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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.
On being blind
Published in John Ravenscroft, The Routledge Handbook of Visual Impairment, 2019
My father and mother carried the gene, ABCA4, recessively, the most common gene that results in Stargardt’s disease. Thus, neither one was visually impaired. They spawned five offspring, three of whom are visually disabled. I am the oldest of the five and two of my sisters are also afflicted with Stargardt’s. I have a brother and a sister who are normally sighted. All of us have children and none of them are visually disabled.
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).
Peripheral pigmented lesions in ABCA4-associated retinopathy
Published in Ophthalmic Genetics, 2021
Haya H. Al-Ani, Leo Sheck, Andrea L. Vincent
The causal role of the ABCA4 gene in autosomal recessive Stargardt disease (arSTGD) is well established with a characteristic clinical presentation of juvenile-onset macular dystrophy with rapid central visual impairment, in addition to the characteristic phenotype of progressive bilateral atrophy of the foveal retinal pigment epithelium (RPE), and the accumulation of lipofuscin deposits manifesting as yellow, pisciform flecks in or around the macula or posterior pole (1,2). In addition to arSTGD, mutations in ABCA4 are associated with other recessively inherited retinal diseases (IRD) of wide phenotypic variance including cone-rod dystrophy (arCRD), and rod-cone dystrophy (arRCD) (3–6). Clinical heterogeneity is complicated by allelic heterogeneity in these conditions, with over 900 variants described in the literature (7).
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
Both rods and cones utilize the chromophore 11-cis retinal. Opsins bind to 11-cis retinal to form visual pigments including rhodopsin and cone opsin. Light striking rhodopsin in the outer rod segments leads to the conversion of 11-cis retinal to all-trans retinal, activating the opsin and initiating a signal transduction cascade. A cyclic guanosine monophosphate-gated cation channel is closed and the and the photoreceptor cell is hyperpolarized. When the Schiff base linking all-trans retinal and opsin is hydrolyzed, free all-trans retinal is released primarily to the cytoplasmic leaflet of the disc membrane where it can be enzymatically reduced. However, a small amount of all-trans retinal is released to the lumenal side of the disc membrane, where it escapes reduction. The role of ABCA4 is to prevent this escape of all-trans retinal from reduction. ABCA4 functions as an ATP-dependent transporter which flips all-trans retinal in the form of N-retinylidene phosphatidylethanolamine from the lumenal side of the disc membrane to the cytoplasmic side [8,9]. All-trans retinal on the cytoplasmic leaflet is reduced to all-trans retinol via a reaction catalyzed by all-trans retinol dehydrogenase. All-trans retinol is shuttled into the RPE, where esterification of all-trans retinol by lethicin retinol acyltransferase (LRAT) produces all-trans retinyl esters. These esters are converted to 11-cis retinol by retinal pigment epithelium-specific 65 kDa protein (RPE65). This 11-cis retinol is oxidized to 11-cis retinal, which is shuttled into the photoreceptor outer segments. Finally, 11-cis retinal combines with opsins, forming visual pigments once again.