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Year : 2021  |  Volume : 1  |  Issue : 4  |  Page : 699-701

Asymmetric maculopathy with mutations in adenosine triphosphate-binding cassette, sub-family A, member 4 and jagged canonical notch ligand 1 after 30 years of monocular aphakia

1 Department of Ophthalmology, UT Southwestern Medical Center, Dallas, Texas, United States
2 Retina Foundation of the Southwest, Rose-Silverthorne Retinal Degenerations Laboratory, Dallas, Texas, United States

Date of Submission02-Dec-2020
Date of Acceptance20-Mar-2021
Date of Web Publication09-Oct-2021

Correspondence Address:
Dr. Rafael L Ufret-Vincenty
Department of Ophthalmology, UT Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, Texas
United States
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/ijo.IJO_3583_20

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We report an unusual case of asymmetric maculopathy in a patient with a 30-year history of monocular aphakia. An 82-year old man presented with unexplained visual loss in his right eye. Examination revealed loss of the ellipsoid zone, abnormal visual fields, and multifocal electroretinogram, all worse in the right eye. Suspecting a genetic predisposition to maculopathy that may have been exacerbated by the asymmetric media, we conducted genetic testing that revealed mutations in adenosine triphosphate-binding cassette, sub-family A, member 4 (ABCA4) and jagged canonical notch ligand 1 (JAG1). This case shows that a genetic predisposition toward maculopathy may be exacerbated by extraretinal factors, including the asymmetric phakic status of the eyes.

Keywords: ABCA4, aphakia, asymmetric maculopathy, genetic variant, JAG1

How to cite this article:
Patel PN, Jones KD, Birch DB, Ufret-Vincenty RL. Asymmetric maculopathy with mutations in adenosine triphosphate-binding cassette, sub-family A, member 4 and jagged canonical notch ligand 1 after 30 years of monocular aphakia. Indian J Ophthalmol Case Rep 2021;1:699-701

How to cite this URL:
Patel PN, Jones KD, Birch DB, Ufret-Vincenty RL. Asymmetric maculopathy with mutations in adenosine triphosphate-binding cassette, sub-family A, member 4 and jagged canonical notch ligand 1 after 30 years of monocular aphakia. Indian J Ophthalmol Case Rep [serial online] 2021 [cited 2022 Aug 17];1:699-701. Available from: https://www.ijoreports.in/text.asp?2021/1/4/699/327677

Damage to the macula can be caused by a wide spectrum of clinical etiologies, including genetic disorders. In inherited maculopathies, different mutations of the same gene often lead to dissimilar presentations, and simultaneous mutations in more than one gene can lead to compound effects on the phenotype. To our knowledge, this is the first description of a gradual, asymmetric maculopathy associated with adenosine triphosphate-binding cassette, sub-family A, member 4 (ABCA4) and jagged canonical notch ligand 1(JAG1) variants in a patient with a long history of monocular aphakia.

  Case Report Top

An 82-year-old man was referred because of unexplained gradual visual loss in his right eye over 10 years. In 2008, he was suspected of an ischemic optic neuropathy. Brain imaging was unremarkable. His only medications were antihypertensives and gabapentin (started using the medicines years after the symptoms started). He had never taken hydroxychloroquine, chloroquine, or antipsychotic medications. He had prostate cancer diagnosed and resected in 1994 with no recurrences. He was in excellent general health and denied weight loss or a history of tobacco use. He denied photopsia or photosensitivity.

On our initial exam in 2016, his vision was 20/20 in both eyes. He had posterior chamber intraocular lens implants in both eyes. Both optic nerves appeared normal, except for some gliosis overlying both nerves. There was some vascular attenuation in both eyes. A macular exam revealed mild retinal pigment epithelium (RPE) mottling in both maculae (suspicious for a bull's eye maculopathy in the right eye). All these changes were still visible in 2020, and in addition some foveal changes suggestive of early vitelliform lesions could be seen [Figure 1].
Figure 1: Fundus photographs in 2019 showing a bull's eye maculopathy in the right eye and mild foveal pigmentary changes suggestive of early vitelliform lesions in both eyes. Mild prepapillary gliosis and attenuation of some vessels can also be seen

