Stargardt Disease/Fundus Flavimaculatus
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Disease Entity
Stargardt disease (STGD), first described by the German ophthalmologist Karl Stargardt in 1909, is the most common childhood recessively inherited macular dystrophy. The genetically based condition is due to mutations in the ABCA4 gene on chromosome 1 that encodes a retinal transported protein. The disease results from the accumulation of visual cycle kinetics-derived byproducts in the retinal pigmented epithelium (RPE) with secondary photoreceptor dysfunction and death.
Incidence and Epidemiology
Stargardt disease accounts for about 7% of all retinal degenerations, grossly affecting 1 out of every 10,000 individuals. The disease usually manifests in early childhood or adolescence, but later onset has also been reported. As with all autosomal conditions, males and females are equally affected. No race predilection has been noted. The disease progression is slow, but all affected individuals ultimately experience severe visual disability between their 4th and 7th decade.[1]
Genetics
In its typical form, STGD1 (OMIM #248200), Stargardt disease is caused by mutations involving the ABCA4 gene through autosomal recessive homozygous or compound heterozygous transmission. Autosomal dominant transmission is also possible through heterozygous mutations in the PROM1 gene (4p), as seen in STGD4 (OMIM #603786),.
Stargardt-like macular dystrophies involving dominant mutations in the ELOVL4 gene (6q14.1) present with overlapping clinical features of Stargardt disease but are not considered typical Stargardt disease; collectively they are referred to as STGD3 (OMIM #600110). The STGD2 form of the disease was discovered to be tied to the same gene as STGD3, so the term STGD2 was discontinued in 2005.
The ABCA4 gene maps to the short arm of chromosome 1 (1p22.1) and presents with extraordinary allelic heterogeneity, with over 490 disease-associated variants discovered thus far, most of which are missense mutations. As a result, the most frequent ABCA4 disease-associated alleles (i.e., G1961E, G863A/delG863, and A1038V) account for only about 10% of patients with STGD, making the gene a rather difficult diagnostic target. Also, the presence of ethnic group–specific ABCA4 alleles is responsible for founder phenomena in different areas of the globe. Examples include the T1428M allele, which is extremely rare in populations of European descent but rather commonly seen among Japanese populations (estimated frequency of approximately 8%), and the G863A/delG863 allele, which is currently considered a founder mutation in Northern Europe. Spanning 150 kb and comprising 50 exons varying in size from 33 bp to 266 bp, ABC4 is a large gene and codes for a 2,273–amino acid protein.
Spectrum of Disease
Given the significant carrier frequency for ABCA4 alleles in the general population (5–10%), the association between ABCA4 variants and retinal pathology is broader than originally thought. Different combinations of ABCA4 alleles are thought to result in distinct phenotypes along a continuum of retinal disease manifestations, and it appears that the severity of disease is inversely proportional to the residual ABCA4 activity. Likewise, there is evidence indicating that ABCA4 is also implicated in the pathogenesis of various other retinal diseases, including age-related macular degeneration (AMD), some cone-rod dystrophies, and forms of retinitis pigmentosa. It is thought that Stargardt disease results from partial (but not complete) inactivation of both alleles, allowing for residual low-level ABCA4 expression, whereas retinitis pigmentosa—the most severe of ABCA4-related conditions—derives from the presence of two null ABCA4 alleles, fully compromising the gene's pattern of genetic expression. These assumptions are further supported by the fact that ABCA4 mutations are thought to be involved in 30–60% of autosomal recessive cone–rod dystrophies. Even within the same family, different ABCA4 allelic combinations can be responsible for distinct disease phenotypes.
Late-onset Stargardt disease appears to be associated with missense mutations that map outside known functional domains of ABCA4, thereby resulting in milder mutant alleles and suggesting that some ABCA4 variants and combinations lead to less severe and later-onset subsets of the disease (e.g., fundus flavimaculatus). Nonetheless, the observed clinical phenotypes of Stargardt disease are also significantly influenced by age at time of diagnosis and, accordingly, progression of the disease. Moreover, other genes and/or environmental factors may contribute to ABCA4 expression, influencing the resulting phenotype.
Substantial evidence supports the fact that some ABCA4 heterozygote carriers may have an increased risk of developing AMD. It was shown in a multicenter international study that heterozygotes for the G1961E ABCA4 allele had a fivefold increased risk of developing AMD, and that carriers of the D2177N variant had a threefold increased risk. However, although some ABCA4 mutations may influence AMD development, they represent only a minor cause. Several smaller-sized mutation screening studies and most of the co-segregation studies in AMD families have failed to establish a direct correlation between AMD and ABCA4. Thus, the exact relationship between AMD and ABCA4 remains speculative.
