Clinical and Molecular Analysis of Stargardt Disease With Preserved Foveal Structure and Function

doi:10.1016/j.ajo.2013.05.003

American Journal of Ophthalmology

Volume 156, Issue 3, September 2013, Pages 487-501.e1

https://doi.org/10.1016/j.ajo.2013.05.003 Get rights and content

Purpose

To describe a cohort of patients with Stargardt disease who show a foveal-sparing phenotype.

Design

Retrospective case series.

Methods

The foveal-sparing phenotype was defined as foveal preservation on autofluorescence imaging, despite a retinopathy otherwise consistent with Stargardt disease. Forty such individuals were ascertained and a full ophthalmic examination was undertaken. Following mutation screening of ABCA4, the molecular findings were compared with those of patients with Stargardt disease but no foveal sparing.

Results

The median age of onset and age at examination of 40 patients with the foveal-sparing phenotype were 43.5 and 46.5 years. The median logMAR visual acuity was 0.18. Twenty-two patients (22/40, 55%) had patchy parafoveal atrophy and flecks; 8 (20%) had numerous flecks at the posterior pole without atrophy; 7 (17.5%) had mottled retinal pigment epithelial changes; 2 (5%) had multiple atrophic lesions, extending beyond the arcades; and 1 (2.5%) had a bull's-eye appearance. The median central foveal thickness assessed with spectral-domain optical coherence tomographic images was 183.0 μm (n = 33), with outer retinal tubulation observed in 15 (45%). Twenty-two of 33 subjects (67%) had electrophysiological evidence of macular dysfunction without generalized retinal dysfunction. Disease-causing variants were found in 31 patients (31/40, 78%). There was a higher prevalence of the variant p.Arg2030Gln in the cohort with foveal sparing compared to the group with foveal atrophy (6.45% vs 1.07%).

Conclusions

The distinct clinical and molecular characteristics of patients with the foveal-sparing phenotype are described. The presence of 2 distinct phenotypes of Stargardt disease (foveal sparing and foveal atrophy) suggests that there may be more than 1 disease mechanism in ABCA4 retinopathy.

Section snippets

Patients

AF images of the right eyes of 438 individuals with a clinical diagnosis of retinopathy compatible with Stargardt disease were surveyed and 40 patients were identified with an apparently normal AF signal at the fovea (foveal sparing). After informed consent, blood samples were collected and genomic DNA was extracted from the peripheral blood leukocytes. The protocol of the study adhered to the provisions of the Declaration of Helsinki and was approved by the local Ethics Committee of Moorfields

Results

The clinical findings in the 40 patients with foveal-sparing Stargardt disease are summarized in Table 1. There were 22 female patients (55%) and 18 male patients (45%). The panel included 2 sibships; a sibling pair (Patients 16 and 32) and 1 set of 3 siblings (Patients 33, 34, and 35). Twenty-five patients (63%) complained of central visual loss and 2 subjects (5%) presented with diplopia, with 13 individuals (32%) having no visual symptoms. The median age of onset was 43.5 years (range, 25-75

Discussion

This report describes the detailed clinical and molecular genetic characteristics of 40 patients with Stargardt disease and foveal sparing on AF imaging; at least 1 disease-causing ABCA4 allele was identified in 78% of subjects.

The median age of onset was 43.5 years, with a median visual acuity of 0.18, and 13 patients (32%) were asymptomatic, in keeping with previous reports.5, 6, 12, 22 Thirty-eight of 40 patients (98%) had logMAR visual acuity better than or equal to 0.48, with the remaining

Kaoru Fujinami, MD is a clinical ophthalmologist and principal investigator at the National Institute of Sensory Organs associated with Keio University, School of Medicine, Tokyo, Japan. He has completed fellowships at Moorfields Eye Hospital and University College London, Institute of Ophthalmology, London, United Kingdom. His research interests include retinal disease, clinical electrophysiology, inherited eye disease and molecular genetics. His current projects relate to genotype-phenotype

References (54)

