Stage II: Summary Report Secondary Findings in Pediatric Subjects Non-diagnostic, excludes newborn screening & prenatal testing/screening Update History Stage 2 Status (Pediatric):Complete (Actionability curation complete.)

Condition: Biallelic RPE65 Mutation-Associated Retinal Dystrophy
Narrative Description of Evidence
1. What is the nature of the threat to health for an individual carrying a deleterious allele?
Prevalence of the Genetic Disorder
Biallelic RPE65 mutation-associated retinal dystrophy has been historically diagnosed phenotypically as Leber congenital amaurosis (LCA), non-syndromic autosomal recessive isolated retinitis pigmentosa (RP), and other various inherited retinal dystrophies (IRDs). LCA is estimated to affect 1 in 81,000 to 1 in 30,000 live births, with RPE65 accounting for 5-10% of these cases. RP affects 1 in 3,000 to 7,000 people, with autosomal recessive RP estimated to account for 5-20% of those cases. Of autosomal recessive RP cases, RPE65 accounts for about 2-5% of cases.
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Clinical Features
(Signs / symptoms)
Biallelic RPE65 mutation-associated retinal dystrophy is a form of IRD caused by biallelic pathogenic variants in RPE65; it presents as a spectrum of disease with variable age of onset and progression of vision loss. Common clinical findings across the spectrum include night blindness, progressive loss of visual fields and loss of central vision. Biallelic RPE65 mutation-associated retinal dystrophy has been historically identified as multiple, heterogeneous diagnostic entities depending on the severity and age of onset. These clinical entities include, but are not limited to, LCA, RP, severe early childhood-onset retinal dystrophy (SECORD) and early-onset severe retinal dystrophy (EOSRD). LCA includes early onset severe retinal dystrophy, profound night blindness from birth, minimal nystagmus, and poor color discrimination; other features may include a blonde fundus and peripheral white, punctate lesions. RP can present with good central vision in the first decade of life, to the point where children may attend regular school during elementary years; at older ages visual acuity is greatly reduced. Fundus appearance depends on stage of disease. All phenotypes feature attenuated retinal vessels and a variable amount of retinal pigmentation in older patients and a reduced or nondetectable electroretinogram (ERG) at all ages. All phenotypic presentations can include cataracts. There is no universal agreement on the phenotypic classification of children with ambulatory vision who lose this useful vision within the first few years of life.
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Natural History
(Important subgroups & survival / recovery)
In LCA, night blindness often occurs from birth. Characteristically, these patients have residual cone-mediated vision in the first to third decades with progressive visual field loss until complete blindness is observed, most often in mid- to late-adulthood. A range of age of onset has been described for night blindness in RP, but it typically onsets in later childhood. Visual acuity disturbance and visual disability onset have reportedly occurred as late as the third decade, though can occur in childhood as well. Women with milder phenotypes have reported decreased vision during pregnancy that did not recover post-partum, though no objective data are available. A natural history chart review study was conducted on patients (n = 70) with confirmed biallelic RPE65 mutation-associated retinal dystrophy and various clinical diagnoses. In this cohort, the average age of first report for poor night vision was 12.0 (range, 2-43 years), although the study authors note the age of report in medical record may not reflect age of onset. Photophobia was reported at an average age of 17.27 years (range, 4-43 years). On average, visual acuity was markedly impaired but stable in the first decade of life, began to decrease around age 15-20, and decreased more rapidly after age 20, although some individuals had normal or near normal visual acuity at young ages. More than half of the patients were legally blind by United States criteria by age 18.
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2. How effective are interventions for preventing harm?
Information on the effectiveness of the recommendations below was not provided unless otherwise stated.