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The optical coherence tomography (OCT; Spectralis, Heidelberg Engineering, Heidelberg, Germany) of the right eye showed significant loss of the ellipsoid in the macula, with foveal preservation [Figure 2]a, which worsened over 3 years [Figure 2]b. The left eye OCT appeared fairly unremarkable in 2017. But by 2020, early parafoveal ellipsoid attenuation and a small vitelliform change were seen. There was no evidence of nerve fiber layer loss on OCT. The Humphrey visual field (HVF; HFA II 750, Carl Zeiss Meditec, Dublin, CA, USA) showed a dramatic worsening in 2016 compared with 2008 [Figure 3]a and [Figure 3]b: the “arcuate field defect” in the right eye had progressed to a ring scotoma, and the left eye showed early field changes. A multifocal electroretinogram (mfERG) revealed striking loss of signal in both eyes (right eye significantly worse) [Figure 4]. However, a full-field ERG (Espion D300, Diagnosys LLC, Lowell, MA, USA) revealed only mild reduction in the left eye and borderline signals in the right eye (data not shown).
Figure 2: OCT shows attenuation of the ellipsoid zone in the right eye but not the left in 2017 (a). By 2020, ellipsoid changes progressed in the right eye and started to appear in the left (plus early vitelliform-like changes) (b)

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Figure 3: Visual fields in 2008 revealed an “arcuate field defect” in the right eye (a), which progressed to a ring scotoma by 2016 (b)

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Figure 4: Multifocal electroretinogram in 2016 revealed a prominent reduction in signal in the right eye worse than the left

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Although paraneoplastic retinopathy should be considered in the differential diagnosis, the clinical history, ocular history, and electrophysiology testing made this diagnosis unlikely.[1] Although testing indicated a bilateral maculopathy rather than an optic neuropathy, the asymmetry was puzzling. Further questioning revealed that the patient had cataract surgery done in the left eye in 1980 and was left aphakic. He used an aphakic contact lens that was designed for long-term use (Permalens – made of Perfilcon A). He had cataract surgery with posterior chamber intraocular lens (IOL) implantation in the right eye in 1982. The left eye had secondary IOL implantation in the sulcus in 2013.

We suspected a genetic predisposition to develop a maculopathy, which had been manifesting asymmetrically due to differences between the IOL and the aphakic contact lens in terms of their effect on light reaching the macula. Genetic testing using next-generation sequencing (Retinal dystrophy panel, Blueprint Genetics, Helsinki, Finland) revealed that the patient is heterozygous for the pathogenic ABCA4 c.6089G>A, p.(Arg2030Gln) variant and heterozygous for the JAG1 c.3347G>A, p.(Arg1116Gln) variant of uncertain significance.

  Discussion Top

Genetic analysis of our patient revealed heterozygosity in JAG1 and ABCA4 variants. More than 230 JAG1 mutations have been reported, with many leading to autosomal dominant Alagille syndrome.[2],[3] The syndrome classically involves the heart, kidney, liver, and eye. Our patient did not have systemic anomalies but did demonstrate the ocular changes, such as prepapillary gliosis and sclerotic vessels [Figure 1]. Although a JAG1 mutation could potentially lead to relatively mild macular changes and no clinically significant systemic findings, the JAG1 variant in our patient (c.3347G>A, p.Arg1116Gln) is classified as a variant of uncertain significance in ClinVar (ID 501666). Computational pathogenicity analysis shows mixed results. Therefore, it is still unclear if it affects gene function.

The ABCA4 gene has been studied extensively in relation to maculopathies, with biallelic mutations shown to cause Stargardt disease. Recent studies have shown maculopathies associated with monoallelic mutations and hypomorphic ABCA4 variants.[4],[5] Consistent with our findings, another study found ABCA4 carriers demonstrating mild macular pigmentary changes but significantly reduced mfERG.[6] Mouse studies found that heterozygous ABCA4 can lead to increased lipofuscin in the RPE.[7] Finally, heterozygous mutations in ABCA4 (p.V2050L) have also been reported to contribute to an exacerbation of the phenotype conferred by a monoallelic mutation in PRPH 2 (p.R172W).[8] A similar scenario in which monoallelic ABCA4 and JAG1 variants work in concert to generate a maculopathy could be envisioned.