Y. Rotenstreich et al.
Visual acuity loss and clinical observations in a large series of patients with Stargardt disease
Ophthalmology
(2003)
V.A. McBain et al.
Progression of retinal pigment epithelial atrophy in stargardt disease
Am J Ophthalmol
(2012)
S.C. Westeneng-van Haaften et al.
Clinical and genetic characteristics of late-onset Stargardt's disease
Ophthalmology
(2012)
W. Cella et al.
G1961E mutant allele in the Stargardt disease gene ABCA4 causes bull's eye maculopathy
Exp Eye Res
(2009)
P.I. Sergouniotis et al.
Retinal structure, function, and molecular pathologic features in gyrate atrophy
Ophthalmology
(2012)
K. Tsunoda et al.
Highly reflective foveal region in optical coherence tomography in eyes with vitreomacular traction or epiretinal membrane
Ophthalmology
(2012)
R.A. Lewis et al.
Genotype/phenotype analysis of a photoreceptor-specific ATP-binding cassette transporter gene, ABCR, in Stargardt disease
Am J Hum Genet
(1999)
A. Rivera et al.
A comprehensive survey of sequence variation in the ABCA4 (ABCR) gene in Stargardt disease and age-related macular degeneration
Am J Hum Genet
(2000)
D.G. Birch et al.
Visual function in patients with cone-rod dystrophy (CRD) associated with mutations in the ABCA4 (ABCR) gene
Exp Eye Res
(2001)
K. Stargardt
Uber familiare progressive degeneration in der makulagegend des auges
Albrecht von Grafes Arch Klin Ophthalmol
(1909)

B.J. Klevering et al.

Phenotypic spectrum of autosomal recessive cone-rod dystrophies caused by mutations in the ABCA4 (ABCR) gene

Invest Ophthalmol Vis Sci

(2002)

M. Michaelides et al.

ABCA4 mutations and discordant ABCA4 alleles in patients and siblings with bull's-eye maculopathy

Br J Ophthalmol

(2007)

Cited by (90)

