Stargardt Disease/fundus Flavimaculatus Research Articles

Antioxidant Saffron and Central Retinal Function in ABCA4-Related Stargardt Macular Dystrophy.

Retinal oxidative damage, associated with an ATP-binding cassette, sub-family A, member 4, also known as ABCA4 gene mutation, has been implicated as a major underlying mechanism for Stargardt disease/fundus flavimaculatus (STG/FF). Recent findings indicate that saffron carotenoid constituents crocins and crocetin may counteract retinal oxidative damage, inflammation and protect retinal cells from apoptosis. This pilot study aimed to evaluate central retinal function following saffron supplementation in STG/FF patients carrying ABCA4 mutations. Methods: in a randomized, double-blind, placebo-controlled study (clinicaltrials.gov: NCT01278277), 31 patients with ABCA4-related STG/FF and a visual acuity >0.25 were randomly assigned to assume oral saffron (20 mg) or placebo over a six month period and then reverted to P or S for a further six month period. Full ophthalmic examinations, as well as central 18° focal electroretinogram (fERG) recordings, were performed at baseline and after six months of either saffron or placebo. The fERG fundamental harmonic component was isolated by Fourier analysis. Main outcome measures were fERG amplitude (in µV) and phase (in degrees). The secondary outcome measure was visual acuity. Results: supplement was well tolerated by all patients throughout follow-up. After saffron, fERG amplitude was unchanged; after placebo, amplitude tended to decrease from baseline (mean change: −0.18 log µV, p < 0.05). Reverting the treatments, amplitude did not change significantly. fERG phase and visual acuity were unchanged throughout follow-up. Conclusions: short-term saffron supplementation was well tolerated and had no detrimental effects on the electroretinographic responses of the central retina and visual acuity. The current findings warrant further long-term clinical trials to assess the efficacy of saffron supplementation in slowing down the progression of central retinal dysfunction in ABCA4-related STG/FF.

Insights into autofluorescence patterns in Stargardt macular dystrophy using ultra-wide-field imaging.

To characterize autofluorescence (AF) patterns occurring in Stargardt macular dystrophy (STGD1) using ultra-wide-field (UWF) imaging. This paper is a cross-sectional observational study of 22 eyes of 11 patients (mean age 23.44years) with Stargardt disease-fundus flavimaculatus who presented with decrease of vision at a tertiary eye care center. UWF short-wave AF images were obtained from all the patients using an Optos TX200 instrument. The main outcome measures were to assess patterns of AF changes seen on UWF AF imaging. All eyes showed a central area of hypoautofluorescence at the macula along with retinal flecks extending centrifugally as well as to the nasal side of the optic disc. Peripapillary sparing was seen in 100% of the eyes. Flecks were seen to be hypoautofluorescent in the center and hyperautofluorescent in the periphery in 77.8% eyes and were only hyperfluorescent in 27.2%. A background-increased fluorescence was visible in 100% of eyes, the outer boundary of which was marked by distribution of flecks in 81.9% eyes. A characteristic inferonasal vertical line was seen separating the nasal hypoautofluorescent area from the temporal hyperautofluorescent area in all the eyes. UWF AF changes in STGD1 are not limited to the posterior pole and may extend more peripherally. UWF imaging is a useful tool for the assessment of patients with Stargardt macular dystrophy.

Multifocal Electroretinograms in Stargardt's Disease/Fundus Flavimaculatus

Purpose: To determine whether the characteristics of multifocal electroretinograms (mfERGs) were correlated with the ophthalmic appearance of the fundus in patients with Stargardt's disease/fundus flavimaculatus (SFF). Methods: Full-field ERGs, mfERGs, and general ophthalmic examinations were performed on 49 eyes with SFF. Results: The SFF patients were divided into four subtypes according to the classification of Noble and Carr [Arch Ophthalmol 1979;97:1281-1285]. The patients with type 1 SFF had severely reduced mfERGs in the macular area and reduced and delayed responses in the mid-periphery. The type 2 SFF patients had reduced but recordable mfERGs from the center of the macula with more depressed responses in the paramacular area, and the type 3 SFF patients had reduced and delayed mfERGs both in the macula and periphery. The patients with type 4 SFF had normal mfERGs in the macular area and delayed responses in all outer zones. Conclusions: These mfERG findings indicate that each subtype of SFF has unique characteristics corresponding to the abnormal retinal functions.

Subretinal deposits, paramacular atrophy and pigmentary retinopathy in mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes.

