Research Article

Clinical Observation and Genotype-Phenotype Analysis of ABCA4- Related Hereditary Retinal Degeneration before Gene Therapy

Author(s): Xuan Xiao, Lin Ye, Changzheng Chen, Hongmei Zheng* and Jiajia Yuan*

Volume 22, Issue 4, 2022

Published on: 25 March, 2022

Page: [342 - 351] Pages: 10

DOI: 10.2174/1566523222666220216101539

open access plus


Background: Hereditary retinal degeneration (HRD) is an irreversible eye disease that results in blindness in severe cases. It is most commonly caused by variants in the ABCA4 gene. HRD presents a high degree of clinical and genetic heterogeneity. We determined genotypic and phenotypic correlations, in the natural course of clinical observation, of unrelated progenitors of HRD associated with ABCA4.

Objective: To analyze the relationship between the phenotypes and genotypes of ABCA4 variants.

Methods: A retrospective clinical study of five cases from the ophthalmology department of the People’s Hospital of Wuhan University from January 2019 to October 2020 was conducted. We tested for ABCA4 variants in the probands. We performed eye tests, including the best-corrected visual acuity, super-wide fundus photography and spontaneous fluorescence photography, optical coherence tomography, and electrophysiological examination.

Results: Disease-causing variants were identified in the ABCA4 genes of all patients. Among these, seven ABCA4 variants were novel. All patients were sporadic cases; only one patient had parents who were relatives, and the other four patients were offspring of unrelated parents. Two patients presented with Stargardt disease, mainly with macular lesions, two presented with retinitis pigmentosa (cone-rod type), and one presented with cone dystrophy. The visual acuity and visual field of the five patients showed varying degrees of deterioration and impairment.

Conclusion: The same ABCA4 mutation can lead to different clinical phenotypes, and there is variation in the degree of damage to vision, visual field, and electrophysiology among different clinical phenotypes. Clinicians must differentiate between and diagnose pathologies resulting from this mutation.

Keywords: ABCA4, stargardt disease, cone cell malnutrition, retinitis pigmentosa (cone type), cone-rod dystrophy, retinal degeneration.

