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Retinal dystrophy: diagnosis and treatment


Dr Heather G Mack
Department of Surgery (Ophthalmology), University of Melbourne
Eye Surgery Associates, Melbourne


Inherited retinal dystrophy (IRD) is now the leading cause of severe, irreversible vision loss in adults of working age in the United Kingdom, following recent advancements in the treatment of diabetic eye disease.1

IRD is a heterogeneous group of genetic disorders resulting in premature death of photoreceptors and/or retinal pigment epithelium. Other mechanisms, such as retinoschisis, can occur.

Different patterns of photoreceptor loss result in different phenotypes: retinitis pigmentosa begins with rod degeneration, and cone dystrophy with cone degeneration. In cone-rod dystrophy, both types of photoreceptors are involved. This article briefly covers diagnosis, genetic diagnosis and treatments of retinal dystrophy. One caveat: the field is moving rapidly so this article may be rendered out of date almost immediately after publication.


Diagnosis of IRD depends on thorough history and examination including:

•          Comprehensive history including presence of nyctalopia (night blindness) and medication history

•       Family ophthalmic history

•       Best corrected visual acuity

•       Assessment of anterior eye including anterior chamber angles to assess suitability for pupil dilation

•       Measurement of intraocular pressure

•       Dilated retinal examination including non-contact fundus lens examination (78 D optimal)

•       Examination of the retinal periphery with indirect binocular ophthalmoscopy.

Ancillary testing includes:

•       Documentation of retinal status with retinal photography (Figures 1 and 2)

•       Assessment of visual field with automated threshold perimetry, both monocularly and binocularly (Figure 3)

•       Retinal autofluorescence imaging (Figure 4)

•       Macular OCT to help detect the pattern of photoreceptor loss and macular abnormalities (cystoid macular oedema, atrophy or schisis) (Figure 5)

•       Electroretinography (ERG) to measure function of rods and cones within the widespread retina. Multifocal ERG to measure macular function.

Figures 1-5 show the left eye of a 56-year-old male with a clinical diagnosis of retinitis pigmentosa. Gene testing has not been performed.



Figure 1. Colour fundus photograph of posterior pole demonstrating disc pallor, attenuated vessels and peripheral intraretinal pigment migration



Figure 2. Colour fundus photograph of nasal retina demonstrating RPE thinning and intraretinal pigment migration



Figure 3. Automated perimetry demonstrating field constriction



Figure 4. Fundus autofluorescence demonstrating multiple small hypoautofluorescent peripheral lesions and a ring of hyperautofluorescence in the macula



Figure 5. Optical coherence tomography demonstrating extensive parafoveal photoreceptor loss


Diagnosis of IRD is made holistically, taking into account history, clinical findings, ERG findings and gene testing when performed.

IRD is not diagnosed solely on the basis of retinal pigmentation or abnormal ERG. In some patients, repeat ERG may be necessary after several years to confirm the condition is progressive.


Autosomal dominant, autosomal recessive, X-linked, mitochondrial, multi-gene related and syndromic patterns of inheritance have been described. Close to 300 genes and loci have been identified as related to IRD to date,2 with an estimated future total of more than 500 responsible genes. Gene testing may be offered to patients over the age of 18 years, particularly for family planning purposes.

Patients need to be counselled that gene testing is ‘negative’, that is, a single responsible gene mutation is identified and responsible for the eye disease in at least 50 per cent of patients. Gene testing produces complex clinical, personal and financial outcomes and must be undertaken only in association with genetic counsellors.


The only current treatment studied in a randomised clinical trial is vitamin A supplementation.3 This treatment is controversial; it has associated risks of teratogenicity during pregnancy and idiopathic intracranial hypertension, and may be offered only in consultation with physicians. Vitamin A supplementation is not recommended in patients with ABCA4 mutations.4

Future treatments of IRD focus on replacing missing elements of the visual pathway from photoreceptors to occipital cortex and may be considered gene-dependent or gene-independent.

Gene-dependent treatments

Gene-dependent treatment replaces or repairs the patient’s abnormal gene. Classical gene therapy replaces defective genes using viral vectors which carry the normal gene. Gene therapy is most suited to conditions with a null mutation, where the problem is due to absent normal protein.

The first classical gene therapy treatment was for Leber’s congenital amaurosis type 2, due to abnormality of the RPE 65 gene located on chromosome 1.5,6

Treatment results in improved visual function but unfortunately, the degeneration progresses. More recently, a phase I/II clinical study using classical gene therapy for choroideraemia has shown improvement in visual function,7 but long-term results in dystrophy progression are not yet available.

Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR) is a new method of gene repair, rather than replacement. CRISPRs are the hallmark of a bacterial defence system which forms the basis of the CRISPR-Cas9 genome editing technology.

In brief, abnormal DNA is cleaved in situ and the cell’s DNA repair mechanism repairs the cleaved DNA using a guide normal DNA molecule. CRISPR has been used to delay retinal degeneration in a rat model of IRD.8 In vitro human retinal cells have been shown to be capable of DNA repair using CRISPR technology.9 CRISPR technology is new and rapidly advancing but there are no current human trials recruiting.

Gene-independent treatments

Gene-independent treatments include growth factors, stem cells, optogenetics and retinal prostheses (bionic eye).

