Parafoveal Photoreceptor Abnormalities in Asymptomatic Patients With <i>RP1L1</i> Mutations in Families With Occult Macular Dystrophy

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Citation: Kameya S, Fujinami K, Ueno S, et al. Phenotypical characteristics of POC1B-associated retinopathy in Japanese cohort: cone dystrophy with normal funduscopic appearance. Invest Ophthalmol Vis Sci. 2019;60:3432-3446. https://doi.org/ 10.1167/iovs.19-26650 PURPOSE. Cone/cone-rod dystrophy is a large group of retinal disorders with both phonotypic and genetic heterogeneity. The purpose of this study was to characterize the phenotype of eight patients from seven families harboring POC1B mutations in a cohort of the Japan Eye Genetics Consortium (JEGC). METHODS.Whole-exome sequencing with targeted analyses identified homozygous or compound heterozygous mutations of the POC1B gene in 7 of 548 families in the JEGC database. Ophthalmologic examinations including the best-corrected visual acuity, perimetry, fundus photography, fundus autofluorescence imaging, optical coherence tomography, and full-field and multifocal electroretinography (ERGs) were performed.RESULTS. There were four men and four women whose median age at the onset of symptoms was 15.6 years (range, 6-23 years) and that at the time of examination was 40.3 years (range, 22-67 years). The best-corrected visual acuity ranged from À0.08 to 1.52 logMAR units. The funduscopic appearance was normal in all the cases except in one case with faint mottling in the fovea. Optical coherence tomography revealed an absence of the interdigitation zone and blurred ellipsoid zone in the posterior pole, but the foveal structures were preserved in three cases. The full-field photopic ERGs were reduced or extinguished with normal scotopic responses. The central responses of the multifocal ERGs were preserved in two cases. The diagnosis was either generalized cone dystrophy in five cases or cone dystrophy with foveal sparing in three cases.CONCLUSIONS. Generalized or peripheral cone dystrophy with normal funduscopic appearance is the representative phenotype of POC1B-associated retinopathy in our cohort.Whole-exome sequencing and targeted sequence analyses of the 301 retinal disease-associated genes (including genes of Retnet; https://sph.uth.edu/retnet/, in the public domain) were done according to the published protocol of the NISO. 35 Paired-end sequence library construction and exome capturing Downloaded from iovs.arvojournals.org on 07/08/2020 FIGURE 8. Horizontal and vertical OCT images of the left eye of patient 1 recorded at the age 35 years (A) and 39 years (B).Longitudinal reflectivity profiles at the fovea are shown below the OCT images. EZ and IZ are preserved in the fovea at the age 35 years but they are blurred at the age of 39 years. The reflectivity profiles show small peaks of IZ at the age 35 years but not at 39 years. The reflectance intensity of the IZ relative to the RPE was 0.82 at the age 35 years and 0.63 at the age 39 years. The reflectance intensity of the EZ relative to the RPE was 0.86 at the age 35 years and 0.77 at the age 39 years. The reflectivity was averaged in width as indicated by the yellow lines. ILM, internal limiting membra...

Section: Discussionmentioning

confidence: 99%

Section: Signal Intensity Profiling Of Faf and Sd-oct Imagesmentioning

confidence: 99%

Phenotypical Characteristics ofPOC1B-Associated Retinopathy in Japanese Cohort: Cone Dystrophy With Normal Funduscopic Appearance

Kameya

Fujinami

Ueno

et al. 2019

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“…13,14 The OCT findings play an important role in the diagnosis of OMD. 5,11,15,16 In an earlier report of a large family having the RP1L1 gene mutation (p.Arg45Trp), Tsunoda et al 5 documented that the photoreceptor structures, assessed by OCT, gradually changed during the course of OMD.…”

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confidence: 99%

Clinical Stages of Occult Macular Dystrophy Based on Optical Coherence Tomographic Findings

