Comparing Rod and Cone Function with Fundus Autofluorescence Images in Retinitis Pigmentosa

In this retrospective, longitudinal, observational cohort study, we investigated the phenotypic and genotypic features of retinitis pigmentosa associated with variants in the PDE6B gene. Patients underwent clinical examination and genetic testing at a single tertiary referral center, including best-corrected visual acuity (BCVA), kinetic visual field (VF), full-field electroretinography, full-field stimulus threshold, spectral domain optical coherence tomography, and fundus autofluorescence imaging. The genetic testing comprised candidate gene sequencing, inherited retinal disease gene panel sequencing, whole-genome sequencing, and testing for familial variants by Sanger sequencing. Twenty-four patients with mutations in PDE6B from 21 families were included in the study (mean age at the first visit: 32.1 ± 13.5 years). The majority of variants were putative splicing defects (8/23) and missense (7/23) mutations. Seventy-nine percent (38/48) of eyes had no visual acuity impairment at the first visit. Visual acuity impairment was mild in 4% (2/48), moderate in 13% (6/48), and severe in 4% (2/48). BCVA was symmetrical in the right and left eyes. The kinetic VF measurements were highly symmetrical in the right and left eyes, as was the horizontal ellipsoid zone (EZ) width. Regarding the genetic findings, 43% of the PDE6B variants found in our patients were novel. Thus, this study contributed substantially to the PDE6B mutation spectrum. The visual acuity impairment was mild in 83% of eyes, providing a window of opportunity for investigational new drugs. The EZ width was reduced in all patients and was highly symmetric between the eyes, making it a promising outcome measure. We expect these findings to have implications on the design of future PDE6B-related retinitis pigmentosa (RP) clinical trials.

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Wide-Field Fundus Autofluorescence Imaging of Retinitis Pigmentosa

Ophthalmology ◽

10.1016/j.ophtha.2013.01.050 ◽

2013 ◽

Vol 120 (9) ◽

pp. 1827-1834 ◽

Cited By ~ 43

Author(s):

Akio Oishi ◽

Ken Ogino ◽

Yukiko Makiyama ◽

Satoko Nakagawa ◽

Masafumi Kurimoto ◽

...

Keyword(s):

Retinitis Pigmentosa ◽

Fundus Autofluorescence ◽

Wide Field ◽

Autofluorescence Imaging

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Fundus autofluorescence and ellipsoid zone (EZ) line width can be an outcome measurement in RHO-associated autosomal dominant retinitis pigmentosa

Graefe s Archive for Clinical and Experimental Ophthalmology ◽

10.1007/s00417-018-04234-6 ◽

2019 ◽

Vol 257 (4) ◽

pp. 725-731 ◽

Cited By ~ 11

Author(s):

Vitor K. L. Takahashi ◽

Júlia T. Takiuti ◽

Jose R. L. Carvalho-Jr ◽

Christine L. Xu ◽

Jimmy K. Duong ◽

...

Keyword(s):

Retinitis Pigmentosa ◽

Line Width ◽

Autosomal Dominant ◽

Outcome Measurement ◽

Fundus Autofluorescence ◽

Autosomal Dominant Retinitis Pigmentosa ◽

Ellipsoid Zone

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Microglia dynamics in retinitis pigmentosa model: formation of fundus whitening and autofluorescence as an indicator of activity of retinal degeneration

Scientific Reports ◽

10.1038/s41598-020-71626-2 ◽

2020 ◽

Vol 10 (1) ◽

Author(s):

Kenichi Makabe ◽

Sunao Sugita ◽

Michiko Mandai ◽

Yoko Futatsugi ◽

Masayo Takahashi

Keyword(s):