Interestingly, a Portuguese group identified that heterozygous carriers of some ABCA4 mutations could have insufficient ABCA4 expression, leading to subnormal visual function, as revealed by psychophysical and electrophysiological testing. In this study, individuals who were normal carriers for Stargardt disease were found to have intermediate visual performance, somewhere between age-matched control subjects and their relatives with active disease. Thus, relatives of Stargardt patients should receive periodic follow up because their visual function as a group seems to be subnormal.
Pathophysiology
The ATP-binding cassette (ABC) superfamily, further organized into 7 subfamilies (ABCA to ABCG), comprises a broad and heterogeneous group of proteins specialized in the active transport of various substrates (e.g., amino acids, small peptides, ions, metals, lipids and fatty acid derivatives, steroids, organic anions, vitamins, and drugs) across cellular membranes against a concentration gradient . ABC proteins exist in virtually every living organism and are involved in various human diseases. Grossly, their molecular structure consists of two transmembrane domains that provide a pathway for substrate translocation and 2 ATP-binding domains that bind and hydrolyze ATP, thereby supplying the energy required for substrate transport. At least 48 genes are known to encode ABC transporters across the genome.
This ABCA subfamily has been implicated in severe inherited diseases involving defects in lipid transport, and such is the case for Stargardt disease (due to its association with the ABCA4 gene). Although ABC transporters are present across the entire human organism, the ABCA4 transporter localized to the disc membranes in cone and rod outer segments in the retina. There, it participates in the retinoid cycle through which the retina recycles 11-cis-retinal, the visual chromophore, and returns the photoreceptor to its dark-adapted state to enable further phototransduction. These reactions take place on the two outermost cellular layers of the human retina: the photoreceptor cell layer (where ABCA4 is expressed) and the RPE. It is theorized that ABCA4 works as a “flippase,” actively transporting the retinal byproduct N-retinylidene-phosphatidylethanolamine (N-retinylidene-PE) across the disc membranes, though this remains to be experimentally confirmed.
Much of our understanding about ABCA4 function derives from knockout experiments in the genetically engineered abca4 mouse. These mice, whether homozygous or heterozygous for abca4, maintain normal retinal appearance and photoreceptor structure (including normally organized outer segments) instead of what is often observed in other degenerative retinal conditions. Also, their electrophysiological studies tend to remain normal, though delayed rod-mediated dark adaptation is a characteristic feature. From a biochemical standpoint, abca4 mice fail to transport N-retinylidene-PE across disc membranes, leading to progressive entrapment of this molecule inside the discs. N-retinylidene-PE reacts with available all-trans-retinal to form an intermediate byproduct, Di-retinoid-pyridinium-phosphatidylethanolamine (A2PE). Upon photoreceptor renewal, byproduct-loaded outer segments are taken up by the adjacent RPE. There, A2PE is converted to Di-retinoid-pyridinium-ethanolamine (A2E), a vitamin A dimer, which becomes permanently trapped in the RPE due to the impossibility of further hydrolyzation. A2E is a major component of lipofuscin, a hallmark of cellular degeneration. These experiments indicate that ABCA4 is not required for normal photoreceptor structure or morphogenesis. In fact, it seems to play a metabolic role, being responsible for the removal of retinoid byproducts from disc membranes after photobleaching of rhodopsin, preventing retinoid accumulation in the subcellular space.
Studies in the abca4 knockout mouse support the pathophysiological model of human disease. Mutant ABCA4 would be unable to transport N-retinylidene-PE across disc membranes, leading to progressive accumulation of N-retinylidene-PE inside disc lumina. All-trans-retinal would also excessively accumulate. When in excess, all-trans-retinal can reassociate with opsin to form a complex that activates the visual cascade, although less efficiently than photoactivated rhodopsin. This low level of activity could explain the prolonged dark adaptation usually found in patients with Stargardt disease and in abca4 knockout mice, and it explains the residual vision often observed in patients with Stargardt disease.
