Previous studies have described peripherin 2 (PRPH2) mutations as causes of vision-threatening diseases such as pattern dystrophy (PD), central areolar choroidal dystrophy, retinitis pigmentosa (RP), and other forms of macular degeneration (MD).1–11PRPH2, or retinal degeneration slow (RDS), is a transmembrane glycoprotein that is crucial for the formation and stabilization of the photoreceptor outer segments.3,12 It stabilizes the outer segment discs by acting as an adhesive element.5 Here we present a family of three affected individuals with a novel C213W (c.639C>G) missense mutation in the PRPH2 gene, which resulted in PD simulating fundus flavimaculatus. We are reporting our findings, including long-term follow-up of four eyes with exudative maculopathy.
Patient A, the proband, a 71-year-old Caucasian woman, initially presented with metamorphopsia in the right eye in November 2005 when she was 58 years old. She had type 2 diabetes and was a nonsmoker. Her medications included aspirin, metformin, lisinopril, hydrochlorothiazide, pravastatin, alprazolam, and vitamin D. Her initial visual acuity (VA) was 20/70 in the right eye with correction −2.75+0.25×160 and 20/20 in the left eye with correction −1.75+1.00×027. Her posterior pole exam revealed bilateral pigmentary changes and numerous yellow flecks in the macula extending beyond the vascular arcades (Figures 1A and 1B). The fluorescein angiography (FA) showed hyperfluorescent flecks bilaterally, and there was unilateral leakage from choroidal neovascularization (CNV) in the right eye (Figures 2A and 2B). The initial treatment in the right eye was full-fluence photodynamic therapy (PDT) with intravitreal triamcinolone injection.
Right (A) and left (B) color fundus images of Patient A showing multiple yellow flecks in the macula extending beyond the vascular arcades in 2005. Right eye exhibits grey lesion nasal of the fovea.
Right (A) and left (B) fluorescein angiography of Patient A demonstrating bilateral hyperfluorescent flecks and leakage from a choroidal neovascularization in the right eye in 2005 (A). (B) Window defect in the left eye.
Seven years later in 2012, she complained of metamorphopsia in the left eye. Her VA was 20/20 in the right eye and 20/40 in the left eye. Her fundus exam revealed macular pigmentary changes most pronounced in the right eye and increased flecks bilaterally. The repeat FA showed occult leakage in the left eye. She then received two intravitreal bevacizumab injections in 2012 and three injections in 2013 in the left eye (Table 1).
The Choroidal Neovascular Membrane Activity and Treatment History of Patient A
In 2015, she agreed to undergo genetic testing. A missense heterozygous c.639C>G mutation was found by EyeGENE (NIH, Bethesda, MD) and confirmed by GeneDx (Gaithersburg, MD). This sequence change replaces cysteine with tryptophan at codon 213 (C213W) of the PRPH2 protein. Genomic DNA was PCR-amplified for exons 1 to 3 of the PRPH2 gene and the corresponding exon/intron splice junctions, and the variant was confirmed by repeat sequence analysis.
The fundus autofluorescence (FAF) photo showed hyper- and hypoautofluorescent flecks in the macula and the midperiphery bilaterally in April 2017 (Figures 3A and 3B). The patient developed a hemorrhage in the right eye associated with subretinal hyperreflective material (SHRM) and recurrent subretinal fluid (SRF) on spectral-domain optical coherence tomography (SD-OCT) in March 2019 (Figure 4). Optical coherence tomography angiography (OCTA) (Heidelberg Engineering, Heidelberg, Germany) showed the CNV in the right eye (Figure 5). She has been treated with as-needed intravitreal anti-vascular endothelial growth factor (VEGF) therapy since 2012 and she retained 20/20 VA bilaterally.
Right (A) and left (B) fundus autofluorescence of Patient A shows scattered hyper- and hypoautofluorescent flecks in the macula and mid-peripheral retina in April 2017.
Right spectral-domain optical coherence tomography of Patient A confirms the presence of subretinal hyperreflective material and subretinal fluid in March 2019 (Heidelberg Engineering, Heidelberg, Germany).
