Neuropathy target esterase activity defines phenotypes among PNPLA6 disorders.

Biallelic pathogenic variants in the PNPLA6 gene cause a broad spectrum of disorders leading to gait disturbance, visual impairment, anterior hypopituitarism and hair anomalies. PNPLA6 encodes neuropathy target esterase (NTE), yet the role of NTE dysfunction on affected tissues in the large spectrum of associated disease remains unclear. We present a systematic evidence-based review of a novel cohort of 23 new patients along with 95 reported individuals with PNPLA6 variants that implicate missense variants as a driver of disease pathogenesis. Measuring esterase activity of 46 disease-associated and 20 common variants observed across PNPLA6-associated clinical diagnoses unambiguously reclassified 36 variants as pathogenic and 10 variants as likely pathogenic, establishing a robust functional assay for classifying PNPLA6 variants of unknown significance. Estimating the overall NTE activity of affected individuals revealed a striking inverse relationship between NTE activity and the presence of retinopathy and endocrinopathy. This phenomenon was recaptured in vivo in an allelic mouse series, where a similar NTE threshold for retinopathy exists. Thus, PNPLA6 disorders, previously considered allelic, are a continuous spectrum of pleiotropic phenotypes defined by an NTE genotype:activity:phenotype relationship. This relationship, and the generation of a preclinical animal model, pave the way for therapeutic trials, using NTE as a biomarker.

Carbonic anhydrase inhibitors limit complications in X-linked retinoschisis.

Purpose: Carbonic anhydrase inhibitors (CAIs) reduce macular schisis in patients with X-linked retinoschisis (XLRS). The purpose of this study was to determine if CAIs reduce the incidence of complications from XLRS, including macular atrophy, retinal tears, and retinal detachment (RD), the most common causes of vision loss in patients with XLRS. Methods: For this retrospective interventional case series, a chart review of patients examined at Cincinnati Children's Hospital Medical Center [CCHMC] and Cincinnati Eye Institute [CEI] between 1/1/2015 and 1/16/2023 was performed. Male patients were included based on genetically-confirmed RS1 or typical clinical presentation with known family history of XLRS with at least two follow-up visits. Results: Twenty-eight patients (56 eyes) with XLRS were included. There were 10 RS1 variants among the 21 genotyped patients. Median age at clinical diagnosis was 10.4 years old (range: 0.4-55.7 years) with median follow-up time of 4.7 years (range: 0.2-38.3 years). Median presenting Snellen visual acuity was 20/60 (logMAR 0.48, range: 0.18-3). In 26 eyes of 15 patients treated with CAIs, median CST pre-treatment was 416 microns (range: 198-701 microns), and median percentage decrease in CST on treatment was 21.8% (range: 0-74.5%) from highest pre-treatment CST. Reduction in CST with CAI use was statistically significant (p = 0.02), but not logMAR VA (p = 0.64). There was no significant difference in CST between patients treated with topical vs. oral CAI (p = 0.95) or between patients with partial or complete CAI adherence (p = 0.60). Ten eyes of seven patients had an RD requiring surgical intervention. No treated eyes developed new macular atrophy, peripheral retinoschisis, retinal tears, or RD; two eyes on topical CAIs had spontaneous resolution of bullous peripheral retinoschisis. Conclusion: During the follow-up period, patients taking CAIs reduced macular schisis and did not experience new complications of macular atrophy, retinal tears, or RD. This is a relatively large cohort with long-term follow-up periods for patients with XLRS. Reduced macular schisis may not require perfect adherence with CAIs. A large, prospective, randomized, controlled clinical trial is needed to determine the potential of CAIs to improve visual function, reduce retinoschisis, and prevent RD.

Panuveitis and optic neuropathy following SARS-COV-2 in the absence of multisystem inflammatory syndrome in a child.

Purpose: To describe the presentation of a healthy 8-year-old female referred to a pediatric ophthalmology clinic with blurred vision and concern for bilateral uveitis. Observations: The patient was diagnosed with COVID-19 two weeks prior to the onset of ocular symptoms. An examination revealed bilateral pan-uveitis and patient underwent an extensive work-up for an underlying cause that was unremarkable. Two years following the initial presentation, she has not had any evidence of recurrence. Conclusions and Importance: This case highlights the potential for COVID-19 to be temporally associated with ocular inflammation and underscores the importance of recognizing and investigating such manifestations in pediatric patients. The mechanism by which COVID-19 may lead to an immune response that affects the eyes is not fully understood, but it is believed to be related to an overactive immune response triggered by the virus. Further studies are needed to better understand the potential relationship between COVID-19 and ocular manifestations in pediatric patients.