Like in abca4 knockout mice, progressive accumulation of A2E in the RPE of patients with Stargardt disease as lipofuscin deposits is a histological hallmark of the disease. In these patients, lipofuscin can accumulate up to 5 times above normal values. Excess A2E in the RPE exerts a negative effect on the epithelium’s function and survival and can act as a biological detergent, compromising normal cellular membrane architecture and inhibiting normal RPE metabolic functions. Additionally, in the presence of oxygen and blue-wavelength light, A2E forms free epoxide radicals which induce RPE cell death and compromise the photoreceptor layer. Beyond giving structural support and promoting photoreceptor renewal, the RPE provides nutritional support to photoreceptors and participates in the regeneration of rhodopsin. Therefore, death of RPE cells inevitably leads to irreversible secondary photoreceptor degeneration and, consequently, loss of vision. However, it is also been postulated that photoreceptor loss might actually precede RPE cell death.
Clinical Features
Patients with Stargardt disease can be asymptomatic, but they commonly present with bilateral central visual loss, photophobia, color vision abnormalities, central scotomas, and slow dark adaptation.
Visual deterioration is rapidly progressive. Though age of onset is highly variable, it most often occurs between childhood and adolescence or early adulthood. At presentation, visual acuity may range between 20/20 and 20/400, with prior visual acuity frequently being normal; very few patients have further visual deterioration to counting fingers or hand motion. It seems that the visual prognosis is highly dependent on the age of disease onset, with poorer outcomes seen in patients presenting with significantly compromised vision at an earlier age.
Color vision is typically compromised with Stargardt disease. Using Hardy-Rand-Rittler or Ishihara color plates, it is possible to detect a mild red–green dyschromatopsia. Moreover, when these patients are submitted to a Farnsworth-Munsell Hue Test, a tritan axis (or short wavelength) deviation may be noted.
Diagnosis
Diagnostic evaluation of Stargardt disease is based on family history, visual acuity, fundus examination, visual field testing, fluorescein angiography, fundus autofluorescence (FAF), electroretinography (ERG), and optical-coherence tomography (OCT). Patients frequently deny a positive family history; when one is identified, an autosomal recessive pattern of inheritance is most common. However, genetic testing is currently not performed on a routine basis.
Physical Examination
Stargardt disease affects the macula with variable centrifugal expansion. Fundus examination is frequently normal early in the course of disease, even when patients already complain of vision loss. At this stage, the clinical diagnosis of Stargardt disease may be missed and patients’ complaints can be easily interpreted as functional visual loss. Later on, typical fundus manifestations arise, including pigment mottling, frank macular atrophy, a bull’s eye maculopathy, sparing of the peripapillary retina, and fundus flecks. However, it should be underscored that Stargardt disease presents with highly variable phenotypes.
Fundus flecks are pisiform, round, or dot-like yellow-white lesions that are typically associated with Stargardt disease and should be present when considering a clinical diagnosis. Flecks indicate the accumulation of lipofuscin in the RPE, but they may also represent areas of regional depigmentation and atrophy. Flecks may form individual or confluent patterns but have a typical central distribution, with variable mid-periphery involvement. Distribution of flecks can change over time and does not correlate well with the visual loss, nor dose there seem to be any intrafamiliar concordance.
Visual field testing in patients with Stargardt disease is often normal in early disease stages. Over time, relative central scotomas develop, further progressing to absolute central scotomas in a variable fashion. Patients with Stargardt disease typically preserve their peripheral visual fields. However, in severe cases with widespread retinal atrophy, visual constriction can occur. Another particularly important finding is the change in preferred retinal locus of fixation. Early in Stargardt natural history, most patients maintain foveal fixation. However, as the disease progresses and absolute central scotomas develop, the preferred retinal fixation becomes eccentric, as demonstrated by microperimetry. In most cases, the new eccentric fixation point localizes above the fovea, where contrast sensitivity to low spatial and high temporal frequency stimuli seems best. This is also consistent with the fact that the superior retina has higher densities of ganglion cells. Furthermore, ABCA4-related disorders (including Stargardt disease) tend to spare the structure and function of the parapapillary retina. A parapapillary ring of normal-appearing fundus autofluorescence can be identified in all disease stages. Additional histological examination shows that the structural abnormalities increase as a function of distance from the optic disc. This area can serve as preferred retinal locus of fixation in up to 30% of patients.
Imaging
Fluorescein angiography currently has a limited role in the diagnostic evaluation of Stargardt disease and is not performed on a routine basis; FAF is less invasive and provides similar data. However, fluorescein angiography can be useful at initial presentation whenever fundus changes are not obvious, and has been known to reveal a “dark-choroid” sign in up to 62% of patients. This sign (not exclusive of Stargardt disease) derives from a lack of early choroidal hyperfluorescence due to high-grade lipofuscin accumulation in the RPE, thus improving visualization of the small retinal capillaries over the dark, non-fluorescent, high-contrast choroid. Fundus flecks, seen as small irregular hyperfluorescent lesions over the “dark-choroid” background, further suggest a diagnosis of Stargardt disease.
