UNDERSTANDING PAEDIATRIC INHERITED RETINAL DISEASES

Inherited retinal diseases are a diverse group of genetic conditions that cause progressive retinal dysfunction and vision loss. Although individually rare, collectively they represent a significant cause of childhood visual impairment and blindness worldwide. Indeed, a recent study from Western Australia showed that IRDs are the second leading cause of childhood low vision in their population.1 It is estimated that approximately 20,000 Australians are living with an IRD, although national prevalence studies have not yet been completed.

IRDs comprise a heterogeneous group of genetic disorders affecting photoreceptors, the retinal pigment epithelium, or other retinal structures. More than 450 genes have been implicated in IRDs, resulting in a wide spectrum of phenotypes and rates of progression.2

IRDs that present in children include:

Leber congenital amaurosis (LCA). A severe inherited retinal disease that causes significant vision impairment from birth or the first few months of life. Children often have very poor vision, nystagmus (involuntary eye movements), and high sensitivity to light. LCA due to biallelic mutations in the RPE65 gene is currently the only IRD that has a commercial therapy approved (gene therapy).

Retinitis pigmentosa (RP). A group of inherited retinal diseases characterised by progressive degeneration of the photoreceptors, usually beginning with night blindness and loss of peripheral vision. Over time, vision may narrow to ‘tunnel vision’ and can progress to severe visual impairment or blindness.

Achromatopsia. A congenital condition in which the cone photoreceptors do not function normally, resulting in little or no colour vision, reduced visual acuity, and extreme light sensitivity (photophobia). Symptoms are usually present from birth and are typically non-progressive or only slowly progressive.

Stargardt disease. The most common inherited macular dystrophy, causing damage to the central retina (macula). It typically begins in childhood or adolescence and leads to progressive loss of central vision, while peripheral vision is often preserved.

Congenital stationary night blindness (CSNB). An inherited retinal disorder characterised by lifelong difficulty seeing in dim light or at night. Unlike many other retinal diseases, vision loss is generally stable rather than progressive, although some individuals also have reduced visual acuity or myopia.

X-linked retinoschisis (XLRS). A genetic retinal disease affecting mainly boys and men, caused by splitting (schisis) of the retinal layers. It usually presents in childhood with reduced central vision and can lead to additional retinal complications later in life.

Usher syndrome. A syndromic inherited retinal disease that combines retinitis pigmentosa with hearing loss and, in some types, balance problems. It is the most common cause of combined deafblindness and leads to progressive vision loss over time.

Best disease. Also known as Best vitelliform macular dystrophy, this inherited condition affects the macula, causing a characteristic yellow ‘egg-yolk’ lesion beneath the retina. Vision is often normal in early childhood but may gradually decline as the disease progresses.

Presentation of these IRDs can occur from birth through adolescence. Children may present with nystagmus, reduced visual acuity, night blindness, photophobia, poor colour discrimination, peripheral visual field loss, delayed visual development, or difficulties navigating unfamiliar environments.

The clinical course is highly variable. Some conditions result in a relatively stable visual status, while others result in rapid deterioration during childhood. This variability highlights the importance of accurate diagnosis and longitudinal monitoring.

Variability is also seen in the inheritance patterns of these IRDs, but a family history of retinal disease and vision loss is important to collect in the medical history taking. A strong family history of an IRD, such as in X-linked or dominant genotypes, can sometimes make initial diagnosis conversations a little easier, as the family will be aware of the conditions, whereas recessive or de novo mutations can be a huge shock for families. Psychological care and support is a vital part of the diagnostic journey of IRDs, and can often be provided through service or patient advocacy organisations (see Table 1).

THE IMPORTANCE OF EARLY RECOGNITION

For many families, obtaining a diagnosis remains a lengthy and frustrating process. Unfortunately, it is quite common for there to be a delay of several years between the first recognition of visual symptoms and confirmation of a genetic diagnosis.

Key clinical indicators that should prompt consideration of an IRD include:

• Unexplained reduced vision in childhood,

• Nystagmus without an obvious neurological cause,

• Night vision difficulties (which can present as a fear of the dark in children),

• Photophobia,

• Constricted visual fields,

• Colour vision abnormalities,

• Strong family history of retinal disease, and

• Developmental concerns associated with visual dysfunction.

Table 1. Support organisations for people with inherited retinal diseases in Australia.

Figure 1. Examples of retinal imaging and clinical findings in some relatively common paediatric inherited retinal diseases.

BEYOND THE RETINA: THE IMPACT OF VISION IMPAIRMENT IN CHILDHOOD

The consequences of paediatric IRDs extend far beyond visual function. Vision plays a central role in cognitive, social, and emotional development.