Neuropathy target esterase activity predicts retinopathy among PNPLA6 disorders.

Biallelic pathogenic variants in the PNPLA6 gene cause a broad spectrum of disorders leading to gait disturbance, visual impairment, anterior hypopituitarism, and hair anomalies. PNPLA6 encodes Neuropathy target esterase (NTE), yet the role of NTE dysfunction on affected tissues in the large spectrum of associated disease remains unclear. We present a clinical meta-analysis of a novel cohort of 23 new patients along with 95 reported individuals with PNPLA6 variants that implicate missense variants as a driver of disease pathogenesis. Measuring esterase activity of 46 disease-associated and 20 common variants observed across PNPLA6 -associated clinical diagnoses unambiguously reclassified 10 variants as likely pathogenic and 36 variants as pathogenic, establishing a robust functional assay for classifying PNPLA6 variants of unknown significance. Estimating the overall NTE activity of affected individuals revealed a striking inverse relationship between NTE activity and the presence of retinopathy and endocrinopathy. This phenomenon was recaptured in vivo in an allelic mouse series, where a similar NTE threshold for retinopathy exists. Thus, PNPLA6 disorders, previously considered allelic, are a continuous spectrum of pleiotropic phenotypes defined by an NTE genotype:activity:phenotype relationship. This relationship and the generation of a preclinical animal model pave the way for therapeutic trials, using NTE as a biomarker.

Prevalence of cerebrotendinous xanthomatosis among patients diagnosed with early-onset idiopathic bilateral cataracts: final analysis.

Cerebrotendinous xanthomatosis (CTX) is a rare, autosomal recessive bile acid synthesis disorder caused by pathologic variants in CYP27A1, a gene involved in bile acid synthesis. Impaired function in this gene leads to accumulation of plasma cholestanol (PC) in various tissues, often in early childhood, resulting in such clinical signs as infantile diarrhea, early-onset bilateral cataracts, and neurological deterioration. The current study aimed to identify cases of CTX in a population of patients with a greater CTX prevalence than the general population, to facilitate early diagnosis. Patients diagnosed with early-onset, apparently idiopathic, bilateral cataracts between the ages of 2 and 21 years were enrolled. Genetic testing of patients with elevated PC and urinary bile alcohol (UBA) levels was used to confirm CTX diagnosis and determine CTX prevalence. Of 426 patients who completed the study, 26 met genetic testing criteria (PC ≥ 0.4 mg/dL and positive UBA test), and 4 were confirmed to have CTX. Prevalence was found to be 0.9% in enrolled patients, and 15.4% in patients who met the criteria for genetic testing.

Dual phenotype: co-occurring Leber congenital amaurosis and familial exudative vitreoretinopathy: a case report.

PURPOSE: To report the concurrent presentation and management of IQCB1-associated Leber Congenital Amaurosis and NDP-associated Familial Exudative Vitreoretinopathy (FEVR). MATERIALS AND METHODS: A 6-month-old Caucasian infant presented with poor visual response, high hypermetropia, and infantile-nystagmus with a provisional diagnosis of Leber Congenital Amaurosis based on clinical findings. Genetic counseling and testing were performed with a 285 gene retinal dystrophy panel (Blueprint Genetics). Clinical characteristics, presentation, ancillary testing results, and management are described. RESULTS: Two previously reported heterozygous pathogenic variants in ICQB1 were identified (c.1518_1519del (p.His506Glnfs*13) and c.1381C>T, p.Arg461*) segregating in trans. In addition, a variation of uncertain significance (VUS) was found in NDP (c.280C>T; p.His94Tyr). Fluorescein angiography was performed demonstrating peripheral avascularity and retinal telangiectasia without frank neovascularization. Peripheral ablative laser was applied to the avascular zone. CONCLUSIONS: The NDP VUS likely represents a pathogenic variant given the FEVR phenotype in addition to retinal degeneration, creating a rare dual phenotype. The combination of low oxygen demand from the IQCB1-associated retinal degeneration and NDP variant may have led to a more attenuated FEVR presentation with uncertain prognosis. A molecular diagnosis informed ocular and renal surveillance, as well as the recurrence risk for future offspring.

