Stargardt disease: clinical features, molecular genetics, animal models and therapeutic options

Stargardt disease (STGD1; MIM 248200) is the most prevalent inherited macular dystrophy and is associated with disease-causing sequence variants in the gene ABCA4 Significant advances have been made over the last 10 years in our understanding of both the clinical and molecular features of STGD1, and also the underlying pathophysiology, which has culminated in ongoing and planned human clinical trials of novel therapies. The aims of this review are to describe the detailed phenotypic and genotypic characteristics of the disease, conventional and novel imaging findings, current knowledge of animal models and pathogenesis, and the multiple avenues of intervention being explored

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

Visual Acuity Loss and Associated Risk Factors in the Retrospective Progression of Stargardt Disease Study (ProgStar Report No. 2)

PURPOSE: To examine the association between characteristics of Stargardt disease and visual acuity (VA), to estimate the longitudinal rate of VA loss, and to identify risk factors for VA loss. DESIGN: Retrospective, multicenter cohort study. PARTICIPANTS: A total of 176 patients (332 eyes) with molecularly and clinically confirmed Stargardt disease enrolled from the United States and Europe. METHODS: Standardized data report forms were used to collect retrospective data on participants' characteristics and best-corrected or presenting VA from medical charts. Linear models with generalized estimating equations were used to estimate the cross-sectional associations, and linear mixed effects models were used to estimate the longitudinal VA loss. MAIN OUTCOME MEASURES: Yearly change in VA. RESULTS: The median duration of observation was 3.6 years. At baseline, older age of symptom onset was associated with better VA, and a longer duration of symptoms was associated with worse VA. Longitudinal analysis estimated an average of 0.3 lines loss (P 30 years showed 0.4 lines slower change of VA per year (P = 0.01) compared with patients with onset age ≤14 years. CONCLUSIONS: Given the overall slow rate of VA loss, VA is unlikely to be a sensitive outcome measure for treatment trials of Stargardt disease. However, given the faster decline in younger patients and those with no or mild visual impairment, VA may be a potential outcome measure for trials targeting such subgroups of patients. These observations will need to be assessed in a prospective study bearing in mind the inherent limitations of retrospective datasets

Comparison of Short-Wavelength Reduced-Illuminance and Conventional Autofluorescence Imaging in Stargardt Macular Dystrophy

Purpose To compare grading results between short-wavelength reduced-illuminance and conventional autofluorescence imaging in Stargardt macular dystrophy. Design Reliability study. Methods setting: Moorfields Eye Hospital, London (United Kingdom). patients: Eighteen patients (18 eyes) with Stargardt macular dystrophy. observation procedures: A series of 3 fundus autofluorescence images using 3 different acquisition parameters on a custom-patched device were obtained: (1) 25% laser power and total sensitivity 87; (2) 25% laser power and freely adjusted sensitivity; and (3) 100% laser power and freely adjusted total sensitivity (conventional). The total area of 2 hypoautofluorescent lesion types (definitely decreased autofluorescence and poorly demarcated questionably decreased autofluorescence) was measured. main outcome measures: Agreement in grading between the 3 imaging methods was assessed by kappa coefficients (κ) and intraclass correlation coefficients. Results The mean ± standard deviation area for images acquired with 25% laser power and freely adjusted total sensitivity was 2.04 ± 1.87 mm2 for definitely decreased autofluorescence (n = 15) and 1.86 ± 2.14 mm2 for poorly demarcated questionably decreased autofluorescence (n = 12). The intraclass correlation coefficient (95% confidence interval) was 0.964 (0.929, 0.999) for definitely decreased autofluorescence and 0.268 (0.000, 0.730) for poorly demarcated questionably decreased autofluorescence. Conclusions Short-wavelength reduced-illuminance and conventional fundus autofluorescence imaging showed good concordance in assessing areas of definitely decreased autofluorescence. However, there was significantly higher variability between imaging modalities for assessing areas of poorly demarcated questionably decreased autofluorescence

Faster Sensitivity Loss around Dense Scotomas than for Overall Macular Sensitivity in Stargardt Disease: ProgStar Report No. 14

