Clinical and Imaging Characteristics of PRPH2 Retinopathies in a Longitudinal Cohort and Diagnostic Implications

Abstract

Purpose: The purpose of this study was to define genotypic-phenotypic correlations related to PRPH2-associated retinopathies in an observational longitudinal cohort and to improve diagnostic accuracy.

Methods: Individuals with PRPH2 variants were identified by genetic sequencing of 263 individuals (including 59 families). Ocular examinations with multimodal imaging were evaluated.

Results: Two pathogenic/likely pathogenic PRPH2 variants were identified in 22 individuals with retinopathies, low genetic susceptibility to age-related macular degeneration (AMD) and younger age of onset. The mean follow-up was 14 years. One family and 4 independent cases (n = 7) were heterozygous for the variant rs121918563 L185P (p.Leu185Pro). The individuals developed retinopathy compatible with autosomal dominant pattern dystrophy (PD), including adult-onset vitelliform macular dystrophy and butterfly macular dystrophy in their fourth to fifth decades of life, evolving to retinal pigment epithelial (RPE) irregularities and central macular atrophy 20 years later. Two families and an independent case (n = 15) had the rs281865373 splice-site variant c.828+3A>T (IVS2+3A>T) presenting as retinal flecks consistent with adult-onset fundus flavimaculatus with macular dystrophy and diffuse RPE atrophy consistent with central areolar chorioretinal dystrophy (CACD) in the fifth decade of life progressing to extensive atrophy in the sixth to eighth decades. The L185P variant was associated with better visual acuity (VA) during follow-up versus c.828+3A>T variant. Some individuals were initially misdiagnosed with geographic atrophy secondary to AMD.

Conclusions: Individuals with the L185P variant had less severe disease with clinical manifestation typical of PD and better VA. More advanced disease with CACD and worse VA were associated with the c.828+3A>T variant. Results contribute to knowledge about genotypic-phenotypic associations of PRPH2 retinopathies and inform clinical and therapeutic end points.

Figure 1.

(A) Pedigree A, heterozygous for the PRPH2 rare variant rs121918563 (L185P). (B) Phenotypes of Proband II:1 (arrow in A). (a, b) Small round yellowish lesion in the center of the macula in both eyes typical of PD presenting as AVMD on CFP. (c, d) Red-free retinography documenting the same central macular lesions in OU. (e, f) OCT with dense hyper-reflective material accumulation in the subretinal space in a vitelliform pattern, typical of AVMD. (g, h) Ultra-high resolution OCT shows pseudo-vitelliform lesions OU with heterogeneous material, and RPE migration at the dome of the pseudo-vitelliform lesions (h). (i, j) CFP 7 years after baseline. (k, l) FAF OD showing mottled hyper and hypo-autofluorescence, and near IR OS showing pigmentary accumulation and clumping, associated with the pseudo-vitelliform lesions typical of AVMD in the center of the macula OU. (m, n) OCT shows thinning and disruption of the retinal layers and disappearance of the foveal lesion OD after a retinal detachment repair, and typical pseudo-vitelliform lesion in the center of the macula OS. (o) OCT OS, 11 years after baseline showing RPE abnormalities and outer retinal atrophy, likely secondary to natural history of the pseudo-vitelliform lesion. (C) Phenotypes of other family members in Pedigree A. I:1 (a, b) CFP and (c, d) OCT of proband's father showing central macular pseudo-vitelliform lesions in different stages OU typical of AVMD. II:2 (a, b) Normal OCT OU from sibling of proband without the variant. II:3 (a–o) Multimodal retinal imaging of the sister of the proband. (a) Red free and (b) FA at baseline showing central foveal lesions typical of AVMD. Images 14 years later include (c, d) CFP, (e, f) FAF, and (g, h) OCT showing RPE and outer retina irregularities including pigmentary clumping in both eyes and incipient central macular atrophy in the OS, typical of AVMD. (i–o) OCT and IR images 17 to 18 years after baseline show RPE irregularities in a pattern configuration, with RPE and outer retina atrophy OU. AVMD, adult-onset vitelliform macular dystrophy; CFP, color fundus photography; FA, fluorescein angiography; FAF, fundus autofluorescence; IR, infrared reflectance; OCT, optical coherence tomography; OD, right eye; OS, left eye; OU, both eyes; PRPH2, peripherin-2 gene; RPE, retinal pigment epithelium.