Patient Management
While guidelines did make note of the availability of the now FDA-approved gene therapy for RPE65 gene therapy, they did not make specific recommendations. (Tier 3)
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In December 2017, the FDA approved LUXTURNA (voretigene neparvovec-rzyl) gene therapy for the treatment of patients with confirmed biallelic RPE65 mutation-associated retinal dystrophy. The FDA’s conclusion of efficacy is based on improvement in a functional vision score over 1 year in a single open-label controlled Phase 3 study of 31 affected patients. The average age of the 31 randomized patients was 15 years (range 4 to 44 years), including 64% pediatric subjects (n=20, age from 4 to 17 years) and 36% adults (n=11). Functional vision was scored by a patient’s ability to navigate a course in various luminance levels. Using both treated eyes of the 21 subjects in the LUXTURNA treatment group, 11 (52%) had a clinically meaningful score improvement, while only one of the ten (10%) subjects in the control group had a clinically meaningful score improvement. Using the first treated eye only, 15/21 (71%) had a clinically meaningful score improvement, while no comparable score improvement was observed in controls. Other secondary clinical outcomes were also examined. Analysis of white light full-field light sensitivity threshold testing showed statistically significant improvement at 1 year in the LUXTURNA treatment group compared to the control group. The change in visual acuity was not significantly different between the LUXTURNA and control groups. (Tier 5)
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Periodic ophthalmic evaluation and assessment of the presence of amblyopia, glaucoma, or cataract should be performed. Generally Goldmann visual field perimetry (GVF) or full-field static perimetry and a full ophthalmoscopic examination with dilation are performed on an annual basis, with more frequent follow up for active complications such as cystoid macular edema. (Tier 4)
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Circumstances to Avoid
Vitamin E may adversely affect the course of disease and so high-dose supplements should be avoided. (Tier 3)
Avoidance of smoking is recommended because it is thought to contribute to retinal damage in IRDs and is a risk factor for age-related macular degeneration. (Tier 4)
Repeated poking and pressing on the eyes should be discouraged. (Tier 4)
Because of the concern of acceleration of retinal degeneration from short wavelength light exposure in RP, use of UV-A and UV-B blocking sunglasses and avoidance of bright light is recommended. This recommendation is based only on animal model studies demonstrating impacts of light exposure. (Tier 3)
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3. What is the chance that this threat will materialize?
Mode of Inheritance
Autosomal Recessive
Biallelic RPE65-associated retinal dystrophy can be inherited in a homozygous or compound heterozygous fashion.
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Prevalence of Genetic Mutations
No population prevalence of RPE65 pathogenic variants has been reported.
Of the population of individuals with LCA, about 5-10% of these are accounted for by biallelic RPE65 pathogenic variants. (Tier 3)
Of the population of individuals with recessive RP, about 2-5% are accounted for by biallelic RPE65 pathogenic variants. (Tier 3)
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Relative Risk
(Include any high risk racial or ethnic subgroups)
About 50% of patients with RP (genotype not specified) develop cataracts requiring lens extraction. (Tier 4)
In a retrospective chart review study of a cohort of 70 patients with confirmed biallelic RPE65 mutation-associated inherited retinal disease, a total of 14 (20.0%) subjects had cataracts or other lens opacities/abnormalities in at least 1 eye; of those 14 subjects, 11 (78.5%) had bilateral lens abnormalities. The mean age of subjects at the time the first lens abnormality was approximately 26 years. (Tier 5)
The penetrance of RPE65 biallelic variants was reported in two families with a clinical phenotype of LCA. The families contained a combined total of 10 affected and 37 unaffected members, several of whom were genotyped. The 8 affected members that were sequenced had one of two homozygous pathogenic variants, whereas all evaluated unaffected family members were either heterozygous or wildtype, suggesting near 100% penetrance for the variants examined when inherited in a biallelic fashion. (Tier 5)
In a retrospective chart review study of a cohort of 70 patients with confirmed biallelic RPE65 mutation-associated inherited retinal disease, poor night vision was reported in 54.3% of patient charts, 88.6% reported photophobia, and 78.6% reported nystagmus. More than half of the cohort were legally blind by US standards by age 18 years and all individuals age 32 or greater were legally blind. (Tier 5)
Information on relative risk was not available.
The same homozygous pathogenic variant has been reported to result in both mild and severe phenotypes, suggesting variable expressivity. (Tier 4)
A retrospective chart review study failed to find any clear correlations between molecular diagnosis (pathogenic variant) and clinical diagnostic entity/phenotype (e.g., RP vs LCA). (Tier 5)
4. What is the Nature of the Intervention?
Nature of Intervention
LUXTURNA is administered subretinally by injection. Per the FDA package insert, the most common adverse reactions (incidence ≥ 5%) in the clinical trials for LUXTURNA included conjunctival hyperemia, cataract, increased intraocular pressure, retinal tear, dellen (thinning of the corneal stroma), and macular hole. Several other ocular adverse effects were also reported, including risk of endophthalmitis. Safety data was included on the basis of 41 patients (81 eyes).
