The Natural History of Inherited Retinal Dystrophy Due to Biallelic Mutations in the RPE65 Gene

Chung, Daniel C.; Bertelsen, Mette; Lorenz, Birgit; Pennesi, Mark E.; Leroy, Bart P.; Hamel, Christian; Pierce, Eric A.; Sallum, Juliana Maria Ferraz; Larsen, Michael; Stieger, Knut; Preising, Markus N.; Weleber, Richard G.; Yang, Paul; Place, Emily; Liu, Emily; Schaefer, Grace; DiStefano-Pappas, Julie; Elci, Okan U.; McCague, Sarah; Wellman, Jennifer; High, Katherine A.; Reape, Kathleen Z.

doi:10.1016/j.ajo.2018.09.024

Cited by 85 publications

(130 citation statements)

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“…Baseline health state distribution CF counting fingers, HM hand motion, HS health state, LP light perception, NLP no light perception, VI visual impairment natural history of biallelic RPE65-mediated IRD (RPE65 NHx) informed the long-term natural history of the disease under standard of care[25]. All patients with confirmed RPE65 mutations, from seven international centres, were enrolled in this study and their charts were collected, following redaction of protected…”

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confidence: 99%

An Economic Evaluation of Voretigene Neparvovec for the Treatment of Biallelic RPE65-Mediated Inherited Retinal Dystrophies in the UK

et al. 2020

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Introduction: Voretigene neparvovec (VN) is a gene therapy and the first approved pharmacological treatment for biallelic RPE65-mediated inherited retinal dystrophies (IRD), a rare condition that starts in early life and causes vision to progressively deteriorate towards complete blindness. In a phase III trial, treatment with VN significantly improved functional vision and visual function, and in October 2019 the National Institute for Health and Care Excellence (NICE) Highly Specialised Technologies Enhanced Digital Features To view enhanced digital features for this article go to https://doi.org/10.6084/ m9.figshare.11637108.

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confidence: 99%

An Economic Evaluation of Voretigene Neparvovec for the Treatment of Biallelic RPE65-Mediated Inherited Retinal Dystrophies in the UK

et al. 2020

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“…Two studies have already reported these variants, but they did not confirm or discuss the pathogenicity of c.247T>C (p.Phe83Leu) or c.560G>A (p.Gly187Glu) [22,46]; moreover, these two reported cases are Brazilian and are included in this study (family B and E probands). Based on current knowledge of these two RPE65 variants, no strong evidence has been identified, as there are no previously reported mutations which, regardless of nucleotide change, result in p.Phe83Leu or p.Gly187Glu, and no functional studies showing that these variants cause deleterious effects.…”

Section: Variant Analysismentioning

confidence: 86%

“…Both variants in this study have already been associated with rare recessive retinal dystrophies, each of which was identified in only one homozygous patient [22,46]. Therefore, the criterion regarding the identification of evaluated variants in trans with known pathogenic mutations was not met (ACMG/AMP pathogenic moderate level of evidence).…”

Section: Variant Analysismentioning

confidence: 95%

“…These two variants were chosen for further analysis because among 513 Brazilian families analyzed with IRD history, 15 potentially disease-causing variants of RPE65 were found. Five of them were missenses and considered pathogenic in the literature: p.Leu22Pro [13][14][15][16][17][18], p.Arg91Pro [19], p.Arg91Gln [16,17,[20][21][22], p.Leu341Ser [22][23][24], and p.Gly528Val [20,25]. Only p.Phe83Leu and p.Gly187Glu were variants of uncertain significance.…”

Section: Subjectsmentioning

confidence: 99%

“…Two other moderate criteria that evaluate the position where the new missense mutation occurs were also not included: (i) outside of these two variants already reported [22,46], no other damaging missense variant in the amino acid residue Phe83 or Gly187 has been reported before and, (ii) the protein region where both variants occur is neither a mutational hot spot nor a well-established functional domain.…”

Section: Variant Analysismentioning

confidence: 99%

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Pathogenicity Reclassification of RPE65 Missense Variants Related to Leber Congenital Amaurosis and Early-Onset Retinal Dystrophy

