Juvenile Macular Degeneration Research Articles

Updates on Emerging Interventions for Autosomal Recessive ABCA4-Associated Stargardt Disease.

Autosomal recessive Stargardt disease (STGD1) is an inherited retinal degenerative disease associated with a mutated ATP-binding cassette, subfamily A, member 4 (ABCA4) gene. STGD1 is the most common form of juvenile macular degeneration with onset in late childhood to early or middle adulthood and causes progressive, irreversible visual impairment and blindness. No effective treatment is currently available. In the present article, we review the most recent updates in clinical trials targeting the management of STGD1, including gene therapy, small molecule therapy, and stem cell therapy. In gene therapy, dual adeno-associated virus and non-viral vectors have been successful in delivering the human ABCA4 gene in preclinical studies. For pharmaceutical therapies ALK-001, deuterated vitamin A shows promise with preliminary data for phase 2 trial, demonstrating a decreased atrophy growth rate after two years. Stem cell therapy using human pluripotent stem cell-derived retinal pigment epithelium cells demonstrated long-term safety three years after implantation and visual acuity improvements in the first two years after initiation of therapy. Many other treatment options have ongoing investigations and clinical trials. While multiple potential interventions have shown promise in attenuating disease progression, further exploration is necessary to demonstrate treatment safety and efficacy.

Artificial intelligence for assessment of Stargardt macular atrophy.

Stargardt disease (also known as juvenile macular degeneration or Stargardt macular degeneration) is an inherited disorder of the retina, which can occur in the eyes of children and young adults. It is the most prevalent form of juvenile-onset macular dystrophy, causing progressive (and often severe) vision loss. Images with Stargardt disease are characterized by the appearance of flecks in early and intermediate stages, and the appearance of atrophy, due to cells wasting away and dying, in the advanced stage. The primary measure of late-stage Stargardt disease is the appearance of atrophy. Fundus autofluorescence is a widely available two-dimensional imaging technique, which can aid in the diagnosis of the disease. Spectral-domain optical coherence tomography, in contrast, provides three-dimensional visualization of the retinal microstructure, thereby allowing the status of the individual retinal layers. Stargardt disease may cause various levels of disruption to the photoreceptor segments as well as other outer retinal layers. In recent years, there has been an exponential growth in the number of applications utilizing artificial intelligence for help with processing such diseases, heavily fueled by the amazing successes in image recognition using deep learning. This review regarding artificial intelligence deep learning approaches for the Stargardt atrophy screening and segmentation on fundus autofluorescence images is first provided, followed by a review of the automated retinal layer segmentation with atrophic-appearing lesions and fleck features using artificial intelligence deep learning construct. The paper concludes with a perspective about using artificial intelligence to potentially find early risk factors or biomarkers that can aid in the prediction of Stargardt disease progression.

Assessing functional reorganization in visual cortex with simulated retinal lesions

Macular degeneration (MD) causes central vision loss, removing input to corresponding representations in the primary visual cortex. There is disagreement concerning whether the cortical regions deprived of input can remain responsive, and the source of reported cortical responses is still debated. To simulate MD in controls, normally sighted participants viewed a bright central disk to adapt the retina, creating a transient ‘retinal lesion’ during a functional MRI experiment. Participants viewed blocks of faces, scrambled faces and uniform grey stimuli, either passively or whilst performing a one-back task. To assess the impact of the simulated lesion, participants repeated the paradigm using a more conventional mean luminance simulated scotoma without adaptation. Our results suggest our attempt to create a more realistic simulation of a lesion did not impact on responses in the representation of the simulated lesion. While most participants showed no evidence of stimulus-driven activation within the lesion representation, a few individuals (22%) exhibited responses similar to a participant with juvenile MD who completed the same paradigm (without adaptation). Reliability analysis showed that responses in the representation of the lesion were generally consistent irrespective of whether positive or negative. We provide some evidence that peripheral visual stimulation can also produce responses in central representations in controls while performing a task. This suggests that the ‘signature of reorganization of visual processing’, is not found solely in patients with retinal lesions, consistent with the idea that activity may be driven by unmasked top–down feedback.

