Clearing the AIR: A PRPH2 mutation identified in the evaluation of presumed autoimmune retinopathy

Abstract

Purpose

To detail the identification of a likely pathogenic variant in PRPH2 in a daughter-father duo, highlighting the diagnostic challenges in differentiating nonparaneoplastic autoimmune retinopathy (npAIR) from inherited retinal degeneration (IRD), particularly in the presence of an underlying autoimmune disease.

Observations

A 49-year-old woman with a history of systemic autoimmune disease presented with progressive peripheral vision loss, retinal vasculitis, and macular vitelliform lesions. The initial diagnosis of npAIR was later revised to an inherited retinal degeneration when her father was also found to be heterozygous for the same missense, likely pathogenic variant in the PRPH2 gene (c.659G > C:p.R220P). This PRPH2-associated retinopathy was associated with photoreceptor and retinal pigmented epithelium degeneration as well as vascular leakage and retinal edema that resolved with intravitreal steroids.

Conclusions and importance

The case of the proband underscores the diagnostic dilemma of differentiating npAIR from an IRD, especially in the presence of preexisting autoimmune disease. The identification of a likely pathogenic variant in PRPH2 adds to the genetic understanding of the spectrum of phenotypes that can be associated with this IRD. The effectiveness of intravitreal steroids in treating retinal edema in the proband supports its utility in recalcitrant cases of IRD-associated CME or retinal edema.

Highlights

• •The diagnostic dilemma of npAIR versus an insidious presentation of IRD are discussed.
• •A PRPH2 variant is linked to retinal degeneration and retinal leakage associated with an area of retinal edema.
• •Intravitreal steroids improved retinal edema in a patient with PRPH2-associated retinopathy.
• •The possible interplay of neuroinflammation and IRDs is discussed.

1. Introduction

Autoimmune retinopathy (AIR) is a rare form of uveitis that can be challenging to identify due to the lack of a gold standard diagnostic tests or pathognomonic clinical findings.^1,2. Instead, AIR is a diagnosis of exclusion made in the correct clinical context and based on consensus guidelines, when other infectious, inflammatory, metabolic, neoplastic, and genetic causes have been excluded.^3,4.

Patients with an AIR typically present with visual symptoms such as photopsias, scotomas, and nyctalopia. Unifying these complaints with objective exam findings often requires the use of visual field testing and fundus imaging since clinical examination of the fundus is generally unremarkable.⁵. Visual field results can vary by patient and range from multifocal scotomata to dense, concentric, peripheral loss. Optical coherence tomography (OCT) imaging can be helpful at detecting the photoreceptor loss typical to an AIR, although early in disease the retinal damage may not be visible and in cases of Melanoma Associated Retinopathy (MAR) OCT imaging is typically unremarkable.⁶. Fundus autofluorescence (FAF) can also demonstrate different patterns of abnormality including hyper-autofluorescence in areas of active photoreceptor loss that become mottled and hypo-autofluorescence with time.⁷. In the presence of macular edema, vascular sheathing or more than mild vitritis, fluorescein and Indocyanine Green (ICG) angiography should be performed to look for evidence of other more common forms of uveitis. In the absence of other findings, an electroretinogram (ERG) can be helpful in confirming dysfunction of the retina consistent with an AIR and suggest the diagnosis of MAR in the case of a “negative ERG” pattern.⁸.

When working up a case of possible AIR, the laboratory evaluation should exclude other diagnoses consistent with the clinical presentation. Relevant differential diagnoses to consider include the variants of autoimmune retinopathy including non-paraneoplastic autoimmune retinopathy [npAIR], cancer associated retinopathy [CAR], bilateral acute zonal occult outer retinopathy (AZOOR), placoid syphilis or syphilitic outer retinopathy, idiopathic retinal vasculitis, and an inherited retinal degeneration. Infectious etiologies of vision loss like syphilis and tuberculosis should be ruled out with serologic tests. A chest X-ray or CT should be performed to look for sarcoidosis. In addition, the possibility of an underlying malignancy needs to be excluded. Serologic detection of anti-recoverin antibodies can help support the diagnosis of CAR, but the presence of other anti-retinal antibodies is neither sensitive or specific for AIR and not routinely recommended.⁹. Differentiating patients with an autoimmune retinopathy from those with some forms of inherited retinal degenerations (IRDs) can be one of the more challenging diagnostic dilemmas as both conditions can present with similar visual symptoms and exam findings.10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22.