To report a case of subretinal deposits, paramacular atrophy, and pigmentary retinopathy associated with mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes. Retrospective review of medical records. A 45-year-old white woman presented with progressive deterioration of vision and dark adaptation over several years. She had a background of an undiagnosed neurodegenerative disorder, including sensorineural hearing loss, cognitive disturbance, and peripheral neuropathy. On examination, subretinal deposits were visible along the superotemporal arcades. A diagnosis of mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes was confirmed by genetic testing (A3243G gene mutation). Four years later, she had developed paramacular atrophy and pigmentary retinopathy. Mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes may be associated with paramacular atrophy and pigmentary retinopathy. Autofluorescent changes may precede these signs and can help distinguish this condition from Stargardt disease-fundus flavimaculatus. As far as we are aware, this is the first report of fundus autofluorescence imaging and optical coherence tomography in mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes-associated retinopathy. Subretinal deposit may be an early sign.

ELECTRORETINOGRAPHIC FINDINGS IN PATIENTS WITH STARGARDT DISEASE AND FUNDUS FLAVIMACULATUS

To characterize the clinical and electroretinogram (ERG) features of our cohort of patients with Stargardt disease (STGD) exhibiting coding sequence variations in the ABCA4 gene. Review of 76 patients with the clinical diagnosis of Stargardt disease/fundus flavimaculatus (STGD/FF) from the University of Iowa Department of Ophthalmology and Visual Sciences (41 patients) and the Casey Eye Institute (35 patients). Clinical examination, Goldmann perimetry, and electroretinography were performed on all 76 patients. Patients were divided into three groups on the basis of their funduscopic and electroretinographic features: (1) a normal ERG by the standards of the laboratory; (2) minimal rod or cone abnormalities; (3) severe ERG dysfunction. The latter category was further subdivided on the basis of a cone-dominated loss of function (C > R or "cone-rod dystrophy") or diffuse depression of rods and cones (C = R). Mutational analysis of the coding sequence of the ABCA4 gene was performed by single strand conformation polymorphism analysis followed by automated DNA sequencing. Each electroretinographic group was analyzed for the presence of disease causing changes using exact tests of binomial proportions corrected for multiple comparisons by Bonferroni method. Quantitative polymerase chain reaction (QPCR) was performed on patients who were homozygous for disease causing changes in the ABCA4 gene to rule out the possibility of deletions. Overall, 56 of 76 patients (and 77 of 152 alleles) exhibited coding sequence variations that were compatible with high-penetrance disease-causing mutations. The most common of these were His423Arg (9), frameshift mutations (7), Ala1038Val (7), and Pro1380Leu (6). Although no patients with His423Arg presented with normal ERGs, no significant correlation was observed between specific sequence variations and the electroretinographic characteristics or fundus appearance. However, a significantly greater fraction of patients with normal ERG studies failed to exhibit detectable disease-causing coding sequence variations in the ABCA4 gene identified on either allele (P = 0.0006). STGD/FF patients in our cohort exhibit a wide range of electroretinographic abnormalities, some of which are more prevalent than previously suspected. No direct correlation between clinical appearance, electrophysiologic characteristics and specific ABCA4 alleles could be identified, although a significantly lower number of our cohort with a normal ERG exhibited detectable coding sequence variations in the ABCA4 gene. However, four patients with ERG dysfunction were homozygous for a His423Arg change proven by QPCR not to be an artifact of a deletion. The presence of electrophysiologic dysfunction is not uncommon in our cohort of patients with STGD. Thus, the ERG provides clinically important information of retinal function for STGD/FF and, as such, is still indicated as part of the evaluation of these patients.

Diagnosis and classification of macular degenerations: an approach based on retinal function testing.

The results from literature concerning some aspects of retinal function in macular degenerations (MDs) were reviewed in order to evaluate whether (a) specific patterns of retinal dysfunction may be linked to different clinical phenotypes, and (b) distinct functional profiles may help in orienting molecular diagnosis of diseases. Examined clinical phenotypes included: Stargardt disease/fundus flavimaculatus (St/FF), age-related maculopathy (ARM) and macular degeneration (AMD), pattern dystrophies (PD), Best vitelliform dystrophy (BVD), Sorsby's fundus dystrophy (SFD), autosomal cone-rod dystrophies (CRD). The following functional tests were evaluated: (1) electroretinogram (ERG) (scotopic and photopic according to ISCEV standards, rod and cone photoresponses, rod and cone b-wave intensity-response function, focal ERGs); (2) dark adaptometry (pre-bleach sensitivity and post-bleach recovery kinetics); (3) fundus reflectometry (pigment density and regeneration kinetics). Specific patterns of retinal dysfunction were identified for St/FF, ARM/AMD, SFD and BVD, whereas partially overlapping profiles were found for PD and CRD. Specific functional patterns were associated with different peripherin/RDS gene mutations, as well as with CRX mutations. Combined analysis of different retinal function tests may help to identify different phenotypes of MD, and to orient molecular diagnosis for selected genotypes.