Fundus autofluorescence provides a fast, non-invasive way to study the health and viability of the RPE. Abnormally increased FAF represents excessive lipofuscin accumulation in the RPE, whereas decreased areas of FAF relate to low metabolic activity, which normally underlies local atrophy with secondary photoreceptor loss. Therefore, FAF is perfectly adequate to stage and diagnose Stargardt disease, especially if combined with ultrastructural data derived from OCT. Abnormalities in FAF intensity are an early sign of ABCA4-related disease and correlate well with local severity. Abnormally high FAF intensity with all other normal parameters suggests that RPE lipofuscin deposition may be the first pathophysiological event in ABCA4-related disease.
Electrophysiological studies have shown that many patients with Stargardt disease typically maintain normal or subnormal full-field electroretinographic scotopic (rods) and photopic (cones) responses. However, patients with widespread disease can present with notably abnormal responses. Given that there is no reliable way to predict the type of functional visual loss based on the fundus examination alone, electrophysiological testing is essential to evaluate patients with Stargardt disease; it holds particular prognostic value for patients that present with early peripheral photoreceptor dysfunction, with a greater chance of developing greater functional losses. Curiously, there seems to be intra-familial homogeneity in the qualitative pattern of functional loss. Electroretinography can further demonstrate the slow dark adaptation typical of Stargardt disease, correlating with underlying slow rod kinetics. Delay of dark adaptation is strongly correlated with the absolute dark-adapted rod sensitivity at the same retinal locus, suggesting a direct relationship between the extent of local rod photoreceptor degeneration and abnormality of retinoid cycle kinetics. More central retinal locations show slower kinetics and lower sensitivities than more peripheral loci. Cone dark-adaptation kinetics have similar results and, thus, rod and cone thresholds present comparable loss. Interestingly, retinoid cycle–slowing tends to progress like the underlying retinal degeneration: younger individuals with less severe disease demonstrate faster photoreceptor responses than older individual with more advanced disease.
Ultrastructural imaging provided by OCT is a fast-evolving tool that has been applied to the real-time, non-invasive, in vivo study of retinal diseases like Stargardt disease. Newer high-resolution tools using super-luminescent diodes and ultrashort pulsed lasers allow sub-micrometer resolution, further improving image detail. Combined with FAF data, OCT can provide valuable information regarding disease staging, and it allows for early detection of lipofuscin accumulation in the RPE and of photoreceptor layer disorganization. In particular, OCT may provide a more precise evaluation of local disease severity than FAF, identifying inner segment/outer segment (IS–OS) junction loss that may precede absent FAF. When areas of absent fluorescence were analyzed using OCT, the degree of photoreceptor loss were greater than expected. These findings led to the assumption that photoreceptor loss may actually precede RPE cell death, bringing new insights into the pathophysiology of Stargardt disease.[2]
Genetic Screening
The ABCR400 microarray was developed to overcome the ABCA4 genetic screening challenges, and it contains all currently known disease-associated genetic variants and many common ABCA4 polymorphisms. Overall detection rates range between 65% and 75%. Several laboratories worldwide provide genetic testing of the ABCA4 gene.
Fundus Flavimaculatus
Once thought to represent a completely distinct condition, fundus flavimaculatus shares obvious phenotypic similarities with Stargardt disease and the two are now thought to be genetically linked. Patients with fundus flavimaculatus often have a later disease onset and slower visual deterioration than those with Stargardt disease, making fundus flavimaculatus a milder condition overall. Surprisingly, fundus photographs of fundus flavimaculatus show more widespread retinal involvement; flecks are more diffusively scattered throughout the posterior pole and extend out to the midperiphery, though the macula is less involved, allowing better visual performance.
Management
General Treatment
Stargardt disease remains an incurable condition. Current therapeutic options include photoprotection and low-vision aids. Pharmacological slow-down of the visual cycle, gene therapy, and other treatment options aim to prevent lipofuscin accumulation and represent prospects of long-term visual rescue.
Unbound all-trans-retinal induces photo-oxidative damage to the unusually sensitive ABCA4, further compromising its function. Patients with Stargardt disease already have impaired ABCA4 function and increased levels of trapped all-trans-retinal. Thus, they are are extremely sensitive to light exposure. Considering also that di-retinoid-pyridinium-ethanolamine (A2E) does not accumulate in the RPE of abca4 knockout mice kept in total darkness, patients with Stargardt disease should be advised to avoid direct sunlight exposure. Ultraviolet-blocking sunglasses are a useful option.
