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Autosomal Dominant Cone-Rod Dystrophy with Mutations in the Guanylate Cyclase 2D Gene Encoding Retinal Guanylate Cyclase-1

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Autosomal Dominant Cone-Rod Dystrophy with Mutations in the Guanylate Cyclase 2D Gene Encoding Retinal Guanylate Cyclase-1 OPHTHALMIC MOLECULAR GENETICS Autosomal Dominant Cone-Rod Dystrophy With Mutations in the Guanylate Cyclase 2D Gene Encoding Retinal Guanylate Cyclase-1 Susan M. Downes, MD; Annette M. Payne, PhD; Rosemary E. Kelsell, PhD; Frederick W. Fitzke, PhD; Graham E. Holder, PhD; David M. Hunt, PhD; Anthony T. Moore, FRCOphth; Alan C. Bird, MD Objective: To describe the phenotype in 4 families with cal testing revealed a marked loss of cone function with dominantly inherited cone-rod dystrophy, 1 with an only minimal rod involvement, even in older subjects. R838C mutation and 1 with an R838H mutation in the Photopic and scotopic static perimetry demonstrated cen- guanylate cyclase 2D (GUCY2D) gene encoding retinal tral and peripheral cone-mediated threshold elevations guanylate cyclase-1. with midperipheral sparing. Methods: Psychophysical and electrophysiological evalu- Conclusion: The phenotype associated with autosomal ation and confocal laser scanning ophthalmoscopic im- dominant cone-rod dystrophy with either an R838C or aging was performed on 10 affected members of 4 Brit- R838H mutation in GUCY2D is distinctive, with predomi- ish families. nantly cone system involvement. There is some variation in severity within the 3 families with the R838C mutation. Results: Although subjects had lifelong poor vision in bright light, a major reduction in visual acuity did not Clinical Relevance: Families with the R838C or R838H occur in most of them until after their late teens. Fun- mutation have a much milder phenotype than the fam- dus abnormalities were confined to the central macula, ily previously described that had 2 sequence changes, and increasing central atrophy was noted with age. In- E837D and R838S, in GUCY2D. creased background autofluorescence was observed sur- rounding the central atrophic area. Electrophysiologi- Arch Ophthalmol. 2001;119:1667-1673 ONE AND cone-rod dystro- tral atrophy occurs. In some cases, tem- phies are a subgroup of poral pallor of the optic nerve head is seen. the inherited retinal dys- Nystagmus may be present in early-onset trophies. Cone dystro- disease. In cone-rod dystrophy, function phies are characterized by that is dependent on rods, including vi- Cpoor central vision and an abnormal cone- sual fields and night vision, will be vari- isolated electroretinogram (ERG). In cone- ably affected according to the degree of in- rod dystrophy, the abnormality of rod volvement. Varying degrees of intraretinal function is less severe than that of cone pigment and vessel attenuation occur. function and may be detected later in the To date, studies have shown that cone course of the disease than cone dysfunc- dystrophy and cone-rod dystrophy are ge- tion.1-3 The diagnosis is established by elec- netically heterogeneous. Dominant, re- trophysiological evaluation; functional re- cessive, and X-linked inheritance pat- sults depend on the stage of the disease and terns have been reported.3 Seven loci have the age of the individual. The diagnosis of been identified in autosomal dominant cone-rod dystrophy may be reinforced by cone and cone-rod dystrophies.4 Loci as- the demonstration of peripheral as well as sociated with known genes include chro- central visual field loss. mosome 6p12 with mutations in periph- The most common symptoms of cone erin/RDS,5-7 chromosome 6p21 with From Moorfields Eye Hospital involvement include varying degrees of mutations in GUCA1A,8 chromosome 17p (Drs Downes, Holder, Moore, photophobia and loss of visual acuity, color with mutations in GUCY2D,9,10 and chro- and Bird) and the Institute of vision, and central visual fields. Retinal ap- mosome 19q with mutations in CRX.11 The Ophthalmology (Drs Downes, 12,13 Payne, Kelsell, Fitzke, Hunt, pearance may be normal in the early stages other loci include 2 in chromosome 6q Moore, and Bird), University of the disease, but with progression the and a presumed autosomal dominant lo- College London, retinal pigment epithelium (RPE) may take cus in chromosome 17q in association with London, England. on a bull’s-eye pattern of change; later, cen- neurofibromatosis.14 A sporadic case due (REPRINTED) ARCH OPHTHALMOL / VOL 119, NOV 2001 WWW.ARCHOPHTHALMOL.COM 1667 ©2001 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 10/01/2021 SUBJECTS AND METHODS Psychophysical Tests MOLECULAR ANALYSIS Static threshold perimetry in the dark- and light-adapted states was performed using a modified Humphrey Field Ana- The methods performed for linkage studies, mutation lyzer (Allergan Humphrey, Hertford, England). Photopic screening, heteroduplex electrophoresis, and direct ge- Humphrey visual fields were assessed using the standard 19 nomic sequencing have been described previously.9 protocol. For the scotopic perimetry, the pupil was di- lated with 