This challenge is exemplified by the following case in which the diagnosis of non-paraneoplastic AIR (npAIR) was eventually revised to an IRD with the identification of a dominantly inherited pathogenic variant in the PRPH2 gene. This case highlights clinical findings useful for suggesting an IRD early in the work up of peripheral vision loss and demonstrates how genetic testing can be used to help distinguish between AIR and an IRD.

2. Case 1

A 49-year-old Caucasian woman was referred to our university-based uveitis clinic for further evaluation of progressive bilateral peripheral vision loss. The referring retina specialist requested an evaluation to rule out an AIR. An IRD was considered less likely due to the absence of typical peripheral “bone spicule” pigmentary changes seen in retinitis pigmentosa (RP). Her symptoms included a 2-year history of central photopsias and progressive nyctalopia. Her past ocular history was significant for bilateral laser assisted in situ keratomileusis (LASIK) and past medical history was significant for axial spondylitis requiring treatment with Methotrexate 15 mg weekly and infliximab (Remicade) 5 mg/kg every four weeks.

At presentation to our clinic, her visual acuity was 20/20 in the right eye and 20/30 in the left eye. Intraocular pressures, extraocular motility, and pupillary function were normal but bilateral peripheral visual field constriction was detected by confrontation. Slit-lamp examination was unremarkable without anterior chamber or vitreous cell and no cataracts. The dilated fundus examination revealed parafoveal drusenoid deposits, subtle retinal pigment epithelium (RPE) atrophy in the superior arcades, and marked vascular attenuation without perivascular hyperpigmentation or sheathing in both eyes. Additionally, in the left eye, a solitary pigmented chorioretinal scar was present nasal to the optic nerve.

Ocular imaging and visual field assessment testing were performed (Fig. 1). Ultra-wide field fundus autofluorescence (FAF) revealed mottled hypo-autofluorescence consistent with RPE loss, especially superior to the macula beyond the superior arcades, and focal parafoveal hyper-autofluorescence associated with the subretinal deposits (Fig. 1B). An OCT of the central macula showed mild blunting of the normal foveal contour without CME and photoreceptor loss sparing the fovea/pericentral retina where there is clear ONL thinning (Fig. 1D). OCT scans of the pericentral retina near the vascular arcades revealed the presence of an epiretinal membrane, cystoid retinal edema, and extensive loss of outer retinal layers (Fig. 1E). Fluorescein angiography (FA) revealed diffuse bilateral retinal leakage in the vascular arcades and mid-periphery with relatively higher intensity leakage in the area associated with cystoid retinal edema on OCT (Fig. 1F–G). Octopus 900 kinetic visual field showed that the far peripheral responses were normal to III4e (red) and V4e (blue), but all other isopters were moderately to severely constricted. In addition, there were arcuate-like relative scotomas emanating from the physiological blind spot superiorly (I4e) and inferiorly (I4e, III4e, V4e), which correlates geographically with the most severe areas of the retinopathy (Fig. 1H). A full field electroretinogram (ffERG) was obtained on a Diagnosys Espion system with the Casey Eye Institute historical standard protocol using DA 6.0 and LA 6.0 rather than ISCEV standards. ERG results identified abnormal amplitudes and abnormal implicit times of the rod-dependent responses consistent with severe rod-cone dysfunction (Fig. 1I). Laboratory tests ordered included a complete blood count (CBC), comprehensive metabolic panel (CMP), QuantiFERON gold, syphilis serology, and a chest X-ray. All results were normal or negative, and due to the presence of retinal leakage with cystoid retinal edema despite on-going treatment with infliximab and methotrexate for her inflammatory arthritis she was offered additional local therapy with periocular steroid injections.