Figure 2.

(A) Pedigree B, heterozygous for the PRPH2 rs281865373 (c.828+3A>T) variant. (B) Phenotypes of proband II:8 (arrow in A) and identical twin sister (II:7). Proband II:8 (a, b) CFP shows bilateral extensive macular and peripapillary retinal atrophy extending beyond the retinal vascular arcades, consistent with CACD. II:7 Identical twin of the proband. (a–d) CFP shows a very similar clinical presentation in comparison to the proband, with further worsening of the diffuse retinal atrophy over a follow-up time of 6 years. II:1 Sibling of the proband. (a, b) Large areas of retinal and RPE atrophy extending throughout the macula (CACD). II:10 Sibling of the proband. (a–d) CFP OU show patches of retinal atrophy in the central macula evolving over a period of 16 years to retinal atrophy involving the entire macular area and extending to the retinal vascular arcades (CACD). (C) III:3 Niece of proband. (a–i) Multimodal retinal imaging from baseline to 19 years of follow-up shows yellow retinal flecks as seen in AFMD on (a, b) CFP and (c, d) FA. Central macular atrophy resembling GA secondary to AMD developed over a follow-up time of 19 years as seen in (e, f) CFP and (g, h) red-free retinography. (i, j) Last documentation with OCT shows outer retinal atrophy throughout the macula OU and residual intraretinal fluid OS after intravitreal anti-vascular endothelial growth factor for secondary macular NV OU. (D) Other nieces and nephews of the proband and 1 great-niece. III:2 Niece of proband. (a–d) CFP demonstrates RPE irregularities and retinal flecks resembling AFMD, which progressed over a period of 16 years to large areas of retinal atrophy affecting the macular area and extending beyond the retinal vascular arcades in OU. III:6 Nephew of the proband. (a–d) CFP OU show central area of macular atrophy that resembles GA secondary to AMD, which evolved over a follow-up time of 14 years to develop extensive retinal atrophy throughout the macular area and extending beyond the retinal vascular arcades, more typical of CACD. III:4 Nephew of the proband. (a, b) CFP OU show central macular atrophy that resemble GA secondary to AMD with foveal sparing, which evolved over 19 years to more widespread retinal atrophy extending nasally to the optic nerve and in the far retinal periphery, as shown on (c, d) CFP and (e, f) FAF. III:5 Niece of the proband. (a, b) CFP OU exhibits large areas of macular atrophy and subretinal fibrosis involving the central macular area with history of bilateral macular NV. III:7 Nephew of the proband. (a, b) CFP and (c, d) FAF show central macular atrophy and significant abnormalities of the retina and RPE extending throughout the macular area and beyond the retinal vascular arcades OU. (e, f) OCT shows outer retinal atrophy and intraretinal cystic spaces in both eyes. IV:1 Daughter of III:2. (a, b) CFP OU show retinal flecks as seen on AFMD at baseline. AFMD, adult-onset fundus flavimaculatus with macular dystrophy; AMD, age-related macular degeneration; CACD, central areolar chorioretinal dystrophy; CFP, color fundus photographs; FA, fluorescein angiography; FAF, fundus autofluorescence; GA, geographic atrophy; NV, neovascularization; OCT, optical coherence tomography; OS, left eye; OU, both eyes; PRPH2, peripherin-2 gene; RPE, retinal pigment epithelium.

Figure 3.