Right en face optical coherence tomography angiography of Patient A exhibits choroidal neovascularization in the avascular complex layer in September 2019 (Heidelberg Engineering, Heidelberg, Germany).
Patient B, a 70-year-old Caucasian woman, the younger sister of the proband, initially presented when she was 54 years old in August 2002 with metamorphopsia in the right eye. She also had type 2 diabetes mellitus and was a nonsmoker. Her medications included aspirin, ramipril, metformin, atenolol, paroxetine, and vitamin D. Her initial VA was 20/30 in the right eye with correction +0.25+0.75×60 and 20/25 in the left eye with correction plano+1.00×125. The fundus exam showed bilateral mid-peripheral yellow flecks, and the right eye showed a grey lesion nasal of the fovea. The initial FA showed bilateral hyperfluorescent flecks in the macula with leakage in the right eye suggestive of CNV (Figures 6A and 6B). We considered treatment with PDT or with oral steroids; however, the leakage ceased spontaneously.
The initial fluorescein angiography of the right (A) and left (B) eye in Patient B shows hyperfluorescent flecks bilaterally in the macula with leakage in the right eye in August 2002.
Seven years later, she demonstrated extension of the flecks toward the vascular arcades and SRF from a CNV in the left eye. She received three intravitreal bevacizumab (Avastin; Genentech, South San Francisco, CA) injections in the left eye for induction therapy and as-needed treatment afterward (Table 2). She underwent genetic testing with The Invitae Inherited Retinal Disease Panel next-generation sequencing (Spark Therapeutics Initiative), which showed the identical heterozygous c.639C>G mutation in PRPH2 gene (C213W).
Choroidal Neovascular Membrane Activity and Treatment History of Patient B
OCTA demonstrated an inactive CNV in both eyes in July 2019 (Figures 7A, 7B, 7C, and 7D). FAF showed bilateral hyper- and hypoautofluorescent flecks in the macula and the mid periphery in November 2019 (Figure 8). SD-OCT demonstrated interval recurrence of SRF and SRHM managed with as-needed intravitreal anti-VEGF therapy. She still maintained 20/20 VA bilaterally.
En face optical coherence tomography (OCT) angiography of the right (A) and left (B) eye and corresponding structural OCT B-scans with flow signal in the right (C) and left (D) eye of Patient B. The presence of choroidal neovascularization (CNV) (red arrows) in the avascular complex layer is revealed in the right (A) and the left (B) eye in July 2019. The structural OCT B-scans exhibited regressed CNV (green arrows) in the right (C) and the left (D) eye (Heidelberg Engineering, Heidelberg, Germany).
Left fundus autofluorescence of Patient B demonstrates multiple hyper- and hypoautofluorescent flecks in the macula and the mid-peripheral retina in November 2019.
Patient C, a 37-year-old Caucasian woman, daughter of the proband, first noticed metamorphopsia in the left eye in 2013 when she was 31 years old. Her initial VA was 20/20 bilaterally.
The posterior pole exam showed multiple yellow flecks in the macula bilaterally, consistent with PD. FAF revealed hyper- and hypoautofluorescent flecks in the macula in February 2017 (Figure 9). OCTA was performed in August 2019, and no CNV was detected. She has been observed without any treatment. She has failed to follow up for complimentary variant testing when it was offered.
Left fundus autofluorescence of Patient C shows pattern dystrophy with hyper- and hypoautofluorescent flecks in the macula.
The pedigree of this family is displayed in Figure 10. Information regarding the grandparents (I-1 and I-2) of the proband was unavailable. The father (II-3) and the uncle (II-2) of the proband (III-4) were previously diagnosed with presumed Stargardt disease. The mother (II-4) of the proband was clinically unaffected. The male cousin (III-1) of the proband was diagnosed with macular degeneration when he was 50 years old. Patient B (III-3), the sister of the proband (III-4), has two clinically unaffected children. The proband (III-4) has two daughters, and one of them is Patient C (IV-4). Patient C (IV-4) has three sons (V-1, V-2, and V-3), and two of them (V-2 and V-3) are identical twins; none of them have been examined yet. Patient C's sister (IV-5) and her son (V-4) are clinically unaffected.