2.5% phenylephrine hydrochloride and 1% cy- SUBJECTS clopentolate hydrochloride, and the eye was dark adapted for at least 45 minutes. An infrared source illuminated the Three families with an R838C mutation and 1 family with bowl, and an infrared monitor (Phillips, Eindhoven, The an R838H mutation were invited to participate in the study. Netherlands) was used to monitor fixation. Fields were re- Five blood samples were available from family A, 8 from corded using programs 30-2 (central), 30-2 and 60-2 (pe- family B, 4 from family C, and 3 from family D. Three af- ripheral), and the macular program. The target size corre- fected members from family A, 4 from family B, 2 from fam- sponded to Goldmann perimeter size V for peripheral testing ily C, and 1 from family D underwent phenotypic charac- and Goldmann size III for macular programs. Each pro- terization. This research was performed in accordance with gram was performed with both a red (predominant wave- the Declaration of Helsinki, developed by the World Medi- length, 650 nm) and blue (predominant wavelength, 450 cal Association, and was approved by the Moorfields Eye nm) filter in the stimulus beam to record cone and rod func- Hospital Ethics Committee (London, England). Informed tion, respectively. consent was obtained from all participants. Color contrast sensitivity was evaluated in 7 of the 11 subjects using published protocols,20 and Hardy-Rand- CLINICAL AND FUNCTIONAL INVESTIGATIONS Rittler color plate testing was performed in the others. Phenotypic characterization included a full ophthalmic his- Imaging tory and detailed fundus examination. Fundus photogra- phy, confocal scanning laser ophthalmoscopy, and psy- Images of the central macular region were obtained using chophysical and electrophysiological evaluations were also a prototype confocal laser scanning ophthalmoscope performed. (cLSO SM 30-4024; Zeiss, Oberkochen, Germany). An argon laser (488 nm, 250 mW) was used for illumination. Electrophysiology Reflectance imaging was undertaken with a 40° field and the argon blue laser with the depth plane adjusted to Subjects underwent electrophysiological investigation us- maximize the visibility of the fundus features. A wide- ing techniques in accord with the recommendations of the band pass filter with a cutoff at 521 nm inserted in front International Society for Clinical Electrophysiology of Vi- of the detector was used to detect autofluorescence, sion.16-18 Electro-oculographic responses, full-field ERGs, which was recorded, measured, and analyzed using pub- and pattern ERGs were recorded for 10 subjects. lished techniques.21 to a balanced translocation between chromosomes 1 and common origin in a relatively distant ancestor. How- 6 has also been recorded.15 ever, it was not possible to prove this conclusively. The phenotype described in this article in 3 fami- lies with R838C and 1 family with R838H is compared CLINICAL FINDINGS with that previously described in a family with 2 se- quence changes in GUCY2D (R838S and E837D) asso- Clinical characteristics are documented in the Table. Most ciated with intense photophobia, poor vision before 6 years subjects became symptomatic during the first 2 decades of age, loss of the peripheral visual field in middle life, of life, and the affected members of family B reported more and loss of detectable ERG responses.10 disabling symptoms in the early stages of their disease than other families. All subjects were aware of lifelong RESULTS poor vision in bright sunlight followed by reduced cen- tral vision and color vision. Eccentric fixation was com- DNA ANALYSIS mon. No subject complained of nyctalopia. Visual acuities in families A, C, and D were found An R838C mutation in GUCY2D was identified in 3 fami- to be better than those of family B at a comparable age. lies (families A, B, and C), and an R838H mutation was However, no subject older than 50 years had a visual acu- discovered in 1 family (family D) (Figure 1). The mu- ity better than 20/200. tation was found to segregate with disease in all 4 fami- lies. Within these 3 families and including the family FUNDUS APPEARANCE with the 2 sequence changes in GUCY2D (R838S and E837D),10 there is some evidence of linkage disequilib- Soon after the onset of visual symptoms, mild RPE granu- rium between the disease allele and one of the flanking lar abnormalities were apparent at the fovea (Figure 2A markers, indicating that this mutation may have had a and 2B). At this stage, autofluorescence imaging showed (REPRINTED) ARCH OPHTHALMOL / VOL 119, NOV 2001 WWW.ARCHOPHTHALMOL.COM 1668 ©2001 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 10/01/2021 A B I:1 I:2 I:1 I:2 I:3 II:1 II:2 II:3 II:4 II:5 II:6 II:7 II:8 II:1 II:2 II:3 II:4 III:1 III:2 III:3 III:4 III:5 III:6 III:7 III:1 III:2 III:3 III:4 III:5 IV:1 IV:2 C D I:1 I:2 I:1 I:2 ? ? II:1 II:2 II:3 II:4 II:5 II:6 II:1 II:2 II:3 II:4 III:1 III:2 III:3 III:4 III:5 III:6 III:7 III:8 III:9 III:10 III:1 III:2 III:3 III:4 III:5 IV:1 IV:2 IV:3 IV:4 IV:5 IV:6 IV:7 IV:8 V:1 V:2 V:3 V:4 V:5 IV:1 IV:2 IV:3 IV:4 IV:5 Figure 1.
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