Phenotyping and genotyping inherited retinal diseases: Molecular genetics, clinical and imaging features, and therapeutics of macular dystrophies, cone and cone-rod dystrophies, rod-cone dystrophies, Leber congenital amaurosis, and cone dysfunction syndromes
2024, Progress in Retinal and Eye Research
Inherited retinal diseases (IRD) are a leading cause of blindness in the working age population and in children. The scope of this review is to familiarise clinicians and scientists with the current landscape of molecular genetics, clinical phenotype, retinal imaging and therapeutic prospects/completed trials in IRD. Herein we present in a comprehensive and concise manner: (i) macular dystrophies (Stargardt disease (ABCA4), X-linked retinoschisis (RS1), Best disease (BEST1), PRPH2-associated pattern dystrophy, Sorsby fundus dystrophy (TIMP3), and autosomal dominant drusen (EFEMP1)), (ii) cone and cone-rod dystrophies (GUCA1A, PRPH2, ABCA4, KCNV2 and RPGR), (iii) predominant rod or rod-cone dystrophies (retinitis pigmentosa, enhanced S-Cone syndrome (NR2E3), Bietti crystalline corneoretinal dystrophy (CYP4V2)), (iv) Leber congenital amaurosis/early-onset severe retinal dystrophy (GUCY2D, CEP290, CRB1, RDH12, RPE65, TULP1, AIPL1 and NMNAT1), (v) cone dysfunction syndromes (achromatopsia (CNGA3, CNGB3, PDE6C, PDE6H, GNAT2, ATF6), X-linked cone dysfunction with myopia and dichromacy (Bornholm Eye disease; OPN1LW/OPN1MW array), oligocone trichromacy, and blue-cone monochromatism (OPN1LW/OPN1MW array)). Whilst we use the aforementioned classical phenotypic groupings, a key feature of IRD is that it is characterised by tremendous heterogeneity and variable expressivity, with several of the above genes associated with a range of phenotypes.
A Retrospective Longitudinal Study of 460 Patients with ABCA4-Associated Retinal Disease
2024, Ophthalmology
To investigate the distribution of genotypes and natural history of ABCA4-associated retinal disease in a large cohort of patients seen at a single institution.
Retrospective, single-institution cohort review.
Patients seen at the University of Iowa between November 1986 and August 2022 clinically suspected to have disease caused by sequence variations in ABCA4.
DNA samples from participants were subjected to a tiered testing strategy progressing from allele-specific screening to whole genome sequencing. Charts were reviewed, and clinical data were tabulated. The pathogenic severity of the most common alleles was estimated by studying groups of patients who shared 1 allele. Groups of patients with shared genotypes were reviewed for evidence of modifying factor effects.
Age at first uncorrectable vision loss, best-corrected visual acuity, and the area of the I2e isopter of the Goldmann visual field.
A total of 460 patients from 390 families demonstrated convincing clinical features of ABCA4-associated retinal disease. Complete genotypes were identified in 399 patients, and partial genotypes were identified in 61. The median age at first vision loss was 16 years (range, 4–76 years). Two hundred sixty-five families (68%) harbored a unique genotype, and no more than 10 patients shared any single genotype. Review of the patients with shared genotypes revealed evidence of modifying factors that in several cases resulted in a > 15-year difference in age at first vision loss. Two hundred forty-one different alleles were identified among the members of this cohort, and 161 of these (67%) were found in only a single individual.
ABCA4-associated retinal disease ranges from a very severe photoreceptor disease with an onset before 5 years of age to a late-onset retinal pigment epithelium–based condition resembling pattern dystrophy. Modifying factors frequently impact the ABCA4 disease phenotype to a degree that is similar in magnitude to the detectable ABCA4 alleles themselves. It is likely that most patients in any cohort will harbor a unique genotype. The latter observations taken together suggest that patients’ clinical findings in most cases will be more useful for predicting their clinical course than their genotype.
Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.
Structure and function of ABCA4 and its role in the visual cycle and Stargardt macular degeneration
2022, Progress in Retinal and Eye Research
ABCA4 is a member of the superfamily of ATP-binding cassette (ABC) transporters that is preferentially localized along the rim region of rod and cone photoreceptor outer segment disc membranes. It uses the energy from ATP binding and hydrolysis to transport N-retinylidene-phosphatidylethanolamine (N-Ret-PE), the Schiff base adduct of retinal and phosphatidylethanolamine, from the lumen to the cytoplasmic leaflet of disc membranes. This ensures that all-trans-retinal and excess 11-cis-retinal are efficiently cleared from photoreceptor cells thereby preventing the accumulation of toxic retinoid compounds. Loss-of-function mutations in the gene encoding ABCA4 cause autosomal recessive Stargardt macular degeneration, also known as Stargardt disease (STGD1), and related autosomal recessive retinopathies characterized by impaired central vision and an accumulation of lipofuscin and bis-retinoid compounds. High resolution structures of ABCA4 in its substrate and nucleotide free state and containing bound N-Ret-PE or ATP have been determined by cryo-electron microscopy providing insight into the molecular architecture of ABCA4 and mechanisms underlying substrate recognition and conformational changes induced by ATP binding. The expression and functional characterization of a large number of disease-causing missense ABCA4 variants have been determined. These studies have shed light into the molecular mechanisms underlying Stargardt disease and a classification that reliably predicts the effect of a specific missense mutation on the severity of the disease. They also provide a framework for developing rational therapeutic treatments for ABCA4-associated diseases.
The Progression of Stargardt Disease Using Volumetric Hill of Vision Analyses Over 24 Months: ProgStar Report No.15
2021, American Journal of Ophthalmology
Citation Excerpt :
Our previous report failed to demonstrate an association of the genotype with the baseline BCVA or the change in BCVA.26 This may not be surprising, since the limitations of BCVA for following STGD1 are known and BCVA largely depends on the status of the fovea and the ability to maintain steady fixation.31,41 Although the VTOT from microperimetry describes the total amount of macular function, we were again not able to demonstrate a difference between the genotype groups.
To report the yearly rate of change in macular function in patients with Stargardt disease type 1 (STGD1) over 24 months and to establish a new volumetric visual function index for use in clinical trials investigating the efficacy on retinal sensitivity.