Children with vision impairment may experience:4

• Delayed developmental milestones,

• Reduced participation in sport and recreation,

• Challenges with literacy and educational attainment,

• Social isolation,

• Increased anxiety and reduced self-confidence, and

• Difficulties developing independence and mobility skills.

For families, the diagnosis may carry substantial emotional and financial burdens. Parents often report uncertainty about prognosis, concerns regarding future independence, and difficulties navigating complex healthcare systems.

Research has demonstrated that early access to low vision rehabilitation, orientation and mobility services, assistive technology, and educational supports can significantly improve outcomes and quality of life.4 Recent research has also suggested that outcomes may be improved with the use of electronic low vision aids, when compared to traditional non-electronic (i.e. optical devices like magnifiers), but further research is needed in this emerging space.4

Figure 2. The broad impact of paediatric vision impairment across developmental domains.

GENETIC TESTING: CENTRAL TO CARE

Historically, genetic diagnosis was primarily used to confirm clinical findings. Today, genetic testing has become a fundamental component of management.

Benefits include:

• Confirmation of molecular diagnosis,

• Improved prognostic information,

• Identification of syndromic disease, including Usher syndrome, Bardet-Biedl syndrome, CHARGE syndrome etc.,

• Improved management of IRDs that do have systemic management options – for example, Refsum disease, which can be managed by a reduction of phytanic acid in the diet,5

• Access to gene-specific clinical trials,

• Eligibility assessment for emerging therapies, and

• Family planning and reproductive counselling.

The availability of genomic testing programs has increased substantially across Australia. Multidisciplinary care involving ophthalmologists, clinical geneticists, genetic counsellors, orthoptists, and optometrists is increasingly recognised as best practice,6 but is limited to a few tertiary hospitals around Australia. As such, it is also important that general eye care providers are aware of the referral pathways for genomic care. For more information, refer to the Royal Australian and New Zealand College of Ophthalmologists Guidelines for the assessment and management of patients with inherited retinal diseases (available at: bit.ly/4cuKB5Q).

We still have work to do in Australia to ensure that all people suspected of having an IRD receive this genomic care. A recent study of an Australian specialist retinal clinic found that only around 10% of patients had a genetic diagnosis, reflecting historical management patterns and accessibility of genetic counselling and testing.7 The results show that younger patients and those with a longer duration of care were more likely to have received genetic testing.7 As the importance of IRD genetic testing continues to increase, we expect to see a change in patient management within the Australian private ophthalmology system and testing rates to increase.

A NEW ERA OF TREATMENT

Until recently, management focused primarily on supportive care. This paradigm is changing rapidly.

In 2017, the world’s first approved ocular gene therapy, voretigene neparvovec, demonstrated that inherited retinal diseases could be treated at a molecular level. This milestone transformed expectations for patients, clinicians, researchers, and industry alike.

Figure 3. Emerging therapeutic approaches for inherited retinal diseases, using the example of retinitis pigmentosa (RP).

The therapy, which is supplied under the trade name Luxturna and distributed by Novartis in Australia, is suitable for people with biallelic mutations in the RPE65 gene.8 This genotype usually leads to an LCA phenotype, with significant vision loss in early childhood. Hence, the most successful treatments with the therapy tend to be in children, with early detection vital.

Today, therapeutic strategies under investigation include:

Gene replacement therapy. Gene replacement, or augmentation, seeks to deliver functional copies of defective genes to retinal cells. This approach is most suitable for conditions caused by loss-of-function mutations. Voretigene neparvovec is an example of gene replacement.

Gene editing. Techniques such as CRISPR-based editing aim to directly modify disease-causing variants within the genome.9

RNA-based therapies. Antisense oligonucleotides and other RNA-targeted approaches may bypass or modify pathogenic genetic sequences.10

Cell therapies. Stem cell-derived retinal cells offer the potential to replace damaged retinal tissue in advanced disease.11

Neuroprotection. A number of trials are underway investigating oral medications for neuroprotection of the retina, particularly focusing on antioxidants, i.e., N-acetylcysteine (NAC, an antioxidant and medication), and N-acetylcysteine-amide (NACA, a related chemical derivative).12

Vision restoration technologies. Vision prostheses and other neurostimulation technologies are being investigated for individuals with profound vision loss, where photoreceptor function has been severely compromised.13

Although most therapies remain investigational, the pace of progress continues to accelerate, reinforcing the importance of obtaining an accurate genetic diagnosis as early as possible.

SUPPORTING CHILDREN THROUGH A LIFELONG JOURNEY

Despite therapeutic advances, many children currently diagnosed with IRDs will continue to require comprehensive vision rehabilitation and ongoing support.

