GUCY2D-Associated Leber Congenital Amaurosis: A Retrospective Natural History Study in Preparation for Trials of Novel Therapies

• Published in: American journal of ophthalmology Vol. 210; pp. 59 - 70
• Main Authors: Bouzia, Zaina, Georgiou, Michalis, Hull, Sarah, Robson, Anthony G., Fujinami, Kaoru, Rotsos, Tryfon, Pontikos, Nikolas, Arno, Gavin, Webster, Andrew R., Hardcastle, Alison J., Fiorentino, Alessia, Michaelides, Michel
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.02.2020; Elsevier Limited; Elsevier Science
• Subjects: Adolescent; Adult; Age; Child; Child, Preschool; Congenital diseases; Diabetic retinopathy; Disease Progression; Families & family life; Female; Genes; Genetic counseling; Genetics; Genomes; Guanylate Cyclase - genetics; Humans; Leber Congenital Amaurosis - genetics; Leber Congenital Amaurosis - pathology; Male; Middle Aged; Patients; Photoreceptor Cells, Vertebrate - pathology; Photoreceptors; Receptors, Cell Surface - genetics; Retinal Pigment Epithelium - pathology; Retrospective Studies; Tomography, Optical Coherence; Vision Disorders - etiology; Visual Acuity; Visual impairment; United Kingdom > UK
• ISSN: 0002-9394; 1879-1891; 1879-1891
• DOI: 10.1016/j.ajo.2019.10.019

To describe the natural history of Leber congenital amaurosis (LCA) associated with GUCY2D variants (GUCY2D-LCA) in a cohort of children and adults, in preparation for trials of novel therapies. Retrospective case series. Participants: Patients with GUCY2D-LCA at a single referral center. Procedures: Review of clinical notes, retinal imaging including fundus autofluorescence (FAF) and optical coherence tomography (OCT), electroretinography (ERG), and molecular genetic testing. Main Outcome Measures: Demographic data, symptoms at presentation, visual acuity, evidence of progression, OCT and FAF findings, ERG assessment, and molecular genetics. Twenty-one subjects with GUCY2D-LCA were included, with a mean follow-up ± standard deviation (SD) of 10 ± 11.85 years. Marked reduction in visual acuity (VA) and nystagmus was documented in all patients within the first 3 years of life. Fifty-seven percent (n = 12) exhibited photophobia and 38% (n = 8) had nyctalopia. VA was worse than hand motion in 71% of the patients (n = 15). Longitudinal assessment of VA showed stability in all patients, except 1 patient who experienced deterioration over a follow-up of 44 years. Hyperopia was reported in 13 of the 17 subjects (71%) with available refraction data. Eighteen subjects had either normal fundus appearance (n = 14) or a blond fundus (n = 3), while only 4 of the eldest subjects had mild retinal pigment epithelium (RPE) atrophy (mean, 49 years; range 40-54 years). OCT data were available for 11 subjects and 4 different grades of ellipsoid zone (EZ) integrity were identified: (1) continuous/intact EZ (n = 6), (2) focally disrupted EZ (n = 2), (3) focally disrupted with RPE changes (n = 2), and (4) diffuse EZ disruption with RPE changes (n = 1). All examined subjects had stable OCT findings over the long follow-up period. Full-field ERGs showed evidence of a severe cone-rod dystrophy in 5 of 6 patients and undetectable ERGs in 1 subject. Novel genotype-phenotype correlations are also reported. GUCY2D-LCA is a severe early-onset retinal dystrophy associated with very poor VA from birth. Despite the severely affected photoreceptor function, the relatively preserved photoreceptor structure based on EZ integrity until late in the disease in the majority of subjects suggests a wide therapeutic window for gene therapy trials. •GUCY2D-associated Leber congenital amaurosis is a severe early-onset retinal dystrophy.•There is severe cone and rod dysfunction but with preserved photoreceptor structure evident on optical coherence tomography.•Stable natural history suggests a wide therapeutic window for intervention.