In vivo imaging of a cone mosaic in a patient with achromatopsia associated with a GNAT2 variant

Ueno, Shinji; Nakanishi, Atsuko; Kominami, Taro; Ito, Yasuki; Hayashi, Takaaki; Yoshitake, Kazutoshi; Kawamura, Y.; Tsunoda, Kazushige; Iwata, Takeshi; Terasaki, Hiroko

doi:10.1007/s10384-016-0484-7

Cited by 24 publications

(15 citation statements)

References 31 publications

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“…There are reports of congenital achromatopsia, which shows similar pattern such as cone dysfunction in the ERG, loss of IZ in the OCT, and D-15 abnormality with confusion lines between deutan and tritan. 77,78 The course of our cases was progressive and was not like that of congenital achromatopsia. However, the relationship between the results of color vision tests and OCT images could not be revealed.…”

Section: Discussionmentioning

confidence: 64%

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

Kameya

Fujinami

Ueno

et al. 2019

Invest. Ophthalmol. Vis. Sci.

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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...

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Section: Discussionmentioning

confidence: 64%

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

Kameya

Fujinami

Ueno

et al. 2019

Invest. Ophthalmol. Vis. Sci.

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“…In 2002, we reported five families with patients affected by ACHM caused by mutations in GNAT2 (Kohl et al, ; Rosenberg et al, ). Since then only few reports of single families have been published (Aligianis et al, ; Piña, Baumert, Loyer, & Koenekoop, ; Ouechtati et al, ; Langlo et al, , Taylor et al, ; Carss et al, ; Ueno et al, ). Herein we report the results of our genetic investigation of our complete ACHM cohort over a period of 16 years, in total identifying 23 affected individuals from 19 independent families carrying likely disease‐causing mutations in GNAT2 , of which 12 mutations have never been reported before.…”

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confidence: 99%

Mutation spectrum and clinical investigation of achromatopsia patients with mutations in the GNAT2 gene

et al. 2019

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Achromatopsia (ACHM) is a hereditary cone photoreceptor disorder characterized by the inability to discriminate colors, nystagmus, photophobia, and low‐visual acuity. Six genes have been associated with this rare autosomal recessively inherited disease, including the GNAT2 gene encoding the catalytic α‐subunit of the G‐protein transducin which is expressed in the cone photoreceptor outer segment. Out of a cohort of 1,116 independent families diagnosed with a primary clinical diagnosis of ACHM, we identified 23 patients with ACHM from 19 independent families with likely causative mutations in GNAT2, representing 1.7% of our large ACHM cohort. In total 22 different potentially disease‐causing variants, of which 12 are novel, were identified. The mutation spectrum also includes a novel copy number variation, a heterozygous duplication of exon 4, of which the breakpoint matches exactly that of the previously reported exon 4 deletion. Two patients carry just a single heterozygous variant. In addition to our previous study on GNAT2‐ACHM, we also present detailed clinical data of these patients.

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“…23,24 The GNAT2-ACHM genotype is associated with the relatively least disrupted photoreceptor mosaic. 6,20 Simultaneous confocal and splitdetection AOSLO has allowed the identification of cone inner segment structure in the previously described "dark spaces." [25][26][27][28] GNAT2-ACHM was only investigated with confocal AOSLO imaging in two pedigrees to date.…”

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confidence: 99%

“…[25][26][27][28] GNAT2-ACHM was only investigated with confocal AOSLO imaging in two pedigrees to date. 6,20 CNGB3 and CNGA3 are responsible for 70% of the reported ACHM cases and are the most well studied genotypes, with on-going gene therapy trials (ClinicalTrials.gov numbers: NCT03758404, NCT02935517 NCT03001310, NCT02599922, and NCT02610582). Three homologous mouse models of GNAT2-ACHM have been described to date.…”

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Photoreceptor Structure inGNAT2-Associated Achromatopsia

Georgiou

Singh

Kane

et al. 2020

Invest. Ophthalmol. Vis. Sci.

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The purpose of this study was to report GNAT2-associated achromatopsia (GNAT2-ACHM) natural history, characterize photoreceptor mosaic, and determine a therapeutic window for potential intervention. METHODS. Patients with GNAT2-ACHM were recruited from a single tertiary referral eye center (Moorfields Eye Hospital, London, UK). We performed longitudinal clinical evaluation and ophthalmic examination, and multimodal retinal imaging, including adaptive optics scanning light ophthalmoscopy, quantitative analysis of the cone mosaic, and outer nuclear layer (ONL) thickness, including cone densities evaluation in selected regions of interest and comparison with reported healthy controls. RESULTS. All nine subjects (3 women) presented with nystagmus, decreased visual acuity (VA), light sensitivity, and highly variable color vision loss. One patient had normal color vision and better VA. Mean VA was 1.01 (±0.10) logarithms of the minimal angle of resolution (LogMAR) at baseline, and 1.04 (±0.10) LogMAR after a mean follow-up (range) of 7.6 years (1.7−12.8 years). Optical coherence tomography showed preservation of the foveal ellipsoid zone (EZ; n = 8; 88.9%), and EZ disruption (n = 1; 11.1%). Mean ONL thickness (range, ± SD) was 84.72 μm (28.57−113.33, ± 25.46 μm) and 86.47 μm (28.57−113.33, ± 24.65 μm) for right and left eyes, respectively. Mean cone densities (±SD) at 190 μm, 350 μm, and 500 μm from the foveal center, were 48.4 (±24.6), 37.8 (±14.7), and 30.7 (±9.9), ×10 3 cones/mm 2 , respectively. Mean cone densities were lower than these of unaffected individuals, but with an overlap. CONCLUSIONS. The cone mosaic in GNAT2-ACHM is relatively well preserved, potentially allowing for a wide therapeutic window for cone-directed interventions.

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In vivo imaging of a cone mosaic in a patient with achromatopsia associated with a GNAT2 variant

Abstract: This is the first description of a Japanese patient with ACHM with a novel GNAT2 variant. The eyes of this patient had a preserved cone structure with loss of function.

Cited by 24 publications

References 31 publications

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

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

Mutation spectrum and clinical investigation of achromatopsia patients with mutations in the GNAT2 gene

Photoreceptor Structure inGNAT2-Associated Achromatopsia

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