Prospective Cohort Study of Childhood-Onset Stargardt Disease: Fundus Autofluorescence Imaging, Progression, Comparison with Adulthood-Onset Disease, and Disease Symmetry

Purpose To determine the reliability and repeatability of quantitative evaluation of areas of decreased autofluorescence (DAF) from fundus autofluorescence (FAF) images and track disease progression in children with Stargardt disease (STGD1), and investigate clinical and genotype correlations, disease symmetry and intra-familial variability. Design Prospective Cohort Study. Methods Children and adults with molecularly confirmed STGD1 (n=90) underwent longitudinal FAF imaging with subsequent semi-automated measurement of the area of DAF and calculation of the annual rate of progression. The age of disease onset was recorded for all subjects, as well as the electroretinography (ERG) group at baseline (n=86). Patients were grouped for analysis based on the age at baseline and age of onset, into children (n=56), adults with childhood-onset STGD1 (n=15), and adults with adulthood-onset (n=19). Fifty FAF images were selected randomly and analysed by two observers to evaluate repeatability and reproducibility. Differences between groups, interocular symmetry, genotype-phenotype correlations and intrafamilial variability were also investigated both for baseline measurements as well as progression rates. Results Visual acuity, molecular genetics, ERG group, FAF metrics and their correlations. Results Mean age of onset ± SD was 9.6 ± 3.4 years for childhood-onset (n=71) and 28.3 ± 7.8 years for adulthood-onset STGD1 (n=19). The intra-observer and inter-observer reliability of DAF quantification was excellent (ICC; 0.995 and 0.987). DAF area was symmetric between eyes and the mean rate of progression (SD) was 0.69 (0.72), 0.78 (0.48) and 0.40 (0.36) mm2/year for children, adults with childhood-onset, and adults with adulthood-onset disease respectively. Patients belonging to a group 3 ERG phenotype (generalised cone and rod dysfunction) had a significantly greater progression rate. Limited intrafamilial variability was observed. Conclusions This is the first large prospective study of FAF in a cohort of molecularly confirmed children with STGD1. DAF area quantification was highly reliable and may thereby serve as a robust structural end-point. A high rate of progression was observed in childhood-onset disease, making this subtype of STGD1 ideally suited to be considered for prioritisation in clinical trials

GUCY2D-Associated Leber Congenital Amaurosis: A Retrospective Natural History Study in Preparation for Trials of Novel Therapies

Purpose To describe the natural history of Leber congenital Amaurosis (LCA) associated with GUCY2D variants (GUCY2D-LCA) in a cohort of children and adults, in preparation for trials of novel therapies. Design Retrospective case series. Participants Patients with GUCY2D-LCA at a single referral center. Methods Review of clinical notes, retinal imaging including fundus autofluorescence (FAF), and optical coherence tomography (OCT), electroretinography (ERG), and molecular genetic testing. Main Outcome Measures Demographic data, symptoms at presentation, visual acuity, evidence of progression, OCT and FAF findings, ERG assessment and molecular genetics. Results Twenty-one subjects with GUCY2D-LCA were included, with a mean follow up ± standard deviation (SD) of 10 ± 11.85 years. Marked reduction in visual acuity (VA) and nystagmus was documented in all patients within the first 3 years of life. Fifty-four percent (n=12) exhibited photophobia and 36% (n=8) had nyctalopia. VA was worse than hand motion in 71% of the patients (n=15). Longitudinal assessment of VA showed stability in all patients, except one patient who experienced deterioration over a follow-up of 44 years. Hyperopia was reported in 13 (71%) of the 17 subjects with available refraction data. Eighteen subjects had either normal fundus appearance (n=14) or a blonde fundus (n=3), while only 4 of the eldest subjects had mild RPE atrophy (mean, 49 years; range 40 - 54 years). OCT data were available for eleven subjects and four different grades of ellipsoid zone (EZ) integrity were identified: (i) continuous/intact EZ (n=6), (ii) focally disrupted EZ (n=2), (iii) focally disrupted with RPE changes (n=2), and (iv) diffuse EZ disruption with RPE changes (n=1). All examined subjects had stable OCT findings over the long follow-up period. Full-field ERGs showed evidence of a severe cone-rod dystrophy in 5 of 6 patients, and undetectable ERGs in one subject. Novel genotype-phenotype correlations are also reported. Conclusion GUCY2D-LCA is a severe early-onset retinal dystrophy associated with very poor VA from birth. Despite the severely affected photoreceptor function, the relatively preserved photoreceptor structure based on EZ integrity till late in the disease in the majority of subjects, suggests a wide therapeutic window for gene therapy trials

Detailed clinical characterisation, unique features and natural history of autosomal recessive RDH12-associated retinal degeneration

