Detection of inherited retinal diseases in primary care

At the completion of this CPD activity, optometrists will have developed their knowledge of the ocular and systemic conditions involved in the care of patients with inherited retinal diseases (IRDs). Including:

Classification of IRDs; common IRD signs and symptoms
Key clinical investigations, including imaging technologies, to determine subtypes of IRDs
Understanding the referral guidelines for patients with IRDs
Knowing the low-vision and blindness support services available for people with IRDs

NOTE: Optomery Australia members can enter their details at the bottom of this article to have it automatically added to their Learning Plan.

In the first of Insight’s two-part series of educational articles on inherited retinal disease, A/PROF LAUREN AYTON and DR TOM EDWARDS discuss the common presentations and when and where optometrists can refer patients who have them.

A/Prof Lauren Ayton [1-3] (BOptom PhD GCOT FAAO FACO)
Dr Thomas Edwards [2,3] (MBBS, PhD, FRANZCO)

Department of Optometry and Vision Sciences, The University of Melbourne
Department of Surgery (Ophthalmology), The University of Melbourne
Centre for Eye Research Australia, The Royal Victorian Eye and Ear Hospital

With the recent regulatory approval of the retinal gene therapy voretigene neparvovec-rzyl (Luxturna) for people with RPE65-associated Leber Congenital Amaurosis, there has been a significant shift in the management of inherited retinal disease (IRD). While challenges remain and emerging treatments such as gene therapy and stem cells will not be for all, it is a time of optimism for people with these conditions.

IRDs comprise a large number of rare single gene disorders, which together form the largest cause of legal blindness in working- aged Australians.¹ IRDs affect up to 1 in 3,000 individuals around the world.²

In recent years, our understanding of IRD has improved dramatically, paralleled by rapid technological advances in gene manipulation and therapeutics. For example, in the 1980s only a handful of genes were known to be responsible for IRD. There are now over 250 known genes, with this number continuing to grow.²

Often people with IRD will initially develop vague and intermittent symptoms. Others are detected incidentally through a routine eye examination. Both scenarios can mean that primary eyecare providers, such as optometrists, can often be the first clinician to detect an abnormality. To ensure early diagnosis, and access to potential therapies as they emerge, it is important optometrists are aware of the common presentations of IRD, including signs, symptoms and family history.

Due to the emerging treatment options, it is also important optometrists are aware of when and where to refer people with IRD. This includes both clinical referral pathways (outlined in
further detail in the RANZCO Guidelines for the Assessment and Management of Inherited Retinal Degenerations⁴) and for access to research opportunities. A companion article in this issue, ‘Inherited Retinal Diseases – The patient journey’ by Profs John Grigg and Robyn Jamieson, will further discuss the challenges and intricacies of management of people with these genetic conditions.

Classification of IRD

To date, several classification schemes have been proposed for IRD. Our group at the Centre for Eye Research Australia (CERA) and The University of Melbourne uses a taxonomy proposed by Coco-Martin et al,⁵ which divides the diseases into i) panretinal pigmentary retinopathies, affecting primarily rods or cones with widespread retinal involvement; ii) macular dystrophies with only central involvement; iii) stationary diseases (non-progressive conditions); and iv) other less frequent IRDs, such as vitreoretinopathies (Table 1).

Table 1: Classification of inherited retinal diseases.

Most classification schemes divide the diseases in this manner, isolating those which affect the macular and central vision (Best disease, Stargardt disease, macular dystrophy) from the more widespread pigmentary retinopathies, which generally (but not always) affect the peripheral vision first.

In general, IRDs are monogenic diseases, which follow Mendelian inheritance patterns (autosomal dominant, autosomal recessive, X-linked, or isolated cases). Some forms of IRD are also passed down through families through mitochondrial inheritance patterns (neuropathy, ataxia and retinitis pigmentosa (NARP) syndrome). Pathological genetic variants may occur in a number of genes which are responsible for the health of retinal photoreceptor cells, retinal pigment epithelium (RPE), or choroid. Within each clinical category, age of onset, mode of inheritance, and rate of progression can all differ substantially, even between affected individuals in the same family.

