Visual Acuity and Age of Symptom Onset in a Large Chinese Cohort of Patients with Stargardt Disease

Research Article

J Ophthalmol & Vis Sci. 2021; 6(2): 1049.

Visual Acuity and Age of Symptom Onset in a Large Chinese Cohort of Patients with Stargardt Disease

Gao F-J1,2,3#, Wang D-D1,2,3#, Hu F-Y1,2,3, Xu P1,2,3, Chang Q1,2,3, Liu W1,2,3, Zhang S-H1,2,3, Huang Y1, Xu G-Z1,2,3* and Wu J-H1,2,3*

1Eye Institute, Eye and ENT Hospital, College of Medicine, Fudan University, Shanghai, China

2Shanghai Key Laboratory of Visual Impairment and Restoration, Science and Technology Commission of Shanghai Municipality, Shanghai, China

3Key Laboratory of Myopia (Fudan University), Chinese Academy of Medical Sciences, National Health Commission, China

#Contributed Equally to this Work

*Corresponding author: Ji-Hong Wu, Eye and ENT Hospital, Fudan University, Shanghai, 83 Fengyang Road, Shanghai, 200031, China

Ge-Zhi Xu, Eye and ENT Hospital, Fudan University, Shanghai, 83 Fengyang Road, Shanghai, 200031, China

Received: April 22, 2021; Accepted: May 20, 2021; Published: May 27, 2021

Abstract

Stargardt disease is the most common form of juvenile-onset inherited macular dystrophy, with high phenotypic heterogeneity. There are limited data documenting the characteristics of Best Corrected Visual Acuity (BCVA) and age of symptom onset of patients with Stargardt disease in Chinese population. In this study, 169 patients with clinical and genetic diagnosis of Stargardt disease were recruited. BCVA, age, age of symptom onset, disease duration time and genetic information were collected and analyzed. We found that the average BCVA was 1.16±0.61 logMAR, 63.6% of patients with severe visual impairment (≤1 logMAR); the mean age of symptom onset was 13.63±12.72 years (yrs) old, 61.36% of patients had an onset earlier than 12; BCVA level was associated with genotype and disease duration, but had no direct correlation with neither age of symptom onset nor age; severe genotype (≥2 severe variants, severe variants were defined as those predicted to introduce a premature truncating codon in the protein or to affect splicing) was also associated with earlier age of symptom onset. Our data will serve as a well-founded reference for genetic counseling and better management of these patients.

Keywords: Stargardt disease; ABCA4 gene; Chinese population; BCVA; Genotype; Age at symptom onset; Disease duration; Age

Abbreviations

BCVA: Best Corrected Visual Acuity Testing; SD-OCT: Spectral Domain Optical Coherence Tomography

Introduction

Stargardt disease is an autosomal recessive retinal dystrophy mainly caused by mutations in the ATP Binding Cassette Subfamily A Member 4 Gene (ABCA4), and a small proportion is caused by PROM1, PRPH2, ELOVL4 mutations [1-3]. It is the most common form of inherited macular dystrophy onset from birth and is characterized by bilateral degeneration of the central retina, and a beaten-bronze aspect of the retina seen during funduscopy with or without yellow-white flecks in the posterior pole [4,5]. The reported prevalence is 1 in 8000-10,000 individuals [6,7].

Stargardt disease has a highly heterogeneous phenotype, ranging from mild to extremely aggressive forms [7-10]. Some patients have disease onset from birth, while others develop disease after the age of 50 years [11,12]. Additionally, although some patients show a rapid loss of Visual Acuity (VA) of 0.066 logMAR per year, some maintain a relatively good VA for decades [13,14]. The VA can also vary in patients with Stargardt disease, ranging from 20/20 to 20/400 or worse [4,15].

Several studies have reported changes in VA loss in Stargardt disease and associated risk factors [13-20]. One of the most famous of these is the ProgStar study, which reported that VA change is associated with foveal phenotype and declines faster in younger patients, but is not associated with genotype [13,18]. However, descriptions of the clinical characteristics of Stargardt disease varied between studies, which may reflect differences in study methods. For example, ProgStar study report No. 10 showed that genotype was neither associated with baseline Best Corrected Visual Acuity (BCVA) nor with the rate of BCVA change [13], while Traboulsi et al reported that patients who harboured two or more mutations presented with disease earlier and had a worse BCVA than those with no or one mutation [20].

Limited data are available about the characteristics of VA and age of symptom onset in Chinese patients with Stargardt disease. Therefore, this study aimed to determine the basic characteristics of Chinese patients with Stargardt disease, including VA, age of symptom onset, and genotype, and to evaluate possible correlations among them.

