CPD - optometry

Inherited retinal diseases – the patient journey


At the completion of this CPD activity, optometrists will have developed their knowledge of the patient journey following referral for inherited retinal diseases (IRDs). Including:

  • The four steps of assessment and management of patients with, or suspected of having, IRDs
  • Investigations assisting diagnosis of IRDs and determining visual function
  • An understanding of the genetic workforce and their role in the diagnosis, management, treatment and counselling of patients with IRDs
  • IRD patient management protocols

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

The next decade will see a rapid increase in gene therapy trials and treatments for inherited retinal disease. In the second article of Insight’s two-part educational series on this topic, PROF JOHN GRIGG and PROF ROBYN JAMIESON discuss the challenges and intricacies in managing patients with these genetic conditions.

Prof John R Grigg [1,2,4,5] (FRANZCO MD)
Prof Robyn V Jamieson [1,2,3,6] (FRACP PhD)

  1. Save Sight Institute, Specialty of Clinical Ophthalmology and Eye Health, Faculty of Medicine and Health, Sydney NSW
  2. Eye Genetics Research Unit, The Children’s Hospital at Westmead, Save Sight Institute, Children’s Medical Research Institute, University of Sydney, Sydney NSW
  3. Specialty of Genomic Medicine, Faculty of Medicine and Health, University of Sydney, Sydney NSW
  4. Department of Ophthalmology, The Children’s Hospital at Westmead, Sydney Children’s Hospitals Network, Westmead, Sydney NSW
  5. Sydney Eye Hospital, Sydney NSW
  6. Department of Clinical Genetics, Western Sydney Genetics Program, Sydney Children’s Hospitals Network, Westmead, Sydney NSW

Inherited retinal diseases (IRDs) are a group of heterogeneous conditions leading to vision loss due to progressive or stationary retinal dysfunction.

IRDs have traditionally been reported as affecting 1:3000 to 1:4000 individuals,1,2 however, recent worldwide carrier frequency data indicates that autosomal recessive IRDs affect more than 1 in 1380 individuals,3 and together all types constitute a significant cause of childhood and adult blindness.4,5

Although the term ‘inherited retinal disease’ refers to a group of related conditions, this may not be readily appreciated by non- clinicians. There is also overlap in terminology with ‘retinal dystrophy’ and ‘inherited retinal disease’, often used interchangeably. Despite similarities among different IRDs, variants in more than 300 genes are associated with IRDs.6

Therefore, accurate and comprehensive molecular diagnosis is critical to confirm the clinical diagnosis and inform disease prognosis. Optometrists play a vital role in identifying patients with these rare conditions, educating them on new treatment options and referral for appropriate genetic testing.

The patient journey 

This review will explore the patient journey including ophthalmic and genetic diagnosis and preparation for therapeutic trials or treatments (Figure 2 below). Collectively IRDs are common, and their cumulative impact on affected families and healthcare systems is substantial due to the earlier onset of blindness compared to many other eye diseases.7-9


Figure 2: The IRD patient journey in Australia. Credit: Prof John Grigg and Prof Robyn Jamieson.

IRD management is similar to other complex conditions. Patients are best managed in a multi-disciplinary setting with ophthalmologists experienced in IRD diagnostic steps and management, and with access to clinical geneticists and genetic counsellor expertise.

Assessment and management for patient with a suspected IRD

The assessment and management for patients with, or suspected of having, an IRD falls into four broad areas:16,17

  1. Establishing the clinical diagnosis of an IRD
  2. Determining the level of visual function and planning/implementing visual rehabilitation
  3. Establishing the genetic diagnosis and genetic management
  4. Monitoring of disease progression (Natural History) and, preparation for therapeutic interventions

Establishing the clinical diagnosis

The clinical diagnosis relies upon a combination of history, examination and investigations directed at the presentations that are common for IRDs. Important patient history details include: rod dysfunction (nyctalopia and often peripheral vision issues), cone dysfunction (photophobia, reduced distance and near visual acuity and dyschromatopsia), age at onset and progression of symptoms.18-20 Traditionally, IRDs have been associated with early onset disease. Increasing evidence indicates a much broader age of onset, extending to the sixth decade, as well as asymptomatic disease.21

There are five major groups of IRDs clinically recognised which include: rod and rod-cone dystrophy, cone and cone-rod dystrophy, chorioretinal degenerations, macular dystrophies and vitreoretinopathies.1,16

Systemic evaluation is a key component of patient assessment to identify syndromic causes. In particular, hearing, renal dysfunction, neurological dysfunction, skeletal anomalies and/or metabolic disturbance need to be specifically inquired about and evaluated. The effects of medication also need to be evaluated.