Common IRD signs and symptoms

While the signs and symptoms can vary significantly between subtypes of IRDs, there are common features. A more thorough review of the likely IRDs for upcoming gene therapy interventions, including Leber congenital amaurosis, Stargardt disease and choroideremia, was recently published by our team at CERA.⁶ That review paper also provides more detailed explanations of the clinical tests of benefit in IRD assessment. A summary of optometric care is also found later in this article.

Primary rod dystrophies

IRDs which firstly affect the rod photoreceptors, such as retinitis pigmentosa, initially cause symptoms such as:

Nyctalopia (night blindness)
Peripheral vision loss. If this commences in the inferior field, patients may complain of tripping over objects.

Retinitis pigmentosa (RP), the most common panretinal pigmentary retinopathy, has a ‘diagnostic triad’ of bone spicule pigmentation, attenuated blood vessels and optic nerve pallor (Figure 1). Patients with RP are prone to the development of posterior subcapsular cataracts and cystoid macular oedema.

Primary cone and macular dystrophies

These IRDs include cone-rod dystrophy and the macular IRDs (such as Best and Stargardt diseases). In contrast to the primary rod dystrophies, these conditions typically affect the macula most severely, and so are more likely to result in:

Central vision loss (usually noted at both distance and near)
Photophobia
Dyschromatopsia (impaired colour vision)

Age of onset of these symptoms can vary from birth until the sixth decade of life, and it is possible for people carrying IRD genetic mutations to remain asymptomatic.⁸ However, typically symptoms will begin in childhood or early adulthood. Not uncommonly, macular dystrophies can be confused with late atrophic age-related macular degeneration or geographic atrophy.

An example of Stargardt’s macular dystrophy is shown in Figure 2. Stargardt’s is characterised by symmetrical yellow-white flecks observed within the central retina, which are due to accumulations of lipofuscin at the level of the retinal pigment epithelium.

Figure 2: An Optos wide-field fundus autofluorescence image from a 24yo male with Stargardt’s disease (ABCA4 gene mutation), demonstrating the typical “flecks” and central atrophy. Autosomal recessive Stargardt disease represents the most common inherited macular dystrophy in children and young adults. Dominant cases are rare and are associated with a later adult onset and milder phenotype.[9] Image courtesy of the VENTURE Study, Centre for Eye Research Australia and The University of Melbourne.

IRDs can also be associated with systemic conditions. The most common of these is Usher syndrome, which results in dual sensory loss of both vision (from RP) and hearing, and can also cause vestibular dysfunction. Usher syndrome accounts for around 18% of cases of RP, and half of all cases of deaf-blindness.¹⁰Other IRDs can form part of multi-system syndromes that can affect kidneys, neurological function, skeletal structure and metabolism). Hence, a full medical history is essential in the diagnosis of IRDs.

Optometric assessment of IRD patients

Initially, rich data can be obtained through a thorough medical history. The age of onset of symptoms, the type of symptoms, and the presence of family history can all be clues as to the subtype of IRD and the inheritance pattern.The key clinical investigations for IRD within optometry scope-of-practice include:

Best corrected visual acuity, ensuring that you document if someone with central vision loss is using eccentric fixation or abnormal head position to read the letters
Pupil responses
Anterior segment examination, checking for associated cataract or raised intraocular pressur
Optical coherence tomography
Fundus autofluorescence
Wide-field colour and FAF imaging, which is particularly important in the pan-retinal pigmentary retinopathies

Visual field assessment. In order to accurately measure residual functional vision in the periphery, a manual perimetry method like Goldmann or Esterman binocular field is often needed.A detailed table of advised clinical evaluations, and timeframes for repeat examinations, is provided in the recent RANZCO guidelines for management of inherited retinal diseases.⁴

Management of IRD

Until recently, there were no commercially available treatments for IRD. The regulatory approval of an in-vivo gene therapy, Luxturna (voretigene neparvovec-rzyl), for people with a form of IRD caused by mutations in the RPE65 gene has changed this dramatically. First available in Australia in late 2020, this treatment not only offers hope to people with this specific IRD, but also those with other sub-types that are amenable to gene therapy.

