Outer retinal tubulations in maternally inherited diabetes and deafness (MIDD)-associated macular dystrophy

Raja, Muhammad; Goldsmith, Craig; Burton, B J L

doi:10.1007/s00417-012-2217-z

Cited by 9 publications

(7 citation statements)

References 5 publications

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“…Tubulations have been described in a range of degenerative retinal disorders, including AMD, Stargardt disease, central serous retinopathy, serpiginous choroiditis, maternally inherited diabetes and deafness, gyrate atrophy, and choroideremia. 6 , 13 , 16 – 21 They likely represent rearrangement of photoreceptors that have lost their outer segments following the degeneration of the underlying RPE cells, but are still close enough to the residual choroid to derive oxygenation and other diffusible substrates required for metabolic survival. This would be consistent with RPE degeneration being a key feature of all the conditions above.…”

Section: Discussionmentioning

confidence: 99%

Correlation of Optical Coherence Tomography and Autofluorescence in the Outer Retina and Choroid of Patients With Choroideremia

Xue

Oldani

Jolly

et al. 2016

Invest. Ophthalmol. Vis. Sci.

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PurposeTo evaluate the relationships between RPE, photoreceptor, and choroidal degeneration in choroideremia.MethodsEnhanced-depth imaging optical coherence tomography (EDI-OCT), scanning laser ophthalmoscopy (SLO), and autofluorescence (AF) were performed on 39 patients (78 eyes) with choroideremia. The edges of surviving outer retina on OCT and residual AF were aligned. The distribution of outer retinal tubulations was mapped over a range of ages (16–71 years), and comparison made between pre- and postsubretinal gene therapy. Subfoveal choroidal thickness (SFCT) was compared between 23 choroideremia patients (42 eyes) and 20 age- and refraction-matched male controls (40 eyes).ResultsThe edges of RPE AF aligned with a reduction in outer nuclear layer thickness (Spearman's rho = 0.9992). Correlation was also found between the quality of AF and integrity of ellipsoid zone within islands of surviving retina. Tubulations existed in 71 of 78 (91%) eyes with choroideremia and remained stable following gene therapy. Subfoveal choroidal thickness was reduced at baseline in choroideremia (179.7 ± 17.2 μm) compared with controls (302.0 ± 4.8 μm; P < 0.0001), but did not undergo significant thinning until end-stage retinal degeneration (43.1 ± 6.5 μm).ConclusionsThe data suggest that RPE loss is the primary cause of photoreceptor degeneration in choroideremia. The choroid is thinner than controls from early stages, in keeping with a mild developmental defect. Photoreceptors appear to lose outer segments following loss of underlying RPE and form tubulations at the edges of degeneration. The preservation of tubulations over time and after subretinal injection would be consistent with these structures maintaining attachment to the inner retina and hence being potentially light responsive (ClinicalTrials.gov, NCT01461213).

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Section: Discussionmentioning

confidence: 99%

Correlation of Optical Coherence Tomography and Autofluorescence in the Outer Retina and Choroid of Patients With Choroideremia

Xue

Oldani

Jolly

et al. 2016

Invest. Ophthalmol. Vis. Sci.

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“…It has been hypothesized that the unique macular specificity in this disease is caused by region-specific dysfunctional RPE cells (56). Another notable anatomical feature of retinal dystrophy caused by m.3243A>G is the presence of outer retinal tubulations (ORT) (24, 37, 38), indicating outer retinal dysfunction and Müller cell activation (49). ORTs are known to form in response to RPE or choroidal malfunction, such as in the age related macular degeneration (AMD) (57) and the monogenetic disease choroideremia (58).…”

Section: Discussionmentioning

confidence: 99%

“…It has been hypothesized that the unique macular specificity in m.3243A>G disease is caused by region- specific dysfunctional RPE cells (54). A notable anatomical feature of retinal dystrophy caused by m.3243A>G is the presence of outer retinal tubulations (ORT) (24, 34, 35), structures formed by cone photoreceptor reorganization driven by Müller cell activation (48). Clinical examination of the retina of MELAS patients suggests a disease process that begins in the RPE and/or choroid, and eventually leads to outer retinal damage.…”

