Long Term Follow-up of a Family with GUCY2D Dominant Cone Dystrophy Running Clinical Features in GUCY2D Dominant Cone Dystrophy

The aim of this manuscript is to describe long term follow-up in a family with GUC2YD dominant cone dystrophy. OCT scans (Triton/OCT-2000 Topcon Ltd, Tokyo, Japan) and Fundus Autofluorescence (FAF) images (Spectralis Heidelberg Engineering, Heidelberg, Germany) were obtained. Goldmann Visual Field (GVF) testing was utilised to monitor the progression of central field loss. Flash and pattern electroretinograms (ERG) and occipital pattern reversal VEPs (VEP) were recorded in accordance with International Society for Clinical Electrophysiology of Vision (ISCEV) standards. Two members of the same family (father and son) were identified to have the heterozygous R838C mutation in the GUC2YD gene. The father presented at the age of 45 with bilateral bull’s eye maculopathy and temporal disc pallor. Over 13 years of serial follow up visits, the bull’s eye maculopathy progressed gradually into macular atrophy. The cone ERGs and visual evoked potentials (VEP) were significantly degraded suggesting poor macular function. Spectral Domain Optical Coherence Tomography (SD-OCT) scans showed progressive loss and disruption of the ellipsoid layer at the foveal level. Autofluorescence showed a central annular area of hypo-autofluorescence corresponding to macular atrophy and retinal pigment epithelial (RPE) loss with a surrounding ring of hyper-autofluorescence indicating the transitional zone between the abnormal-normal tissue. Goldmann Visual Fields (GVFs) showed enlargement of a central scotoma. His son presented at the age of 16 with bilateral granular RPE changes in both maculae. Electrophysiological testing was initially borderline normal but has gradually deteriorated to show reduced cone ERGs and macula function. SD-OCT demonstrated gradual macular thinning and atrophy bilaterally. Unlike his father, there was no disruption of the ellipsoid layer. GVFs showed progression of central visual field loss. In conclusion, both family members with cone dystrophy exhibited gradual changes in their fundi, electrophysiological testing and multimodal imaging. Changes were milder than those observed in other mutations of the same gene. 5’-triphosphate (GTP) to cyclic guanosine monophosphate (cGMP) [4] . Like other membrane guanylyl cyclases, this enzyme has a hydrophobic amino-terminal signal sequence followed by a large extracellular domain, a single membrane spanning domain, a kinase homology domain, and a guanylyl cyclase catalytic domain. In contrast to other membrane guanylyl cyclases, this enzyme is not activated by natriuretic peptides. The Retinal Guanylyl Cyclase 1 helps photoreceptors return to their dark-adapted state after light exposure; cGMP plays a significant role as the second messenger molecule in the phototransduction cascade by keeping the voltage-gated sodium and calcium channels of photoreceptors open [4] . Photoactivation leads to conversion of cGMP to guanosine 5’-monophophate (GMP) by phosphodiesterase and this results in the closure of voltage-gated sodium and calcium channels and to hyperpolarization of the photoreceptor outer segments [4] . When the concentration of calcium cations is reduced, the Retinal Guanylyl Cyclase 1 restores the levels of cGMP and this allows the reopening of the relevant channels [4] . Restoration of cGMP levels is achieved by the presence of the guanylate cyclase-activating protein [4] . Mutations in GUCY2D gene have been described in cone-rod dystrophy-6 and Leber congenital amaurosis [5] .