Purpose: Mean sensitivity (MS) derived from a standard test grid using microperimetry is a sensitive outcome measure in clinical trials investigating new treatments for degenerative retinal diseases. This study hypothesizes that the functional decline is faster at the edge of the dense scotoma (eMS) than by using the overall MS. Design: Multicenter, international, prospective cohort study: ProgStar Study. Methods: Stargardt disease type 1 patients (carrying at least 1 mutation in the ABCA4 gene) were followed over 12 months using microperimetry with a Humphrey 10-2 test grid. Customized software was developed to automatically define and selectively follow the test points directly adjacent to the dense scotoma points and to calculate their mean sensitivity (eMS). Results: Among 361 eyes (185 patients), the mean age was 32.9 ± 15.1 years old. At baseline, MS was 10.4 ± 5.2 dB (n = 361), and the eMS was 9.3 ± 3.3 dB (n = 335). The yearly progression rate of MS (1.5 ± 2.1 dB/year) was significantly lower (β = −1.33; P < .001) than that for eMS (2.9 ± 2.9 dB/year). There were no differences between progression rates using automated grading and those using manual grading (β = .09; P = .461). Conclusions: In Stargardt disease type 1, macular sensitivity declines significantly faster at the edge of the dense scotoma than in the overall test grid. An automated, time-efficient approach for extracting and grading eMS is possible and appears valid. Thus, eMS offers a valuable tool and sensitive outcome parameter with which to follow Stargardt patients in clinical trials, allowing clinical trial designs with shorter duration and/or smaller cohorts

Mindfulness-based interventions for people diagnosed with a current episode of an anxiety or depressive disorder: a meta-analysis of randomised controlled trials

Objective Mindfulness-based interventions (MBIs) can reduce risk of depressive relapse for people with a history of recurrent depression who are currently well. However, the cognitive, affective and motivational features of depression and anxiety might render MBIs ineffective for people experiencing current symptoms. This paper presents a meta-analysis of randomised controlled trials (RCTs) of MBIs where participants met diagnostic criteria for a current episode of an anxiety or depressive disorder. Method Post-intervention between-group Hedges g effect sizes were calculated using a random effects model. Moderator analyses of primary diagnosis, intervention type and control condition were conducted and publication bias was assessed. Results Twelve studies met inclusion criteria (n = 578). There were significant post-intervention between-group benefits of MBIs relative to control conditions on primary symptom severity (Hedges g = −0.59, 95% CI = −0.12 to −1.06). Effects were demonstrated for depressive symptom severity (Hedges g = −0.73, 95% CI = −0.09 to −1.36), but not for anxiety symptom severity (Hedges g = −0.55, 95% CI = 0.09 to −1.18), for RCTs with an inactive control (Hedges g = −1.03, 95% CI = −0.40 to −1.66), but not where there was an active control (Hedges g = 0.03, 95% CI = 0.54 to −0.48) and effects were found for MBCT (Hedges g = −0.39, 95% CI = −0.15 to −0.63) but not for MBSR (Hedges g = −0.75, 95% CI = 0.31 to −1.81). Conclusions This is the first meta-analysis of RCTs of MBIs where all studies included only participants who were diagnosed with a current episode of a depressive or anxiety disorder. Effects of MBIs on primary symptom severity were found for people with a current depressive disorder and it is recommended that MBIs might be considered as an intervention for this population

Cross-Sectional and Longitudinal Assessment of Retinal Sensitivity in Patients With Childhood-Onset Stargardt Disease

PURPOSE: We assess cross-sectional and longitudinal microperimetry and full-field static perimetry-derived retinal sensitivity with conventional and volumetric indices of retinal function in childhood-onset Stargardt disease (STGD1). METHODS: Subjects with molecularly confirmed childhood-onset STGD1 underwent full-field static perimetry and/or microperimetry using custom designed grids. Mean sensitivity (MS) and total volume (V_{TOT}) were computed for each microperimetry test. MS, V_{ToT}, and central field volume (V₃₀) were computed for each full-field static perimetry test. Subjects under 18 years old at baseline were classified as children and subjects 18 years or older as adults. RESULTS: A total of 43 children (mean age at baseline, 13.0 years; range, 8–17) and 13 adults (mean age at baseline, 23.1 years; range, 18–32) were included in the analysis. For full-field static perimetry and microperimetry for both subgroups, intraclass correlation coefficient results for MS and volumetric indices were good to excellent, indicating strong test–retest reliability. Interocular symmetry in terms of baseline measurements and the annual rate of progression was observed. A greater rate of progression was observed in childhood. CONCLUSIONS: To our knowledge, this is the first prospective study of retinal sensitivity in a large cohort of molecularly confirmed subjects with childhood-onset STGD1 demonstrating that children with STGD1 can reliably undertake detailed functional testing. Moreover, using custom designed grids and subsequent topographic analysis, volumetric indices of retinal function provide a reliable measure of retinal sensitivity. TRANSLATIONAL RELEVANCE: This study highlights the use of microperimetry and full-field static perimetry, as well as volumetric indices of retinal function, in monitoring disease progression

