STGD1 and contribute to pathogenesis in Dry AMD. Bisretinoids are formed as by-products of vitamin A in the visual cycle. Tinlarebant works by reducing the level of serum RBP4, the carrier protein which transports the retinol to the eye. By modulating the amount of retinol entering the eye, Tinlarebant reduces the formation of bisretinoids to preserve the health of retinal tissues.

(b) Metformin

Metformin hydrochloride is a well-characterized, commonly prescribed oral anti-diabetic medication that acts by suppressing liver gluconeogenesis and increasing peripheral insulin sensitivity. An additional effect of metformin is to increase macro-autophagy via the mammalian target of rapamycin complex 1 (mTORC1)/AMP-activated Kinase (AMPK) pathway. Stimulation of this pathway is predicted to enable the RPE to more efficiently handle lipofuscin, which suggests an association between metformin use and slowing of retinal degeneration. A phase 1/2 trial for this is currently underway.

(c) ALK-001

ALK-001 is a deuterated Vitamin A molecule that reduces A2E formation by slowing the rate of Vitamin A dimerisation. Visual disturbance such as those encountered with emixustat are rare with ALK-001 as photoreceptors are not deprived of Vitamin A nor that the ocular retinal concentration is altered. Preliminary results of the ongoing phase 2 trial indicate that it is well-tolerated with no ocular side effects reported.

(d) Zimura

A2E is thought to activate the complement system in RPE which leads to early cell death. Avacincaptad pegol (Zimura) is a C5 complement inhibitor that aims to inhibit this pro-inflammatory effect which has been shown to rescue retinal photoreceptors in a Stargardt mouse model.

(e) Other compounds

Metabolism of docosahexaenoic acid (DHA), a major component in photoreceptor outer segments, is believed to be altered in ABCA4-retinopathies. Oral DHA supplementation has been previously studied in late-onset Stargardt patients but only 4 out of the 20 participants experienced a slight visual improvement. The recently completed MADEOS trial assessed the efficacy of omega-3 acid supplementation in both patients with AMD and ABCA4-retinopathies.

Soraprazan is a treatment for gastro-oesophageal reflux disease which was discovered to degrade lipofuscin in monkeys. It was assessed in a phase 2 trial registered with the EU Clinical Trials Register.

Emixustat inhibits a key visual cycle enzyme called retinoid isomerase (encoded by the RPE65 gene) in the RPE, thus reducing A2E accumulation. Whilst the SeaStar phase 3 trial failed to reach it’s primary or secondary endpoints, post hoc multi-factor analysis was performed on the subgroup of subjects with smaller lesions at baseline, controlling for the baseline factors identified in univariate and multi-factor analyses to affect lesion progression in this subgroup. This analysis determined that emixustat treatment resulted in a 40.8% reduction in lesion progression compared to placebo at Month 24 (P=0.0206, emixustat n=34, placebo n=21).

2) Gene therapy

Gene therapy works by introducing a healthy gene copy of interest (transgene) into the appropriate cells to compensate for the mutated gene that is not producing enough functional protein. The transgene is carried by a viral vector, usually adeno-associated virus (AAV) and delivered to the target cells through sub-retinal/intravitreal injections.

Sub-retinal delivery of AAV-mediated gene therapy has a well-established safety profile, culminating in the approval of voretigene neparvovec (Luxturna) for the treatment of autosomal recessive RPE65-retinopathies. However, similar approach cannot be applied to treat ABCA4-retinopahties as the size of the ABCA4 gene (just over 7 kilobases) exceeds the carrying capacity of standard AAV vectors (5 kilobases).  

Several alternative techniques have been investigated to overcome this issue:

  • Splitting the ABCA4 transgene into two separate AAV vectors which will recombine into a full-length gene upon co-infection of the same cell (dual-AAV therapy)
  • Lentiviral-based gene therapy (capacity of 9-10 kilobases)

Through animal models, dual-AAV therapy has been shown to safe and efficacious in improving the retinal phenotype despite having lower transgene expression than single AAV vectors.[25]

The safety and tolerability of lentiviral-based gene therapy (SAR 422459) was investigated in a phase 1/2 trial (StarGen, NCT 01367444) which unfortunately terminated prematurely as the trial sponsor decided to cease product development. The 1-year result showed that SAR 422459 was safe and well-tolerated with no clear evidence of visual improvement. A long-term follow-up study (NCT 01736592) of the treated participants is currently ongoing.

