Genetics of retinal degeneration in 2023

Authors

  • Elise Héon, MD, FRCPC
  • Ajoy Vincent, MBBS, MS, FRCSC
  • Alaa Tayyib, MD

DOI:

https://doi.org/10.58931/cect.2023.2122

Abstract

Inherited retinal degenerations (IRDs) are of great interest with the development of novel therapies, thereby allowing this group of conditions to be “actionable” for the first time.

A molecular diagnosis can be obtained in nearly 70% of cases of IRD, with over 300 IRD-linked genes having been identified to date. Numerous animal models of different genetic subtypes of IRDs replicated the human phenotypes enough to develop and test novel therapies to improve outcomes for IRD patients. The first gene replacement therapy indicated for IRD, Luxturna (voretigene neparvovec-rzyl), was approved by Health Canada in October 2020 and is now available to patients with vision loss due to inherited retinal dystrophy caused by confirmed biallelic RPE65 mutations. Clinicians from Ontario, Quebec and Alberta can now access this treatment through their province’s public health plan.

This article aims to review some basic information and present new knowledge about IRDs to allow clinicians to better understand diagnosis and disease management.

Author Biographies

Elise Héon, MD, FRCPC

Dr. Elise Héon has been staff ophthalmologist at SickKids since 1996. Her career focusses on inherited eye disorders, now mostly on inherited retinal diseases. She directs the Ocular Genetics program providing comprehensive assessment, genetic testing and counseling of patients affected with inherited retinal disorders. She became Chief of Ophthalmology in 2003 when her laboratory was moved from the Toronto Western to SickKids Research Institute. She has trained numerous students of various academic levels from around the world. Dr. Héon’s current research focusses on the genetic characterization of inherited retinal disorders when clinical genetic testing did not identify the disease-causing variant(s). Using Genome sequencing and sophisticated analytical protocol, her group has been successful in deciphering nearly 80% of cases. Dr. Héon has a specific interest in disease cause by genes affecting cilia, ciliopathy, namely Bardet Biedl syndrome. Using cells from patients and high throughput drug screening through the SPARC facility, her groups is trying to identify small molecules that may improve patient outcome. Lastly, Dr. Héon is exploring patient reported outcome measures (PROM) for IRD and especially in children, which would best represent the impact of the visual impairment on the patient daily living.

Ajoy Vincent, MBBS, MS, FRCSC

Dr. Ajoy Vincent is trained in the field of Eye Genetics and Electrophysiology. He cares for patients with isolated and complex inherited retinal dystrophies (IRDs). He also serves as the Medical Director of Visual Electrophysiology Unit (VEU) at SickKids. He is actively involved in teaching Ophthalmology residents and fellows at SickKids. Dr. Vincent’s research endeavors include discovering novel genes underlying inherited retinal dystrophies (IRDs), characterizing novel genotype-phenotype correlations in IRDs, uncovering disease pathways and mechanisms in IRDs, and conducting innovative pediatric clinical trials; all with the aim of improving patient outcomes.

Alaa Tayyib, MD

Dr. Alaa Tayyib earned her Bachelor of Medicine and Surgery from King Abdulaziz University in Saudi Arabia, followed by her ophthalmology residency training at the Saudi Ophthalmology Residency Program. She is currently completing her clinical ocular genetics and inherited retinal diseases fellowship at the University of Toronto.

References

Switonski M. Impact of gene therapy for canine monogenic diseases on the progress of preclinical studies. J Appl Genet. 2020 May;61(2):179-186. doi:10.1007/s13353-020-00554-8 DOI: https://doi.org/10.1007/s13353-020-00554-8

Guziewicz KE, McTish E, Dufour VL, et al. Underdeveloped RPE Apical Domain Underlies Lesion Formation in Canine Bestrophinopathies. Adv Exp Med Biol. 2018;1074:309-315. doi:10.1007/978-3-319-75402-4_38 DOI: https://doi.org/10.1007/978-3-319-75402-4_38

Newsome DA. Retinal dystrophies and degenerations., . Lippincott Williams & Wilkins; 1988. DOI: https://doi.org/10.1097/00003226-198903000-00015

Yatsenko AN SN, Lewis RA, Lupski JR. Late-onset Stargardt disease is associated with missense mutations that map outside known functional regions of ABCR (ABCA4). Hum Genet. 2001;108(4):346-355. doi:10.1007/s004390100493 DOI: https://doi.org/10.1007/s004390100493

Al-Khuzaei S, Broadgate S, Foster CR, et al. An Overview of the Genetics of ABCA4 Retinopathies, an Evolving Story. Genes (Basel). 2021 Aug 13;12(8). doi:10.3390/genes12081241 DOI: https://doi.org/10.3390/genes12081241

Wuthisiri W, Lingao MD, Capasso JE, Levin AV. Lyonization in ophthalmology. Curr Opin Ophthalmol. 2013 Sep;24(5):389-97. doi:10.1097/ICU.0b013e3283641f91 DOI: https://doi.org/10.1097/ICU.0b013e3283641f91

Strauss RW KX, Ho A, et al. Progression of Stargardt Disease as Determined by Fundus Autofluorescence Over a 12-Month Period: ProgStar Report No. 11. JAMA Ophthalmol. 2019;137(10):1134-1145. doi:10.1001/jamaophthalmol.2019.2885 DOI: https://doi.org/10.1001/jamaophthalmol.2019.2885