A qualitative study of independent fast food vendors near secondary schools in disadvantaged Scottish neighbourhoods

Background: Preventing and reducing childhood and adolescent obesity is a growing priority in many countries. Recent UK data suggest that children in more deprived areas have higher rates of obesity and poorer diet quality than those in less deprived areas. As adolescents spend a large proportion of time in school, interventions to improve the food environment in and around schools are being considered. Nutrient standards for school meals are mandatory in the UK, but many secondary pupils purchase foods outside schools at break or lunchtime that may not meet these standards. Methods: Qualitative interviews were conducted with fast food shop managers to explore barriers to offering healthier menu options. Recruitment targeted independently-owned shops near secondary schools (pupils aged c.12-17) in low-income areas of three Scottish cities. Ten interviews were completed, recorded, and transcribed for analysis. An inductive qualitative approach was used to analyse the data in NVivo 10. Results: Five themes emerged from the data: pride in what is sold; individual autonomy and responsibility; customer demand; profit margin; and neighbourhood context. Interviewees consistently expressed pride in the foods they sold, most of which were homemade. They felt that healthy eating and general wellbeing are the responsibility of the individual and that offering what customers want to eat, not necessarily what they should eat, was the only way to stay in business. Most vendors felt they were struggling to maintain a profit, and that many aspects of the low-income neighbourhood context would make change difficult or impossible. Conclusions: Independent food shops in low-income areas face barriers to offering healthy food choices, and interventions and policies that target the food environment around schools should take the neighbourhood context into consideration

Cross-Sectional and Longitudinal Assessment of the Ellipsoid Zone in Childhood-Onset Stargardt Disease

Purpose: To evaluate the reliability of ellipsoid zone (EZ) loss width and area measurements from spectral-domain optical coherence tomography (SD-OCT) images and track disease progression in childhood-onset Stargardt disease (STGD1). Methods: Children with molecularly confirmed STGD1 (n = 46, mean age 12.4 years) underwent SD-OCT for the measurement of the transverse (width) loss of the EZ and en face analysis to quantify the area of EZ loss. All scans were analyzed twice by two graders to evaluate reliability. The annual rate of EZ width and area loss were calculated. Results: The intra- and intergrader reliability of transverse EZ loss and area of EZ loss measurements at baseline for both graders was 0.99. The mean annual rate of transverse EZ loss (±standard deviation) was 279.5 ± 259.9 μm/y. The mean rate of area of EZ loss (±standard deviation) was 1.20 ± 1.29 mm2/y. The percentage transverse EZ loss was 10.2 ± 9.9%/y, which was significantly lower than the area of EZ loss at 19.4 ± 16.3%/y. High degree of interocular symmetry was observed. Conclusions: This is a prospective study on the quantification of EZ loss in children with STGD1 and highlights the reliability of SD-OCT in measuring EZ loss. High intra- and intergrader reliability was observed, with good ability to detect changes over time. Translational Relevance: Measuring the area of EZ loss was more sensitive compared with transverse EZ width loss measurements and will be valuable for natural history studies and clinical trials requiring sensitive and reliable structural endpoints

Meditation-induced near-death experiences: a 3-year longitudinal study

Near-death experiences (NDEs) are life transformational events that are increasingly being subjected to empirical research. However, to date, no study has investigated the phenomenon of a meditation-induced near-death experience (MI-NDE) that is referred to in ancient Buddhist texts. Given that some advanced Buddhist meditators can induce NDEs at a pre-planned point in time, the MI-NDE may make NDEs more empirically accessible and thus advance understanding into the psychology of death-related processes. The present study recruited 12 advanced Buddhist meditators and compared the MI-NDE against two other meditation practices (i.e. that acted as control conditions) in the same participant group. Changes in the content and profundity of the MI-NDE were assessed longitudinally over a 3-year period. Findings demonstrated that compared to the control conditions, the MI-NDE prompted significantly greater pre-post increases in NDE profundity, mystical experiences and non-attachment. Furthermore, participants demonstrated significant increases in NDE profundity across the 3-year study period. Findings from an embedded qualitative analysis (using grounded theory) demonstrated that participants (i) were consciously aware of experiencing NDEs, (ii) retained volitional control over the content and duration of NDEs and (iii) elicited a rich array of non-worldly encounters and spiritual experiences. In addition to providing corroborating evidence in terms of the content of a “regular” (i.e. non-meditation-induced) NDE, novel NDE features identified in the present study indicate that there exist unexplored and/or poorly understood dimensions to NDEs. Furthermore, the study indicates that it would be feasible - including ethically feasible - for future research to recruit advanced meditators in order to assess real-time changes in neurological activity during NDEs