Family history is important as all forms of inheritance (autosomal dominant, autosomal recessive, X-linked or mitochondrial inheritance) are reported. A family pedigree should be recorded in the clinical record.

Investigations assisting diagnosis and determining visual function 

The investigations directed at identifying IRDs include: optical coherence tomography (OCT), fundus autofluorescence (widefield), visual field assessment (peripheral field – Goldmann semi-automated or manual perimetry, Esterman binocular field), dark adaptation, International Society for Clinical Electrophysiology of Vision (ISCEV) standard visual electrophysiology (pattern electroretinogram, full field electroretinogram, multifocal electroretinogram).

The specialised investigations, including visual electrophysiology, are best performed in centres with expertise in meeting international standards. The diagnostic tests at baseline will provide an initial visual function measure which is important for education, work, statutory requirements and rehabilitation assessments.

Establishing the genetic diagnosis 

IRDs are phenotypically and genetically heterogeneous. Clinical genetic and molecular assessments have advanced significantly in recent years.22-25 A causative mutation can now be identified in up to 60-80% of patients with IRDs.1, 23, 26

In an autosomal recessive disease, testing unaffected parents or other family members is essential in assisting confirmation of biallelic pathogenic variants which is a key inclusion criterion for some therapies and clinical trials.27 For autosomal dominant retinal disease, it is important to examine parents and siblings, to identify variable penetrance. Frequently new or ‘de novo’ autosomal dominant pathogenic variants require parental genetic testing to establish pathogenicity. Similarly, in X-linked retinal dystrophies, there may be asymptomatic obligate carrier females and further family members who would benefit from genetic testing, that aren’t always obvious on first consultation.

Figure 1: A montage for Stargardt disease (ABCA4 retinopathy) showing widefield pseudo colour image with yellow flecks, widefield fundus autofluorescence with hyper and hypo autofluorescent flecks. Then OCT scan with loss of outer retina structures including disruption of the ellipsoid zone.

Genetic testing is now standard of care for these patients. Multigene-based testing strategies, including targeted next-generation sequencing panels, whole exome sequencing (WES) or whole genome sequencing (WGS) are necessary to identify the molecular aetiology in the IRD group of disorders where more than 300 causative genes have been identified. (See RetNet, the Retinal Information Network).

This information helps provide a more accurate diagnosis, prognosis, provides individuals and families with specific recurrence risks, aids informed reproductive decisions and guides treatment decisions. Routine genetic testing is also required to enable enrolment in treatment studies as well as determine suitability for approved therapies such as voretigene neparvovec (Luxturna).

Unnderstanding the genetic workforce 

Clinical geneticists are medical specialists who have completed either paediatric or adult basic physician training and then completed advanced training in clinical genetics supervised by the Royal Australasian College of Physicians in collaboration with the Human Genetics Society of Australasia.

Clinical geneticists specialise in medicine that involves the interaction between genes and health. They are trained to evaluate, diagnose, manage, treat and counsel individuals of all ages with hereditary disorders.28,29 In these roles, clinical geneticists use genomic molecular testing to implement needed therapeutic interventions and provide genetic counselling regarding prenatal and preimplantation diagnosis.30

In Australia and New Zealand, genetic counsellor roles include: referral assessment, collecting personal and family history, risk assessment, patient education regarding genetic concepts to facilitate informed decision‐making and addressing the psychosocial impacts of a diagnosis.31 In Australia, genetic counselling is not a nationally regulated or registered profession, which means that they can facilitate genetic/genomic testing when working under the medico‐ legal supervision of a clinical geneticist.32