Multimodal Imaging in Hypotrichosis with Juvenile Macular Degeneration

Multimodal Imaging in Hypotrichosis with Juvenile Macular Degeneration

Impaired cholesterol efflux in retinal pigment epithelium of individuals with juvenile macular degeneration

Macular degeneration (MD) is characterized by the progressive deterioration of the macula and represents one of the most prevalent causes of blindness worldwide. Abnormal intracellular accumulation of lipid droplets and pericellular deposits of lipid-rich material in the retinal pigment epithelium (RPE) called drusen are clinical hallmarks of different forms of MD including Doyne honeycomb retinal dystrophy (DHRD) and age-related MD (AMD). However, the appropriate molecular therapeutic target underlying these disorder phenotypes remains elusive. Here, we address this knowledge gap by comparing the proteomic profiles of induced pluripotent stem cell (iPSC)-derived RPEs (iRPE) from individuals with DHRD and their isogenic controls. Our analysis and follow-up studies elucidated the mechanism of lipid accumulation in DHRD iRPE cells. Specifically, we detected significant downregulation of carboxylesterase 1 (CES1), an enzyme that converts cholesteryl ester to free cholesterol, an indispensable process in cholesterol export. CES1 knockdown or overexpression of EFEMP1R345W, a variant of EGF-containing fibulin extracellular matrix protein 1 that is associated with DHRD and attenuated cholesterol efflux and led to lipid droplet accumulation. In iRPE cells, we also found that EFEMP1R345W has a hyper-inhibitory effect on epidermal growth factor receptor (EGFR) signaling when compared to EFEMP1WT and may suppress CES1 expression via the downregulation of transcription factor SP1. Taken together, these results highlight the homeostatic role of cholesterol efflux in iRPE cells and identify CES1 as a mediator of cholesterol efflux in MD.

The Direct Healthcare Cost of Stargardt Disease: A Claims-Based Analysis

ABSTRACT Purpose: Stargardt disease (SD) is the most common juvenile macular degeneration and a leading cause of uncorrectable childhood blindness. The progressive and incurable nature of this chronic condition entails a long-term financial burden on affected individuals. The economic costs of SD have not been characterized in detail, so we aimed to estimate the direct healthcare cost of SD. Methods: Outpatient administrative claims data (2010–2014) for patients with SD were analyzed from the IBM® MarketScan® Commercial Claims and Encounters Database. Two comparison groups were selected: nonexudative age-related macular degeneration (AMD) and bilateral sensorineural hearing loss (SHL). Gross median payments per year of insurance coverage were calculated. Results: A total of 472,428 patients were analyzed (5,015 SD, 369,750 SHL and 97,663 AMD patients respectively). The payment per year of insurance coverage for SD (median: 105.58 USD, IQR: 50.53 USD–218.71 USD) was higher than that of SHL (median: 51.01 USD, IQR: 25.66 USD–121.66 USD, p < .001) and AMD (median: 76.20 USD, IQR: 38.00 USD–164.86 USD, p < .001). When adjusted for age, sex, year of first service, and type of benefit plan, the annual payment for SD was 47.83 USD higher than SHL (p < .001) and 17.34 USD higher than AMD (p < .001). Conclusions: There is a significant direct healthcare cost associated with SD. The annual per-patient cost of SD was higher than SHL, another condition that causes sensory impairment in people of all ages, and nonexudative AMD which causes a similar pattern of visual loss that typically begins later in life. The total lifetime per-patient cost of SD may exceed that of nonexudative AMD.

Motion-Based Acuity Task: Full Visual Field Measurement of Shape and Motion Perception.

PurposeDamage of retinal representation of the visual field affects its local features and the spared, unaffected parts. Measurements of visual deficiencies in ophthalmological patients are separated for central (shape) or peripheral (motion and space perception) properties, and acuity tasks rely on stationary stimuli. We explored the benefit of measuring shape and motion perception simultaneously using a new motion-based acuity task.MethodsEight healthy control subjects, three patients with retinitis pigmentosa (RP; tunnel vision), and 2 patients with Stargardt disease (STGD) juvenile macular degeneration were included. To model the peripheral loss, we narrowed the visual field in controls to 10 degrees. Negative and positive contrast of motion signals were tested in random-dot kinematograms (RDKs), where shapes were separated from the background by the motion of dots based on coherence, direction, or velocity. The task was to distinguish a circle from an ellipse. The difficulty of the task increased as ellipse became more circular until reaching the acuity limit.ResultsHigh velocity, negative contrast was more difficult for all, and for patients with STGD, it was too difficult to participate. A slower velocity improved acuity for all participants.ConclusionsProposed acuity testing not only allows for the full assessment of vision but also advances the capability of standard testing with the potential to detect spare visual functions.Translational RelevanceThe motion-based acuity task might be a practical tool for assessing vision loss and revealing undetected, undamaged, or strengthened properties of the injured visual system by standard testing, as suggested here for two patients with STGD and three patients with RP.

