The weird and wonderful: Inherited Retinal Degenerations

CSHP is delighted to share with you our second installment in a new series of Weird and Wonderful conditions that you may encounter in your practice. Click here to read our first Weird and Wonderful piece in December.

Inherited Retinal Degenerations (IRDs), also known as Inherited retinal diseases or hereditary retinal dystrophies, are a diverse group of rare genetic diseases that can lead to vision loss.1,2,3 IRDs occur due to a genetic mutation that progressively inhibits both the development and function of photoreceptors in the retina.4,5 This article will briefly discuss the epidemiology, signs and symptoms, diagnosis, goals of therapy, and treatment of most prevalent IRDs.  

Epidemiology 

IRDs have an estimated incidence of 1:2000 and have become the leading cause of vision loss for individuals between the ages of 15-45.6  

IRD’s are genetically heterogeneous and encompass just over 260 mutations that have been identified to date.4 Variants are identified based on 1 of 3 inheritance patterns: autosomal dominant, autosomal recessive, and x-linked disorders.4 Recent studies have estimated 2.7 billion individuals worldwide (~36%) of the population are healthy carriers of at least one mutation that can cause autosomal recessive IRDs.

Most Prevalent IRDs  

Retinitis Pigmentosa (RP) 

Retinitis Pigmentosa (RP) is a group of retinal disorders that occur due to variations in 60 different genes.4 Individuals with RP will experience vision loss gradually as the retinal photoreceptor cells degrade over time.4 The rate of degradation can vary based on the individual and can begin at any age.4 A key characteristic for early identification of RP is night blindness.4 This eventually progresses into peripheral blind spots, and then eventually affects central vision.4  

Choroideremia 

Choroideremia is a progressive condition that occurs due to cellular degradation in the retina and choroid (vascular layer of the eye).4 This condition first presents as night-blindness in early childhood and progresses into tunnel vision with loss of details, and may lead to complete vision loss by late adulthood.4

Stargardt Disease 

Stargardt Disease, also known as Stargardt macular dystrophy, results in a damaged macula (the central part of the retina, which is responsible for sharp, straight-ahead vision).4 This disease presents during childhood or adolescence as central vision loss and in some cases is not detected until adulthood as it rarely causes total loss of vision.

Cone-rod Dystrophy (CRD) 

Cone-rod Dystrophy (CRD) is a group of just over 30 IRDs that affect the light-sensitive cones and rods in the retina.4 CRDs first present as blurred vision and increased sensitivity to light during childhood.4 These symptoms further develop into central blind spots, color-blindness, and loss of peripheral vision, with significant visual impairment by mid-adulthood.4 

Leber Congenital Amaurosis (LCA) 

Leber Congenital Amaurosis (LCA) is a severe retinal disorder that presents during infancy.4 Common symptoms associated with LCA include increased sensitivity to light, nystagmus (uncontrolled eye movements), farsightedness, slow-reacting pupils, misshaped corneas, and strabismus (crossed-eyed).4  

Diagnosis   

As many of these conditions have similar symptoms, patients who are suspected of having an IRD are often referred to an ophthalmologist.4 The ophthalmologist will then use patient and family history, a clinical eye exam, ocular imaging, visual field testing, and electroretinography paired with genetic testing done by a genetic counselor to determine a diagnosis, prognosis, and therapy route.4   

Goals of Therapy and Treatment  

Unfortunately, there is no widely accepted treatment plan for IRD’s, however, studies are being currently conducted on new therapies for individual IRD treatment.4 Most recently, IRD’s with an identified mutated gene have been treated with gene therapy, while IRD’s without an identified mutated gene are managed with therapies that aim to slow IRD progression, return some vision function to the patient or simulate sight through other means.4 The most common IRD therapies include: 

Gene Therapy 

In 2020 Health Canada approved the first gene therapy treatment for an autosomal recessive IRD.8 This form of treatment has been found to be effective against IRD’s with an identified mutated gene, in this case being RPE65.8 Gene therapy associated with the RPE65 gene demonstrated improved retinal function and mobility initially in animal models.8 This was done via subretinal injection of the normal-sequence RPE65 transgene packaged into inactivated viral particles, also known as an adeno-associated virus, AAV-2.8 This virus then delivers the RPE65 gene construct to the retinal pigment epithelium (RPE) cells, which leads to the restoration of the vitamin A cycle.8 This cycle produces photon-capturing 11 cis retinal, a critical Vitamin A metabolite in photoreceptors which was previously absent with this IRD.8,9 In 2008, these principals were tested on humans and found that they have improvements in vision.8 These studies eventually lead phase 3 clinical trial demonstrating safety and improvements of at low luminance and improved visual fields in children and adults lasting up to 10 years.8 This gene therapy treatment, called Luxturna, was then approved in October of 2020 by Health Canada for individuals greater than 3 years old carrying 2 disease-causing RPE65 mutations with a viable retina. This approval is a landmark moment for the broad use of gene therapy as a treatment method with IRDs.8  