Long-Term Anatomic and Visual Outcomes of Planned Preterm Delivery and Treatment of Norrie Disease.

We previously reported that planned preterm delivery at 34 weeks gestational age provided an opportunity to treat Norrie disease in the vasoproliferative phase, prevented infantile retinal detachment, and preserved functional vision without further treatment after infancy. Although retinal vascularization did not proceed postnatally, after 8 years of follow-up, the retinas remained attached, and rudimentary foveal development was observed by optical coherence tomography. Best corrected visual acuity gradually improved to 20/80 with both eyes, and visual fields and real-world visual performance were remarkably functional. Global development progressed appropriately, and no long-term sequelae of premature delivery were observed. [Ophthalmic Surg Lasers Imaging Retina 2022;53:464-467.].

Alternative Biologic Therapy in Children Failing Conventional TNFα Inhibitors for Refractory, Noninfectious, Chronic Anterior Uveitis.

PURPOSE: A significant number of children with noninfectious, chronic anterior uveitis (CAU) fail to respond to conventional therapy; however, successful alternative biologic treatments (ABT) have not been well described. This study aims to review the clinical and treatment characteristics of children with CAU who require ABT. DESIGN: Retrospective, nonrandomized clinical study. METHODS: Setting: Tertiary center. STUDY POPULATION: Children with noninfectious CAU. OBSERVATION PROCEDURES: Clinical characteristics, uveitis course, complications, and treatment were compared among patients treated with methotrexate (MTX) monotherapy, conventional TNFα inhibitors (cTNFi), and ABT for >3 months. MAIN OUTCOME MEASURE: Success of ABT (abatacept, tocilizumab, and/or golimumab) in children failing conventional treatment. RESULTS: Of the 52 children with CAU, 75% had juvenile idiopathic arthritis. CAU was controlled in 15 children receiving MTX monotherapy, 28 receiving cTNFi, and 9 receiving ABT (n = 1, abatacept; n = 3, tocilizumab; n = 5, golimumab). Patients in the ABT group had a greater number of total ocular complications per person before ABT than those in the control groups (3.4 vs 0.7 [MTX], P < .001, and 1.5 [cTNFi], P < .001, respectively). In all 9 children on ABT, treatment led to control of CAU and topical glucocorticoids tapered to ≤2 drops/d with no new ocular complications. CONCLUSIONS: In this study, alternative biologics (abatacept, golimumab, and tocilizumab) were useful for treating CAU in children who fail MTX and cTNFi therapy. Patients who were controlled on ABT had more disease activity, ocular complications, and anti-cTNFi neutralizing antibodies (before ABT) than those managed with conventional therapy. Larger studies are required to confirm these findings.

The risk of uveitis due to prostaglandin analogs in pediatric glaucoma.

PURPOSE: To examine the incidence of uveitis in children prescribed prostaglandin analogs (PGAs) for glaucoma. METHODS: In this dual-center cohort study, the medical records of consecutive patients <18 years old treated with a PGA between January 1, 2012, and December 31, 2018, were reviewed retrospectively. Patients with all forms of glaucoma, including those with a prior history of uveitis, were included. Patients who had been on a PGA prior to their first recorded visit were excluded. Patient charts were reviewed for new or recurrent uveitis during the first year of PGA therapy. RESULTS: A total of 103 children (147 eyes) were included, with a total PGA exposure of 1,352 child-months. Ninety-eight children (142 eyes) tolerated the PGA without an episode of uveitis. Five patients with a documented prior history of uveitis experienced a unilateral episode of uveitis. A review of their medical records identified prescribed or unscheduled decrease in topical steroids or immunosuppressive medication as the most likely cause of uveitis recurrence. CONCLUSIONS: This study provides further evidence that PGAs are unlikely to induce uveitis in children being treated for glaucoma and suggests that this may also be true in those with a history of uveitis. We are unable to evaluate whether PGAs make recurrence more likely or the tapering of steroids more difficult.

Planned Preterm Delivery and Treatment of Severe Infantile FEVR With Osteoporosis-Pseudoglioma Syndrome.