Graphical Abstract
Nassisi M, Mohand-Saïd S, Andrieu C, et al. Prevalence of ABCA4 deep-intronic variants and related phenotype in an unsolved “One-Hit” cohort with Stargardt disease. Int J Mol Sci 2019; 20(20): 5053.
[] [PMID: 31614660]
Chen L, Lee W, de Carvalho JRL Jr, et al. Multi-platform imaging in ABCA4-associated disease. Sci Rep 2019; 9(1): 6436.
[] [PMID: 31015497]
Sbrollini A, Agostini V, Cavallini C, Burattini L, Knaflitz M. Postural data from Stargardt’s syndrome patients. Data Brief 2020; 30: 105452.
[] [PMID: 32280738]
Huang D, Thompson JA, Charng J, et al. Phenotype-genotype correlations in a pseudodominant Stargardt disease pedigree due to a novel ABCA4 deletion-insertion variant causing a splicing defect. Mol Genet Genomic Med 2020; 8(7): e1259.
[] [PMID: 32627976]
Bhayana A, Azad SV, Kumar V, Neupane S. Focal choroidal excavation in Stargardt’s dystrophy. BMJ Case Rep 2020; 13(8): e237584.
[] [PMID: 32843395]
Tsang SH, Sharma T. Stargardt disease. Adv Exp Med Biol 2018; 1085: 139-51.
[] [PMID: 30578500]
Sofi F, Sodi A, Franco F, et al. dietary profile of patients with stargardt’s disease and retinitis pigmentosa: Is there a role for a nutritional approach? BMC Ophthalmol 2016; 16(1): 13.
[] [PMID: 26801981]
Ozdek S, Onaran Z, Gürelik G, Bilgihan K, Acar C, Hasanreisoglu B. Stargardt’s disease and retinitis pigmentosa: Different phenotypic presentations in the same family. Eye (Lond) 2005; 19(11): 1222-5.
[] [PMID: 15889047]
Cremers FP, van de Pol DJ, van Driel M, et al. Autosomal recessive retinitis pigmentosa and cone-rod dystrophy caused by splice site mutations in the Stargardt’s disease gene ABCR. Hum Mol Genet 1998; 7(3): 355-62.
[] [PMID: 9466990]
Kohl S, Kitiratschky V, Papke M, Schaich S, Sauer A, Wissinger B. Genes and mutations in autosomal dominant cone and cone-rod dystrophy. Adv Exp Med Biol 2012; 723: 337-43.
[] [PMID: 22183351]
Toulis V, Cortés-González V, Castro-Miró M, et al. Increasing the genetic diagnosis yield in inherited retinal dystrophies: Assigning pathogenicity to novel non-canonical splice site variants. Genes (Basel) 2020; 11(4): 378.
[] [PMID: 32244552]
Ścieżyńska A, Soszyńska M, Komorowski M, et al. Molecular analysis of the ABCA4 gene mutations in patients with Stargardt disease using human hair follicles. Int J Mol Sci 2020; 21(10): 3430.
[] [PMID: 32413971]
Jauregui R, Cho A, Lee W, et al. Progressive choriocapillaris impairment in ABCA4 maculopathy is secondary to retinal pigment epithelium atrophy. Invest Ophthalmol Vis Sci 2020; 61(4): 13.
[] [PMID: 32298433]
Molday LL, Wahl D, Sarunic MV, Molday RS. Localization and functional characterization of the p.Asn965Ser (N965S) ABCA4 variant in mice reveal pathogenic mechanisms underlying Stargardt macular degeneration. Hum Mol Genet 2018; 27(2): 295-306.
[] [PMID: 29145636]
Weng J, Mata NL, Azarian SM, Tzekov RT, Birch DG, Travis GH. Insights into the function of Rim protein in photoreceptors and etiology of Stargardt’s disease from the phenotype in abcr knockout mice. Cell 1999; 98(1): 13-23.
[] [PMID: 10412977]
Azarian SM, Travis GH. The photoreceptor rim protein is an ABC transporter encoded by the gene for recessive Stargardt’s disease (ABCR). FEBS Lett 1997; 409(2): 247-52.
[] [PMID: 9202155]
Kjellström U. Reduced macular function in ABCA4 carriers. Mol Vis 2015; 21: 767-82.
[PMID: 26261413]
D’Angelo R, Donato L, Venza I, Scimone C, Aragona P, Sidoti A. Possible protective role of the ABCA4 gene c.1268A>G missense variant in Stargardt disease and syndromic retinitis pigmentosa in a Sicilian family: Preliminary data. Int J Mol Med 2017; 39(4): 1011-20.
[] [PMID: 28290600]
Sun D, Schur RM, Sears AE, et al. Non-viral gene therapy for stargardt disease with ECO/pRHO-ABCA4 self-assembled nanoparticles. Mol Ther 2020; 28(1): 293-303.
