July 2018
Volume 59, Issue 9
Open Access
ARVO Annual Meeting Abstract  |   July 2018
Characterization of retinal structure in ATF6-associated achromatopsia
Author Affiliations & Notes
  • Rebecca Mastey
    Ophthalmology & Visual Sciences, Medical College of Wisconsin, Milwaukee, Wisconsin, United States
  • Michalis Georgiou
    Genetics, University College London Institute of Ophthalmology, London, United Kingdom
    Moorfields Eye Hospital, London, United Kingdom
  • Christopher S Langlo
    Ophthalmology & Visual Sciences, Medical College of Wisconsin, Milwaukee, Wisconsin, United States
    Cell Biology, Neurobiology, & Anatomy, Medical College of Wisconsin, Milwaukee, Wisconsin, United States
  • Angelos Kalitzeos
    Genetics, University College London Institute of Ophthalmology, London, United Kingdom
    Moorfields Eye Hospital, London, United Kingdom
  • Ajoy Vincent
    Ophthalmology and Vision Sciences, The Hospital for Sick Children, Toronto, Ontario, Canada
  • Anthony T Moore
    Ophthalmology, University of California San Francisco Medical School, San Francisco, California, United States
  • Stephen H. Tsang
    Ophthalmology, Columbia University, New York, New York, United States
  • Jonathan H Lin
    Ophthalmology, University of California San Diego, La Jolla, California, United States
    Pathology, University of California San Diego, La Jolla, California, United States
  • Marielle Young
    Moran Eye Center, University of Utah, Salt Lake City, Utah, United States
  • M Elizabeth Hartnett
    Moran Eye Center, University of Utah, Salt Lake City, Utah, United States
  • Elise Heon
    Ophthalmology and Vision Sciences, The Hospital for Sick Children, Toronto, Ontario, Canada
  • Susanne Kohl
    Centre for Ophthalmology at The Institute for Ophthalmic Research, University of Tübingen, Tübingen, Germany
  • Michel Michaelides
    Genetics, University College London Institute of Ophthalmology, London, United Kingdom
    Moorfields Eye Hospital, London, United Kingdom
  • Joseph Carroll
    Ophthalmology & Visual Sciences, Medical College of Wisconsin, Milwaukee, Wisconsin, United States
    Cell Biology, Neurobiology, & Anatomy, Medical College of Wisconsin, Milwaukee, Wisconsin, United States
  • Footnotes
    Commercial Relationships   Rebecca Mastey, None; Michalis Georgiou, None; Christopher Langlo, None; Angelos Kalitzeos, None; Ajoy Vincent, None; Anthony Moore, None; Stephen Tsang, None; Jonathan Lin, None; Marielle Young, None; M Elizabeth Hartnett, None; Elise Heon, None; Susanne Kohl, None; Michel Michaelides, MeiraGTx (C); Joseph Carroll, AGTC (F), MeiraGTx (C)
  • Footnotes
    Support  Wellcome Trust and NIH Grants: R01EY017607, P30EY001931, R01EY027355, R01EY018213, T32GM080202
Investigative Ophthalmology & Visual Science July 2018, Vol.59, 669. doi:
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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.

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      © ARVO (1962-2015); The Authors (2016-present)

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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.

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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