Genetic management for IRDs

Informed genetic consent – a key component of managing the patient with a suspected heritable disorder is the process of informed consent. Genetic counselling is an essential role to facilitate informed consent.33 Patients will expect the return of primary results. However, they may not anticipate genetic testing may reveal unexpected, embarrassing, stigmatising, or deeply upsetting medical information. For example, patients need to be forewarned about the risk of revealing mis-attributed parentage, unexpected incidental findings such as an oncogene variant, and variants of uncertain significance (VUS). These VUSs, and the uncertainty raised by them, can be a source of significant misunderstanding and concern for the recipient.34

Interpreting the genetic results including: Multidisciplinary team review – next-generation sequencing technology has led to greatly improved mutation detection rates. The advances have also highlighted variants of uncertain significance (VUS) that are simultaneously identified. The American College of Medical Genetics and Genomics (ACMG) provides a systematic methodology to classify these variants.35 Specific guidelines are followed to determine if a genetic variant is pathogenic/likely pathogenic or a variant of uncertain significance (VUS) for a patient. At times, it may be necessary to perform segregation genetic testing in family members to determine if a VUS can be upgraded to ‘likely pathogenic’ or ‘pathogenic.’

Multi-disciplinary team (MDT) meetings are frequently required to determine the pathogenicity and significance of some variants, especially the VUSs. Critical contributions from ophthalmologists, clinical geneticists, genetic pathologists, molecular biologists and genetic counsellors provide phenotype and genotype assessments to assist in the determination of genetic variant pathogenicity.

Despite these processes, a genetic answer may not be found with the current technology in up to 20-40% of cases. Whole genome sequencing, RNA sequencing and functional genomic studies including RPE and retinal organoid modelling are research tools addressing this challenge.36-41 Understanding the precise molecular defect is crucial for the implementation of genomic therapies.42

Return of genetic results – an important component of the management of patients with an IRD is the return of genetic testing results. As can be seen there are critical steps that should occur to optimise the return of genetic results. This process begins with establishing expectations during pre-test genetic counselling which will enable patients to feel educated and psychologically better prepared for the implications of the results. Managing patient expectations remains an ongoing challenge and highlights the need to address this issue throughout the testing process.43

The wider introduction of genetic testing will lead to a reduction in morbidity, improved patient disease understanding, improved reproductive decision-making and improved clinical care pathways.44-47

Preparing for therapies – Natural history assessments – the development of specific gene-based therapies 12, 48-54 raises the question of the ideal time to intervene. To answer this question, an understanding of the natural history of the IRD is required.55 Monitoring the natural history of IRDs requires consistent assessments and protocols. A term that is used for clinical trial or therapeutic eligibility is ‘viable retinal cells’. For gene replacement and genomic engineering approaches, viable retinal cells are required for the therapies to work.

Assessment of viable retinal cells is made by combining the information derived from the clinical assessment including BCVA, OCT, visual field assessment, visual electrophysiology (including full field scotopic threshold testing and patient reported outcomes). The assessment will include a combination of all the investigations, and this will vary from patient to patient.

IRD management is similar to other complex conditions. The management around this process is critical to ensure that patients receive the appropriate ophthalmic and genetic advice.56-58 Patients are best managed in a multi-disciplinary clinic with ophthalmologists experienced in IRD diagnostic steps and management, and with access to clinical geneticists and genetic counsellor expertise

The four steps outlined in this review will lead to improved patient care with streamlined ophthalmic diagnosis, molecular diagnosis and counselling, management of visual dysfunction and preparation for clinical trials and therapies.

The complexity of IRDs requires input from both ophthalmology and clinical genetics.44 The benefits of modern genetic diagnostics and counselling supports the introduction of equitable genetic testing for patients with presumed genetically-caused retinal diseases.5

NOTE: Some of the material has been adapted from the RANZCO Guidelines for the assessment and management of patients with inherited retinal diseases, which Profs Grigg and Jamieson co-authored with seven other experts. 


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