Figure 3: An Optos wide-field colour fundus photo from a 50yo male with RPGR-associated X-linked RP, showing bone spicule pigmentation, waxy optic nerve pallor and blood vessel attenuation. The RPGR gene is estimated to cause up to 20% of cases of RP.[7] Image courtesy of the VENTURE Study, Centre for Eye Research Australia and The University of Melbourne.

However, as detailed in the accompanying article by Profs Grigg and Jamieson, there are still significant challenges with the implementation of these emerging treatments. Other treatment options may also one day be available for people with IRD. These include more specialised gene editing treatments (using CRISPR technologies), stem cell therapies, and electrical stimulation devices (either vision prostheses for end-stage vision loss, or ‘electroceuticals’ – devices which help preserve neural function through low level stimulation of remaining nerves).

For now, the mainstay of management for IRD is supportive. Regular eye examinations are key, to monitor disease progression. This is important as some of the co-morbidities of IRD, such as posterior subcapsular cataract, epiretinal membranes and macular holes, can be treated. Patients with RP are also prone to developing cystoid macular oedema – again, a complication which can be managed to improve vision.

Many people with photophobia, such as in cone-rod and macular dystrophies, benefit from sunglasses. Room lighting and improving contrast can significantly improve people struggling with nyctalopia.

Management of people with IRD usually requires co-management; an ophthalmologist to diagnose and manage medical issues, optometrist to provide monitoring and provide refractive solutions and low vision therapists (including orientation and mobility instructors and occupational therapists).

In addition, many patients will elect to undergo genetic testing to determine the causative mutation, which may mean further interaction with clinical geneticists and genetic counsellors. Indeed, RANZCO now states that genetic testing is the standard of care for people with IRD, using multigene testing strategies such as targeted next-generation sequencing panels, whole exome and whole genome sequencing.⁴ With current technologies, a causative mutation can be identified in up to 80% of IRD patients.¹¹ More details on genetic testing are available in Profs Grigg and Jamieson’s accompanying article.

Low vision and blindness support services

When a person is diagnosed with a progressive eye condition, such as an IRD, optometrists should also consider access to low vision and blindness support services. A recent referral pathway from Vision 2020 Australia suggests a referral to these services is offered at initial diagnosis, and then again at the point where the patient presents with visual acuity of less than 6/12, or comparable visual field loss.¹²

Some key support groups for people with IRD are:

Retina Australia, www.retinaaustralia.com.au
Blind Citizens Australia, www.bca.org.au
Vision Australia, www.visionaustralia.org
Guide Dogs Australia, www.guidedogs.com.au
Macular Disease Foundation Australia, www.mdfoundation.com.au

There are also several support groups for specific IRDs; for example, Usher Kids Australia (www.usherkidsaustralia).

A key form of support, which can sometimes be forgotten in the rush to provide practical vision solutions, is psychological care.

The providers above can provide access to psychologists and counsellors, and the patient’s general practitioner should be involved in these discussions and referrals.

Referral guidelines

The initial referral from primary optometric practice if an IRD is suspected is generally to an ophthalmologist with a speciality interest in the conditions. In addition to community providers, several states now have specialist hubs within the public health system (for example, the Ocular Genetics Clinic at the Royal Victorian Eye and Ear Hospital and the Clinical Electrophysiology Service at Sydney Eye Hospital). The ophthalmologist will likely complete additional testing, including electroretinography, dark adaptation and perimetry, to confirm diagnosis.

