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 to investigate clinical and genotype correlations, disease symmetry, and intrafamilial variability.DESIGN: Prospective cohort study. METHODS: Children and adults with molecularly confirmed STGD1 (n [ 90) underwent longitudinal FAF imaging with subsequent semiautomated 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 adult-onset (n [ 19). Fifty FAF images were selected randomly and analyzed by 2 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. We measured visual acuity, molecular genetics, ERG group, FAF metrics, and their correlations.RESULTS: The mean age of onset ± SD was 9.6 ± 3.4 years for childhood-onset (n [ 71) and 28.3 ± 7.8 years for adult-onset STGD1 (n [ 19). The intra-and interob-Supplemental Material available at AJO.com.

The Wellcome Trust (099173/Z/12/Z), Moorfields Eye Hospital Special Trustees, Moorfields Eye Charity, Retina UK, Fight for Sight UK, and the Foundation Fighting Blindness (USA). Financial Disclosures: Michalis Georgiou and Michel Michaelides consult for MeiraGTx. The other authors have no financial disclosures. All authors attest that they meet the current ICMJE criteria for authorship. Zaina Bouzia and Michalis Georgiou contributed equally and should be considered equivalent authors.

BackgroundDefects 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.MethodsA retrospective chart review was performed in individuals with retinal degeneration and two likely disease-causing variants in RDH12.Results57 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.ConclusionsThis 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.