Retinitis Pigmentosa ◽

Retinal Degeneration ◽

Outer Nuclear Layer ◽

Fundus Autofluorescence ◽

Fundus Photography ◽

Photoreceptor Outer Segments ◽

Diagnostic Interpretation ◽

Model Formation ◽

Thinning Rate

Abstract In patients with retinitis pigmentosa (RP), color fundus photography and fundus autofluorescence (FAF) have been used to estimate the disease progression. To understand the origin and the diagnostic interpretation of the fundus color and FAF, we performed in vivo imaging of fundus color and FAF together with histological analyses of the retinal degeneration process using the RP model mice, rd10. FAF partly represented the accumulation of microglia in the photoreceptor outer segments. Fundus whitening suggested the presence of apoptotic cells, which spatiotemporally preceded increase in FAF. We observed two patterns of FAF localization, arcuate and diffuse, each indicating different pattern of apoptosis, wavy and diffuse, respectively. Diffuse pattern of apoptosis was suppressed in dark-raised rd10 mice, in which outer nuclear layer (ONL) loss was significantly suppressed. The occupancy of FAF correlated with the thinning rate of the ONL. Fractalkine, a microglia chemotactic factor, was detected in apoptotic photoreceptors, suggesting chemokine-induced recruitment of microglia into the ONL, which paralleled with accelerated ONL loss and increased FAF occupancy. Thus, we propose that the degree of photoreceptor apoptosis and the rate of ONL thinning in RP patients might be read from the fundus color and the FAF.

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Novel mutations in the 3-box motif of the BACK domain of KLHL7 associated with nonsyndromic autosomal dominant retinitis pigmentosa

Orphanet Journal of Rare Diseases ◽

10.1186/s13023-019-1275-2 ◽

2019 ◽

Vol 14 (1) ◽

Cited By ~ 2

Author(s):

Jin Kyun Oh ◽

Jose Ronaldo Lima de Carvalho ◽

Young Joo Sun ◽

Sara Ragi ◽

Jing Yang ◽

...

Keyword(s):

Retinitis Pigmentosa ◽

Autosomal Dominant ◽

Fundus Autofluorescence ◽

Retinal Dystrophy ◽

Protein Modeling ◽

Fundus Photography ◽

Imaging Biomarkers ◽

Loss Of Function ◽

Gene Panel Testing ◽

Sd Oct

Abstract Background Mutations in the Kelch-like protein 7 (KLHL7) represent a recently described and, to date, poorly characterized etiology of inherited retinal dystrophy. Dominant mutations in KLHL7 are a cause of isolated, non-syndromic retinitis pigmentosa (RP). In contrast, recessive loss-of-function mutations are known to cause Crisponi or Bohring-Opitz like cold induced sweating syndrome-3 (BOS-3). In this study, the phenotype and progression of five unrelated patients with KLHL7 mediated autosomal dominant RP (adRP) are characterized. Clinical evaluation of these patients involved a complete ophthalmic exam, full-field electroretinography (ffERG), and imaging, including fundus photography, spectral domain optical coherence tomography (SD-OCT), short wavelength fundus autofluorescence (SW-AF), and near-infrared fundus autofluorescence (NIR-AF). Molecular diagnoses were performed using whole-exome sequencing or gene panel testing. Disease progression was monitored in three patients with available data for a mean follow up time of 4.5 ± 2.9 years. Protein modeling was performed for all variants found in this study in addition to those documented in the literature for recessive loss-of-function alleles causing Crisponi or Bohring-Opitz like cold-induced sweating syndrome. Results Genetic testing in three patients identified two novel variants within the 3-box motif of the BACK domain: c.472 T > C:p.(Cys158Arg) and c.433A > T:p.(Asn145Tyr). Clinical imaging demonstrated hyperautofluorescent ring formation on both SW-AF and NIR-AF in three patients, with diffuse peripheral and peripapillary atrophy seen in all but one case. SD-OCT demonstrated a phenotypic spectrum, from parafoveal atrophy of the outer retina with foveal sparing to widespread retinal thinning and loss of photoreceptors. Incidence of cystoid macular edema was high with four of five patients affected. Protein modeling of dominant alleles versus recessive loss-of-function alleles showed dominant alleles localized to the BTB and BACK domains while recessive alleles were found in the Kelch domain. Conclusions We report the phenotype in five patients with KLHL7 mediated adRP, two novel coding variants, and imaging biomarkers using SW-AF and NIR-AF. These findings may influence future gene-based therapies for adRP and pave the way for mechanistic studies that elucidate the pathogenesis of KLHL7-mediated RP.

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