Grand Rounds Conference

Jinghua Chen, MD, PhDUniversity of Louisville

Department of Ophthalmology and Visual SciencesApril 3, 2015

HistoryCC: Progressive decreased central vision

OU for one year.

HPI: 27 year old white male presented with progressive decrease central vision with spots in front of both eyes for one year. Patient has known macular

changes since 2006.

Past Medical History

POH: Moderate myopia (-3.50 D OU) Known “macular issue” since

2006PMH: NoneAllergy: NKDAFH: Mother “night vision issue” Medication: None

Exam OD OSBCVA: 20/20 20/20Pupils: 42 42

No RAPD OU

IOP: 12 11EOM/CVF: Full OUAnt. Seg: Normal OUColor vision: 9/12

11/12

IR Photos

Grainy perifoveal RPE stippling (hyperplasia/atrophy)

OCT Retina

Central macular atrophy, RPE foveal thinning with overlying loss of photoreceptors, OD>OS

FA

FA: Bull’s eye maculopathy with perifoveal patchy ring window defect OU, no leakage

Late Phase FA

Central hypofluorescence with perifoveal hyperfluorescence fading of window defect

Assessment and Plan 27 year old male with known macular changes since 2006

with more eccentric fixation in last year with Bull’s eye maculopathy OU.

Differential Diagnosis Cone dystrophy Stargardt’s disease Cone-rod dystrophy Central areolar choroidal atrophy Chronic macular hole Fenestrated sheen macular dystrophy Benign concentric annular macular dystrophy Olivopontocerebellar atrophy (OPCA) Ceroid lipofuscinosis

Plan: mf ERG, HVF 10-2BSCS 2014-2015 Book 12, Retina and Vitreous: 236

mf ERG

Extinguished foveal and decreased parafoveal and peripheral responses OU

Delayed P1 implicit time involving fovea OU and parafovea and periphery OD

mf ERG First Order Traces

Cone photoreceptor dysfunction

HVF 10-2

OU: central scotoma OD > OS

Diagnosis and Management

Diagnosis: Progressive cone dystrophy

Management: Observation Sunglasses for photophobia Macular Dystrophy Support Group (per

patient’s request)

Photoreceptor Degeneration

Cone dystrophy (photophobia, abnormal color vision and diminished central vision)

Cone-rod dystrophy (early decrease in central visual acuity, photophobia, color vision defects, and nystagmus, with later development of night blindness (nyctalopia).

Rod-cone dystrophy (nyctalopia and progressive peripheral vision loss.)

Progressive Cone Dystrophy

The prevalence of cone-rod dystrophy is approximately 1/40,000

Heterogeneous group of diseases Onset in teenage or later adult years Secondary rod photoreceptor involvement Overlap between progressive cone and

cone-rod dystrophy Abnormal photopic ERG, normal rod-

isolated ERG

Hamel CP. Orphanet J Rare Dis. 2007; 2:7. Thiadens AA, Ophthalmology. 2012; 119:819–26

Genetics Dominant cone dystrophy

6p21.1 is caused by mutations in the GUCA1A gene, which codes for guanylate cyclase activator, a calcium-binding protein in photoreceptor outer segments

Mutation in GUCY2D at 17p13.1

Autosomal recessive cone dystrophy ABCA4 (1p21-p23) gene, which encodes an ATP-binding

cassette (ABC) transporter protein expressed by rod and cone disc membrane and is involved in the transport of vitamin A derivatives to RPE. (ABCA4 also have been implicated in Stargardt’s disease, cone-rod dystrophy, and ‘‘retinitis pigmentosa.’’)

X-linked recessive: Tapetal-like sheen, Mizuo-Nakamura phenomenon

Management Cone photoreceptor transplantation:

Adult Nrl‐/‐ mice expressed only cone-specific genes (PNA, s‐opsin and cone arrestin) in photoreceptors, and did not express rod‐specific genes (Nrl or rhodopsin)

Purified these cone photoreceptors from the mouse retina based on the CD73 cell surface antigen.

Transplantation of postnatal day 4 cells into wild type mouse retina mediated optimal integration into the outer nuclear layer (ONL) generating morphologically mature photoreceptors.

