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 American Academy of Ophthalmology. All rights reserved.
PY - 2022/8
Y1 - 2022/8
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 end points and optimal patient selection for future therapeutic trials.DESIGN: International, multicenter, retrospective cohort study.SUBJECTS: Eighty-two patients with GUCY2D-associated LCA or CORD from 54 families.METHODS: Medical records were reviewed for medical history, best-corrected visual acuity (BCVA), ophthalmoscopy, visual fields, full-field electroretinography, and retinal imaging (fundus photography, spectral-domain OCT [SD-OCT], fundus autofluorescence).MAIN OUTCOMES MEASURES: Age of onset, evolution of BCVA, 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 times were 5.2 years (interquartile range [IQR] 2.6-8.8 years) for LCA and 7.2 years (IQR 2.2-14.2 years) for CORD. Generally, LCA presented in the first year of life. The BCVA in patients with LCA ranged from no light perception to 1.00 logarithm of the minimum angle of resolution (logMAR) and remained relatively stable during follow-up. Imaging for LCA was limited but showed little to no structural degeneration. In patients with CORD, progressive vision loss started around the second decade of life. The BCVA declined annually by 0.022 logMAR (P < 0.001) with no difference between patients with the c.2513G>A and the c.2512C>T GUCY2D variants (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 that of the external limiting membrane (ELM) on SD-OCT correlated significantly with BCVA (Spearman ρ = 0.744, P = 0.001, and ρ = 0.712, P < 0.001, respectively) in those with CORD.CONCLUSIONS: Leber congenital amaurosis associated with GUCY2D caused severe congenital visual impairment with relatively intact macular anatomy on funduscopy and available imaging, suggesting 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 end points for therapeutic studies of 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 end points and optimal patient selection for future therapeutic trials.DESIGN: International, multicenter, retrospective cohort study.SUBJECTS: Eighty-two patients with GUCY2D-associated LCA or CORD from 54 families.METHODS: Medical records were reviewed for medical history, best-corrected visual acuity (BCVA), ophthalmoscopy, visual fields, full-field electroretinography, and retinal imaging (fundus photography, spectral-domain OCT [SD-OCT], fundus autofluorescence).MAIN OUTCOMES MEASURES: Age of onset, evolution of BCVA, 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 times were 5.2 years (interquartile range [IQR] 2.6-8.8 years) for LCA and 7.2 years (IQR 2.2-14.2 years) for CORD. Generally, LCA presented in the first year of life. The BCVA in patients with LCA ranged from no light perception to 1.00 logarithm of the minimum angle of resolution (logMAR) and remained relatively stable during follow-up. Imaging for LCA was limited but showed little to no structural degeneration. In patients with CORD, progressive vision loss started around the second decade of life. The BCVA declined annually by 0.022 logMAR (P < 0.001) with no difference between patients with the c.2513G>A and the c.2512C>T GUCY2D variants (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 that of the external limiting membrane (ELM) on SD-OCT correlated significantly with BCVA (Spearman ρ = 0.744, P = 0.001, and ρ = 0.712, P < 0.001, respectively) in those with CORD.CONCLUSIONS: Leber congenital amaurosis associated with GUCY2D caused severe congenital visual impairment with relatively intact macular anatomy on funduscopy and available imaging, suggesting 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 end points for therapeutic studies of GUCY2D-associated CORD.
UR - https://www.mendeley.com/catalogue/d3e4b192-aafe-38e3-8bd4-b86ab159be75/
U2 - 10.1016/j.oret.2022.03.008
DO - 10.1016/j.oret.2022.03.008
M3 - Article
C2 - 35314386
SN - 2468-7219
VL - 6
SP - 711
EP - 722
JO - Ophthalmology. Retina
JF - Ophthalmology. Retina
IS - 8
ER -