Another referral option is to research organisations, who are currently developing databases of people with IRDs for both natural history investigations, and as a registry of people who are interested in upcoming clinical trials

These organisations can be found in Table 2 below.

Table 2: Research organisations developing databases of people with IRDs for natural history investigations, as well as registries of people interested in upcoming clinical trials.

Conclusion

The promise of emerging therapies such as gene therapy and stem cells will only be realised if we are able to appropriately identify and treat people. This means it is important patients with IRD are detected, diagnosed, and referred to clinical care pathways and, if interested, to research platforms like the above natural history registries. In this way, we will be able to ensure that as treatments reach the shores of Australia, we are ready to offer them to patients.

Other resources

For optometrists who wish to further upskill in the areas of IRD and retinal gene therapy, further details are available in these recent publications:

O’Hare F, Edwards TL, Hu ML, et al. An optometrist’s guide to the top candidate inherited retinal diseases for gene therapy. Clin Exp Optom 2021;104(4):431-43.

Hu ML, Edwards TL, O’Hare F, et al. Gene therapy for inherited retinal diseases: progress and possibilities. Clin Exp Optom 2021;104(4):444-54.

References

1. Heath Jeffery RC, Mukhtar SA, McAllister IL, et al. Inherited retinal diseases are the most common cause of blindness in the working-age population in Australia. Ophthalmic Genet 2021: 1-9.

2. Hamblion EL, Moore AT, Rahi JS, British Childhood Onset Hereditary Retinal Disorders N. Incidence and patterns of detection and management of childhood-onset hereditary retinal disorders in the UK. Br J Ophthalmol 2012; 96 (3): 360-5.

3. University of Texas-Houston Health Science Center Laboratory for the Molecular Diagnosis of Inherited Eye Diseases. www.sph.uth.edu/retnet/. Accessed 8 November 2021.

4. Grigg J, Jamieson R, Chen F, et al. Guidelines for the Assessment and Management of Patients with Inherited Retinal Degenerations (IRD). www.ranzco.edu.au 2020.

5. Coco-Martin RM, Diego-Alonso M, Orduz-Montana WA, et al. Descriptive Study of a Cohort of 488 Patients with Inherited Retinal Dystrophies. Clin Ophthalmol 2021; 15: 1075-84.

6. O’Hare F, Edwards TL, Hu ML, et al. An optometrist’s guide to the top candidate inherited retinal diseases for gene therapy. Clin Exp Optom 2021; 104 (4): 431-43.

7. Bader I, Brandau O, Achatz H, et al. X-linked retinitis pigmentosa: RPGR mutations in most families with definite X linkage and clustering of mutations in a short sequence stretch of exon ORF15. Invest Ophthalmol Vis Sci 2003; 44 (4): 1458-63.

8. Na KH, Kim HJ, Kim KH, et al. Prevalence, Age at Diagnosis, Mortality, and Cause of Death in Retinitis Pigmentosa in Korea-A Nationwide Population-based Study. Am J Ophthalmol 2017; 176: 157-65.

9. Vasireddy V, Wong P, Ayyagari R. Genetics and molecular pathology of Stargardt-like macular degeneration. Prog Retin Eye Res 2010; 29 (3): 191-207.

10. Boughman JA, Vernon M, Shaver KA. Usher syndrome: definition and estimate of prevalence from two high-risk populations. J Chronic Dis 1983; 36 (8): 595-603.

11. Nash BM, Wright DC, Grigg JR, et al. Retinal dystrophies, genomic applications in diagnosis and prospects for therapy. Transl Pediatr 2015; 4 (2): 139-63.

12. Vision 2020 Australia. Adult Referral Pathway for Blindness and Low Vision Services. www.vision2020australia.org.au 2021.

13. de Roach JN, McLaren TL, Thompson JA, et al. The Australian Inherited Retinal Disease Registry and DNA Bank. Tasman Medical Journal 2020; 2 (3): 60-7.\