Design: International, multicenter, prospective cohort study with 5 study visits every 6 months over 24 months. Participants: A total of 233 individuals with genetically confirmed STGD1 (≥1 disease-causing ABCA4 variant). Main Outcome Measures: The total volume (V_TOT) beneath the sensitivity surface of a 3-D model of the hill of vision and mean sensitivity (MS) derived from mesopic microperimetry performed with a white stimulus. Changes of V_TOT over time and its correlation with the ABCA4 genotype and baseline features.
At baseline, 440 eyes (233 patients) with a mean (SD) age of 33.7 (15.0) years, mean (SD) visual acuity of 46.08 (16.03) ETDRS letters were analyzed with an average V_TOT of 0.91 decibel-steradian (dB-sr) and an MS of 10.73 dB. The overall mean rate of decrease in sensitivity [95% confidence interval] was 0.077 [0.064, 0.090] dB-sr/y for V_TOT and 0.87 [0.72, 1.02] dB/year for MS. The progression rate of V_TOT depended on baseline visual function (0.029 dB-sr/year for low and 0.120 dB-sr/year for high baseline V_TOT; P < .001) and exhibited a difference in the first vs second year of follow-up (0.065 dB-sr/year vs 0.089 dB-sr/year, respectively; P < .001). The absence of pigmentary abnormalities of the retinal pigment epithelium at baseline was found to be associated with a faster progression rate (P < .001), whereas a significant association with the genotype was not detected (P = .7).
In STGD1, both microperimetric outcomes demonstrate statistically significant and clinically meaningful changes after relatively short follow-up periods. Volumetric modeling may be useful in future interventional clinical trials that aim to improve retinal sensitivity or to slow down its decline and for structure-function correlations.
Clinical and genetic analysis of the ABCA4 gene associated retinal dystrophy in a large Chinese cohort
2021, Experimental Eye Research
Citation Excerpt :
Arg602Trp), with an allele frequency of 5.2%, 3.9%, 3.9%, 3.9%, 2.6%, and 2.6%, respectively. According to previous reports attempting to investigate genotype-phenotype correlations in patients with ABCA4-RD (Fujinami et al., 2013b, 2015), variants have been classified as “null” (including stop codon variants, frameshift, and splicing defects) and “none-null” (including missense variants and in-frame insertion or deletion variants). Consequently, genotypes of patients with two ABCA4 mutations could be classified into 3 groups: 1) two “non-null” variants (group 1, n = 31), 2) one “non-null” variant and one “null” variant (group 2, n = 46), and 3) two “null” variants (group 3, n = 24).
ABCA4 gene associated retinal dystrophies (ABCA4-RD) are a group of inherited eye diseases caused by ABCA4 gene mutations, including Stargardt disease, cone-rod dystrophy and retinitis pigmentosa. With the development of next-generation sequencing (NGS), numerous clinical and genetic studies on ABCA4-RD have been performed, and the genotype and phenotype spectra have been elucidated. However, most of the studies focused on the Caucasian population and limited studies of large Chinese ABCA4-RD cohorts were reported. In this study, we summarized the phenotypic and genotypic characteristics of 129 Chinese patients with ABCA4-RD. We found a mutation spectrum of Chinese patients which is considerably different from that of the Caucasian population and identified 35 novel ABCA4 mutations. We also reported some rare and special cases, such as, pedigrees with patients in two generations, patients diagnosed with cone-rod dystrophy or retinitis pigmentosa, patients with subretinal fibrosis and patients with preserved foveal structure. At the same time, we focused on the correlation between the genotypes and phenotypes. By the comprehensive analysis of multiple clinical examinations and the application of multiple regression analysis, we proved that patients with two “null” variants had a younger onset age and reached legal blindness earlier than patients with two “none-null” variants. Patients with one or more "none-null" variants tended to have better visual acuity and presented with milder fundus autofluorescence changes and more preserved rod functions on the full-field electroretinography than patients with two “null” variants. Furthermore, most patients with the p.(Phe2188Ser) variant shared a mild phenotype with a low fundus autofluorescence signal limited to the fovea and with normal full-field electroretinography responses. Our findings expand the variant spectrum of the ABCA4 gene and enhance the knowledge of Chinese patients with ABCA4-RD.
Spatial Functional Characteristics of East Asian Patients With Occult Macular Dystrophy (Miyake Disease); EAOMD Report No. 2
2021, American Journal of Ophthalmology
Citation Excerpt :
The functional/structural damages in the parafovea were found correspondently in our cohort, although further detailed analysis in the natural course is required to reveal which of function and structure is impaired earlier. Interestingly, similar patterns were also found in other macular dystrophies or cone/cone-rod dystrophies—for example, ABCA4-associated, POC1B-associated, CRX-associated, and GUCY2D-associated retinal disorders.27,31–35 However, the underlying mechanism to explain this phenotype of preceding parafoveal changes is still uncertain.
To describe the functional phenotypic features of East Asian patients with RP1L1-associated occult macular dystrophy (ie, Miyake disease).
An international multicenter retrospective cohort study.
Twenty-eight participants (53 eyes) with Miyake disease were enrolled at 3 centers (in Japan, China, and South Korea). Ophthalmologic examinations including spectral-domain optical coherence tomography (SDOCT) and multifocal electroretinogram (mfERG) were performed. Patients were classified into 3 functional groups based on mfERG: Group 1, paracentral dysfunction with relatively preserved central/peripheral function; Group 2, homogeneous central dysfunction with preserved peripheral function; and Group 3, widespread dysfunction over the recorded area. Three functional phenotypes were compared in clinical parameters and SDOCT morphologic classification (severe phenotype, blurred/flat ellipsoid zone and absence of the interdigitation zone; mild phenotype, preserved ellipsoid zone).
There were 8 eyes in Group 1, 40 eyes in Group 2, and 5 eyes in Group 3. The patients in Group 1 showed significantly later onset (P = .005) and shorter disease duration (P = .002), compared with those in Group 2. All 8 eyes in Group 1 showed the mild morphologic phenotype, while 43 of 45 eyes in Groups 2 and 3 presented the severe phenotype, which identified a significant association between the functional grouping and the morphologic classification (P < .001).
A spectrum of functional phenotypes of Miyake disease was first documented with identification of 3 functional subtypes. Patients with paracentral dysfunction had the mildest phenotype, and those with homogeneous central or widespread dysfunction showed overlapping clinical findings with severe photoreceptor changes, suggesting various extents of visual impairment.

