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The Cone Dysfunction Syndromes Jonathan Aboshiha,1,2 Adam M Dubis,1,2 Joseph Carroll,3 Alison J Hardcastle,1,2 Michel Michaelides1,2

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The Cone Dysfunction Syndromes Jonathan Aboshiha,1,2 Adam M Dubis,1,2 Joseph Carroll,3 Alison J Hardcastle,1,2 Michel Michaelides1,2 Downloaded from http://bjo.bmj.com/ on January 7, 2016 - Published by group.bmj.com Review The cone dysfunction syndromes Jonathan Aboshiha,1,2 Adam M Dubis,1,2 Joseph Carroll,3 Alison J Hardcastle,1,2 Michel Michaelides1,2 1UCL Institute of ABSTRACT briefly review the management and latest progress Ophthalmology, University The cone dysfunction syndromes are a heterogeneous towards developing effective treatments. College London, London, UK 2Moorfields Eye Hospital, group of inherited, predominantly stationary retinal London, UK disorders characterised by reduced central vision and CONE DYSFUNCTION SYNDROMES 3Department of varying degrees of colour vision abnormalities, Complete achromatopsia Ophthalmology, Medical nystagmus and photophobia. This review details the Complete ACHM (syn. typical ACHM or rod mono- College of Wisconsin, following conditions: complete and incomplete chromatism) is an autosomal-recessive condition Milwaukee, Wisconsin, USA achromatopsia, blue-cone monochromatism, oligocone associated with a lack of cone function,5 which 2 Correspondence to trichromacy, bradyopsia and Bornholm eye disease. We affects about 1 in 30 000 people. It is characterised Michel Michaelides, UCL describe the clinical, psychophysical, electrophysiological by presentation at birth/early infancy with pendular Institute of Ophthalmology, and imaging findings that are characteristic to each nystagmus, poor visual acuity (approximately loga- 11-43 Bath Street, London EC1V 9EL, UK; michel. condition in order to aid their accurate diagnosis, as well rithm of the minimum angle of resolution (logMAR) [email protected] as highlight some classically held notions about these 1.0), a lack of colour vision and marked photopho- diseases that have come to be challenged over the bia/hemeralopia. Patients may also demonstrate para- Received 8 December 2014 recent years. The latest data regarding the genetic doxical pupillary constriction when transitioned Accepted 9 February 2015 aetiology and pathological changes observed in the cone from light to dark ambient conditions; the so-called Published Online First 6 13 March 2015 dysfunction syndromes are discussed, and, where Flynn phenomenon. Electroretinography (ERG) relevant, translational avenues of research, including typically demonstrates absent cone responses and completed and anticipated interventional clinical trials, normal rod responses,78and psychophysical testing for some of the diseases described herein will be also reveals normal rod function but absent cone presented. Finally, we briefly review the current function.9 Hypermetropic refractive errors are management of these disorders. common10 and fundus appearance is often normal, although macular changes can be observed that range from subtle retinal pigment epithelium (RPE) abnor- malities to atrophy. INTRODUCTION To date, five genes have been associated with The cone dysfunction syndromes (CDS) are a ACHM, all encoding components of the cone- collection of heterogeneous inherited conditions, specific phototransduction cascade. Disease-causing both in terms of their clinical characteristics and sequence variants in these genes have been esti- molecular genetic basis. They represent an import- mated to account for approximately 90% of ant cause of lifelong visual impairment, with inher- ACHM cases.11 The first discovered, and most ited retinal disorders being the second commonest common, of these genes are CNGA312 and cause of legal blindness in childhood and the CNGB3,13 which encode the α-subunits and leading cause among the working-age population in β-subunits of the cGMP-gated cation channel, England and Wales.1 CDS have varying modes of respectively. CNGB3 mutations were first identified genetic inheritance and have been classically in a population of Micronesian islanders where the described as stationary conditions in contrast to the prevalence of complete ACHM was up to 3000 progressive cone dystrophies.23 times that of other general populations; this was Clinically, CDS are characterised by presentation thought to be due to a typhoon that devastated the at birth/early infancy with visual loss and variable island in the 18th century,14 with all affected islan- degrees of colour vision abnormalities, nystagmus ders able to trace their ancestry to a single typhoon and photophobia, all of which reflect the dysfunc- survivor.13 Mutations in these two genes account tion of the foveally concentrated cone cells that for approximately 80% of all complete ACHM – constitute approximately 5% of human photore- cases.21517 Open Access fi Scan to access more ceptors. Given