Effective management extends beyond monitoring disease progression. Clinicians should consider:

• Educational support requirements,

• Access to low vision services,

• Assistive technology,

• Mental health and psychosocial support,

• Transition planning into adolescence and adulthood, and

• Family education and peer support networks.

A strengths-based approach is particularly important. Many children with inherited retinal diseases develop remarkable adaptability and resilience when provided with appropriate support and opportunities.

Eye care providers remain central to this process, often serving as long-term clinical partners for children and families throughout their visual journey.

CONCLUSION

Paediatric IRDs remain a leading cause of childhood blindness and vision impairment, yet the outlook for affected children is changing rapidly. Advances in retinal imaging, molecular diagnostics, genomic medicine, and emerging therapies are creating opportunities that were unimaginable only a decade ago. Early recognition, timely referral for specialist assessment and genetic testing, and access to comprehensive support services are critical to achieving the best possible outcomes. As the therapeutic landscape continues to evolve, paediatric eye care professionals will play an increasingly important role in connecting children and families with diagnosis, support, and hope for the future.

Artificial intelligence tools were used to assist with editing this manuscript for clarity, and to reduce scientific jargon. Figures 1–3 were generated with the use of Microsoft Co-Pilot. The author reviewed and verified the content prior to submission.

References
1. Heath Jeffery RC, Mukhtar SA, Chen FK, et al. Inherited retinal diseases are the most common cause of blindness in the working-age population in Australia. Ophthalmic Genet. 2021;42(4):431-439. doi: 10.1080/13816810.2021.1913610.
2. Quinodoz M, Celik E, Rivolta C, et al. RetiGene, a comprehensive gene atlas for inherited retinal diseases (IRDs). bioRxiv. [Preprint]. 2025 Jun 8:2025.06.08.653722. doi: 10.1101/2025.06.08.653722. Update in: Am J Hum Genet. 2025 Oct 2;112(10):2253-2265. doi: 10.1016/j.ajhg.2025.08.017.
3. Jolly JK, Rodda BM, Edwards TL, Ayton LN, Ruddle JB. Optical coherence tomography in children with inherited retinal disease. Clin Exp Optom. 2024;107(3):255-66. doi: 10.1080/08164622.2023.2294807.
4. Okasheh-Otoom A. Outcomes of low vision rehabilitation programs for children: a prospective observational cohort study. Children. 2026;13(8):1030. doi: 10.3390/ children13081030.
5. Truong P, Mack HG, Ayton LN, et al. Forty-year odyssey to Refsum disease diagnosis: impact of diagnostic delay on effective treatment. Clin Exp Optom. 2025;108(5):636-9. doi: 10.1080/08164622.2024.2401509.
6. Surendran SA, Gocuk SA, Ayton LN, et al. Three-year outcomes of a multidisciplinary ocular genetics clinic: Diagnostic yield and workflow insights from an Australian tertiary center. Am J Ophthalmol Int. 2025;2(3):100163. doi: 10.1016/j.ajoint.2025.100163.
7. Gocuk SA, Jiao Y, Britten-Jones AC, Kerr NM, Lim L, Skalicky S, et al. Genetic testing of inherited retinal disease in Australian private tertiary ophthalmology practice. Clin Ophthalmol. 2022;16:1127-38. doi: 10.2147/OPTH. S353787.
8. Russell S, Bennett J, Maguire AM, 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. The Lancet. 2017;390(10097):849-60. doi: 10.1016/S0140-6736(17)31868-8.
9. Fenner BJ, Tan TE, Teo KYC, et al. Gene-based therapeutics for inherited retinal diseases. Front Genet. 2021;12:794805. doi: 10.3389/fgene.2021.794805.
10. Kumar S, Fry LE, Liu GS, et al. RNA-targeting strategies as a platform for ocular gene therapy. Prog Retin Eye Res. 2023;92:101110. doi: 10.1016/j.preteyeres.2022.101110.
11. Cehajic-Kapetanovic J, Singh MS, Zrenner E, MacLaren RE. Bioengineering strategies for restoring vision. Nat Biomed Eng. 2023 Apr;7(4):387-404. doi: 10.1038/s41551-021-00836-4.
12. Campochiaro PA, Iftikhar M, Hafiz G, Akhlaq A, Tsai G, Wehling D, et al. Oral N-acetylcysteine improves cone function in retinitis pigmentosa patients in phase I trial. J Clin Invest. 2020 Mar 2;130(3):1527-1541. doi: 10.1172/ JCI132990.
13. Ayton LN, Barnes N, Petoe MA, et al. An update on retinal prostheses. Clin Neurophysiol. 2020;131(6):1383-98. doi: 10.1016/j.clinph.2019.11.029.