Fig. 1.

Presentation with Symmetric Outer Retinal Degeneration, Retinal Leakage and Peripheral Vision Loss.

Legend: A. Ultrawide-field fundus photo right eye (OD), Optos (Optos PLC, Dunfermline, United Kingdom). B. FAF OD, Optos. C. En face OCT macular thickness map overlay OD, Heidelberg Spectralis (Heidelberg Engineering, Heidelberg, Germany). D. OCT fovea OD. E. OCT through the inferior arcade OD. F-G. FA OD, minutes 1 and 3, Heidelberg Spectralis. H. Kinetic visual field OD, Octopus 900. Isopters I2e (purple), I3e (yellow), I4e (green) are severely constricted. Isopters III4e (red) and V4e (blue) are relatively preserved. In addition, arcuate-like relative scotomas emanate from the physiological blind spot superiorly (I4e) and inferiorly (I4e, III4e, V4e), which correlates geographically with the most severe areas of the retinopathy. I. Electroretinography (ERG), Diagnosys Espion system (Diagnosys LLC, Lowell, MA, USA), findings for the right and left eyes compared to a normal eye, demonstrating symmetric diffuse attenuation of amplitudes and prolongation of timing across all scotopic and photopic responses in both eyes with a pattern of severe rod-dependent dysfunction and mild cone-dependent dysfunction. Arrowheads indicate areas of RPE atrophy. Arrows in C, E, F, and G indicate areas of retinal edema in the peripheral macula. (For interpretation of the references to color in this figure legend, the reader is referred to the Web version of this article.)

Bilateral injections improved but did not resolve the retina edema, so she was subsequently treated with intravitreal injection of 0.7 mg dexamethasone implants (Ozurdex®). Following sequential bilateral injections, the retinal leakage and cystoid retinal edema resolved on FA and OCT (Fig. 2A–F). Over the next two years she experienced recurrences of peripheral macular edema at roughly 5-month intervals and received three bilateral dexamethasone implants before transitioning to the longer acting 0.18 mcg fluocinolone acetonide implant (Yutiq®). Following bilateral injections of fluocinolone acetonide implant, her macular edema did not recur for over 12 months. Bilateral fluocinolone acetonide implant injections were repeated once more and subsequently the edema has remained controlled at her most recent follow up. Overall, her visual fields demonstrate preservation of her central visual field, but there was evidence of progressive RPE loss particularly in the superior arcade as seen on wide field FAF (Fig. 2G–J).

Fig. 2.

Treatment with Intravitreal Steroid Implants Controls Retinal Leakage but does not Prevent Retinal Pigment Epithelium Atrophy.

Legend: A. Baseline foveal OCT right eye (OD). B. Baseline OCT through the inferior peripheral macula OD. C. Baseline FA OD at 3 min. D. 1 month follow up foveal OCT OD. E. 1 month follow up OCT through the inferior peripheral macula OD. F. 1 month follow up FA at 5 min OD. G. Baseline ultrawide-field FAF, left eye (OS). H. Baseline 30-2 HVF OS. I. 5 year follow up FAF OS. J. 5 year follow up 30-2 HVF OS. Arrowheads in A-F indicate the location of retinal edema from vascular leakage that improved after intravitreal steroid injection. Arrows in G-J indicate locations of progressive RPE atrophy that correlate with progressive visual field loss over time.

Concurrent with the management above, CLIA-certified genetic testing was performed at the Massachusetts Eye and Ear Ocular Genomics Institute with the Genetic Eye Disease Panel for Retinal Genes, which consist of next-generation sequencing with Sanger sequencing confirmation for 250 genes associated with IRD. A heterozygous variant in PRPH2 (c.659G > C:p.R220P) was detected and interpreted to be likely pathogenic based on the following: 1) disease causing by in silico algorithm prediction, 2) absent from the ExAC national genomics database, 3) two other mutations at this amino acid position have been reported to cause pattern dystrophy,^15,23 4) functional data was available for one of the known mutations,^15,23,24 and 5) one previous report of this variant.²⁵. Subsequent family history elicited vision loss in her brother and father and 3 years after her initial exam with us, her father agreed to a retinal examination and genetic testing.

