Advances in Retinal Imaging of Achromatopsia Joseph Carroll, PhD Departments of Ophthalmology, Biophysics, and Cell Biology, Neurobiology, & Anatomy Medical College of Wisconsin Achromatopsia Convention August 2, 2011
Acknowledgements Medical College of Wisconsin Kim Stepien, MD Alf Dubra, PhD JungtaeRha, PhD Robert Cooper Adam Dubis Brett Schroeder Phyllis Summerfelt Chicago Lighthouse/UIC Gerald Fishman, MD Mohamed Genead, MD University of Washington Jay Neitz, PhD Maureen Neitz, PhD $$$$ - NIH EY017607, EY001931, Research to Prevent Blindness, E. Matilda Ziegler Foundation for the Blind, Kirchgessner Foundation, Gene & Ruth Posner Foundation, RD & Linda Peters Foundation, Hope for Vision, Vision for Tomorrow Foundation, & Fight for Sight
Complex layered structure which is made up of different types of cells. Picture from Webvision: The Organization of the Retina and Visual System
Webvision Ann Milam Fine & Yanoff (1979)
In achromatopsia, we are interested in studying photoreceptor structure – as this is likely to be helpful in the translation of gene-based therapies to the condition. Two imaging techniques have emerged that allow us to directly assess photoreceptor structure in patients with achromatopsia and other retinal disorders…
Optical Coherence Tomography
Used in astronomy to correct for turbulence in the atmosphere.
Spot Array Wave Aberration Dd f The Human Eye is Highly Aberrated CCD Lenslet Array Array Ideal, Diffraction-Limited Eye Normal, Aberrated Eye Courtesy: Jason Porter
Carroll et al., (2005)
Adaptive Optics Imaging 30 deg 3 deg 2 mm resolution
Imaging the Rod and Cone Mosaic Dubra, Sulai, Norris, Cooper, Dubis, Williams, Carroll(2011)
With the ability to resolve the entire photoreceptor mosaic, we can quantify different aspects of the rod and cone mosaics… Dubra, Sulai, Norris, Cooper, Dubis, Williams, Carroll(2011)
Recent success in retinal gene therapy indicate that it may be possible to restore cone function in individuals with ACHM and BCM:
modest visual function recovered in patients with LCA (Maguire et al., 2008; Bainbridge et al., 2008; Cideciyanet al., 2008),
cone function improved in dog and mouse models of congenital achromatopsia (Komáromyet al., 2010; Alexander et al., 2007),
trichromatic color vision achieved in a primate model of human dichromacy (Mancuso et al., 2009)
A better understanding of photoreceptor structure is needed in order to assess the therapeutic potential in human patients with AHCM & BCM.
Autosomal recessive; ≈1 in 33,000 incidence
Caused by defect in CNGA3, CNG3, GNAT2, or PDE6C.
Affected individuals are thought to have no cone function (though see Nishiguchi, et al. 2005).
Clinically presents very similarly to BCM.
Histology data varies: from suggesting normal peripheral cones (Larsen, 1921), reduced numbers throughout (Harrison et al., 1960; Glickstein & Heath, 1975), or normal numbers in the fovea (Falls et al., 1965).
OCT data suggests progressive loss of cone layers (Thiadens et al. 2010)…
IS OS RPE
Variable IS/OS Photoreceptor Structure Present in ACHM Geneadet al. (2011)
Foveal Hypoplasia Albinism ACHM
Assessing Cone Structure in ACHM Geneadet al. (2011)
Assessing Cone Structure in ACHM Geneadet al. (2011)
Variation in cone structure within individual retina. Geneadet al. (2011)
ACHM: Imaging Summary
OCT reveals foveal hypoplasia in a number of patients. Unclear what the link is to the pathophysiology of achromatopsia is.
OCT reveals significant variation in the disruption of the IS/OS, and variable thinning of the ONL – suggesting variable degrees of photoreceptor loss.
Imaging with AO reveals significant cone structure in most patients, with some even retaining both an inner and outer segment to the cone. These cones are not functioning normally, but appear to be intact structurally, at least in part.
Significant work remains:
Examine differences across genotypes
Examine longitudinal cone loss in these conditions
Correlate structural differences with functional measures
abs l Normal Human Color Vision Hofer et al. (2006)
Blue Cone Monochromacy
Rare X-linked condition characterized
by an absence of L- and M-cone function. - (L + M) = ~95% of all cones
Individuals with BCM present with poor
color discrimination, reduced central vision, nystagmus, & myopia, but otherwise normal fundus findings.
Two primary genetic pathways in BCM – “one-step” involve a deletion of the LCR whereas “two-step” include a reduction in gene number to 1 and incorporation of a missense mutation in the remaining opsin gene.
- Accumulating evidence for macular atrophy and progressive loss of visual function in BCM (Ayyagari et al., 1999, 2000; Kellner et al., 2004; Michaelides et al., 2004; Mizrahi-Meissonnier et al., 2010). Hofer et al. (2005)
JC_0183 JC_0184 Curcio et al. (1991) 2,626 cones/mm2 4,116 cones/mm2 2,000 – 5,000 cones/mm2 S-Cone Free Zone - Data is consistent with the S-cone free zone being variable in size (Williams et al., 1981; de Monasterioet al., 1985; Norket al., 1990; Curcio et al., 1991). - Residual packing density of S-cones may contribute to phenotypic heterogeneity.
Peripheral BCM Mosaic Rods begin to appear. Large, bright S cones no longer visible, rather cones appear dark (inner segment). Fewer in number than AHCM.
ACHM & BCM
It appears that there are reliable imaging biomarkers that distinguish these two conditions:
BCM has thinner ONL than ACHM
S-cone free zone visible in BCM, not ACHM
No foveal hypoplasia seen in BCM
As genetic testing can often be inconclusive and expensive, use of high resolution imaging to guide genetic testing may be helpful.
Imaging the retina in both conditions may be an important part of the success of emerging treatments – both in selecting patients and in monitoring outcomes.
Need for continued imaging of patients with a variety of presentations with documented genotypes.
Continued development of hardware that will allow more routine imaging of the retina in patients with nystagmus.
Need for better software for more robust analysis of retinal images – still evolving.
Need to expand access to high-resolution imaging tools.
All of this requires commitment and investment from funding agencies, researchers, and patients alike.