Methods

Subjects and ethical statement

This is a retrospective observational study approved by the Ethics Committee of the Eye and ENT Hospital of Fudan University, which adheres to the Declaration of Helsinki. A total of 169 patients with a definitive clinical and genetic diagnosis of Stargardt disease were recruited from our ophthalmology department between January 2015 and November 2019. A clinical diagnosis was based on one or more of the following features as reported previously [14,26,27]; macular changes such as atrophy or a beaten-bronze metal appearance, and the presence of a well-defined atrophic lesion with or without characteristic white-yellow flecks at the level of the retinal pigment epithelium involving the posterior pole or extending to the midperipheral retina flecks on fundus auto fluorescence studies. The main genetic diagnostic criteria were at least two likely disease causing ABCA4 variants or one or more likely disease-causing PROM1 variant associated with a typical Stargardt disease phenotype. Exclusion criteria included any other ocular diseases that may confound morphologically and functional assessment of the retina, ophthalmologic surgery within the previous 90 days, any systemic condition potentially affecting the analyses, and previous or current participation in any drug trial or clinical trial to treat Stargardt disease. Written informed consent was obtained from all participants and/or legal guardians before peripheral blood samples were collected.

Genetic analysis

Molecular testing and data analysis was performed as previously reported [28-32]. We designed a high-through put targeted enrichment approach to exon-capture regions of 762 genes involved in common inherited eye diseases (BGI, Shenzhen, China). For acquisition of probe sequences, the exon sequence and its flank ±30bp from a reference human genome (UCSC hg 38) was obtained. Each reference sequence begins at one end of a reference sequence and selects the reference sequence of the predetermined length to obtain the probe sequence so that the last total probe can cover the reference sequence at least once. The probe length of the panel is 90nt, the total target area obtained is 2.3M. On average, the mean coverage depth was more than 400X, and the coverage of target region was ~99.9% using BGISEQ-2000. Subsequent points for sample quality control were also added to the probe design process. The following databases were then used for annotation of all identified variants with Minor Allele Frequency (MAF) >0.1% to eliminate benign variants: dbSNP137, HapMap Project, 1000 Genomes Project, YH database4, ESP6500, and Exome Variant Server. Finally, the variant prioritizations were performed, combining total depth, quality score, MAF, potential deleterious effect (five prediction algorithms: SIFT, Polyphen2, LRT, Mutation Taster, and FATHMM) and the existence of mutation reports in common databases such as the Human Gene Mutation Database (HGMD, professional version 2020 [4]), ClinVar, Retinal Information Network (RetNet), or Online Mendelian Inheritance in Man (OMIM). The prediction of novel missense variants is listed in Supplementary Table 2. Variants were classified as pathogenic, likely pathogenic, and novel variants of uncertain clinical significance according to the American College of Medical Genetics. Based on the pathogenicity, number, and severity of the ABCA4 or PROM1 mutations identified in each patient, patients harbouring two or more mutations were divided into three groups: genotype A group (severe): patients with ≥2 severe variants; genotype B group: patients with one severe variant and one missense mutation or in-frame insertion/deletion; and the genotype C group (moderate): patients with no severe variant but ≥2 missense variants or in-frame insertions/deletions. Severe variants were defined as those predicted to introduce a premature truncating codon in the protein or to affect splicing, such as frameshift, nonsense, or intronic or exonic variants causing major splice site alterations [11,13].

Clinical examination

All participants underwent a full ophthalmologic examination including the following assessments: best Snellen-corrected visual acuity testing (converted to an equivalent value of the logarithm of the minimal angle of resolution (logMAR) unit), slitlamp biomicroscopy of anterior and posterior segments, sweptdomain optical coherence tomography (Spectralis HRA+OCT, Heidelberg Engineering Inc., Heidelberg, Germany), and full-field electroretinography according to the standards of the International Society for Clinical Electrophysiology of Vision (www.iscev.org). The following conversions were made to provide numeric values for low BCVAs: hand motion (HM), 3 logMAR; and counting fingers, 2 logMAR [33,34]. Age at symptom onset was defined as the age when the patient first experienced symptoms associated with the disease (VA decline, loss of colour vision, and central and paracentral visual field defects), while disease duration was calculated by subtracting the onset date from the examination date. Right eye was used for VA analysis.

Statistical analysis

Measurement values of the groups were compared using the t-test and one-way analysis of variance test. Correlations were evaluated using Pearson, Spearman, or linear regression analyses. Statistical analyses were performed using SPSS version 20.0 software (SPSS Inc./IBM Corp., Chicago, IL) and Microsoft Excel (2010). Statistical significance for all tests was set at p <0.05.

Results

Cohort characteristics

A total of 169 patients of Chinese origin with clinically and molecularly confirmed Stargardt disease were enrolled (Supplementary Table 1). Table 1 summarizes baseline demographic and clinical characteristics of all participants. The 169 patients were from 157 families and included 102 men (60.4%) and 67 women (39.6%) with an age range of 5-64 years (mean, 28.28 ± 14.56 years; median, 26 years).