View all citing articles on Scopus

View full text

Original articleClinical and Molecular Analysis of Stargardt Disease With Preserved Foveal Structure and Function

Purpose

Design

Methods

Results

Conclusions

Section snippets

Patients

Results

Discussion

Ophthalmology

Am J Ophthalmol

Ophthalmology

Exp Eye Res

Ophthalmology

Ophthalmology

Am J Hum Genet

Am J Hum Genet

Exp Eye Res

Uber familiare progressive degeneration in der makulagegend des auges

Albrecht von Grafes Arch Klin Ophthalmol

A photoreceptor cell-specific ATP-binding transporter gene (ABCR) is mutated in recessive Stargardt macular dystrophy

Nat Genet

The genetics of inherited macular dystrophies

J Med Genet

Allelic and phenotypic heterogeneity in ABCA4 mutations

Ophthalmic Genet

Stargardt disease with preserved central vision: identification of a putative novel mutation in ATP-binding cassette transporter gene

Acta Ophthalmol

Long-term follow-up of Stargardt's disease and fundus flavimaculatus

Ophthalmology

Variation of clinical expression in patients with Stargardt dystrophy and sequence variations in the ABCR gene

Arch Ophthalmol

Phenotypic subtypes of Stargardt macular dystrophy-fundus flavimaculatus

Arch Ophthalmol

Late-onset Stargardt disease is associated with missense mutations that map outside known functional regions of ABCR (ABCA4)

Hum Genet

Correlation between photoreceptor layer integrity and visual function in patients with Stargardt disease: implications for gene therapy

Invest Ophthalmol Vis Sci

Pattern electroretinography of larger stimulus field size and spectral-domain optical coherence tomography in patients with Stargardt disease

Br J Ophthalmol

A comparison of fundus autofluorescence and retinal structure in patients with Stargardt disease

Invest Ophthalmol Vis Sci

Transition zones between healthy and diseased retina in choroideremia (CHM) and Stargardt disease (STGD) as compared to retinitis pigmentosa (RP)

Invest Ophthalmol Vis Sci

Spectral-domain OCT peripapillary retinal nerve fibre layer thickness measurements in patients with Stargardt disease

Br J Ophthalmol

Cone photoreceptor abnormalities correlate with vision loss in patients with Stargardt disease

Invest Ophthalmol Vis Sci

Quantification of peripapillary sparing and macular involvement in Stargardt Disease (STGD1)

Invest Ophthalmol Vis Sci

Phenotypic spectrum of autosomal recessive cone-rod dystrophies caused by mutations in the ABCA4 (ABCR) gene

Invest Ophthalmol Vis Sci

ABCA4 mutations and discordant ABCA4 alleles in patients and siblings with bull's-eye maculopathy

Br J Ophthalmol

Original article
Clinical and Molecular Analysis of Stargardt Disease With Preserved Foveal Structure and Function