Mao J FD, Chen Y, et al. Prediction of Visual Acuity After Cataract Surgery Using Optical Coherence Tomography Findings in Eyes With Retinitis Pigmentosa. Ophthalmic Surg Lasers Imaging Retina. 2018;49(8):587-594. doi:10.3928/23258160-20180803-06

Olchawa M, Krzysztynska-Kuleta O, Duda M, et al. In vitro phototoxicity of rhodopsin photobleaching products in the retinal pigment epithelium (RPE). Free Radic Res. 2019 Apr;53(4):456-471. doi:10.1080/10715762.2019.1603377 DOI: https://doi.org/10.1080/10715762.2019.1603377

Cremers FPM, Lee W, Collin RWJ, Allikmets R. Clinical spectrum, genetic complexity and therapeutic approaches for retinal disease caused by ABCA4 mutations. Prog Retin Eye Res. 2020 Nov;79:100861. doi:10.1016/j.preteyeres.2020.100861 DOI: https://doi.org/10.1016/j.preteyeres.2020.100861

MacDonald IM, Lee T, Lawrence J. Bestrophinopathies. In: Adam MP, Everman DB, Mirzaa GM, et al, eds. GeneReviews. 1993.

Pfister TA, Zein WM, Cukras CA, et al. Phenotypic and Genetic Spectrum of Autosomal Recessive Bestrophinopathy and Best Vitelliform Macular Dystrophy. Invest Ophthalmol Vis Sci. 2021 May 3;62(6):22. doi:10.1167/iovs.62.6.22 DOI: https://doi.org/10.1167/iovs.62.6.22

Yoshida N, Ikeda Y, Murakami Y, et al. Factors affecting visual acuity after cataract surgery in patients with retinitis pigmentosa. Ophthalmology. 2015 May;122(5):903-8. doi:10.1016/j.ophtha.2014.12.003 DOI: https://doi.org/10.1016/j.ophtha.2014.12.003

Mao J FD, Chen Y, et al. Prediction of Visual Acuity After Cataract Surgery Using Optical Coherence Tomography Findings in Eyes With Retinitis Pigmentosa. Ophthalmic Surg Lasers Imaging Retina. 2018;49(8):587-594. doi:10.3928/23258160-20180803-06 DOI: https://doi.org/10.3928/23258160-20180803-06

Dikopf MS, Chow CC, Mieler WF, Tu EY. Cataract extraction outcomes and the prevalence of zonular insufficiency in retinitis pigmentosa. Am J Ophthalmol. 2013 Jul;156(1):82-88 e2. doi:10.1016/j.ajo.2013.02.002 DOI: https://doi.org/10.1016/j.ajo.2013.02.002

Berson EL, Rosner B, Sandberg MA, et al. A randomized trial of vitamin A and vitamin E supplementation for retinitis pigmentosa. Arch Ophthalmol. 1993 Jun;111(6):761-72. doi:10.1001/archopht.1993.01090060049022 DOI: https://doi.org/10.1001/archopht.1993.01090060049022

Traboulsi EI, ed. Genetic Diseases of the Eye. 2nd ed. Oxford University Press; 2011. DOI: https://doi.org/10.1093/med/9780195326147.001.0001

Singh RB, Gupta P, Kartik A, et al. Ocular Manifestations of Neuronal Ceroid Lipofuscinoses. Semin Ophthalmol. 2021 Oct 3;36(7):582-595. doi:10.1080/08820538.2021.1936571 DOI: https://doi.org/10.1080/08820538.2021.1936571

Steinberg SJ, Raymond GV, Braverman NE, Moser AB. Zellweger Spectrum Disorder. In: Adam MP, Everman DB, Mirzaa GM, et al, eds. GeneReviews. 1993.

Lee J, Hegele RA. Abetalipoproteinemia and homozygous hypobetalipoproteinemia: a framework for diagnosis and management. J Inherit Metab Dis. 2014 May;37(3):333-9. doi:10.1007/s10545-013-9665-4 DOI: https://doi.org/10.1007/s10545-013-9665-4

Russell S, Bennett J, Wellman JA, et al. Efficacy and safety of voretigene neparvovec (AAV2-hRPE65v2) in patients with RPE65-mediated inherited retinal dystrophy: a randomised, controlled, open-label, phase 3 trial. Lancet. 2017 Aug 26;390(10097):849-860. doi:10.1016/S0140-6736(17)31868-8 DOI: https://doi.org/10.1016/S0140-6736(17)31868-8

Edwards AO. Genetic testing for age-related macular degeneration. Ophthalmology. 2006 Apr;113(4):509-10. doi:10.1016/j.ophtha.2006.01.018 DOI: https://doi.org/10.1016/j.ophtha.2006.01.018

Stone EM. Genetic testing for age-related macular degeneration: not indicated now. JAMA Ophthalmol. 2015 May;133(5):598-600. doi:10.1001/jamaophthalmol.2015.0369 DOI: https://doi.org/10.1001/jamaophthalmol.2015.0369

Warwick A, Lotery A. Genetics and genetic testing for age-related macular degeneration. Eye (Lond). 2018 May;32(5):849-857. doi:10.1038/eye.2017.245 DOI: https://doi.org/10.1038/eye.2017.245

Downloads

Published

2023-02-01

How to Cite

1.
Héon E, Vincent A, Tayyib A. Genetics of retinal degeneration in 2023. Can Eye Care Today [Internet]. 2023 Feb. 1 [cited 2024 Nov. 21];2(1):15–24. Available from: https://canadianeyecaretoday.com/article/view/2-1-3

Issue

Volume 2, Issue 1, February 2023

Section

Articles

License

Creative Commons License

This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.