[] [PMID: 31611143]
Khan M, Cornelis SS, Pozo-Valero MD, et al. Resolving the dark matter of ABCA4 for 1054 Stargardt disease probands through integrated genomics and transcriptomics. Genet Med 2020; 22(7): 1235-46.
[] [PMID: 32307445]
Cremers FPM, Lee W, Collin RWJ, Allikmets R. Clinical spectrum, genetic complexity and therapeutic approaches for retinal disease caused by ABCA4 mutations. Prog Retin Eye Res 2020; 79: 100861.
[] [PMID: 32278709]
Strauss RW, Kong X, Ho A, et al. Progression of stargardt disease as determined by fundus autofluorescence over a 12-month period: Progstar report No. 11. JAMA Ophthalmol 2019; 137(10): 1134-45.
[] [PMID: 31369039]
Piccardi M, Fadda A, Martelli F, et al. Antioxidant saffron and central retinal function in ABCA4-related stargardt macular dystrophy. Nutrients 2019; 11(10): 2461.
[] [PMID: 31618812]
Mäkeläinen S, Gòdia M, Hellsand M, et al. An ABCA4 loss-of-function mutation causes a canine form of Stargardt disease. PLoS Genet 2019; 15(3): e1007873.
[] [PMID: 30889179]
Dyka FM, Molday LL, Chiodo VA, Molday RS, Hauswirth WW. Dual ABCA4-AAV vector treatment reduces pathogenic retinal A2E accumulation in a mouse model of autosomal recessive stargardt disease. Hum Gene Ther 2019; 30(11): 1361-70.
[] [PMID: 31418294]
Cicinelli MV, Battista M, Starace V, Battaglia Parodi M, Bandello F. Monitoring and management of the patient with stargardt disease. Clin Optom (Auckl) 2019; 11: 151-65.
[] [PMID: 31819694]
Trapani I. Dual AAV vectors for stargardt disease. Methods Mol Biol 2018; 1715: 153-75.
[] [PMID: 29188512]
Maugeri A, van Driel MA, van de Pol DJ, et al. The 2588G-->C mutation in the ABCR gene is a mild frequent founder mutation in the Western European population and allows the classification of ABCR mutations in patients with Stargardt disease. Am J Hum Genet 1999; 64(4): 1024-35.
[] [PMID: 10090887]
van Driel MA, Maugeri A, Klevering BJ, Hoyng CB, Cremers FP. ABCR unites what ophthalmologists divide(s). Ophthalmic Genet 1998; 19(3): 117-22.
[] [PMID: 9810566]
Shroyer NF, Lewis RA, Allikmets R, et al. The rod photoreceptor ATP-binding cassette transporter gene, ABCR, and retinal disease: From monogenic to multifactorial. Vision Res 1999; 39(15): 2537-44.
[] [PMID: 10396622]
Shroyer NF, Lewis RA, Lupski JR. Complex inheritance of ABCR mutations in Stargardt disease: Linkage disequilibrium, complex alleles, and pseudodominance. Hum Genet 2000; 106: 244-8.
[] [PMID: 10746567]
Riveiro-Alvarez R, Lopez-Martinez MA, Zernant J, et al. Outcome of ABCA4 disease-associated alleles in autosomal recessive retinal dystrophies: Retrospective analysis in 420 Spanish families. Ophthalmology 2013; 120(11): 2332-7.
[] [PMID: 23755871]
Takahashi VKL, Takiuti JT, Jauregui R, Tsang SH. Gene therapy in inherited retinal degenerative diseases, a review. Ophthalmic Genet 2018; 39(5): 560-8.
[] [PMID: 30040511]
Moody KJ, Tinklepaugh J, Obert E, et al. Recombinant manganese peroxidase reduces A2E burden in age-related and Stargardt’s macular degeneration models. Rejuvenation Res 2018; 21(6): 560-71.
[] [PMID: 30516450]
Choi R, Gorusupudi A, Bernstein PS. Long-term follow-up of autosomal dominant Stargardt macular dystrophy (STGD3) subjects enrolled in a fish oil supplement interventional trial. Ophthalmic Genet 2018; 39(3): 307-13.
[] [PMID: 29377748]
Tanna P, Strauss RW, Fujinami K, Michaelides M. Stargardt disease: Clinical features, molecular genetics, animal models and therapeutic options. Br J Ophthalmol 2017; 101(1): 25-30.
[] [PMID: 27491360]
Lu LJ, Liu J, Adelman RA. Novel therapeutics for Stargardt disease. Graefes Arch Clin Exp Ophthalmol 2017; 255(6): 1057-62.
[] [PMID: 28285324]