The pedigree. The proband of this family is indicated with the black arrow. STGD = Stargardt disease; AMD = age-related macular degeneration
CNV has been described as a major cause of vision loss in PRPH2-associated PD.1,2,4,6,7,13–15 The long-term clinical data and treatment guidelines are scarce because CNV is rare in PD simulating fundus flavimaculatus.16,17 A PRPH2 variant (p.Cys250Gly) was previously reported in a patient who developed CNV with autosomal dominant RP.8 The precise mechanism of CNV development in PRPH2 mutation has not been established. Previous studies suggest that the mutant structure in the highly conserved intradiscal (D2) loop of the PRPH2 protein could lead to an abnormal formation of the photoreceptor outer segments.3,12,18 Recently Chakraborty et al. reported a study involving a knockin mouse line with the C213Y mutation in PRPH2.18 These C213Y knockin mice exhibited retinal flecking suggestive of pattern dystrophy, and their histologic analyses demonstrated evidence of accumulation of mutant PRPH2 protein in the inner segment and outer nuclear layer. In addition, it was hypothesized that the metabolic byproducts may accumulate after the retinal pigment epithelium digests the mutant PRPH2 proteins, which may disrupt the extracellular matrix that help maintain the barrier against choroidal neovascularization.9,12,19
Parodi et al. reported the successful stabilization of subfoveal CNV and improvement in visual acuity after intravitreal bevacizumab treatment in 12 individuals with PD.20 Vaclavik et al. described a family with PD-associated CNV and Y141C RDS gene mutation and the successful outcome in one individual after intravitreal ranibizumab treatment.6 Recently, Nangia et al. reported a case of CNV secondary to PD simulating fundus flavimaculatus, which responded well to intravitreal ranibizumab (Lucentis; Genentech, South San Fancisco, CA).21
We report a family of three individuals with a clinical diagnosis of autosomal dominant PD secondary to a novel C213W missense mutation in the PRPH2 gene. This disrupted amino acid residue in the D2 loop of the PRPH2 was likely the underlying cause of their disease, given that other variants affecting this residue have been classified as pathogenic.13,18,22 Inter- and intrafamilial phenotype variability in PD and the founder effect have been previously described.2,6,10,11 In our family, the older two siblings have demonstrated similar clinical findings of PD with CNV without significant atrophy or RP. They developed numerous flecks, which were both hyper- and hypofluorescent and confluent in the macula and a dark choroid on FA. They both initially presented with metamorphopsia and were diagnosed with subretinal CNV in their 60s.
Their clinical course was complicated by CNV, causing recurrent SRF and subretinal hemorrhage. One eye had PDT and intravitreal triamcinolone nearly 10 years before starting anti-VEGF treatments. Both sisters received as-needed anti-VEGF injections bilaterally and responded well during their follow-up period and maintained 20/20 VA bilaterally. It will be imperative to closely monitor the younger affected patient for CNV development.
In conclusion, this is the first study of three related individuals with a novel C213W mutation in PRPH2 gene, which is associated with autosomal dominant PD-simulating fundus flavimaculatus. This family shared similar clinical courses of PD with CNV. Patient B had 17 years of follow-up, which is the longest in PD-associated CNV to the best of our knowledge. The findings of this family suggest that intravitreal anti-VEGF treatments can offer significant clinical benefits in patients with PD-associated CNV. This study advances our understanding of the phenotypes and long-term prognosis related to a novel PRPH2 mutation (C213W), which may contribute to further genetic counseling and management of vision-threatening complications due to this mutation.