Penetration, distribution, and elimination of remofuscin/soraprazan in Stargardt mouse eyes following a single intravitreal injection using pharmacokinetics and transmission electron microscopic autoradiography: Implication for the local treatment of Stargardt's disease and dry age-related macular degeneration.

Age‐related macular degeneration (AMD) is the leading cause of blindness in older people in the developed world while Stargardt's disease (SD) is a juvenile macular degeneration and an orphan disease. Both diseases are untreatable and are marked by accumulation of lipofuscin advancing to progressive deterioration of the retinal pigment epithelium (RPE) and retina and subsequent vision loss till blindness. We discovered that a small molecule belonging to the tetrahydropyridoether class of compounds, soraprazan renamed remofuscin, is able to remove existing lipofuscin from the RPE. This study investigated the drug penetration, distribution, and elimination into the eyes of a mouse model for increased lipofuscinogenesis, following a single intravitreal injection. We measured the time course of concentrations of remofuscin in different eye tissues using high‐performance liquid chromatography combined with mass spectroscopy (HPLC‐MS). We also visualized the penetration and distribution of 3H‐remofuscin in eye sections up to 20 weeks post‐injection using transmission electron microscopic (TEM) autoradiography. The distribution of silver grains revealed that remofuscin accumulated specifically in the RPE by binding to the RPE pigments (melanin, lipofuscin and melanolipofuscin) and that it was still detected after 20 weeks. Importantly, the melanosomes in choroidal melanocytes only rarely bind remofuscin emphasizing its potential to serve as an active ingredient in the RPE for the treatment of SD and dry AMD. In addition, our study highlights the importance of electron microscopic autoradiography as it is the only method able to show drug binding with a high intracellular resolution.

V1 Projection Zone Signals in Human Macular Degeneration Depend on Task Despite Absence of Visual Stimulus

Identifying the plastic and stable components of the visual cortex after retinal loss is an important topic in visual neuroscience and neuro-ophthalmology.1-5 Humans with juvenile macular degeneration (JMD) show significant blood-oxygen-level-dependent (BOLD) responses in the primary visual area (V1) lesion projection zone (LPZ),6 despite the absence of the feedforward signals from the degenerated retina. Our previous study7 reported that V1 LPZ responds to full-field visual stimuli during the one-back task (OBT), not during passive viewing, suggesting the involvement of task-related feedback signals. Aiming to clarify whether visual inputs to the intact retina are necessary for the LPZ responses, here, we measured BOLD responses to tactile and auditory stimuli for both JMD patients and control participants with and without OBT. Participants were instructed to close their eyes during the experiment for the purpose of eliminating retinal inputs. Without OBT, no V1 responses were detected in both groups of participants. With OBT, to the contrary, both stimuli caused substantial V1 responses in JMD patients, but not controls. Furthermore, we also found that the task-dependent activity in V1 LPZ became less pronounced when JMD patients opened their eyes, suggesting that task-related feedback signals can be partially suppressed by residual feedforward signals. Modality-independent V1 LPZ responses only in the task condition suggest that V1 LPZ responses reflect task-related feedback signals rather than reorganized feedforward visual inputs.

Cerebral Modifications and Visual Pathway Reorganization in Maculopathy: A Systematic Review.

BackgroundMacular degeneration (MD) is one of the most frequent causes of visual deficit, resulting in alterations affecting not only the retina but also the entire visual pathway up to the brain areas. This would seem related not just to signal deprivation but also to a compensatory neuronal reorganization, having significant implications in terms of potential rehabilitation of the patient and therapeutic perspectives.ObjectiveThis paper aimed to outline, by analyzing the existing literature, the current understanding of brain structural and functional changes detected with neuroimaging techniques in subjects affected by juvenile and age-related maculopathy.MethodsArticles using various typologies of central nervous system (CNS) imaging in at least six patients affected by juvenile or age-related maculopathy were considered. A total of 142 were initially screened. Non-pertinent articles and duplicates were rejected. Finally, 19 articles, including 649 patients, were identified.ResultsIn these sources, both structural and functional modifications were found in MD subjects’ CNS. Changes in visual cortex gray matter volume were observed in both age-related MD (AMD) and juvenile MD (JMD); in particular, an involvement of not only its posterior part but also the anterior one suggests further causes besides an input-deprivation mechanism only. White matter degeneration was also found, more severe in JMD than in AMD. Moreover, functional analysis revealed differences in cortical activation patterns between MD and controls, suggesting neuronal circuit reorganization. Interestingly, attention and oculomotor training allowed better visual performances and correlated to a stronger cortical activation, even of the area normally receiving inputs from lesioned macula.ConclusionIn MD, structural and functional changes in cerebral circuits and visual pathway can happen, involving both cerebral volume and activation patterns. These modifications, possibly due to neuronal plasticity (already observed and described for several brain areas), can allow patients to compensate for macular damage and gives therapeutic perspectives which could be achievable through an association between oculomotor training and biochemical stimulation of neuronal plasticity.