3) Cell-based therapy

ABCA4-retinopathy causes progressive atrophy of the outer retinal layers, RPE and choriocapillaris especially in the macula. RPE cells derived from pluripotent stem cells such as human embryonic stem cells (hESC) or partially differentiated progenitor cells may be transplanted to replace the degenerated cells. Transplantation of hESC-RPE in patients with ABCA4-retinopathies has been proven to be safe up to 3 years after surgery (longest follow-up thus far) but with variable visual outcome.[26,27] The main adverse events reported were either related to the surgical procedure itself (pars plana vitrectomy) or immunosuppression. It is hypothesised that RPE replacement itself will not likely achieve long-term benefit as ABCA4 is mainly expressed in the photoreceptors.[12]

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Further information and support

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  1.  Rahman N, Georgiou M, Khan KN, Michaelides M. Macular dystrophies: clinical and imaging features, molecular genetics and therapeutic options. Br J Ophthalmol. Nov 8 2019;doi:10.1136/bjophthalmol-2019-315086
  2.  Lambertus S, van Huet RA, Bax NM, et al. Early-onset stargardt disease: phenotypic and genotypic characteristics. Ophthalmology. Feb 2015;122(2):335-44. doi:10.1016/j.ophtha.2014.08.032
  3.  Fujinami K, Zernant J, Chana RK, et al. Clinical and molecular characteristics of childhood-onset Stargardt disease. Ophthalmology. Feb 2015;122(2):326-34. doi:10.1016/j.ophtha.2014.08.012
  4.  Lambertus S, Lindner M, Bax NM, et al. Progression of Late-Onset Stargardt Disease. Invest Ophthalmol Vis Sci. Oct 1 2016;57(13):5186-5191. doi:10.1167/iovs.16-19833
  5.  Fujinami K, Sergouniotis PI, Davidson AE, et al. Clinical and molecular analysis of Stargardt disease with preserved foveal structure and function. Am J Ophthalmol. Sep 2013;156(3):487-501.e1. doi:10.1016/j.ajo.2013.05.003
  6.  van Huet RA, Bax NM, Westeneng-Van Haaften SC, et al. Foveal sparing in Stargardt disease. Invest Ophthalmol Vis Sci. Oct 16 2014;55(11):7467-78. doi:10.1167/iovs.13-13825
  7.  Zernant J, Lee W, Collison FT, et al. Frequent hypomorphic alleles account for a significant fraction of ABCA4 disease and distinguish it from age-related macular degeneration. J Med Genet. Jun 2017;54(6):404-412. doi:10.1136/jmedgenet-2017-104540
  8.  Fujinami K, Strauss RW, Chiang JP, et al. Detailed genetic characteristics of an international large cohort of patients with Stargardt disease: ProgStar study report 8. Br J Ophthalmol. Mar 2019;103(3):390-397. doi:10.1136/bjophthalmol-2018-312064
  9.  Cella W, Greenstein VC, Zernant-Rajang J, et al. G1961E mutant allele in the Stargardt disease gene ABCA4 causes bull’s eye maculopathy. Exp Eye Res. Jun 15 2009;89(1):16-24. doi:10.1016/j.exer.2009.02.001
  10.  Burke TR, Fishman GA, Zernant J, et al. Retinal phenotypes in patients homozygous for the G1961E mutation in the ABCA4 gene. Invest Ophthalmol Vis Sci. Jul 3 2012;53(8):4458-67. doi:10.1167/iovs.11-9166
  11.  Gerth C, Andrassi-Darida M, Bock M, Preising MN, Weber BH, Lorenz B. Phenotypes of 16 Stargardt macular dystrophy/fundus flavimaculatus patients with known ABCA4 mutations and evaluation of genotype-phenotype correlation. Graefes Arch Clin Exp Ophthalmol. Aug 2002;240(8):628-38. doi:10.1007/s00417-002-0502-y
  12.  Cremers FPM, Lee W, Collin RWJ, Allikmets R. Clinical spectrum, genetic complexity and therapeutic approaches for retinal disease caused by ABCA4 mutations. Prog Retin Eye Res. Apr 9 2020:100861. doi:10.1016/j.preteyeres.2020.100861