Restoring daylight vision to AMD, cone‐rod dystrophies, or late-stage RP

Gene therapy RPGRIP1-deficient dog: a large animal model of cone-rod

dystrophy. (Mol Ther. 2014 Feb) Non allele-specific RNAi knockdown of GCAP1 as a general

therapeutic strategy to rescue any GCAP1-based dominant cone-rod dystrophy in human patients. (PLoS One. 2013)

Suppressing thyroid hormone Signaling Preserves cone photoreceptors in mouse models of retinal

degeneration. Thyroid hormone (TH) signaling regulates cell proliferation, differentiation, and apoptosis, plays a central role in cone opsin expression and patterning in the retina.(Proc Natl Acad Sci U S A. 2014 Mar)

Low vision aidshttp://www.stemcellsportal.com/first-step-towards-treating-cone-photoreceptor-degeneration

References BSCS 2014-2015 Book 12, Retina and Vitreous: 232-236 Berger W, Kloeckener-Gruissem B, and Neidhardt J The molecular basis of human

retinal and vitreoretinal diseases. Prog Retin Eye Res 2010;29:335-375 Gardner JC, Liew G, Quan YH. Three different cone opsin gene array

mutational mechanisms with genotype-phenotype correlation and functional investigation of cone opsin variants.,Hum Mutat. 2014 Nov;35(11):1354-62. doi: 10.1002/humu.22679.

Durlu YK, Köroğlu Ç, Tolun A. Novel recessive cone-rod dystrophy caused by POC1B mutation. JAMA Ophthalmol. 2014 Oct;132(10):1185-91.

Rabin J. Quantification of color vision with cone contrast sensitivity. Vis Neurosci. 2004 May-Jun;21(3):483-5.

Kearns TP, Hollenhorst RW. Chloroquine retinopathy: evaluation by fluorescein fundus angiography. Arch Ophthalmol. 1966;76: 378–384.

Deutman AF. Benign concentric annular macular dystrophy. Am J Ophthalmol. 1974;78:384–396.

Fishman GA, Fishman M, Maggiano J. Macular lesions associated with retinitis pigmentosa. Arch Ophthalmol. 1977;95:798–803.

Michaelides M, Hardcastle AJ, Hunt DM, Moore AT. Progressive cone and cone-rod dystrophies: phenotypes and underlying molecular genetic basis. Surv Ophthalmol. 2006;51:232–258.

O’Donnell FE Jr, Welch RB. Fenestrated sheen macular dystrophy: a new autosomal dominant maculopathy. Arch Ophthalmol. 1979; 97:1292–1296.

Kurz-Levin MM, Halfyard AS, Bunce C, et al. Clinical variations in assessment of bull’s-eye maculopathy. Arch Ophthalmol. 2002; 120:567–575.

References Hartong, D.T., Berson, E.L., and Dryja, T.P. (2006). Retinitis pigmentosa. Lancet 368,

1795–1809. El Shamieh S, Neuillé M, Terray A, Orhan E, Whole-exome sequencing identifies KIZ

as a ciliary gene associated with autosomal-recessive rod-cone dystrophy. The American Journal of Human Genetics 94, 625–633

Nogueira HM1, Gama RD. Images in clinical medicine. Bull's-eye maculopathy. N Engl J Med. 2009 May 21;360(21):2224. doi: 10.1056/NEJMicm0708021.

Hamel CP. Cone rod dystrophies. Orphanet J Rare Dis. 2007;2:7. Thiadens AA, Phan TM, Lotery AJ. Clinical Course, Genetic Etiology, and Visual

Outcome in Cone and Cone-Rod Dystrophy. Ophthalmology. 2012;119:819–26. Lhériteau E, Petit L, Weber M. Successful gene therapy in the RPGRIP1-

deficient dog: a large model of cone-rod dystrophy. Mol Ther. 2014 Feb;22(2):265-77. doi: 10.1038/mt.2013.232. Epub 2013 Oct 4.

Jiang L, Li TZ, Boye SE. RNAi-mediated gene suppression in a GCAP1(L151F) cone-rod dystrophy mouse model. PLoS One. 2013;8(3):e57676. doi: 10.1371/journal.pone.0057676. Epub 2013 Mar 5.

Ma H, Thapa A, Morris L. Suppressing thyroid hormone signaling preserves cone photoreceptors in mouse models of retinal degeneration. Proc Natl Acad Sci U S A. 2014 Mar 4;111(9):3602-7. doi: 10.1073/pnas.1317041111. Epub 2014 Feb 18.