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IRDs are a major cause of familial blindness worldwide and are associated with an inherited gene mutation affecting the function of the retina.2,3
- The IRD phenotype retinitis pigmentosa is the most common IRD,4 with 1 in 3000–1 in 7000 people living with this disease.2
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IRDs differ in onset, severity and progression of the diseases2
- IRDs are characterised by the progressive deterioration of the rods and cones.2
- There are >270 genes associated with IRDs.3
- Retinitis pigmentosa (RP) and Leber congenital amaurosis (LCA) both have subtypes related to pathogenic variants in RPE65.5
- Other IRD phenotypes include: achromatopsia, choroideremia, Stargardt disease, Best disease, Sorsby fundus dystrophy, Usher syndrome, Bardet-Biedl syndrome.2,6
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The majority of patients with an RPE65-mutation-associated IRD have vision impairment in early childhood.5
- If untreated, patients usually progress to near-total blindness.5,7
Gene
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Retinal pigment epithelium-specific protein 65-kDa (RPE65) gene encodes the RPE65 protein.1
- RPE65 is an all-trans-retinal isomerase. This key enzyme is expressed in the retinal pigment epithelium (RPE) and is responsible for regeneration of 11-cis-retinal in the visual cycle.1
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Individuals with biallelic mutations in RPE65 may experience a reduction or absence in the RPE65 enzyme activity.1
- This leads to build-up of toxic precursors and damage to RPE cells, loss of photoreceptors and eventually complete blindness.1
Estimated prevalence of RPE65-mutation-associated IRDs
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RPE65-mutation-associated IRD can be diagnosed as:
- Leber congenital amaurosis (LCA)/early-onset retinitis pigmentosa – 2–3:100,000 births (RPE65 mutations: 3–16% of all LCA).11
- Retinitis pigmentosa (RP) – 1:300 – 1:5000 births (RPE65 mutations: 2–5 % of all non-syndromic autosomal recessive RP).10,12
Clinical signs and symptoms
The hallmark of an RPE65-mutation-associated IRD (RPE65-IRD) is an inability to see in low-light conditions (night blindness, nyctalopia).5
RPE65 mutation-associated IRDs have overlapping signs and symptoms with other IRD phenotypes.15
> Light-seeking behaviour in children15
Difficulty with dark adaptation2,5,11
Nystagmus15–17
- Uncontrolled/repetitive eye movements.
- Early onset in children (common aspect of a rod-cone dystrophy).
Loss of visual acuity2,4,5
Reduced colour vision2,5,16
Reduced/undetectable ERG2,5,11
Lack of fundus autofluorescence2,5,16
Failure to fix and follow15
In infants
Restricted visual fields2,5,16
- Patients may report that they have “tunnel vision”.
- Annual rate of decline of 2% to 12% for V4e of the Goldmann perimeter ranges.
- Varies among gene-specific subtypes.
- Young patients may bump into things in low light
Retinal degeneration5,9
- Reduced retinal thickness
- Loss of outer segment/outer nuclear layer
Fundus abnormalities2,5,16†
Pigmentary changes, retinal atrophy, vessel attenuation, optic nerve pallor
†This image was originally published in the Retina Image Bank. David Callan, MD. Retinitis Pigmentosa. Retina Image Bank. 2014; 17341.
© The American Society of Retina Specialists.
Understanding the condition: See what they see.
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The videos depict a mother walking with her son (Alex) who has an RPE65-IRD. “Alex cam” shows what Alex sees in various light (Lux) levels. “Mum cam” shows what Alex's mum sees at the same Lux level.
Alex and his mother are actors . The videos were developed by Novartis in collaboration with FundamentalVR. The representation of Alex’s vision is based upon the natural history study of patients with RPE65-mediated IRD and Phase III clinical trial. This has been confirmed by IRD experts to demonstrate an accurate representation of a real RPE65-mediated IRD patient.
ERG, electroretinography.
IRDs have overlapping signs and symptoms: The only way to fully diagnose an IRD is a genetic test.
Now that there is an approved gene therapy,1,7 an early and complete diagnosis of an IRD is more important than ever.
>270 genes are associated with IRDs and with multiple phenotypes.3,4
Genetic tests can improve the accuracy of diagnoses and prognoses.17
Establishing a complete diagnosis offers patients more information about their IRD.
of IRD patients are interested in having a genetic diagnosis for their disease.7*
Identifying patients earlier with genetic testing can17:
Address uncertainty
Permit early intervention
Improve decision-making and management
Provide insight into prognosis
*In a survey of IRD patients.7
Click here to know more about genetic testing and referring for a genetic test
IRD, inherited retinal dystrophy; RPE, retinal pigment epithelium.
Indication: Luxturna is indicated for the treatment of adult and paediatric patients with vision loss due to inherited retinal dystrophy caused by confirmed biallelic RPE65 mutations and who have sufficient viable retinal cells.1
References
- Luxturna SmPC, 2020.
- Sahel JA et al. Cold Spring Harb Perspect Biol 2015;5(2):a017111.
- RetNet: Summaries. 2019. Available at: https://sph.uth.edu/retnet/sum-dis.htm (Accessed August 2020).
- Verbakel SK et al. Prog Retin Eye Res 2018;66:157–186.
- Chung DC et al. Am J Opthalmol 2019;199:58–70.
- Nash BM et al. Trans Pediatr 2015;4(2):139–163.
- Voretigene neparvovec for treating inherited retinal dystrophies caused by RPE65 gene mutations. Highly specialised technologies guidance [HST11]. Available at: https://www.nice.org.uk/guidance/hst11/chapter/2-The-condition (Accessed August 2020).
- Palczewski K. Invest Opthalmol Vis Sci 201;55(10):6651–6672.
- Russell S et al. Lancet 2017;390(10097):849–860.
- Orphanet. 2019. Available at: www.orpha.net (Accessed August 2020).
- Fahim AT et al. Nonsyndromic Retinitis Pigmentosa Overview. 2000. https://ncbi.nlm.nih.gov/books/NBK1417/ (Accessed August 2020).
- Weleber RG et al. Leber Congenital Amaurosis. 2004. Available at: http://www.ncbi.nlm.nih.gov/pubmed/20301475/ (Accessed August 2020).
- Data on file. Spark Therapeutics.
- Astuti GDN et al. Genes 2018; 9:21.
- Henderson R. Paediatrics and Child Health 2020;30:19–27.
- Di Iorio V et al. Genes 2017;8:280–297.
- American Academy of Ophthalmology®, IRD Clinical Statement. 2016. Available at: https://www.aao.org/clinical-statement/recommendations-on-clinical-assessment-of-patients (Accessed August 2020).