Arai E, Maeda A, Murakami A. New treatments for Stargardt disease and related retinal degenerative diseases. Nippon Ganka Gakkai Zasshi 2017; 121(1): 7-16.
[PMID: 30079717]
Sciezynska A, Ozieblo D, Oldak M. Experimental studies on medical treatments of retinal dystrophies with a particular focus on ABCA4 retinopathies. Klin Oczna 2016; 118(1): 59-65.
[PMID: 29715411]
Ďuďáková Ľ, Kousal B, Kolářová H, Hlavatá L, Lišková P. Gene Therapy for inherited retinal and optic nerve disorders: Current knowledge. Cesk Slov Oftalmol 2016; 72(4): 128-36.
[PMID: 27860478]
Dalkara D, Goureau O, Marazova K, Sahel JA. Let there be Light: Gene and cell therapy for blindness. Hum Gene Ther 2016; 27(2): 134-47.
[] [PMID: 26751519]
Trapani I, Toriello E, de Simone S, et al. Improved dual AAV vectors with reduced expression of truncated proteins are safe and effective in the retina of a mouse model of Stargardt disease. Hum Mol Genet 2015; 24(23): 6811-25.
[] [PMID: 26420842]
Auricchio A, Trapani I, Allikmets R. Gene therapy of ABCA4-associated diseases. Cold Spring Harb Perspect Med 2015; 5(5): a017301.
[] [PMID: 25573774]
Wiley LA, Burnight ER, Mullins RF, Stone EM, Tucker BA. Stem cells as tools for studying the genetics of inherited retinal degenerations. Cold Spring Harb Perspect Med 2014; 5(5): a017160.
[] [PMID: 25502747]
Testa F, Melillo P, Di Iorio V, et al. Macular function and morphologic features in juvenile Stargardt disease: Longitudinal study. Ophthalmology 2014; 121(12): 2399-405.
[] [PMID: 25097154]
Han Z, Conley SM, Naash MI. Gene therapy for Stargardt disease associated with ABCA4 gene. Adv Exp Med Biol 2014; 801: 719-24.
[] [PMID: 24664763]
Colella P, Trapani I, Cesi G, et al. Efficient gene delivery to the cone-enriched pig retina by dual AAV vectors. Gene Ther 2014; 21(4): 450-6.
[] [PMID: 24572793]
Haji Abdollahi S, Hirose T. Stargardt-fundus flavimaculatus: Recent advancements and treatment. Semin Ophthalmol 2013; 28(5-6): 372-6.
[] [PMID: 24138045]
Wert KJ, Skeie JM, Davis RJ, Tsang SH, Mahajan VB. Subretinal injection of gene therapy vectors and stem cells in the perinatal mouse eye. J Vis Exp 2012; (69): 4286.
[] [PMID: 23207897]
Thumann G. Prospectives for gene therapy of retinal degenerations. Curr Genomics 2012; 13(5): 350-62.
[] [PMID: 23372421]
Kong J, Kim SR, Binley K, et al. Correction of the disease phenotype in the mouse model of Stargardt disease by lentiviral gene therapy. Gene Ther 2008; 15(19): 1311-20.
[] [PMID: 18463687]
Koenekoop RK, Lopez I, den Hollander AI, Allikmets R, Cremers FP. Genetic testing for retinal dystrophies and dysfunctions: Benefits, dilemmas and solutions. Clin Exp Ophthalmol 2007; 35(5): 473-85.
[] [PMID: 17651254]
Terrell D, Comander J. Current stem-cell approaches for the treatment of inherited retinal degenerations. Semin Ophthalmol 2019; 34(4): 287-92.
[] [PMID: 31188052]
Yue L, Weiland JD, Roska B, Humayun MS. Retinal stimulation strategies to restore vision: Fundamentals and systems. Prog Retin Eye Res 2016; 53: 21-47.
[] [PMID: 27238218]
Bosking WH, Beauchamp MS, Yoshor D. Electrical stimulation of visual cortex: Relevance for the development of visual cortical prosthetics. Annu Rev Vis Sci 2017; 3: 141-66.
[] [PMID: 28753382]
Trapani I, Auricchio A. Seeing the light after 25 years of retinal gene therapy. Trends Mol Med 2018; 24(8): 669-81.
[] [PMID: 29983335]
Amato A, Arrigo A, Aragona E, et al. Gene therapy in inherited retinal diseases: An update on current state of the art. Front Med (Lausanne) 2021; 8: 750586.
[] [PMID: 34722588]
McClements ME, Barnard AR, Singh MS, et al. An AAV dual vector strategy ameliorates the Stargardt phenotype in adult Abca4-/- mice. Hum Gene Ther 2019; 30(5): 590-600.
[] [PMID: 30381971]

© 2024 Bentham Science Publishers | Privacy Policy