BACKGROUND: Defects in retinol dehydrogenase 12 (RDH12) account for 3.4%-10.5 % of Leber congenital amaurosis and early-onset severe retinal dystrophy (EOSRD) and are a potential target for gene therapy. Clinical trials in inherited retinal diseases have unique challenges, and natural history studies are critical to successful trial design. The purpose of this study was to characterise the natural history of RDH12-associated retinal degeneration. METHODS: A retrospective chart review was performed in individuals with retinal degeneration and two likely disease-causing variants in RDH12. RESULTS: 57 subjects were enrolled from nine countries. 33 subjects had clinical records available from childhood. The data revealed an EOSRD, with average age of onset of 4.1 years. Macular atrophy was a universal clinical finding in all subjects, as young as 2 years of age. Scotopic and photopic electroretinography (ERG) responses were markedly reduced in all subjects, and a non-recordable ERG was documented as young as 1 year of age. Assessment of visual acuity, visual field and optical coherence tomography revealed severe loss of function and structure in the majority of subjects after the age of 10 years. Widefield imaging in 23 subjects revealed a unique, variegated watercolour-like pattern of atrophy in 13 subjects and sparing of the peripapillary area in 18 subjects. CONCLUSIONS: This study includes the largest collection of phenotypic data from children with RDH12-associated EOSRD and provides a comprehensive description of the timeline of vision loss in this severe, early-onset condition. These findings will help identify patients with RDH12-associated retinal degeneration and will inform future design of therapeutic trials

GUCY2D-Associated Leber Congenital Amaurosis: A Retrospective Natural History Study in Preparation for Trials of Novel Therapies

Purpose: To describe the natural history of Leber congenital amaurosis (LCA) associated with GUCY2D variants (GUCY2D-LCA) in a cohort of children and adults, in preparation for trials of novel therapies. Design: Retrospective case series. Methods: PARTICIPANTS: Patients with GUCY2D-LCA at a single referral center. PROCEDURES: Review of clinical notes, retinal imaging including fundus autofluorescence (FAF) and optical coherence tomography (OCT), electroretinography (ERG), and molecular genetic testing. MAIN OUTCOME MEASURES: Demographic data, symptoms at presentation, visual acuity, evidence of progression, OCT and FAF findings, ERG assessment, and molecular genetics. Results: Twenty-one subjects with GUCY2D-LCA were included, with a mean follow-up ± standard deviation (SD) of 10 ± 11.85 years. Marked reduction in visual acuity (VA) and nystagmus was documented in all patients within the first 3 years of life. Fifty-seven percent (n = 12) exhibited photophobia and 38% (n = 8) had nyctalopia. VA was worse than hand motion in 71% of the patients (n = 15). Longitudinal assessment of VA showed stability in all patients, except 1 patient who experienced deterioration over a follow-up of 44 years. Hyperopia was reported in 13 of the 17 subjects (71%) with available refraction data. Eighteen subjects had either normal fundus appearance (n = 14) or a blond fundus (n = 3), while only 4 of the eldest subjects had mild retinal pigment epithelium (RPE) atrophy (mean, 49 years; range 40-54 years). OCT data were available for 11 subjects and 4 different grades of ellipsoid zone (EZ) integrity were identified: (1) continuous/intact EZ (n = 6), (2) focally disrupted EZ (n = 2), (3) focally disrupted with RPE changes (n = 2), and (4) diffuse EZ disruption with RPE changes (n = 1). All examined subjects had stable OCT findings over the long follow-up period. Full-field ERGs showed evidence of a severe cone-rod dystrophy in 5 of 6 patients and undetectable ERGs in 1 subject. Novel genotype-phenotype correlations are also reported. Conclusion: GUCY2D-LCA is a severe early-onset retinal dystrophy associated with very poor VA from birth. Despite the severely affected photoreceptor function, the relatively preserved photoreceptor structure based on EZ integrity until late in the disease in the majority of subjects suggests a wide therapeutic window for gene therapy trials. © 2019 The Author(s

Association of Preoperative Basal Inflammatory State, Measured by Plasma suPAR Levels, with Intraoperative Sublingual Microvascular Perfusion in Patients Undergoing Major Non-Cardiac Surgery

It remains unknown whether chronic systemic inflammation is associated with impaired microvascular perfusion during surgery. We evaluated the association between the preoperative basal inflammatory state, measured by plasma soluble urokinase-type plasminogen activator receptor (suPAR) levels, and intraoperative sublingual microcirculatory variables in patients undergoing major non-cardiac surgery. Plasma suPAR levels were determined in 100 non-cardiac surgery patients using the suPARnostic® quick triage lateral flow assay. We assessed sublingual microcirculation before surgical incision and every 30 min during surgery using Sidestream Darkfield (SDF+) imaging and determined the De Backer score, the Consensus Proportion of Perfused Vessels (Consensus PPV), and the Consensus PPV (small). Elevated suPAR levels were associated with lower intraoperative De Backer score, Consensus PPV, and Consensus PPV (small). For each ng mL−1 increase in suPAR, De Backer score, Consensus PPV, and Consensus PPV (small) decreased by 0.7 mm−1, 2.5%, and 2.8%, respectively, compared to baseline. In contrast, CRP was not significantly correlated with De Backer score (r = −0.034, p = 0.36), Consensus PPV (r = −0.014, p = 0.72) or Consensus PPV Small (r = −0.037, p = 0.32). Postoperative De Backer score did not change significantly from baseline (5.95 ± 3.21 vs. 5.89 ± 3.36, p = 0.404), while postoperative Consensus PPV (83.49 ± 11.5 vs. 81.15 ± 11.8, p < 0.001) and Consensus PPV (small) (80.87 ± 13.4 vs. 78.72 ± 13, p < 0.001) decreased significantly from baseline. In conclusion, elevated preoperative suPAR levels were associated with intraoperative impairment of sublingual microvascular perfusion in patients undergoing elective major non-cardiac surgery. © 2022 by the authors. Licensee MDPI, Basel, Switzerland