Section: Discussionmentioning

confidence: 99%

“…Fundus examination of the proband revealed macular atrophy typical of the m.3243A>G variant (Figure 1A, B) (22). Optical coherence tomography (OCT) of the retina showed outer retinal tubulations (ORTs) (Figure 1C), a clinical finding known to be associated with m.3243A>G associated disease and with RPE/choroid dysfunction leading to retinal dystrophy more broadly (37)(38)(39). The proband had been previously confirmed to carry the m.3243A>G variant by sequencing and digital PCR (Figure S1A), and the pedigree structure was compatible with mitochondrial inheritance.…”

Section: Clinical Ophthalmologic History Of M3243a>g Diseasementioning

confidence: 99%

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Multimodal single-cell analysis of non-random heteroplasmy distribution in human retinal mitochondrial disease

Mullin

Voigt

Flamme-Wiese

et al. 2022

Preprint

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Variants within the mitochondrial genome (mtDNA) disrupt organelle function and lead to severe multi-system disease. mtDNA partitioning in complex tissues has implications for how cellular dosing of genetic variants governs pathogenesis. Here, we profiled the transcriptome, chromatin accessibility state, and heteroplasmy of the most common pathogenic mitochondrial mutation, m.3243A>G, in single cells from the retina and choroid of a patient with retinal and systemic disease. We found that the proportion of the pathogenic m.3243G allele was neither evenly nor randomly distributed across ocular cell types. All classes of cells in the neural retinal exhibited a high percentage of the mutant variant. However, endothelial and lymphocyte populations of the choroid were near homoplasmic for the wildtype allele. Gene expression analysis revealed that the presence of m.3243G deranges expression and causes upregulation of MTRNR2L1, a pseudogene of humanin, known to be protective against oxidative damage. We further found by joint multimodal sequencing of the retinal pigment epithelium that a high proportion of 3243G variant was associated with transcriptionally and morphologically abnormal cells. Together, these findings illuminate the non-random nature of mitochondrial variant partitioning and demonstrate that m.3243A>G causes non-cell autonomous dysfunction in the complex and metabolically linked light-sensing tissue of the eye.

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“…Multimodal imaging demonstrates hyperautofluorescent spots on AF, often more diffuse than seen on clinical examination, with corresponding subretinal deposits on OCT; AF can further highlight lobular areas of atrophy corresponding to areas of retinal and RPE atrophy on OCT and fundus exam [51 & ]. Unlike in SD, outer retinal tubulations are commonly seen on OCT and can be highlighted with en face structural slabs from OCT angiography [52][53][54].…”

Section: Other Masqueradesmentioning

confidence: 99%

Stargardt disease masquerades

Ricca

Han

Sohn

2021

Current Opinion in Ophthalmology

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Purpose of reviewStargardt disease is the most common inherited macular dystrophy but has a wide clinical spectrum, and several inherited macular dystrophies have phenotypic similarities that can make clinical diagnosis challenging. This review seeks to highlight key clinical and multimodal imaging features to aid clinicians in accurate diagnosis. Recent findingsMultimodal imaging has provided additional information to aid in the diagnosis of Stargardt disease and its masquerades. These data from multimodal imaging are important to correlate with findings from clinical examination to help support the clinical diagnosis or guide molecular investigations.

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Outer retinal tubulations in maternally inherited diabetes and deafness (MIDD)-associated macular dystrophy

Cited by 9 publications

References 5 publications

Correlation of Optical Coherence Tomography and Autofluorescence in the Outer Retina and Choroid of Patients With Choroideremia

Correlation of Optical Coherence Tomography and Autofluorescence in the Outer Retina and Choroid of Patients With Choroideremia

Multimodal single-cell analysis of non-random heteroplasmy distribution in human retinal mitochondrial disease

Stargardt disease masquerades

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