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The natural history of leber congenital amaurosis and cone–rod dystrophy associated with variants in the GUCY2D gene

Leo C. Hahn, Michalis Georgiou, Hind Almushattat, Mary J. van Schooneveld, Emanuel R. de Carvalho, Nieneke L. Wesseling, Jacoline B. ten Brink, Ralph J. Florijn, Birgit I. Lissenberg-Witte, Ine Strubbe (UGent) , et al.
(2022) OPHTHALMOLOGY RETINA. 6(8). p.711-722
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Abstract
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 signifi-cantly with BCVA (Spearman r = 0.744, P = 0.001, and r = 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 pres-ervation 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. Ophthalmology Retina 2022;6:711-722 (c) 2022 by the American Academy of Ophthalmology. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/ licenses/by-nc-nd/4.0/).
Keywords
Ophthalmology, Cone-rod dystrophy, GUCY2D, Inherited retinal dystrophies, Leber congenital amaurosis, Phenotype, MUTATION, GUCY2D, BIOSTATISTICS, PHENOTYPE, TUTORIAL, VISION, TRIALS, EYE

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MLA
Hahn, Leo C., et al. “The Natural History of Leber Congenital Amaurosis and Cone–Rod Dystrophy Associated with Variants in the GUCY2D Gene.” OPHTHALMOLOGY RETINA, vol. 6, no. 8, 2022, pp. 711–22, doi:10.1016/j.oret.2022.03.008.
APA
Hahn, L. C., Georgiou, M., Almushattat, H., van Schooneveld, M. J., de Carvalho, E. R., Wesseling, N. L., … Boon, C. J. F. (2022). The natural history of leber congenital amaurosis and cone–rod dystrophy associated with variants in the GUCY2D gene. OPHTHALMOLOGY RETINA, 6(8), 711–722. https://doi.org/10.1016/j.oret.2022.03.008
Chicago author-date
Hahn, Leo C., Michalis Georgiou, Hind Almushattat, Mary J. van Schooneveld, Emanuel R. de Carvalho, Nieneke L. Wesseling, Jacoline B. ten Brink, et al. 2022. “The Natural History of Leber Congenital Amaurosis and Cone–Rod Dystrophy Associated with Variants in the GUCY2D Gene.” OPHTHALMOLOGY RETINA 6 (8): 711–22. https://doi.org/10.1016/j.oret.2022.03.008.
Chicago author-date (all authors)
Hahn, Leo C., Michalis Georgiou, Hind Almushattat, Mary J. van Schooneveld, Emanuel R. de Carvalho, Nieneke L. Wesseling, Jacoline B. ten Brink, Ralph J. Florijn, Birgit I. Lissenberg-Witte, Ine Strubbe, Caroline Van Cauwenbergh, Julie De Zaeytijd, SOPHIE WALRAEDT, Elfride De Baere, Rajarshi Mukherjee, Martin McKibbin, Magda A. Meester-Smoor, Alberta A.H.J. Thiadens, Saoud Al-Khuzaei, Engin Akyol, Andrew J. Lotery, Maria M. van Genderen, Jeannette Ossewaarde-van Norel, L. Ingeborgh van den Born, Carel B. Hoyng, Caroline C.W. Klaver, Susan M. Downes, Arthur A. Bergen, Bart Leroy, Michel Michaelides, and Camiel J.F. Boon. 2022. “The Natural History of Leber Congenital Amaurosis and Cone–Rod Dystrophy Associated with Variants in the GUCY2D Gene.” OPHTHALMOLOGY RETINA 6 (8): 711–722. doi:10.1016/j.oret.2022.03.008.
Vancouver
1.
Hahn LC, Georgiou M, Almushattat H, van Schooneveld MJ, de Carvalho ER, Wesseling NL, et al. The natural history of leber congenital amaurosis and cone–rod dystrophy associated with variants in the GUCY2D gene. OPHTHALMOLOGY RETINA. 2022;6(8):711–22.
IEEE
[1]
L. C. Hahn et al., “The natural history of leber congenital amaurosis and cone–rod dystrophy associated with variants in the GUCY2D gene,” OPHTHALMOLOGY RETINA, vol. 6, no. 8, pp. 711–722, 2022.
@article{8770506,
  abstract     = {{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 signifi-cantly with BCVA (Spearman r = 0.744, P = 0.001, and r = 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 pres-ervation 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. Ophthalmology Retina 2022;6:711-722 (c) 2022 by the American Academy of Ophthalmology. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/ licenses/by-nc-nd/4.0/).}},
  author       = {{Hahn, Leo C. and Georgiou, Michalis and Almushattat, Hind and van Schooneveld, Mary J. and de Carvalho, Emanuel R. and Wesseling, Nieneke L. and ten Brink, Jacoline B. and Florijn, Ralph J. and Lissenberg-Witte, Birgit I. and Strubbe, Ine and Van Cauwenbergh, Caroline and De Zaeytijd, Julie and WALRAEDT, SOPHIE and De Baere, Elfride and Mukherjee, Rajarshi and McKibbin, Martin and Meester-Smoor, Magda A. and Thiadens, Alberta A.H.J. and Al-Khuzaei, Saoud and Akyol, Engin and Lotery, Andrew J. and van Genderen, Maria M. and Ossewaarde-van Norel, Jeannette and van den Born, L. Ingeborgh and Hoyng, Carel B. and Klaver, Caroline C.W. and Downes, Susan M. and Bergen, Arthur A. and Leroy, Bart and Michaelides, Michel and Boon, Camiel J.F.}},
  issn         = {{2468-6530}},
  journal      = {{OPHTHALMOLOGY RETINA}},
  keywords     = {{Ophthalmology,Cone-rod dystrophy,GUCY2D,Inherited retinal dystrophies,Leber congenital amaurosis,Phenotype,MUTATION,GUCY2D,BIOSTATISTICS,PHENOTYPE,TUTORIAL,VISION,TRIALS,EYE}},
  language     = {{eng}},
  number       = {{8}},
  pages        = {{711--722}},
  title        = {{The natural history of leber congenital amaurosis and cone–rod dystrophy associated with variants in the GUCY2D gene}},
  url          = {{http://doi.org/10.1016/j.oret.2022.03.008}},
  volume       = {{6}},
  year         = {{2022}},
}
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