Nakamura

Tsunoda

Mizuno

et al. 2019

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PURPOSE. To determine the course of occult macular dystrophy (OMD, Miyake's disease) and to propose stages of OMD based on the optical coherence tomographic (OCT) findings. METHODS. Sixty-one patients from 33 families with OMD who carried one of the proven variants of the RP1L1 gene were studied at seven centers in Japan. Ophthalmological examinations including the best-corrected visual acuity (BVCA) and OCT were performed. RESULTS. The median age at the last visit was 50 years with a range of 10 to 88 years, and the median age at the symptom onset was 30 years with a range of 3 to 60 years. There were significant negative correlations between the duration of OMD and BCVA, the central retinal thickness (CRT) and the thickness between external limiting membrane and retinal pigment epithelium (ERT). The BCVA gradually decreased for 10 years after symptom onset and was stable thereafter. Kaplan-Meier survival curves of the BCVA and retinal thickness showed that all of the patients had retained a vision of 1.0 logMAR, and over 80% of the patients had retained 50% thickness of the normal CRT and ERT for at least 60 years after symptom onset. The stages of OMD based on the visual symptoms and OCT findings are proposed. CONCLUSIONS. The photoreceptors do not become completely atrophic even at the late stage, which may account for the good retinal pigment epithelium (RPE) structure and normalappearing fundus. The proposed stages facilitate the investigation of the pathogenicity of OMD and provide information to determine the effectiveness of therapeutic procedures.

“…The vari-ant p.S1199C is not found in the ExAC or 1000 Genomes Project database, but all 12 reported patients harboring this variant were East Asian. 4,19,20 This indicated that these two variants were more common in the East Asian population than in other populations. Previous studies showed that the penetrance of the variant p.R45W was incomplete, ranging from 38% to 85%.…”

Section: Discussionmentioning

confidence: 96%

“…The IZ absence and EZ blurring of photoreceptor microstructures observed by SD-OCT are classical changes in OMD patients and were observed in all probands of our cohort. However, Kato et al 20 found that central foveal microstructures could be spared in some patients carrying pathogenic RP1L1 variants; the visual acuity of these patients was generally well preserved, and mfERG results could even be normal, but SD-OCT revealed abnormal microstructures in the parafoveal regions. This finding demonstrated that SD-OCT is more sensitive in detecting pathologic changes of OMD than other examination methods and contributes to the improvement of early diagnostics.…”

Section: Discussionmentioning

confidence: 99%

Clinical and Genetic Characteristics of Chinese Patients with Occult Macular Dystrophy

Wang

Gao

et al. 2020

et al. Clinical and genetic characteristics of Chinese patients with occult macular dystrophy. Invest Ophthalmol Vis Sci. 2020;61(3):10. https://doi.org/10.1167/iovs.61.3.10 PURPOSE.To investigate the clinical and genetic characteristics of occult macular dystrophy (OMD) based on a Chinese patient cohort. METHODS.Fifteen Chinese OMD patients from nine unrelated families underwent genetic testing, and all of them harbored a pathogenic RP1L1 variant. Comprehensive ophthalmic examinations were performed in nine probands, including spectral-domain optical coherence tomography (SD-OCT), near-infrared reflectance (NIR), fundus autofluorescence (AF), and multifocal electroretinography. RESULTS.The RP1L1 variants p.R45W and p.S1199C were identified in 13 patients and two patients, respectively, and one was a de novo mutation. Among the nine probands, the median ages at onset and examination were 25.0 years (range, 6-51 years) and 27.0 years (range, 14-55 years), respectively. The median decimal visual acuity was 0.20 (range, 0.04-0.5). Foveal photoreceptor thickness and visual acuity showed a significant correlation (r = 0.591; P = 0.01). All eyes presented with an absent interdigitation zone and blurred ellipsoid zone of photoreceptors when examined by SD-OCT. In addition, central round lesions with low NIR reflectance were observed in 66.7% (12/18) of eyes by NIR reflectance imaging, corresponding to the regions with abnormal photoreceptor microstructures observed by SD-OCT. Of the 18 eyes, only four eyes showed ring-like faint hyperfluorescence around the macula by AF. CONCLUSIONS.To the best of our knowledge, this is the largest study in a cohort of Chinese OMD patients with RP1L1 mutations. Our findings revealed that the two recurrent RP1L1 variants are related to OMD in the Chinese population. Furthermore, multimodal imaging combined with genetic testing is valuable for diagnosing and monitoring OMD progression.