Familial exudative vitreoretinopathy (FEVR) is a rare hereditary vitreoretinopathy resulting from mutations in the wnt signaling pathway leading to abnormalities in fetal retinal vasculogenesis, angiogenesis, and retinal vascular maintenance. Severe FEVR may result in congenital retinal detachment resembling Norrie disease. The authors report the first case of planned preterm delivery and treatment of a patient with severe FEVR from biallelic LRP5 mutations whose siblings had congenital tractional retinal detachments with light perception vision outcomes after conventional care. Early intervention allowed laser ablation of avascular retina and functional visual outcome despite a successfully repaired unilateral tractional retinal detachment. [Ophthalmic Surg Lasers Imaging Retina. 2022;53(4):228-232.].

Assessing the Validity and Reliability of the Effects of Youngsters' Eyesight on Quality of Life Questionnaire Among Children With Uveitis.

OBJECTIVE: The Effects of Youngsters' Eyesight on Quality of Life (EYE-Q) questionnaire measures vision-related functioning (VRF) and vision-related quality of life (VRQoL) in children with uveitis. Our aim was to revise the alpha version of the EYE-Q to refine VRF and VRQoL subscales and to assess the validity of the EYE-Q. METHODS: Children with juvenile idiopathic arthritis (JIA), JIA-associated uveitis, and other noninfectious uveitis were enrolled. Patients and parents completed the EYE-Q, Pediatric Quality of Life Inventory (overall quality of life), and Childhood Health Assessment Questionnaire (physical functioning). The development site completed the alpha version of the EYE-Q, and the composite sites completed the beta version. We compared item-subscale correlations, internal consistency, and construct and discriminant validity among the different versions. RESULTS: Of the 644 patients enrolled, 61.6% completed the alpha version, and 38.4% the beta version of the EYE-Q. Mean ± SD patient age was 11.1 ± 4.2 years, and 70% were female. Fewer White patients (73.5%) completed the alpha version compared to the beta version (86.2%; P < 0.001). With the exception of patient-reported VRF, both versions had similar item-subscale correlations. Version comparisons on scale internal consistencies indicated significant differences for parent- and patient-reported VRF, but each scale had a Cronbach's α of >0.80 beta. When data were combined, the EYE-Q showed significant differences between JIA-only and uveitis patients on all parent and patient scores, except for patient-reported VRF. CONCLUSION: The EYE-Q appears to be a valid measure of VRF and VRQoL in pediatric uveitis. Our results suggest it may be used as an outcome measure in multicenter pediatric uveitis studies.

Comprehensive Assessment of Quality of Life, Functioning, and Mental Health in Children With Juvenile Idiopathic Arthritis and Noninfectious Uveitis.

OBJECTIVE: Pediatric uveitis can lead to sight-threatening complications and can impact quality of life (QoL) and functioning. We aimed to examine health-related QoL, mental health, physical disability, vision-related functioning (VRF), and vision-related QoL in children with juvenile idiopathic arthritis (JIA), JIA-associated uveitis (JIA-U), and other noninfectious uveitis. We hypothesized that there will be differences based on the presence of eye disease. METHODS: A multicenter cross-sectional study was conducted at four sites. Patients with JIA, JIA-U, or noninfectious uveitis were enrolled. Patients and parents completed the Pediatric Quality of Life Inventory (PedsQL; health-related QoL), the Revised Childhood Anxiety and Depression Scale (RCADS; anxiety/depression), the Childhood Health Assessment Questionnaire (C-HAQ; physical disability), and the Effects of Youngsters' Eyesight on Quality of Life (EYE-Q) (VRF/vision-related QoL). Clinical characteristics and patient-reported outcome measures were compared by diagnosis. RESULTS: Of 549 patients, 332 had JIA, 124 had JIA-U, and 93 had other uveitis diagnoses. Children with JIA-U had worse EYE-Q scores compared to those with JIA only. In children with uveitis, those with anterior uveitis (JIA-U and uveitis only) had less ocular complications, better EYE-Q scores, and worse C-HAQ and PedsQL physical summary scores compared to those with nonanterior disease. In children with anterior uveitis, those with JIA-U had worse PedsQL physical summary and C-HAQ scores than anterior uveitis only. Further, EYE-Q scores were worse in children with bilateral uveitis and more visual impairment. There were no differences in RCADS scores among groups. CONCLUSION: We provide a comprehensive outcome assessment of children with JIA, JIA-U, and other uveitis diagnoses. Differences in QoL and function were noted based on underlying disease. Our results support the addition of a vision-specific measure to better understand the impact of uveitis.