Neuroprotective Agents 

Neuroprotective agents aim to decrease photoreceptor degeneration.4 In specific, oral Vitamin A (15,000 IU daily), oral docosahexaenoic acid (400 mg daily), and in some cases oral valproic acid (400mg daily) have been found to slow RP disease progression.4,10,11,12 In addition, clinical trials are currently being conducted on the use of N-acetylcysteine (NAC) and N-acetylcysteine amide (NACA) in the prevention of retinal degeneration.13,14  

Retinal Prosthetic 

A retinal prosthetic can restore vision to those with total vision loss by using a micro-camera to send impulses wirelessly to the brain.4 In 2013, the first epiretinal prosthetic device received human use device (HUD) was approved by the FDA for patients with near-total vision loss from RP.4 Following this, over 200 patients around the world have received similar retinal prosthetics and have had their vision restored.4  

Future of IRD Treatment 

As much research is still be done both in the diagnosis and treatment of IRDs, specific knowledge gaps have been identified and are currently being studied.4 The use of retinal stem cells has recently become a great interest in treating IRDs and recent studies have suggested that transplanting photoreceptor precursors into animal models may have therapeutic effects and aid in treating in IRDs.4 Other research areas of interest in treating and managing IRDs include genetics, cell and molecular mechanisms, clinical-structure and function, novel medical therapies, gene therapy, regenerative medicine, and prosthetic procedures.4 

Sources: 

  1. Duncan JL, Pierce EA, Laster AM, et al. Inherited Retinal Degenerations: Current Landscape and Knowledge Gaps. Transl Vis Sci Technol. 2018;7(4):6. Published 2018 Jul 18. doi:10.1167/tvst.7.4.6  

  2. Sahel JA, Marazova K, Audo I. Clinical characteristics and current therapies for inherited retinal degenerations. Cold Spring Harb Perspect Med. 2014;5(2):a017111. Published 2014 Oct 16. doi:10.1101/cshperspect.a017111 

  3. Hohman TC. Hereditary Retinal Dystrophy. Handb Exp Pharmacol. 2017;242:337-367. doi:10.1007/164_2016_91  

  4. Preventblindness.org. 2020. Inherited Retinal Diseases. [online] Available at: <https://preventblindness.org/wp-content/uploads/2020/05/FS121-IRD2020formatF.pdf>. 

  5. Veleri S, Lazar CH, Chang B, Sieving PA, Banin E, Swaroop A. Biology and therapy of inherited retinal degenerative disease: insights from mouse models. Dis Model Mech. 2015;8(2):109-129. doi:10.1242/dmm.017913  

  6. Cremers FPM, Boon CJF, Bujakowska K, Zeitz C. Special Issue Introduction: Inherited Retinal Disease: Novel Candidate Genes, Genotype-Phenotype Correlations, and Inheritance Models. Genes (Basel). 2018;9(4):215. Published 2018 Apr 16. doi:10.3390/genes9040215 

  7. Hanany M, Rivolta C, Sharon D. Worldwide carrier frequency and genetic prevalence of autosomal recessive inherited retinal diseases. Proc Natl Acad Sci U S A. 2020;117(5):2710-2716. doi:10.1073/pnas.1913179117  

  8. Heon E, Koenekoop R. Treatments for inherited retinal degenerations are coming to Canada: Brief update on a new standard of care for inherited retinal degenerations [published online ahead of print, 2020 Nov 19]. Can J Ophthalmol. 2020;S0008-4182(20)30789-4. doi:10.1016/j.jcjo.2020.10.019 

  9. Saari JC. Vitamin A metabolism in rod and cone visual cycles. Annu Rev Nutr. 2012;32:125-145. doi:10.1146/annurev-nutr-071811-150748  

  10. Berson EL, Rosner B, Sandberg MA, et al. A randomized trial of vitamin A and vitamin E supplementation for retinitis pigmentosa. Arch Ophthalmol. 1993;111(6):761-772. doi:10.1001/archopht.1993.01090060049022 

  11. Wheaton DH, Hoffman DR, Locke KG, Watkins RB, Birch DG. Biological Safety Assessment of Docosahexaenoic Acid Supplementation in a Randomized Clinical Trial for X-Linked Retinitis Pigmentosa. Arch Ophthalmol. 2003;121(9):1269–1278. doi:10.1001/archopht.121.9.1269  

  12. Iraha S, Hirami Y, Ota S, et al. Efficacy of valproic acid for retinitis pigmentosa patients: a pilot study. Clin Ophthalmol. 2016;10:1375-1384. Published 2016 Jul 25. doi:10.2147/OPTH.S109995 

  13. Schimel AM, Abraham L, Cox D, et al. N-acetylcysteine amide (NACA) prevents retinal degeneration by up-regulating reduced glutathione production and reversing lipid peroxidation. Am J Pathol. 2011;178(5):2032-2043. doi:10.1016/j.ajpath.2011.01.036  

  14. Campochiaro PA, Iftikhar M, Hafiz G, et al. Oral N-acetylcysteine improves cone function in retinitis pigmentosa patients in phase I trial. J Clin Invest. 2020;130(3):1527-1541. doi:10.1172/JCI132990