Motta

Martin

Porto

et al. 2019

Genes

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A challenge in molecular diagnosis and genetic counseling is the interpretation of variants of uncertain significance. Proper pathogenicity classification of new variants is important for the conclusion of molecular diagnosis and the medical management of patient treatments. The purpose of this study was to reclassify two RPE65 missense variants, c.247T>C (p.Phe83Leu) and c.560G>A (p.Gly187Glu), found in Brazilian families. To achieve this aim, we reviewed the sequencing data of a 224-gene retinopathy panel from 556 patients (513 families) with inherited retinal dystrophies. Five patients with p.Phe83Leu and seven with p.Gly187Glu were selected and their families investigated. To comprehend the pathogenicity of these variants, we evaluated them based on the American College of Medical Genetics and Genomics and the Association for Molecular Pathology (ACMG/AMP) classification guidelines. Initially, these RPE65 variants met only three pathogenic criteria: (i) absence or low frequency in the population, (ii) several missense pathogenic RPE65 variants, and (iii) 15 out of 16 lines of computational evidence supporting them as damaging, which together allowed the variants to be classified as uncertain significance. Two other pieces of evidence were accepted after further analysis of these Brazilian families: (i) p.Phe83Leu and p.Gly187Glu segregate with childhood retinal dystrophy within families, and (ii) their prevalence in Leber congenital amaurosis (LCA)/early-onset retinal dystrophy (EORD) patients can be considered higher than in other inherited retinal dystrophy patients. Therefore, these variants can now be classified as likely pathogenic according to ACMG/AMP classification guidelines.

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Cost-effectiveness of Voretigene Neparvovec-rzyl vs Standard Care forRPE65-Mediated Inherited Retinal Disease

Johnson¹,

Buessing²,

O'Connell³

et al. 2019

JAMA Ophthalmol

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IMPORTANCE Voretigene neparvovec-rzyl, the first gene therapy approved by the US Food and Drug Administration, was approved for the treatment for RPE65-mediated inherited retinal disease (IRD) in December 2017. This gene therapy is associated with high up-front costs and high efficacy, although of unknown duration, and its cost-effectiveness has not been assessed with RPE65 IRD-specific, longitudinal, patient-observation-level data. OBJECTIVE To assess the incremental cost-effectiveness ratio (ICER) of voretigene neparvovec-rzyl compared with standard care for RPE65-mediated inherited retinal disease. DESIGN, SETTING, AND PARTICIPANTS In this economic analysis, a health state transition model based on visual acuity and field with a lifetime horizon was developed to estimate the cost-effectiveness of voretigene neparvovec-rzyl. The model was populated with data from a clinical trial of voretigene neparvovec-rzyl to evaluate treatment outcome and a natural history study of RPE65-mediated IRD to examine disease progression. Direct costs were derived from the literature. Indirect costs, including educational attainment, productivity, caregiver burden, and governmental programs, were estimated using published literature and data analysis of public national surveys. A health utility vignette study specific to RPE65-mediated IRD was used for health utility inputs. The cost-effectiveness study described in this article was conducted from September 15, 2017, to August 23, 2018. EXPOSURES Bilateral voretigene neparvovec-rzyl therapy or standard care. MAIN OUTCOMES AND MEASURES Incremental cost-effectiveness ratio. RESULTS The model population included 70 patients with RPE65-mediated IRD, with a mean age of 15 years; 42 of 70 patients (60%) were female. In the base case, voretigene neparvovec-rzyl compared with standard care was associated with lower total costs ($2.2 million vs $2.8 million) and higher quality-adjusted life-years (18.1 vs 8.6). Voretigene neparvovec-rzyl remains cost-effective if at least 8.8% of the long-term treatment effect continues after year 3 when including indirect costs and 43.3% when excluding indirect costs, assuming a cost threshold of $150 000 per quality-adjusted life-year. CONCLUSIONS AND RELEVANCE Results of this study suggest that voretigene neparvovec-rzyl is cost-effective compared with standard care when using a lifetime horizon, excluding indirect costs, and using a threshold of $150 000 per quality-adjusted life-year.

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The Natural History of Inherited Retinal Dystrophy Due to Biallelic Mutations in the RPE65 Gene

Cited by 85 publications

References 10 publications

An Economic Evaluation of Voretigene Neparvovec for the Treatment of Biallelic RPE65-Mediated Inherited Retinal Dystrophies in the UK

An Economic Evaluation of Voretigene Neparvovec for the Treatment of Biallelic RPE65-Mediated Inherited Retinal Dystrophies in the UK

Pathogenicity Reclassification of RPE65 Missense Variants Related to Leber Congenital Amaurosis and Early-Onset Retinal Dystrophy

Cost-effectiveness of Voretigene Neparvovec-rzyl vs Standard Care forRPE65-Mediated Inherited Retinal Disease

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