(A) Pedigree C, heterozygous for the PRPH2 rs281865373 (c.828+3A>T) variant. (B) Phenotypes of Proband II:1. (a, b) FA OU shows central macular atrophy that may resemble GA secondary to AMD, but with RPE abnormalities in spoke-like configuration similar to pattern dystrophy more evident OS. (c, d) CFP OU demonstrates worsening of central macular atrophy that could be confounded with GA secondary to AMD but also fit in the differential diagnosis of early CACD. II:2 Sibling of the Proband. (a–d) CFP OU exhibits clinical presentation very similar to the Proband, with central macular atrophy in the differential diagnosis of GA secondary to AMD or CACD, with enlargement of the lesions 7 years after baseline. AMD, age-related macular degeneration; CACD, central areolar chorioretinal dystrophy; CFP, color fundus photographs; FA, fluorescein angiography; GA, geographic atrophy; OS, left eye; OU, both eyes; PRPH2, peripherin-2 gene; RPE, retinal pigment epithelium.

Figure 4.

Phenotypes of independent cases, heterozygous for the PRPH2 rs121918563 (L185P) variant (cases A–-D) and the PRPH2 rs281865373 (c.828+3A>T) variant (case E). Case A. (a, b) CFP OU show central pseudo-vitelliform macular lesions which evolved to small circular area of central RPE and outer retinal atrophy, also shown on (c, d) fundus autofluorescence (FAF) and (e, f) near IR as well as on (g, h) OCT typical of AVMD. Of note, IR images show a pattern configuration of pigmentary clumps. Case B. (a, b) CFP exhibits RPE irregularities in a butterfly shape OD and central atrophy OS. Case C. (a, b) FA OU show small central macular atrophy surrounded by increased fluorescence due to pigmentary mobilization and marked fluorescein staining, and (c, d) FAF OU shows small areas of distinct hypo-autofluorescence correspondent to the central macular atrophy, and increased areas of FAF in a distinct butterfly pattern correspondent to the areas of pigmentary mobilization. (e, f) OCT OU show small focal areas of RPE and outer retinal atrophy, and shallow “low-lying” RPE detachments in both eyes, without evident signs of exudation. (g, h) OCTA OU show macular NV. Case D. (a, b) Red-free retinography in both eyes show RPE abnormalities in a butterfly pattern configuration. (c, d) FAF OU show progression to central macular atrophy 9 years after baseline, and in the same visit (e, f) OCT OU show central macular atrophy and subretinal fibrosis secondary to macular NV. Case E. (a, b) CFP OU show multifocal areas of RPE atrophy. (c, d) CFP OU show that 6 years after baseline the areas of macular atrophy enlarged, resembling GA secondary to AMD earlier in the disease presentation but that could fit in the differential diagnosis of CACD as the disease progressed. AMD, age-related macular degeneration; CACD, central areolar chorioretinal dystrophy; CFP, color fundus photographs; FA, fluorescein angiography; FAF, fundus autofluorescence; GA, geographic atrophy; IR, infrared reflectance; NV, neovascularization; OCT, optical coherence tomography; OCTA, optical coherence tomography angiography; OD, right eye; OS, left eye; OU, both eyes; PRPH2, peripherin-2 gene; RPE, retinal pigment epithelium.

Figure 5.

(A) Violin plots showing initial and final visual acuity (logMAR) for individuals heterozygous for PRPH2 rs281865373 (c.828+3A>T) (orange) and PRPH2 rs121918563 (L185P) (blue) variants. The width of each violin plot is proportional to the density for the range of values and the medians are represented by horizontal bars within the boxplots. (B) Comparison of change in visual acuity (logMAR) per year between individuals heterozygous for PRPH2 rs281865373 (c.828+3A>T) (orange) and PRPH2 rs121918563 (L185P) (blue) estimated using a mixed effects linear regression with a compound symmetry correlation structure. Standard error is illustrated by vertical error bars (***P < 0.001). logMAR, logarithm of the minimal angle of resolution; PRPH2, peripherin-2 gene.