3. Case 2

At the time of his exam, her father was 78 years old and reported a history of chronic and progressive vision loss. His past ocular history included low-tension glaucoma and myopia prior to cataract surgery as well as a remote diagnosis of a pattern dystrophy. His visual acuity was 20/25 in the right eye and 20/600 in the left eye. Eye pressure, extraocular motility and pupillary function were all normal, but bilateral nasal visual field loss was detected by confrontation. His posterior segment exam was notable for the presence of bilateral peripapillary and macular RPE atrophy, attenuated vessels, and bone spicules in the periphery (Fig. 3). FAF imaging highlighted a symmetric pattern of RPE atrophy involving the vascular arcades and the central macula as well as a ring of hyper autofluorescence in the perifoveal macula. OCT images demonstrated extensive retinal atrophy with central foveal sparing on the right, but loss of foveal photoreceptors on the left. No macular edema was identified centrally or peripherally in either eye.

Fig. 3.

Advanced Retinal Degeneration Identified in the Proband's Father.

Legend: A. 45° color fundus photo. B. Fundus autofluorescence. C. Infrared en face image and foveal OCT B-scan image. Heidelberg Spectralis (Heidelberg Engineering, Heidelberg, Germany). Top row: OD, right eye. Bottom row: OS, left eye. Arrowheads indicate areas of advanced RPE atrophy in the macula, the arcades, and around the optic nerve head in the proband's father. Arrows indicate atrophy of the retina and RPE in the fovea of the left eye. Asterisk indicates an area of bone spicules in the left eye. (For interpretation of the references to color in this figure legend, the reader is referred to the Web version of this article.)

Both of the proband's parents underwent genetic testing, which detected the same c.659G > C:p.R220P variant in PRPH2 for the father, but not the mother. The similarities in the retinal findings segregate with the genetic test results in the proband and her father, which is consistent with the expected autosomal dominant inheritance pattern PRPH2-associated retinopathy. Thus, her diagnosis was revised to PRPH2-associated retinopathy complicated by retinal edema.

4. Discussion

In this case, the patient's preexisting systemic autoimmune disease and equivocal genetic testing initially supported the diagnosis of npAIR. However, her diagnosis was ultimately determined to be an IRD complicated by retinal edema, which was confirmed by genetic testing and phenotype-genotype segregation with the proband's affected father. Both were heterozygous for the same likely pathogenic missense variant in the PRPH2 gene (c.659G > C:p.R220P). Our case underscores the importance of combining family and personal history with genetic testing in the right clinical context to help uncover an undiagnosed IRD masquerading an AIR.

One clinical difference that can help distinguish between an AIR and IRD is the rate of progression of retinal degeneration. AIR typically progresses quickly, with rapid vision loss and retinal degeneration detectable over the course of months.³ In contrast, IRDs tend to progress more slowly on the scale of years or decades. However, the subjective detection of vision loss and when in the course of a patient presents for evaluation can impact accuracy in determining a true rate of progression.²⁶. In the proband's case, one important clinical clue to the underlying IRD rather than AIR was the presence of the bilaterally symmetric pericentral to near midperipheral pigmentary retinopathy. This finding was common among patients in a recently published large case series of PRPH2 patients.²⁷.

The PRPH2 (Peripherin 2) gene is responsible for encoding a photoreceptor-specific transmembrane glycoprotein involved in photoreceptor outer segment formation, maintenance, and shedding.^28,29. Mutations in this gene have been described in association with a wide range of clinical phenotypes ranging from RP to the macular pattern dystrophies and adult vitelliform macular dystrophies.^27,30. Most mutant alleles lead to a loss of functional protein and are associated with an autosomal dominant inheritance pattern suggesting that haploinsufficiency of PRPH2 or a deleterious gain of function is responsible for disease pathogenesis.^28,31.