•             Growth factors

This approach utilises growth factors which are known to be important in retinal health and disease to support residual photoreceptors. Trials of ciliary neurotrophic growth factor delivered by encapsulated cells in an intraocular implant demonstrated safety and suggested improvement in vision in patients with retinitis pigmentosa,10 but not in CNGB3 achromatopsia.11 Rod-derived cone viability factor, in which abnormalities are the cause of cone loss in patients with retinitis pigmentosa, shows promise as a treatment to support abnormal cones.12

•             Stem cells

This approach aims to replace missing retinal cell types. Pluripotential stem cells have been recently isolated from fibroblasts obtained during skin biopsy. These cells can be differentiated as retinal progenitor cells, retinal ganglion cells and retinal pigment epithelium in vitro using specific growth factors. Pluripotent stem cells may have gene editing performed on them using CRISPR technology prior to differentiation to specific retinal cell types. Differentiated cells are injected into the subretinal space during vitrectomy or can be injected into the vitreous cavity with a single intravitreal injection. Phase I/II clinical trials are underway in Best disease13 and retinitis pigmentosa.14,15

•             Optogenetics

This approach bypasses diseased photoreceptors and relies on the incorporation of molecules which respond to light (channelrhodopsin, halorhodopsin or melanopsin) into healthy inner retinal cells. Incorporation of channelrhodopsin into On-bipolar and rod-bipolar cells, or halorhodopsin into On- and Off-retinal ganglion cells allows both on- and off-responses to light stimuli. A phase I/II gene therapy trial of channelrhodopsin-2 in retinitis pigmentosa is underway.16

•             Bionic eye

This approach relies on the use of implants which can respond to light and send stimuli to the patient’s remaining visual pathway. Implants can be epiretinal, subretinal, suprachoroidal, in the optic nerve, in the lateral geniculate nucleus and in the occipital cortex. This approach relies on neuroplasticity as patients adapt to using the implant.

Pre-clinical studies are underway for a suprachoroidal implant at the Royal Victorian Eye and Ear Hospital17 and an occipital implant at Monash University.18


Rapid progress is being made in understanding the genetic basis of IRD. Although new treatments are in development which aim to replace or repair defective genes or to support or replace defective tissues, they are not yet available to offer to patients in routine clinical care.


1.         Liew G, Michaelides M, Bunce C. A comparison of the causes of blindness certifications in England and Wales in working age adults (16–64 years), 1999-2000 with 2009-2010. BMJ Open 2014; 4:e004015 doi:10.1136/bmjopen-2013-004015.

2.         RetNet. Retinal Information Network. Available from: Accessed: June 2016.

3.         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: 761-772.

4.         Radu RA, Yuan Q, Hu J, et al. Accelerated accumulation of lipofuscin pigments in the RPE of a mouse model for ABCA4-mediated retinal dystrophies following vitamin A supplementation. Invest Ophthalmol Vis Sci 2008; 19: 3821-3829.

5.         Bainbridge JWB, Smith AJ, Barker SS, et al. Effect of gene therapy on visual function in Leber’s congenital amaurosis. N Engl J Med 2008; 358: 2231-2239.

6.         Maguire AM, Simonelli F, Pierce EA, et al. Safety and efficacy of gene transfer for Leber’s congenital amaurosis. New Engl J Med 2008; 358: 2240-2248.

7.         MacLaren RE, Groppe M, Barnard AR, et al. Retinal gene therapy in patients with choroideremia: initial findings from a phase 1/2 clinical trial. Lancet 2014; 383: 1129-1137.

8.         Bakondi B, Lv W, Lu B, et al. In vivo CRISPR/Cas9 gene editing corrects retinal dystrophy in the S334ter-3 rat model of autosomal dominant retinitis pigmentosa. Molecular Therapy 2016; 24: 556-563.

9.         Bassuk AG, Zheng A, Li Y, et al. Precision Medicine: genetic repair of retinitis pigmentosa in patient-derived stem cells. Sci Rep 6,19969; doi: 10.1038/srep19969 (2016).

10.       Sieving PA, Caruso RC, Tao W, et al. Ciliary neurotrophic factor (CNTF) for human retinal degeneration: Phase I trial of CNTF delivered by encapsulated cell intraocular implants. Proc Natl Acad Sci 2000; 103: 3896-3901.

11.       Zein WM, Jeffrey BG, Wiley HE, et al. CNGB3-achromatopsia clinical trial with CNTF: diminished rod pathway responses with no evidence of improvement in cone function. Inv Ophthalmol Vis Sci 2014; 55: 6301-6308.

12.       Byrne LC, Dalkara D, Luna G, et al. Viral-mediated RdCVF and RdCVFL expression protects cone and rod photoreceptors in retinal degeneration. J Clin Invest 2015; 125: 105-116.

13.       Clinical Available at: Accessed June 2016.

14.       Clinical Available at: Accessed June 2016.

15.       Clinical Available at: Accessed June 2016.

16.       Clinical Available at: Accessed June 2016.

17.       Alexia L Saunders AL, Williams CE, Heriot W, et al. Development of a surgical procedure for implantation of a prototype suprachoroidal retinal prosthesis. Clin Exp Ophthalmol 2014; 42: 665-674.

18.       Monash Vision. Available at: Accessed: June 2016.

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