Long-term safety and tolerability of subretinal transplantation of embryonic stem cell-derived retinal pigment epithelium in Asian Stargardt disease patients

BackgroundAlthough human embryonic stem cells (hESCs) have been considered a potential therapeutic option for regenerative medicine, there are some concerns regarding tumorigenicity, immunogenicity and ethical considerations. Stargardt macular dystrophy (SMD)...

The Effect of Perceptual Learning on Face Recognition in Individuals with Central Vision Loss.

PurposeTo examine whether perceptual learning can improve face discrimination and recognition in older adults with central vision loss.MethodsTen participants with age-related macular degeneration (ARMD) received 5 days of training on a face discrimination task (mean age, 78 ± 10 years). We measured the magnitude of improvements (i.e., a reduction in threshold size at which faces were able to be discriminated) and whether they generalized to an untrained face recognition task. Measurements of visual acuity, fixation stability, and preferred retinal locus were taken before and after training to contextualize learning-related effects. The performance of the ARMD training group was compared to nine untrained age-matched controls (8 = ARMD, 1 = juvenile macular degeneration; mean age, 77 ± 10 years).ResultsPerceptual learning on the face discrimination task reduced the threshold size for face discrimination performance in the trained group, with a mean change (SD) of –32.7% (+15.9%). The threshold for performance on the face recognition task was also reduced, with a mean change (SD) of –22.4% (+2.31%). These changes were independent of changes in visual acuity, fixation stability, or preferred retinal locus. Untrained participants showed no statistically significant reduction in threshold size for face discrimination, with a mean change (SD) of –8.3% (+10.1%), or face recognition, with a mean change (SD) of +2.36% (–5.12%).ConclusionsThis study shows that face discrimination and recognition can be reliably improved in ARMD using perceptual learning. The benefits point to considerable perceptual plasticity in higher-level cortical areas involved in face-processing. This novel finding highlights that a key visual difficulty in those suffering from ARMD is readily amenable to rehabilitation.

Molecular Analysis of the ABCA4 Gene Mutations in Patients with Stargardt Disease Using Human Hair Follicles

ABCA4 gene mutations are the cause of a spectrum of ABCA4 retinopathies, and the most common juvenile macular degeneration is called Stargardt disease. ABCA4 has previously been observed almost exclusively in the retina. Therefore, studying the functional consequences of ABCA4 variants has required advanced molecular analysis techniques. The aim of the present study was to evaluate whether human hair follicles may be used for molecular analysis of the ABCA4 gene splice-site variants in patients with ABCA4 retinopathies. We assessed ABCA4 expression in hair follicles and skin at mRNA and protein levels by means of real-time PCR and Western blot analyses, respectively. We performed cDNA sequencing to reveal the presence of full-length ABCA4 transcripts and analyzed ABCA4 transcripts from three patients with Stargardt disease carrying different splice-site ABCA4 variants: c.5312+1G>A, c.5312+2T>G and c.5836-3C>A. cDNA analysis revealed that c.5312+1G>A, c.5312+2T>G variants led to the skipping of exon 37, and the c.5836-3C>A variant resulted in the insertion of 30 nucleotides into the transcript. Our results strongly argue for the use of hair follicles as a model for the molecular analysis of the pathogenicity of ABCA4 variants in patients with ABCA4 retinopathies.

Outcome measures in juvenile X-linked retinoschisis: A systematic review.