S100 proteins, cytokines, and chemokines as tear biomarkers in children with juvenile idiopathic arthritis-associated uveitis.

PURPOSE: Biomarkers for juvenile idiopathic arthritis-associated uveitis (JIA-U) are needed. We aimed to measure inflammatory biomarkers in tears as a non-invasive method to identify biomarkers of uveitis activity. METHODS: Tears were collected from children with JIA-U (n=20) and pediatric controls (n=20) using Schirmer strips. S100A8, A9, A12, IL-18, IL-8, IP-10, MCP-1, RANTES, and sICAM-1 were measured by ELISA and Luminex assays. Levels of biomarkers were compared between children with JIA-U and controls, and active and inactive JIA-U. RESULTS: IL-8, sICAM-1, and S100A12 levels were similar between JIA-U and controls, but differed by activity. Active JIA-U had significantly increased S100A12 compared to inactive JIA-U (mean 27,722.5 pg/ML (SE 1.3) vs. 5,937.2 (1.3), p=0.002), IL-8 (73.5 [1.2] vs. 36.2 [1.2], p=0.009), and sICAM-1 (15,822.7 [1.2) vs. 8,778.0 [1.6], p=0.024). CONCLUSION: We detected inflammatory biomarkers non-invasively in tears of children with JIA-U. IL-8, sICAM-1, and S100A12 are potential biomarkers for uveitis activity.

Systemic and ocular manifestations of a patient with mosaic ARID1A-associated Coffin-Siris syndrome and review of select mosaic conditions with ophthalmic manifestations.

Mosaic genetic mutations may be somatic, germline, or "gonosomal" and have the potential to cause genetic syndromes, disorders, or malformations. Mutations can occur at any point in embryonic development and the timing determines the extent of distribution of the mutation throughout the body and different tissue types. The eye and visual pathway offer a unique opportunity to study somatic and gonosomal mosaic mutations as the eye consists of tissues derived from all three germ layers allowing disease pathology to be assessed with noninvasive imaging. In this review, we describe systemic and ocular manifestations in a child with mosaic Coffin-Siris syndrome. The patient presented with a significant medical history of accommodative esotropia and hyperopia, macrocephaly, polydactyly, global developmental delay, hypotonia, ureteropelvic junction (UPJ) obstruction, and brain MRI abnormalities. The ophthalmic findings in this patient were nonspecific, however, they are consistent with ocular manifestations reported in other patients with Coffin-Siris syndrome. We also review ophthalmic findings of select mosaic chromosomal and single-gene disorders. Ophthalmic assessment alongside clinical genetic testing may play an important role in diagnosis of genetic syndromes as well as understanding disease pathology, particularly when mosaicism plays a role.

Bilateral rhegmatogenous retinal detachments from giant retinal tears in an infant with abusive head trauma and Stickler syndrome.

PURPOSE: To present a rare presentation of abusive head trauma (AHT) in an infant with a hereditary vitreoretinopathy. OBSERVATIONS: A two-month-old infant female victim of AHT presented with bilateral rhegmatogenous retinal detachments from giant retinal tears. She had rib fractures, a subdural hematoma, and hyphemas bilaterally. Retinal hemorrhages were not observed. The left eye was repaired by vitrectomy with intermediate-term perfluorocarbon liquid tamponade. Genetic testing demonstrated a pathogenic COL2A1 mutation confirming Stickler syndrome. CONCLUSIONS AND IMPORTANCE: Ophthalmic complications of AHT classically manifest as retinal hemorrhages in multiple layers. Instead, bilateral RRDs from GRTs were observed in this infant with Stickler syndrome.

Chlamydia Conjunctivitis in 2 Prepubertal Children: An Uncommon Presentation of Child Sexual Abuse.

Sexually transmitted infection as the result of child sexual abuse in prepubertal children is uncommon. Chlamydia trachomatis conjunctivitis is an even less common entity in prepubertal children outside the newborn period. This report details the presentation of 2 children with conjunctivitis who were subsequently diagnosed as having C. trachomatis conjunctivitis. One child was also diagnosed as having rectal and pharyngeal C. trachomatis infection, and the other also had genital C. trachomatis infection. Even with multisite C. trachomatis infection as an indication of sexual abuse, neither child gave a detailed disclosure of abuse to account for their infections. The absence of a clear disclosure is not uncommon. Previous literature reports that a disclosure in these circumstances occurs in less than half of cases. In this report, we review the recommendations for diagnosis of C. trachomatis using nucleic acid amplification testing and culture as well as treatment. Specific clinical features should alert the clinician to C. trachomatis conjunctivitis and lead to timely diagnosis and protection of the child from further sexual abuse.

