Characterization of retinal structure in ATF6-associated achromatopsia

Abstract

Purpose : 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.[1] 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.

Methods : 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 scale[2]and foveal outer nuclear layer (ONL) thickness was measured. Photoreceptor density was manually derived from confocal AOSLO images at 5 & 10 degrees when possible.

Results : 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.[3] 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).

Conclusions : 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.

[1] PMID: 26029869
[2] PMID: 24148654
[3] 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.