TY - JOUR
T1 - The Natural History of Leber Congenital Amaurosis and Cone-Rod Dystrophy Associated with Variants in the GUCY2D Gene
AU - Hahn, Leo C
AU - Georgiou, Michalis
AU - Almushattat, Hind
AU - van Schooneveld, Mary J
AU - de Carvalho, Emanuel R
AU - Wesseling, Nieneke L
AU - Ten Brink, Jacoline B
AU - Florijn, Ralph J
AU - Lissenberg-Witte, Birgit I
AU - Strubbe, Ine
AU - van Cauwenbergh, Caroline
AU - de Zaeytijd, Julie
AU - Walraedt, Sophie
AU - de Baere, Elfride
AU - Mukherjee, Rajarshi
AU - McKibbin, Martin
AU - Meester-Smoor, Magda A
AU - Thiadens, Alberta A H J
AU - Al-Khuzaei, Saoud
AU - Akyol, Engin
AU - Lotery, Andrew J
AU - van Genderen, Maria M
AU - Norel, Jeannette Ossewaarde-van
AU - Ingeborgh van den Born, L
AU - Hoyng, Carel B
AU - Klaver, Caroline C W
AU - Downes, Susan M
AU - Bergen, Arthur A
AU - Leroy, Bart P
AU - Michaelides, Michel
AU - Boon, Camiel J F
N1 - Copyright © 2022. Published by Elsevier Inc.
PY - 2022/3
Y1 - 2022/3
N2 - OBJECTIVE: To describe the spectrum of Leber congenital amaurosis (LCA) and cone-rod dystrophy (CORD) associated with the GUCY2D gene, and to identify potential clinical endpoints and optimal patient selection for future therapeutic trials.DESIGN: International multicenter retrospective cohort study.SUBJECTS: 82 patients with GUCY2D-associated CORD and LCA from 54 molecularly confirmed families.METHODS: Data were gathered by reviewing medical records for medical history, symptoms, best-corrected visual acuity (BCVA), ophthalmoscopy, visual fields, full-field electroretinography and retinal imaging (fundus photography, spectral-domain optical coherence tomography (SD-OCT), fundus autofluorescence).MAIN OUTCOMES MEASURES: Age of onset, annual decline of visual acuity, estimated visual impairment per age, genotype-phenotype correlations, anatomic characteristics on funduscopy, and multimodal imaging.RESULTS: Fourteen patients with autosomal recessive LCA and 68 with autosomal dominant CORD were included. The median follow-up time was 5.2 years (interquartile range (IQR), 2.6-8.8) for LCA, and 7.2 years (IQR, 2.2-14.2) for CORD. Generally, LCA presented in the first year of life. The BCVA in LCA ranged from no light perception to 1.00 logMAR, and remained relatively stable during follow-up. Imaging for LCA was limited, but showed little to no structural degeneration. In CORD, progressive vision loss started around the second decade of life. The annual decline rate of visual acuity was 0.022 logMAR (P < 0.001), which did not differ between the c.2513G>A and the c.2512C>T GUCY2D variant (P = 0.798). At the age of 40 years the probability of being blind or severely visually impaired was 32%. The integrity of the ellipsoid zone (EZ) and external limiting membrane (ELM) on SD-OCT were correlated significantly with BCVA (Spearman's ρ = 0.744, P = 0.001 and ρ = 0.712, P < 0.001, respectively) in CORD.CONCLUSION: LCA due to variants in GUCY2D results in severe congenital visual impairment with relatively intact macular anatomy on funduscopy and available imaging, suggesting a long preservation of photoreceptors. Despite large variability, GUCY2D-associated CORD generally presented during adolescence with a progressive loss of vision and culminated in severe visual impairment during mid to late-adulthood. The integrity of the ELM and EZ may be suitable structural endpoints for therapeutic studies in GUCY2D-associated CORD.
AB - OBJECTIVE: To describe the spectrum of Leber congenital amaurosis (LCA) and cone-rod dystrophy (CORD) associated with the GUCY2D gene, and to identify potential clinical endpoints and optimal patient selection for future therapeutic trials.DESIGN: International multicenter retrospective cohort study.SUBJECTS: 82 patients with GUCY2D-associated CORD and LCA from 54 molecularly confirmed families.METHODS: Data were gathered by reviewing medical records for medical history, symptoms, best-corrected visual acuity (BCVA), ophthalmoscopy, visual fields, full-field electroretinography and retinal imaging (fundus photography, spectral-domain optical coherence tomography (SD-OCT), fundus autofluorescence).MAIN OUTCOMES MEASURES: Age of onset, annual decline of visual acuity, estimated visual impairment per age, genotype-phenotype correlations, anatomic characteristics on funduscopy, and multimodal imaging.RESULTS: Fourteen patients with autosomal recessive LCA and 68 with autosomal dominant CORD were included. The median follow-up time was 5.2 years (interquartile range (IQR), 2.6-8.8) for LCA, and 7.2 years (IQR, 2.2-14.2) for CORD. Generally, LCA presented in the first year of life. The BCVA in LCA ranged from no light perception to 1.00 logMAR, and remained relatively stable during follow-up. Imaging for LCA was limited, but showed little to no structural degeneration. In CORD, progressive vision loss started around the second decade of life. The annual decline rate of visual acuity was 0.022 logMAR (P < 0.001), which did not differ between the c.2513G>A and the c.2512C>T GUCY2D variant (P = 0.798). At the age of 40 years the probability of being blind or severely visually impaired was 32%. The integrity of the ellipsoid zone (EZ) and external limiting membrane (ELM) on SD-OCT were correlated significantly with BCVA (Spearman's ρ = 0.744, P = 0.001 and ρ = 0.712, P < 0.001, respectively) in CORD.CONCLUSION: LCA due to variants in GUCY2D results in severe congenital visual impairment with relatively intact macular anatomy on funduscopy and available imaging, suggesting a long preservation of photoreceptors. Despite large variability, GUCY2D-associated CORD generally presented during adolescence with a progressive loss of vision and culminated in severe visual impairment during mid to late-adulthood. The integrity of the ELM and EZ may be suitable structural endpoints for therapeutic studies in GUCY2D-associated CORD.
U2 - 10.1016/j.oret.2022.03.008
DO - 10.1016/j.oret.2022.03.008
M3 - Article
C2 - 35314386
SN - 2468-6530
VL - 6
SP - 711
EP - 722
JO - Ophthalmology Retina
JF - Ophthalmology Retina
ER -