  13.  Strauss RW, Munoz B, Ho A, et al. Progression of Stargardt Disease as Determined by Fundus Autofluorescence in the Retrospective Progression of Stargardt Disease Study (ProgStar Report No. 9). JAMA Ophthalmol. Nov 1 2017;135(11):1232-1241. doi:10.1001/jamaophthalmol.2017.4152
  14.  Khan KN, Kasilian M, Mahroo OAR, et al. Early Patterns of Macular Degeneration in ABCA4-Associated Retinopathy. Ophthalmology. May 2018;125(5):735-746. doi:10.1016/j.ophtha.2017.11.020
  15.  Parodi MB, Cicinelli MV, Iacono P, Bolognesi G, Bandello F. Multimodal imaging of foveal cavitation in retinal dystrophies. Graefes Arch Clin Exp Ophthalmol. Feb 2017;255(2):271-279. doi:10.1007/s00417-016-3450-7
  16.  Fujinami K, Lois N, Davidson AE, et al. A longitudinal study of stargardt disease: clinical and electrophysiologic assessment, progression, and genotype correlations. Am J Ophthalmol. Jun 2013;155(6):1075-1088.e13. doi:10.1016/j.ajo.2013.01.018
  17.  Tanna P, Georgiou M, Aboshiha J, et al. Cross-Sectional and Longitudinal Assessment of Retinal Sensitivity in Patients With Childhood-Onset Stargardt Disease. Translational Vision Science & Technology. 2018;7(6):10-10. doi:10.1167/tvst.7.6.10
  18.  Koh V, Naing T, Chee C. Fundus flavimaculatus and choroidal neovascularization in a young patient with normal electroretinography: case report. Can J Ophthalmol. Jun 2012;47(3):e3-5. doi:10.1016/j.jcjo.2012.03.003
  19.  Huckfeldt RM, East JS, Stone EM, Sohn EH. Phenotypic Variation in a Family With Pseudodominant Stargardt Disease. JAMA Ophthalmol. May 1 2016;134(5):580-583. doi:10.1001/jamaophthalmol.2015.5471
  20.  Battaglia Parodi M, Munk MR, Iacono P, Bandello F. Ranibizumab for subfoveal choroidal neovascularisation associated with Stargardt disease. Br J Ophthalmol. Sep 2015;99(9):1268-70. doi:10.1136/bjophthalmol-2014-305783
  21.  Charbel Issa P, Barnard AR, Herrmann P, Washington I, MacLaren RE. Rescue of the Stargardt phenotype in Abca4 knockout mice through inhibition of vitamin A dimerization. Proc Natl Acad Sci U S A. Jul 7 2015;112(27):8415-20. doi:10.1073/pnas.1506960112
  22.  Sears AE, Bernstein PS, Cideciyan AV, et al. Towards Treatment of Stargardt Disease: Workshop Organized and Sponsored by the Foundation Fighting Blindness. Transl Vis Sci Technol. Sep 2017;6(5):6. doi:10.1167/tvst.6.5.6
  23.  Zhou J, Jang YP, Kim SR, Sparrow JR. Complement activation by photooxidation products of A2E, a lipofuscin constituent of the retinal pigment epithelium. Proc Natl Acad Sci U S A. Oct 31 2006;103(44):16182-7. doi:10.1073/pnas.0604255103
  24.  Berchuck JE, Yang P, Toimil BA, Ma Z, Baciu P, Jaffe GJ. All-trans-retinal sensitizes human RPE cells to alternative complement pathway-induced cell death. Invest Ophthalmol Vis Sci. Apr 12 2013;54(4):2669-77. doi:10.1167/iovs.12-11020
  25.  Trapani I, Colella P, Sommella A, et al. Effective delivery of large genes to the retina by dual AAV vectors. EMBO Mol Med. Feb 2014;6(2):194-211. doi:10.1002/emmm.201302948
  26.  Schwartz SD, Regillo CD, Lam BL, et al. Human embryonic stem cell-derived retinal pigment epithelium in patients with age-related macular degeneration and Stargardt’s macular dystrophy: follow-up of two open-label phase 1/2 studies. Lancet. Feb 7 2015;385(9967):509-16. doi:10.1016/s0140-6736(14)61376-3
  27.  Mehat MS, Sundaram V, Ripamonti C, et al. Transplantation of Human Embryonic Stem Cell-Derived Retinal Pigment Epithelial Cells in Macular Degeneration. Ophthalmology. Nov 2018;125(11):1765-1775. doi:10.1016/j.ophtha.2018.04.037

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Updated on January 31, 2024
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