- Boon CJ, den Hollander AI, Hoyng CB, Cremers FP, Klevering BJ, Keunen JE. The spectrum of retinal dystrophies caused by mutations in the peripherin/RDS gene. Prog Retin Eye Res. 2008;27(2):213–235. doi:10.1016/j.preteyeres.2008.01.002 [CrossRef] PMID:18328765
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- Moshfeghi DM, Yang Z, Faulkner ND, et al. Choroidal neovascularization in patients with adult-onset foveomacular dystrophy caused by mutations in the RDS/peripherin gene. Adv Exp Med Biol. 2006;572:35–40. doi:10.1007/0-387-32442-9_6 [CrossRef] PMID:17249552
- Cheng J, Fu J, Zhou Q, et al. A novel splicing mutation in the PRPH2 gene causes autosomal dominant retinitis pigmentosa in a Chinese pedigree. J Cell Mol Med. 2019;23(5):3776–3780. doi:10.1111/jcmm.14278 [CrossRef] PMID:30892800
- Vaclavik V, Tran HV, Gaillard MC, Schorderet DF, Munier FL. Pattern dystrophy with high intrafamilial variability associated with Y141C mutation in the peripherin/RDS gene and successful treatment of subfoveal CNV related to multifocal pattern type with anti-VEGF (ranibizumab) intravitreal injections. Retina. 2012;32(9):1942–1949. doi:10.1097/IAE.0b013e31824b32e4 [CrossRef] PMID:22466463
- Francis PJ, Schultz DW, Gregory AM, et al. Genetic and phenotypic heterogeneity in pattern dystrophy. Br J Ophthalmol. 2005;89(9):1115–1119. doi:10.1136/bjo.2004.062695 [CrossRef] PMID:16113362
- Katagiri S, Hayashi T, Mizobuchi K, Yoshitake K, Iwata T, Nakano T. Autosomal dominant retinitis pigmentosa with macular involvement associated with a disease haplotype that included a novel PRPH2 variant (p.Cys250Gly). Ophthalmic Genet. 2018;39(3):357–365. doi:10.1080/13816810.2018.1459737 [CrossRef] PMID:29630435
- Khani SC, Karoukis AJ, Young JE, et al. Late-onset autosomal dominant macular dystrophy with choroidal neovascularization and nonexudative maculopathy associated with mutation in the RDS gene. Invest Ophthalmol Vis Sci. 2003;44(8):3570–3577. doi:10.1167/iovs.02-1287 [CrossRef] PMID:12882809
- Shankar SP, Birch DG, Ruiz RS, et al. Founder effect of a c.828+3a>t splice site mutation in peripherin 2 (prph2) causing autosomal dominant retinal dystrophies. JAMA Ophthalmol. 2015;133(5):511–517. doi:10.1001/jamaophthalmol.2014.6115 [CrossRef] PMID:25675413
- Shankar SP, Hughbanks-Wheaton DK, Birch DG, et al. Autosomal dominant retinal dystrophies caused by a founder splice site mutation, c.828+3a>t, in prph2 and protein haplotypes in trans as modifiers. Invest Ophthalmol Vis Sci. 2016;57(2):349–359. doi:10.1167/iovs.15-16965 [CrossRef] PMID:26842753
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The Choroidal Neovascular Membrane Activity and Treatment History of Patient A
|Right Eye||Left Eye|
|PDT and intravitreal triamcinolone injection in November 2005||Intravitreal bevacizumab in February/March 2012;June/August/December 2013|
|Intravitreal bevacizumab in January 2014|
|Intravitreal aflibercept in September/December 2016; January/October 2017; January/March/May 2018; March/May/September/December 2019|
Choroidal Neovascular Membrane Activity and Treatment History of Patient B
|Right Eye||Left Eye|
|The presence of CNV was identified in 2002; however, it resolved untreated.||Intravitreal bevacizumab in April/May/June 2009.|
|Intravitreal bevacizumab in May/June 2015.|
|Intravitreal aflibercept in October 2015; December 2016; October/November 2019; January 2020||Intravitreal ranibizumab in September 2011.|
|Intravitreal bevacizumab in November 2011; February/June/July/September/October 2012; June/November/December 2013; January 2014; June/July 2015|
|Intravitreal aflibercept in August/November 2015; August 2017; July/August 2019|