Unique clinical features of our case include the asymmetrical presentation of the maculopathy and the 30-year aphakic status of the left eye. The relationship between macular dystrophies and asymmetric lens status has not been well studied. One study of Stargardt patients reported that unilateral protection from light exposure led to reduced progression of maculopathy, suggesting a reduction in the rate of RPE damage in the protected eye.[9] We propose that the aphakic status of the left eye in our patient may have been protective by leading to a decrease in light damage in that eye. Two potential mechanisms are as follows: (1) lack of focused light in the aphakic left eye when not wearing contact lens correction and (2) an alteration of the light spectrum reaching the retina due to the properties of the rigid contact lens. It is possible that the Permalens contact lens may have had an impact on the expression of the maculopathy by affecting the spectrum or intensity of the light reaching the macula. This lens has now been discontinued and the spectral properties are not known, making it difficult to test this hypothesis.

  Conclusion Top

Our case demonstrates that genetic mutations leading to macular degeneration may have an atypical, asymmetric presentation due to the modifying effect of extraretinal factors such as the phakic status. Specifically, that the lack of focused light in the aphakic left eye may have served as a protective factor against the progression of retinal dystrophy. Furthermore, the fact that our patient had monoallelic mutations in ABCA4 and JAG1 led to an interesting discussion regarding the potential role of these mutations individually or in combination in the maculopathy.


We thank the patient for allowing us to submit this case report.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Financial support and sponsorship

This work was supported by an unrestricted grant from Research to Prevent Blindness.

Conflicts of interest

There are no conflicts of interest.

  References Top

Przeździecka-Dołyk J, Brzecka A, Ejma M, Misiuk-Hojło M, Torres Solis LF, Solís Herrera A, et al. Ocular paraneoplastic syndromes. Biomedicines 2020;8:490.  Back to cited text no. 1
Kim BJ, Fulton AB. The genetics and ocular findings of Alagille syndrome. Semin Ophthalmol 2007;22:205-10.  Back to cited text no. 2
Spinner NB, Colliton RP, Crosnier C, Krantz ID, Hadchouel M, Meunier-Rotival M. Jagged1 mutations in alagille syndrome. Hum Mutat 2001;17:18-33.  Back to cited text no. 3
Fritsche LG, Fleckenstein M, Fiebig BS, Schmitz-Valckenberg S, Bindewald-Wittich A, Keilhauer CN, et al. A subgroup of age-related macular degeneration is associated with mono-allelic sequence variants in the ABCA4 gene. Invest Ophthalmol Vis Sci 2012;53:2112-8.  Back to cited text no. 4
Zernant J, Lee W, Collison FT, Fishman GA, Sergeev YV, Schuerch K, et al. Frequent hypomorphic alleles account for a significant fraction of ABCA4 disease and distinguish it from age-related macular degeneration. J Med Genet 2017;54:404-12.  Back to cited text no. 5
Kjellström U. Reduced macular function in ABCA4 carriers. Mol Vis 2015;21:767-82.  Back to cited text no. 6
Mata NL, Tzekov RT, Liu X, Weng J, Birch DG, Travis GH. Delayed dark-adaptation and lipofuscin accumulation in abcr+/− mice: Implications for involvement of ABCR in age-related macular degeneration. Invest Ophthalmol Vis Sci 2001;42:1685-90.  Back to cited text no. 7
Poloschek CM, Bach M, Lagrèze WA, Glaus E, Lemke JR, Berger W, et al. ABCA4 and ROM1: Implications for modification of the PRPH 2-associated macular dystrophy phenotype. Invest Ophthalmol Vis Sci 2010;51:4253-65.  Back to cited text no. 8
Teussink MM, Lee MD, Smith RT, van Huet RA, Klaver CC, Klevering BJ, et al. The effect of light deprivation in patients with Stargardt disease. Am J Ophthalmol 2015;159:964-72.e2.  Back to cited text no. 9


  [Figure 1], [Figure 2], [Figure 3], [Figure 4]


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