X-linked retinoschisis (XLRS) is a leading cause of hereditary juvenile macular degeneration in males resulting in significant vision impairment. Outcome measures to monitor disease progression or therapeutic interventions have evolved with technology. A systematic review was undertaken to evaluate outcome measures for XLRS. Inclusion criteria were all publications examining outcome measures for natural history studies or following an interventional approach for patients with XLRS. Studies which did not present follow-up data were excluded. We searched medical databases including CENTRAL, Ovid Medline, pre-Medline and ahead of Print up to February 2019. Two authors independently assessed the risk of bias. Twelve studies meet the inclusion criteria with four prospective and eight retrospective case series. Five series were natural history observational studies and seven were interventional series using either topical or systemic carbonic anhydrase inhibitors. Visual acuity (VA) declined very slowly in the natural history studies equivalent to 0.22–0.5 letters per year. Five of the six interventional studies showed an improvement in VA and four a reduction in spectral domain optical coherence tomography (SD-OCT) parameters for central macular thickness (CMT). The full-field electroretinogram identified the 30-Hz latency as a further parameter to monitor function. VA was the measure most likely to show a statistically significant outcome. How functionally meaningful this is, requires further evaluation. CMT SD-OCT outcomes are variable depending on cystic changes. More refined measures are required to better correlate structure with function.

Case report of instantaneous resolution of juvenile macular degeneration blindness after proximal intercessory prayer

An 18-year-old female lost the majority of her central vision over the course of three months in 1959. Medical records from 1960 indicate visual acuities (VA) of less than 20/400 for both eyes corresponding to legal blindness. On fundus examination of the eye there were dense yellowish-white areas of atrophy in each fovea and the individual was diagnosed with juvenile macular degeneration (JMD). In 1971, another examination recorded her uncorrected VA as finger counting on the right and hand motion on the left. She was diagnosed with macular degeneration (MD) and declared legally blind. In 1972, having been blind for over 12 years, the individual reportedly regained her vision instantaneously after receiving proximal-intercessory-prayer (PIP). Subsequent medical records document repeated substantial improvement; including uncorrected VA of 20/100 in each eye in 1974 and corrected VAs of 20/30 to 20/40 were recorded from 2001 to 2017. To date, her eyesight has remained intact for forty-seven years.

Aging and central vision loss: Relationship between the cortical macro-structure and micro-structure

Aging and central vision loss are associated with cortical atrophies, but little is known about the relationship between cortical thinning and the underlying cellular structure. We compared the macro- and micro-structure of the cortical gray and superficial white matter of 38 patients with juvenile (JMD) or age-related (AMD) macular degeneration and 38 healthy humans (19–84 years) by multimodal MRI including diffusion-tensor imaging (DTI). A factor analysis showed that cortical thickness, tissue-dependent measures, and DTI-based measures were sensitive to distinct components of brain structure. Age-related cortical thinning and increased diffusion were observed across most of the cortex, but increased T1-weighted intensities (frontal), reduced T2-weighted intensities (occipital), and reduced anisotropy (medial) were limited to confined cortical regions. Vision loss was associated with cortical thinning and enhanced diffusion in the gray matter (less in the white matter) of the occipital central visual field representation. Moreover, AMD (but not JMD) patients showed enhanced diffusion in lateral occipito-temporal cortex and cortical thinning in the posterior cingulum. These findings demonstrate that changes in brain structure are best quantified by multimodal imaging. They further suggest that age-related brain atrophies (cortical thinning) reflect diverse micro-structural etiologies. Moreover, juvenile and age-related macular degeneration are associated with distinct patterns of micro-structural alterations.

Hypotrichosis with juvenile macular dystrophy: Combination of whole-genome sequencing and genome-wide homozygosity mapping identifies a large deletion in CDH3 initially undetected by whole-exome sequencing-A lesson from next-generation sequencing.

BackgroundHypotrichosis with juvenile macular dystrophy (HJMD) is an autosomal recessive disorder characterized by abnormal growth of scalp hair and juvenile macular degeneration leading to blindness. We have explored the genetic basis of HJMD in a large consanguineous family with 12 affected patients, 1–76 years of age, with characteristic phenotypes.MethodsWe first applied genome‐wide homozygosity mapping to 10 affected individuals for linkage analysis to identify the genomic region of the defective gene. All affected individuals shared a 7.2 Mb region of homozygosity on chromosome 16q21‐22.3, which harbored 298 genes, including CDH3, previously associated with HJMD. However, whole‐exome sequencing (WES) failed to identify the causative mutation in CDH3.ResultsFurther investigation revealed a missense variant in a gene closely linked to CDH3 (1.4 Mb distance: FHOD1: c.1306A>G, p.Arg436Gly). This variant was homozygous in all affected individuals and heterozygous in 18 out of 19 obligate carriers. While this variant was found by bioinformatics predictions to be likely pathogenic, a knock‐in mouse for this variant, made by the CRISPR/Cas, showed no disease phenotype. However, using whole‐genome sequencing (WGS), we were able to identify a novel Alu recombination‐mediated deletion in CDH3:c.del161‐811_246 + 1,044.ConclusionWGS was able to identify a deep intronic deletion mutation, not detected by WES.