Bianco et al. proposed a classification system for PRPH2-associated retinopathy based on clinical presentation, imaging, and genetics.^10,30. Based on this system, the proband's phenotype would be categorized as a severe missense variant due to the severe rod-cone dysfunction identified on the full-field ERG. The same c.659G > C:p.R220P allele mutation had been reported previously in a mother daughter pair. In this case, the mother's disease was described as more severe and with an earlier onset (age 16) than in the daughter (age 40). In contrast to our case, no inflammatory features or CME was reported. This type of variable disease phenotype has been well reported for PRPH2-associated retinopathy.^30,32.

While these cases suggests that the degree of retinal inflammation seen in our proband daughter may be due to patient-specific factors, there is mounting evidence, based on both animal and some clinical studies, that an overly activated innate immune system may promote neuroinflammation in IRD.³³. This case adds to the body of knowledge indicating that neuroinflammation may play a role in the pathogenesis of IRDs.^19,33, 34, 35. Clinical biomarkers of inflammation have been described in several IRDs, including vitritis and CME in enhanced S-cone syndrome,³⁶ and mild to moderate vitritis, CME, and retinal or vascular leakage in RP.10, 11, 12, 13, 14^,20,21. Elevated levels of pro-inflammatory cytokines in the vitreous and aqueous humors of patients with RP further support the presence of a sustained immune response.¹⁹. In other cases, the activation of innate and adaptive inflammation have been described in animal models.^34,35,37,38. While it is still unclear whether inflammation contributes to the initial retinal degeneration or results from a secondary response triggered by photoreceptor cell death,^22,33,39 our case further supports the complex interplay between IRDs and inflammation.

The etiology of CME in IRD is not well understood, and up to 50 % of the RP-associated CME do not leak on fluorescein angiography.⁴⁰. Our patient's retinal edema, unresponsive to systemic anti-inflammatory treatments for spondylitis, improved with intravitreal steroids. While topical or oral carbonic anhydrase inhibitors (CAI) are generally proposed to be first line treatment for CME in IRD due to their safety profile, their effectiveness varies.40, 41, 42. While most CME cases in IRD are mild and do not significantly impact visual acuity, severe cases may resemble uveitic CME, necessitating more aggressive treatments have been employed, such as intravitreal steroids or anti-vascular endothelial growth factor (VEGF) therapies, despite evidence that VEGF levels are already low in eyes with RP.⁴³. The choice of treatment, including the use of the longer-acting fluocinolone acetonide implant, which offers a more favorable risk-to-benefit ratio than the more potent dexamethasone implant, should be tailored to each patient's specific condition and potential long-term therapy risks.

5. Conclusion

This study highlights the importance of considering an undiagnosed IRD masquerading as npAIR and contributes to a growing body of literature characterizing the phenotypic variation of PRPH2 mutations. Furthermore, this case suggests that the intravitreal 0.18 mg fluocinolone acetonide implant may be helpful for long-term control of retinal edema in patients with IRDs.

CRediT authorship contribution statement

Francisco J. Bonilla-Escobar: Writing – review & editing, Writing – original draft, Visualization, Project administration, Investigation, Conceptualization. Charlie Sawyer: Writing – review & editing, Writing – original draft, Investigation, Conceptualization. Paul Yang: Writing – review & editing, Supervision, Investigation, Conceptualization. Kathryn L. Pepple: Writing – review & editing, Visualization, Project administration, Investigation, Conceptualization.

Patient consent

The patients provided written consent to the publication of this case series.

Authorship

All authors attest that they meet the current ICMJE criteria for Authorship.

Funding

KP: Research to prevent blindness unrestricted departmental award, Foundation Fighting Blindness translational research acceleration award, National Institutes of Health (NIH), National Eye Institute (NEI), Bethesda, Maryland, NEI R01EY030431, University of Washington (UW) Vision Research Core Grant (NEI P30EY01730). PY: National Institutes of Health (Bethesda, MD) P30 EY010572 core grant, Malcolm M. Marquis, MD Endowed Fund for Innovation, unrestricted grant from Research to Prevent Blindness (New York, NY) to Casey Eye Institute, Oregon Health & Science University.

Declaration of competing interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.