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Rebecca Mastey, Michalis Georgiou, Christopher S Langlo, Angelos Kalitzeos, Ajoy Vincent, Anthony T Moore, Stephen H. Tsang, Jonathan H Lin, Marielle Young, M Elizabeth Hartnett, Elise Heon, Susanne Kohl, Michel Michaelides, Joseph Carroll; Characterization of retinal structure in ATF6-associated achromatopsia. Invest. Ophthalmol. Vis. Sci. 2018;59(9):669. doi: https://doi.org/.
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© ARVO (1962-2015); The Authors (2016-present)
ATF6 mutations have been associated with achromatopsia (ACHM). In contrast to CNGA3/B3-associated ACHM, it has been suggested that these individuals have disrupted parafoveal cone structure but supranormal cone density outside the central 1.5 mm. The degree of remnant cone structure is important for defining therapeutic potential in these patients. Here we examined retinal structure in subjects with ATF6-associated ACHM.
Seven subjects from 5 independent families with genetically confirmed ATF6-associated ACHM were imaged with optical coherence tomography (OCT) and adaptive optics scanning light ophthalmoscopy (AOSLO) at UCL or MCW. Ellipsoid zone (EZ) disruption was graded on OCT images using a previously defined scaleand foveal outer nuclear layer (ONL) thickness was measured. Photoreceptor density was manually derived from confocal AOSLO images at 5 & 10 degrees when possible.
All subjects had severe foveal hypoplasia on OCT. Interestingly, 43% (3/7) had grade 3 EZ disruption, in contrast to only 11% (9/82) of previously reported non-ATF6 subjects[2,3] (Fisher’s Test, p=0.0376). Foveal ONL thickness ranged from 39.2-174.0µm (mean=96µm). AOSLO images were interpretable in 3 of 7 subjects: all showed a central foveal lesion devoid of cone inner segment structure, in stark contrast to prior reports for CNGA3/B3-associated ACHM. In 2 of these subjects, confocal AOSLO images revealed a contiguous photoreceptor mosaic (Figure) with a density that was more consistent with normal rod, rather than cone, density (Table).
ATF6 mutations manifest a distinct form of ACHM. The 100% rate of foveal hypoplasia is consistent with previous work and suggestive of a more severe defect in foveal development. Prior AOSLO studies of CNGA3/B3 subjects with grade 3 or 4 EZ appearance always showed remnant foveal cone structure. The absence of foveal cones on AOSLO here suggests a markedly different cone phenotype. Moreover, the stereotypical “dark cone” phenotype seen parafoveally in other ACHM patients was absent in ATF6 subjects. Our data suggest that subjects with ATF6-associated ACHM have few cellular targets for cone-directed gene therapies. PMID: 26029869 PMID: 24148654 PMID: 27479814
This is an abstract that was submitted for the 2018 ARVO Annual Meeting, held in Honolulu, Hawaii, April 29 - May 3, 2018.
AOSLO images showing the “dark cone” phenotype in the perifovea of a CNGA3subject (top). The ATF6 subject (bottom) contains a contiguous array of presumed rods. Scale bar = 25µm.
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