5. Would the underlying risk or condition escape detection prior to harm in the settting of recommended care?
Chance to Escape Clinical Detection
Patients with RP present at older ages and the earliest signs of disease (e.g., night blindness) often are not the symptom that causes the patient to seek treatment. (Tier 3)
Although mid-peripheral vision loss occurs early in the RP phenotype, it is rarely recognized by the affected individual and is usually not a presenting symptom. Affected individuals may be misconstrued as "clumsy" before constriction of visual fields. (Tier 4)

Final Consensus Scores
Outcome / Intervention Pair
Nature of the
Progression of visual impairment / Evaluation by retinal specialist to determine when gene therapy is appropriate
To see the scoring key, please go to:
Description of sources of evidence:
Tier 1: Evidence from a systematic review, or a meta-analysis or clinical practice guideline clearly based on a systematic review.
Tier 2: Evidence from clinical practice guidelines or broad-based expert consensus with non-systematic evidence review.
Tier 3: Evidence from another source with non-systematic review of evidence with primary literature cited.
Tier 4: Evidence from another source with non-systematic review of evidence with no citations to primary data sources.
Tier 5: Evidence from a non-systematically identified source.
Reference List
1. Leber congenital amaurosis. Orphanet encyclopedia,
2. Retinitis pigmentosa. Orphanet encyclopedia,
3. Online Medelian Inheritance in Man, OMIM®. Johns Hopkins University, Baltimore, MD. Retinitis pigmentosa; rp. MIM: 268000: 2019 Mar 04. World Wide Web URL:
4. Online Medelian Inheritance in Man, OMIM®. Johns Hopkins University, Baltimore, MD. Leber congenital amaurosis 1; lca1. MIM: 204000: 2018 Feb 08. World Wide Web URL:
5. AT Fahim, SP Daiger, RG Weleber. Nonsyndromic retinitis pigmentosa overview. 2000 Aug 04 [Updated 2017 Jan 19]. In: MP Adam, HH Ardinger, RA Pagon, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2019. Available from:
6. N Kumaran, ME Pennesi, P Yang, KM Trzupek, C Schlechter, AT Moore, RG Weleber, M Michaelides. Leber congenital amaurosis / early-onset severe retinal dystrophy overview. 2018 Oct 04. In: MP Adam, HH Ardinger, RA Pagon, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2019. Available from:
7. Online Medelian Inheritance in Man, OMIM®. Johns Hopkins University, Baltimore, MD. Retinitis pigmentosa 20; rp20. MIM: 613794: 2016 May 24. World Wide Web URL:
8. Online Medelian Inheritance in Man, OMIM®. Johns Hopkins University, Baltimore, MD. Leber congenital amaurosis 2; lca2. MIM: 204100: 2016 Dec 08. World Wide Web URL:
9. Chung DC, Bertelsen M, Lorenz B, Pennesi ME, Leroy BP, Hamel CP, Pierce E, Sallum J, Larsen M, Stieger K, Preising M, Weleber R, Yang P, Place E, Liu E, Schaefer G, DiStefano-Pappas J, Elci OU, McCague S, Wellman JA, High KA, Reape KZ. The natural history of inherited retinal dystrophy due to biallelic mutations in the rpe65 gene. Am J Ophthalmol. (2019) 199:58-70.
10. Russell S, Bennett J, Wellman JA, Chung DC, Yu ZF, Tillman A, Wittes J, Pappas J, Elci O, McCague S, Cross D, Marshall KA, Walshire J, Kehoe TL, Reichert H, Davis M, Raffini L, George LA, Hudson FP, Dingfield L, Zhu X, Haller JA, Sohn EH, Mahajan VB, Pfeifer W, Weckmann M, Johnson C, Gewaily D, Drack A, Stone E, Wachtel K, Simonelli F, Leroy BP, Wright JF, High KA, Maguire AM. Efficacy and safety of voretigene neparvovec (aav2-hrpe65v2) in patients with rpe65-mediated inherited retinal dystrophy: a randomised, controlled, open-label, phase 3 trial. Lancet. (2017) 390(10097):849-860.
11. Luxturna (voretigene neparvovec-rzyl) [package insert]. Publisher: Spark Therapeutics, Inc. (2017) Accessed: 2018-12-18. Website:
12. Li Y, Wang H, Peng J, Gibbs RA, Lewis RA, Lupski JR, Mardon G, Chen R. Mutation survey of known lca genes and loci in the saudi arabian population. Invest Ophthalmol Vis Sci. (2009) 50(3):1336-43.
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