Differences in Intraretinal Pigment Migration Across Inherited Retinal Dystrophies

Oh, Jin Kyun; Levi, Sarah R.; Kim, Joonpyo; Carvalho, José Ronaldo Lima de; Ryu, Joseph; Sparrow, Janet R.; Tsang, Stephen H.

doi:10.1016/j.ajo.2020.05.010

Cited by 7 publications

(5 citation statements)

References 37 publications

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“…In a recent study of intraretinal pigment migration across inherited retinal dystrophies, we found that pigment migration is rarer in patients with disease caused by mutations in genes specific to the RPE (34.0%) as compared to patients with mutations in genes specific to the photoreceptors (75.8%). 30 The absence of pigment in disease due to mutations in RPE-specific genes becomes even more pronounced (6.9%) when cases of choroideremia, a disease in which photoreceptors and RPE have been suggested to degenerate independently, were excluded. 30 Mutations in RPE-specific genes were hypothesized to lead to primary RPE degeneration prior to photoreceptor loss, thereby preventing pigment migration.…”

Section: Discussionmentioning

confidence: 99%

“… 30 The absence of pigment in disease due to mutations in RPE-specific genes becomes even more pronounced (6.9%) when cases of choroideremia, a disease in which photoreceptors and RPE have been suggested to degenerate independently, were excluded. 30 Mutations in RPE-specific genes were hypothesized to lead to primary RPE degeneration prior to photoreceptor loss, thereby preventing pigment migration. Although the absence of pigment is not a specific finding of mutations in RPE-specific genes, in all five patients with MIDD, we observed the absence of intraretinal pigment migration, which may suggest that mutations in MT-TL1 also lead to primary degeneration of the RPE.…”

Section: Discussionmentioning

confidence: 99%

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Retinal Manifestations of Mitochondrial Oxidative Phosphorylation Disorders

Carvalho

Nuzbrokh

et al. 2020

Invest. Ophthalmol. Vis. Sci.

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The purpose of this paper was to discuss manifestations of primary mitochondrial dysfunctions and whether the retinal pigment epithelium or the photoreceptors are preferentially affected. METHODS. A retrospective analysis was performed of patients with clinically and laboratory confirmed diagnoses of maternally inherited diabetes and deafness (MIDD) or Kearns-Sayre syndrome (KSS). Patients underwent full ophthalmic examination, full-field electroretinogram, and multimodal imaging studies, including short-wavelength autofluorescence, spectral domain-optical coherence tomography, and color fundus photography. RESULTS. A total of five patients with MIDD and four patients with KSS were evaluated at two tertiary referral centers. Mean age at initial evaluation was 50.3 years old. Nascent outer retinal tubulations corresponding with faint foci of autofluorescence were observed in two patients with MIDD. Characteristic features of this cohort included a foveal sparing phenotype observed in 13 of 18 eyes (72%), global absence of intraretinal pigment migration, and preserved retinal function on full-field electroretinogram testing in 12 of 16 eyes (75%). One patient diagnosed with MIDD presented with an unusual pattern of atrophy surrounding the parapapillary region and one patient with KSS presented with an atypical choroideremia-like phenotype. CONCLUSIONS. MIDD and KSS are phenotypically heterogeneous disorders. Several features of disease suggest that primary mitochondrial dysfunction may first affect the retinal pigment epithelium followed by secondary photoreceptor loss. Similarities between primary mitochondrial degenerations and retinal disorders, such as age-related macular degeneration may suggest a primary role of mitochondria in the pathogenesis of these oligogenic disorders.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Retinal Manifestations of Mitochondrial Oxidative Phosphorylation Disorders

Carvalho

Nuzbrokh

et al. 2020

Invest. Ophthalmol. Vis. Sci.

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“…In addition, the tomography showed outer retinal tubulations at the edges of preserved islands and peripheral retinal thinning. Moreover, an optical coherence tomography cross-section (Figure 1D) through peripheral pigment clumps in an area marked with a white line in Figure 1A showed predominantly subretinal pigment location (red arrowhead) as seen in choroideremia and other pathogenic RPE variants, although in some instances, the pigment location was suggestive of intraretinal pigment migration (white arrowhead) as described in 79% of patients with pathogenic variants in ciliary genes including the RPGR …”

Section: Resultsmentioning

confidence: 86%

Association of a Novel Intronic Variant in RPGR With Hypomorphic Phenotype of X-Linked Retinitis Pigmentosa

et al. 2020

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IMPORTANCE Pathogenic variants in retinitis pigmentosa GTPase regulator (RPGR) gene typically lead to a severe form of X-linked retinitis pigmentosa, which is associated with early severe vision loss.OBJECTIVE To investigate an X-linked retinal degeneration family with atypical preservation of visual acuity in the presence of a novel deep intronic splice site RPGR c.779-5T>G variant. DESIGN, SETTING, AND PARTICIPANTSIn this case series, 3 members of an X-linked retinal degeneration family were studied by in-depth phenotyping and genetic screening at a single center. Data were collected and analyzed from November 2018 to March 2020.MAIN OUTCOMES AND MEASURES Data were collected on full ophthalmic history, examination, and retinal imaging. A full retinitis pigmentosa gene panel was analyzed by next-generation sequencing. The pathogenicity of the RPGR c.779-5T>G variant was assessed by in silico splice prediction tools and by purpose-designed in vitro splicing assay.RESULTS An 84-year-old man was referred with clinical diagnosis of choroideremia and possible inclusion into a gene therapy trial. He presented with late-stage retinal degeneration and unusually preserved visual acuity (78 and 68 ETRDS letters) that clinically resembled choroideremia. His 23-year-old grandson was still in early stages of degeneration but showed a very different clinical picture, typical of retinitis pigmentosa. Next-generation sequencing identified a sole RPGR c.779-5T>G variant of undetermined pathogenicity in both cases. The daughter of the proband showed an RPGR carrier phenotype and was confirmed to carry the same variant. The molecular analysis confirmed that the RPGR c.779-5T>G variation reduced the efficiency of intron splicing compared with wild type, leading to a population of mutant and normal transcripts. The predicted consequences of the pathogenic variant are potential use of an alternative splice acceptor site or complete skipping of exon 8, resulting in truncated forms of the RPGR protein with different levels of glutamylation.CONCLUSIONS AND RELEVANCE These results support the importance of careful interpretation of inconsistent clinical phenotypes between family members. Using a molecular splicing assay, a new pathogenic variant in a noncoding region of RPGR was associated with a proportion of normal and hypomorphic RPGR, where cones are likely to survive longer than expected, potentially accounting for the preserved visual acuity observed in this family.

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“…Early-phase indocyanine green angiography (Figs. 1G, H) of the upper quadrant revealed mid-peripheral chorioretinal atrophy and the presence of pigment overlying retinal vessels at the margins of atrophy, confirming that the pigment is at least partially intraretinal and suggesting photoreceptor loss prior to colocalized retinal pigment epithelium loss 1 . An optical coherence tomography vertical scan passing through the fovea revealed preservation of retinal layering in the central macula and abrupt transition to full thickness retinal atrophy at the margin of the macular region (Figs.…”

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confidence: 72%