03 Examining the Resiliency of Visually Impaired Older Adults with Cognitive Decline Aging in Place

Abstract Background Visual impairment is a leading chronic condition among older adults and is usually connected with a decline in their performance of instrumental activities of daily living. Understanding the challenges of those with visual impairment is paramount as the population ages over the next four decades. This study examined the hypothesis that older adults who were diagnosed with juvenile macular degeneration as young adults and now have a mild cognitive impairment have better coping mechanisms than older adults who were recently diagnosed with age-related macular degeneration. Methods This study utilized a mixed-methods approach to address the complexities in health science research and align with the interdisciplinary field of gerontology. Results Participants were 27 older adults aged 65 years of age and older. There was no quantitative difference in resiliency between participants with juvenile macular degeneration (n = 7, M = 77.71, SD = 9.46) and those with age-related macular degeneration (n = 10, M = 72.60, SD = 8.25), t(15) = 1.185, p = .254. Conclusion The qualitative results revealed that older adults living with visual impairment develop strategies to improve their quality of life and help them age in place.

Factors influencing the choice of low‐vision devices for visual rehabilitation in Stargardt disease

BackgroundStargardt disease is the most common cause of juvenile macular degeneration leading to early central visual loss. Dispensing of correct low‐vision devices based on the residual visual function and specific visual requirements of a patient can result in a positive outcome. It is important to know the factors involved in the selection of these devices. This study was undertaken to assess these factors.MethodsPatients with Stargardt disease referred to a low‐vision clinic underwent evaluation of visual status, disease stage, visual requirements and lifestyle. They were evaluated for suitability for successful use of various low‐vision devices. Their education level and occupation were noted. They were counselled regarding the proper use of the devices and lifestyle modifications. For patients with extensive use of computers, modifications related to contrast, font size and audio software were explained.ResultsAmong the 97 patients in the study (age range 7–66-years, mean 23.7 ± 13.1), there were 49 (50.5 per cent) students, 36 (37.1 per cent) employed, eight (8.2 per cent) unemployed, and four (4.2 per cent) homemakers. Except for seven patients (7.2 per cent), all were literate, with education ranging from primary school to college graduation. The presenting visual acuity for distance was 0.10–1.47 (0.79 ± 0.28), and for near was N4–N40 (N9.95 ± 6.65). This acuity showed positive correlation with age (p < 0.0001, R2 = 0.16) and with magnification required (p < 0.0001, R2 = 0.26). Patients above 40-years preferred higher adds and half‐eye glasses, whereas younger patients preferred dome magnifiers. The occupation also influenced the choice. Disease stage was seen to affect the choice with advanced stages requiring higher magnifiers (p = 0.03, R2 = 0.11). Duration of disease and the magnification of low‐vision devices showed a positive correlation (p = 0.03, R2 = 0.049).ConclusionsAge, presenting visual acuity, disease stage, duration, education and occupation influenced the choice of low‐vision devices in patients with Stargardt disease. However, they appear to be interdependent and a larger, controlled study is required to provide information on the individual effect.

Identification of novel pathogenic ABCA4 variants in a Han Chinese family with Stargardt disease.

Stargardt disease (STGD1, OMIM 248200) is a common hereditary juvenile or early adult onset macular degeneration. It ultimately leads to progressive central vision loss. Here, we sought to identify gene mutations associated with STGD1 in a three-generation Han Chinese pedigree by whole exome sequencing and Sanger sequencing. Two novel potentially pathogenic variants in a compound heterozygous state, c.3607G>T (p.(Gly1203Trp)) and c.6722T>C (p.(Leu2241Pro)), in the ATP binding cassette subfamily A member 4 gene (ABCA4) were identified as contributing to the family’s STGD1 phenotype. These variants may impact the ABCA4 protein structure and reduce the retinal-activated ATPase activity, leading to abnormal all-trans retinal accumulation in photoreceptor outer segments and in retinal pigment epithelium cells. The present study broadens the mutational spectrum of the ABCA4 responsible for STGD1. A combination of whole exome sequencing and Sanger sequencing is likely to be a time-saving and cost-efficient approach to screen pathogenic variants in genetic disorders caused by sizable genes, as well as avoiding misdiagnosis. These results perhaps refine genetic counseling and ABCA4-targetted treatments for families affected by STGD1.