Effectiveness of long-term infliximab use and impact of treatment adherence on disease control in refractory, non-infectious pediatric uveitis.

BACKGROUND: Refractory non-infectious uveitis is a serious condition that leads to ocular complications and vision loss and requires effective systemic treatment to control disease. The effectiveness of long-term infliximab [IFX] in refractory non-infectious childhood uveitis and the impact of treatment adherence on disease control were evaluated. METHODS: Retrospective, single-center study between December 2002 and April 2016 of 27 children with refractory non-infectious uveitis [17 with juvenile idiopathic arthritis, JIA] treated with long-term IFX [9+ months]. Disease activity was assessed prior to and while on IFX using the Standardization of Uveitis Nomenclature [SUN]. Number of visits per year with active uveitis was analyzed by repeated measures logistic regression analysis from 2 years prior to IFX initiation or from onset of uveitis until most recent visit on IFX. Incomplete treatment adherence was assessed for each visit and defined as any deviance in corticosteroid use, prescribed infusion frequency, and/or follow-up examination frequency. RESULTS: Primary outcomes were sustained uveitic and systemic disease control prior to and during IFX treatment and the impact of incomplete adherence on uveitic disease control while on IFX. Secondary outcomes included corticosteroid and glaucoma medication requirement, ocular complications and need for surgical intervention. Mean age at IFX initiation was 10.4 ± 4.5 years; initial mean dose was 6.6 ± 2.2 mg/kg [and given at weeks 0, 2, 4 and q4 weeks thereafter for 93%]. Median duration on IFX was 35 [range 9-128] months. Prior to IFX, 14/27 patients had failed adalimumab ± methotrexate [MTX]; 21/27 failed MTX. IFX led to uveitis control in 89% and arthritis control in 76% (13/17). The odds ratio of having controlled disease after IFX was 4.1 (2.6, 6.4) compared to pre-treatment visits. Topical corticosteroids and glaucoma medications were statistically decreased (p = 0.007 right eye [OD], 0.003 left eye [OS] and p = 0.001 OD, p = 0.028 OS respectively). Incomplete adherence to treatment showed 10.3 times greater odds (7.1, 15.0) of having disease activity than full adherence. CONCLUSIONS: This study adds significantly to the IFX literature by documenting outstanding uveitis control with long-term IFX treatment in non-infectious pediatric uveitis patients. Higher dosage and shorter interval were utilized without adverse effects. Importantly, this is the first study, to our knowledge, to document the significant impact of treatment adherence on uveitis control.

Survey of practice patterns for the management of ophthalmic genetic disorders among AAPOS members: report by the AAPOS Genetic Eye Disease Task Force.

To better understand AAPOS member pediatric ophthalmologists' knowledge and needs regarding genetic eye disorders, the AAPOS Genetic Eye Disease Task Force developed a 16-question survey that was circulated to national and international AAPOS members. Responses to questions on practice patterns, baseline knowledge, and educational interests regarding patients with suspected ophthalmic genetic disorders were collected. A majority of respondents (93%) evaluate patients with suspected genetic disorders. Knowledge gaps were present in heritability of certain conditions, genetic testing strategies, and referral to clinical trials. Most respondents expressed interest in further education in these areas. A model for care is proposed as a first step in the education process.

Gene therapy for RPE65-related retinal disease.

Significant discoveries in the etiology and pathogenesis of inherited retinal diseases (IRDs) have been made in the last few decades. Of the large number genes that cause IRDs, bi-allelic mutations in RPE65 lead to Leber Congenital Amaurosis type 2 (LCA 2), and can also result in phenotypes described as severe early childhood onset retinal dystrophy (SECORD) and Retinitis pigmentosa 20 (RP20). Following the publication of the successful Phase-III clinical trials of gene augmentation surgery for RPE65-related IRDs with voretigene neparvovec, the FDA approved the commercial use of this pharmacologic agent in December 2017. In this perspective, ongoing and completed gene therapy trials for RPE65-related dystrophies are reviewed and challenges in patient selection, counseling and informed consent, as well as financial considerations of commercial treatment are discussed.