that these disease characteristics The most frequently identi ed mutation in free content have an early onset and severely impair important CNGB3 is the 1 base pair frameshift deletion behaviours of daily living such as facial recognition, c.1148delC (p.Thr383Ile fs*13), which accounts – reading and daylight vision, the consequent debili- for >70% of CNGB3 disease-causing alleles.16 18 tating impact on patients’ lives is considerable. There is far greater allelic heterogeneity in CNGA3 In this review, we describe the phenotypic and disease-causing variants (over 80 described) com- genotypic features of CDS (excluding those solely pared with CNGB3 (∼40). The majority of CNGB3 of colour vision deficiency), including complete variants identified to date are nonsense mutations, and incomplete achromatopsia (ACHM), blue-cone in direct contrast to the high proportion of To cite: Aboshiha J, monochromatism (BCM), oligocone trichromacy missense mutations observed in CNGA3, suggesting Dubis AM, Carroll J, et al. (OT), bradyopsia and Bornholm eye disease (BED) that mutations that compromise the structural and Br J Ophthalmol (table 1). Given the new era of gene therapy inter- functional integrity of the CNGA3 α-subunits are – 2016;100:115 121. ventions in human retinal disease,4 we will also less well tolerated. Aboshiha J, et al. Br J Ophthalmol 2016;100:115–121. doi:10.1136/bjophthalmol-2014-306505 115 116 Table 1 Summary of the clinical, genetic and electrophysiological characteristics of the cone dysfunction syndromes Review Successful Typical rescue of Mode of BCVA Typical Fundus Functional Associated gene(s) (cytogenetic animal Syndrome Prevalence inheritance (logMAR) refractive error Nystagmus findings Colour vision Typical ERG findings photoreceptors location) model/s Complete achromatopsia syn. 1 in 30 000 Autosomal 1.0 Often Present Usually Absent Absent cone responses; often normal rod LW-cones: no CNGA3 (2q11.2) Yes typical achromatopsia; rod recessive hypermetropic normal responses MW-cones: no CNGB3 (8q21-q22) monochromatism SW-cones: no GNAT2 (1p13) Rods: yes PDE6C (10q24) Downloaded from PDE6H (12p13) Incomplete achromatopsia Uncertain Autosomal 0.6–1.0 Often Present Usually Residual Reduced or absent cone responses; often LW-cones: possible CNGA3 (2q11.2) Yes syn. atypical achromatopsia recessive hypermetropic normal normal rod responses MW-cones: possible CNGB3 (8q21-q22) SW-cones: possible GNAT2 (1p13) Rods: yes Blue-cone monochromatism 1in X-linked 0.6–1.0 Often myopic Present Usually Residual tritan Reduced cone responses but with preserved LW-cones: no Principal opsin array mutational Yes syn. S-cone monochromatism; 100 000 recessive myopic discrimination S-cone responses; normal rod responses MW-cones: no mechanisms on Xq28: (i) LCR http://bjo.bmj.com/ X-linked incomplete SW-cones: yes deletion (approx. 40% cases) achromatopsia; X-linked Rods: yes (ii) Non-homologous recombination atypical achromatopsia between OPN1LW/OPN1MW resulting in a single gene in the array with a subsequent inactivating point mutation Aboshiha J, (approximately 60% of cases) onJanuary7,2016-Publishedby Oligocone trichromacy Uncertain Autosomal 0.2–0.6 Equal prevalence Often Normal Normal Reduced or absent cone responses; normal LW-cones: yes Possibly hypomorphic variants in No recessive of myopia and absent rod responses MW-cones: yes the genes associated with hypermetropia SW-cones: yes achromatopsia et al Rods: yes . Bradyopsia syn. RGS9/ Rare Autosomal 0.2–0.6 Equal prevalence Often Normal Normal Reduced/absent cone responses; the LW-cones: yes RGS9 (17q23-q24) No Br J Ophthalmol R9AP-retinopathy recessive of myopia and absent rod-specific ERG and the SBWF with ISI of MW-cones: yes R9AP (19q13.11) hypermetropia 2 min are normal—however, the SBWF SW-cones: yes ERG with an ISCEV standard ISI of 20 s Rods: yes shows amplitude reduction, which is progressively less severe with increasing ISI, 2016; consistent with delayed recovery following the flash—thereby demonstrating the need 100 for more extended testing than that group.bmj.com :115 mandated by ISCEV in the ERG Standard protocol – 121. doi:10.1136/bjophthalmol-2014-306505 Bornholm eye disease syn. Uncertain X-linked 0–0.8 Moderate to high Absent Usually Deuteranopia Reduced cone responses; normal rod LW-cones: yes, when L/M interchange haplotypes (opsin No X-linked cone dysfunction recessive myopia with myopic or protanopia responses observed with array on Xq28) syndrome with dichromacy astigmatism deuteranopia; no, when and myopia observed with protanopia MW-cones: yes, when observed with protanopia; no, when observed with deuteranopia SW-cones: yes Rods: yes BCVA, best-corrected visual acuity; ERG, electroretinography; ISCEV, International Society for Clinical Electrophysiology of Vision; ISI, inter-stimulus interval; LCR, locus control region; logMAR, logarithm of the minimum angle of resolution; LW, long wavelength; MW, middle
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