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Non-Organic Vision Loss
Published in Vivek Lal, A Clinical Approach to Neuro-Ophthalmic Disorders, 2023
Ashwini Kini, Mangayarkarasi Thandampallayam Ajjeya, Padmaja Sudhakar
Stargardt disease: It is the single most common inherited single gene retinal disease. It is characterized by macular degeneration that begins in childhood, adolescence or adulthood, resulting in progressive loss of vision that is uncorrectable with glasses. They may also have impaired color vision, delayed dark adaptation, loss of depth perception and peripheral vision that is less affected than central vision. Ophthalmology evaluation will show yellow flecks of lipofuscin deposits in the macula that could be missed on examination.
The eye
Published in Angus Clarke, Alex Murray, Julian Sampson, Harper's Practical Genetic Counselling, 2019
Many late-onset macular dystrophies follow an autosomal dominant pattern, as well as the early-onset best macular degeneration (for which the BEST1 gene on chromosome 11q is the principal locus), while the juvenile Stargardt form is autosomal recessive. Stargardt disease shows locus heterogeneity; one form is associated with mutations in the ABCA4 ion transport gene on chromosome 1. Another rare but treatable recessive type is gyrate atrophy associated with a metabolic defect in ornithine aminotransferase. Cone dystrophies are a further heterogeneous group, associated with deterioration in colour vision.
Multiphoton imaging of the retina
Published in Pablo Artal, Handbook of Visual Optics, 2017
Robin Sharma, Jennifer J. Hunter
Retinal diseases involving the visual cycle can impact the concentration and distribution of retinoids and lipofuscin in the photoreceptors and RPE. Manipulating the visual cycle in mice either with drugs or transgenic models has been shown to alter the amount and type of fluorophore. In a model of Leber congenital amaurosis (RPE65−/−), mice are unable to synthesize 11-cis-retinol. These mice showed enlarged retinosomes compared to wild-type mice, no change in fluorescence in response to flashes of visible light, and no lipofuscin fluorescence (Imanishi et al, 2004; Palczewska et al, 2014). A mouse model of Stargardt disease and AMD (Abca4−/−Rdh8−/−) presents insufficient clearance of all-trans-retinal and an excess accumulation of lipofuscin (Maeda et al., 2005). Days following exposure to bright light, two-photon fluorescence imaging showed enlargement of rod outer segments and overaccumulation of fluorescent granules in RPE (Maeda et al., 2005; Palczewska et al., 2014). Pretreatment with retinylamine, a retinoid cycle inhibitor, prevented this lipofuscin accumulation in RPE of these mice (Palczewska et al., 2014). Such investigations may accelerate the drug development cycle as retinoids have been suggested as a potential therapeutic target (Travis et al., 2007).
Circumventing the packaging limit of AAV-mediated gene replacement therapy for neurological disorders
Published in Expert Opinion on Biological Therapy, 2022
Lara Marrone, Paolo M. Marchi, Mimoun Azzouz
Stargardt disease (STGD1, MIM 248200) is a common form of hereditary recessive macular dystrophy caused by mutations in the ABCA4 gene, which encodes the retinal-specific ABCA4 protein involved in transporting retinoids from photoreceptors to the retinal pigment epithelium. Losing this protein leads to a progressive bilateral decline in central vision that begins in adolescence, accompanied by lipofuscin deposits around the macula. Because of the large size of the ABCA4 coding sequence (6.8 kb), dual AAV strategies have been explored to deliver the ABCA4 gene product for gene replacement therapy [100]. Subretinal administration of AAV2/8 using trans-splicing and hybrid vector strategies has shown efficient retinal pigment epithelium and photoreceptor transduction [29,30,101]. Intein vectors have also been used, particularly targeting mice, pigs and human retinal organoids. Although some of these studies have revealed amelioration of retinal phenotypes in STGD1 mouse models [29,64,102], the low transduction efficiencies as well as the aberrant production of truncated proteins from single AAV vectors have been two major limitations [103,104]. Including degradation sequences in the 5′-half-containing vector has successfully minimized the untoward generation of truncated proteins [30], achieving improved features that may prove beneficial for the clinical application of dual AAVs to target this disease.
An optometrist’s guide to the top candidate inherited retinal diseases for gene therapy
Published in Clinical and Experimental Optometry, 2021
Fleur O’Hare, Thomas L Edwards, Monica L Hu, Doron G Hickey, Alexis C Zhang, Jiang-Hui Wang, Zhengyang Liu, Lauren N Ayton
Stargardt disease is most often recessively inherited and associated with mutations in the ABCA4 gene. This gene encodes an ABC transporter protein that is involved in retinoid cycling thus deficiencies in ABCA4 lead to impaired phagocytosis and intracellular accumulation of toxins (i.e. lipofuscin) in the outer retina and photoreceptor degeneration.56 Autosomal recessive Stargardt disease represents the most common inherited macular dystrophy in children and young adults. Dominant cases are rare and are associated with a later adult onset and milder phenotype.57 Mutations in ABCA4 are the most prevailing cause of IRDs, so it has become a focus for gene therapy research. To facilitate proof of gene therapy efficacy, quality natural history data is required to demonstrate that a therapy can modify the natural course of the disease. Therefore, significant efforts have been invested in establishing multicentre natural history studies, such as the ProgStar study.58
Understanding the genetic pathology of Stargardt disease: a review of current findings and challenges
Published in Expert Opinion on Orphan Drugs, 2021
David A. Camp, Michael C. Gemayel, Thomas A. Ciulla
Identification of specific disease-causing genetic variations in ABCA4 has explained most cases of STGD1, but a portion of cases remain unsolved. Further investigation is warranted to identify disease-causing variations, particularly those that occur in regulatory regions or deep-intronic regions. Disease severity for many variants remains unknown. Characterizing gene mutations and combinations of gene mutations by disease severity will require large amounts of data and analysis and will add to our understanding of ABCA4-associated retinopathies. Improving correlation models between mutation combinations and phenotypes will facilitate counseling and therapeutic trials. Collecting data of patient of all ethnicities will allow us to potentially develop targeted therapies effective for more patients. There are no commercially available treatments for STGD1; broadening our understanding of the genetic pathology of Stargardt disease will shape future therapeutic developments.