While vitamin A supplementation has been regarded as a possible therapeutic option for certain retinal degenerative conditions (e.g., retinitis pigmentosa), recent data suggests that in ABCA4-mediated disease, it accelerates the accumulation of lipofuscin pigments in the RPE. Long-term vitamin supplementation increases the formation of vitamin A dimers, which favors lipofuscin synthesis and deposition. Therefore, patients with Stargardt disease should avoid vitamin A supplementation.
Isotretinoin has reportedly been capable of dampening A2E deposition in the RPE of abca4 knockout mice. However, considerable side effects associated with chronic intake of isotretinoin prevent its chronic use in humans.
Phase 1, 2, and 3 drug trials have investigated the use of agents like ALK-001, soraprazan, LBS-008, STG-001, fenretinide, and vutrisiran for decreasing formation of A2E and lipofuscin.
Gene Therapy
Stargardt disease is a preferred target for gene replacement therapy. Like in Leber Congenital Amaurosis (LCA), the replacement of the mutant ABCA4 gene by its wild-type counterpart can produce positive results, as was observed in RPE65 gene trials.
Animal testing of gene therapy for Stargardt disease remains limited. Kong and colleagues were able to successfully treat the Stargardt phenotype in abca4 knockout mice using lentiviral gene therapy. Each mouse received a single unilateral subretinal injection of ABCA4-carrying equine infectious anemia viral vectors, which resulted in significant rescue of the retinal phenotype. Treated eyes showed marked reduction in retinal A2E accumulation, and 1 year after gene transfer, A2E accumulation in treated eyes matched the A2E levels of normal wild-type controls.
The relatively large ABCA4 gene (6.8 kb) presents a unique packaging challenge with the available viral vectors. Lentiviral vectors are the most suitable for ABCA4 gene transfer. Other packaging options include AAV2/5 chimeras, Hd-Ad vectors, and other non-viral vectors.
Given that Stargardt is a retinal degeneration disease, retinal imaging is essential for identifying viable photoreceptors and selecting patients who may benefit from gene therapy. High-definition OCT and Adaptive Optics technology enhance lateral resolution in retinal images up to 3–4 μm, allowing the visualization of individual photoreceptors.
Years of gene therapy research for LCA and underlying RPE65 mutations have produced breakthroughs that will invariably serve as a foundation for further research involving other retinal dystrophies. In December 2009, Oxford BiomedicaTM announced that StarGenTM, a gene-based therapy that uses the company’s LentiVector technology for the treatment of Stargardt disease, had received orphan designation from the Committee for Orphan Medicinal Products of the European Medicines Agency (EMEA). In collaboration with Sanofi-Aventis, both companies advanced StarGenTM into PhaseI/II development in 2010. The US charity Foundation Fighting Blindness is also supporting the program and previously funded its preclinical development. With this initiative, Oxford BiomedicaTM is poised to bring considerable hope to the 600 new cases of Stargardt disease diagnosed every year and for Stargardt patients that currently await treatment for their visually-debilitating condition. Further trials to investigate the efficacy of complement inhibitors, stem cell transplantation, and ABCA4 gene therapy are in order.
Acknowledgements
To Prof. Eduardo J. G. Duarte Silva for his significant contribution.
Additional Resources
- Boyd K, Janigian RH. Juvenile Macular Degeneration. American Academy of Ophthalmology. EyeSmart/Eye health. https://www.aao.org/eye-health/diseases/juvenile-macular-degeneration-list. Accessed March 14, 2019.
- Boyd K, Vemulakonda GA. Stargardt Disease. American Academy of Ophthalmology. EyeSmart/Eye health. https://www.aao.org/eye-health/diseases/stargardt-disease-list. Accessed March 25, 2019.
- 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 Nov;79:100861. doi: 10.1016/j.preteyeres.2020.100861. Epub 2020 Apr 9. PMID: 32278709; PMCID: PMC7544654.
References
- ↑ Cremers FPM et al. Clinical spectrum, genetic complexity and therapeutic approaches for retinal disease caused by ABCA4 mutations. Prog Retin Eye Res. 2020:100861.
- ↑ Gomes NL et al. A comparison of fundus autofluorescence and retinal structure in patients with Stargardt disease. Invest Ophthalmol Vis Sci. 2009 Aug;50(8):3953-9. doi: 10.1167/iovs.08-2657. Epub 2009 Mar 25. PMID: 19324865; PMCID: PMC2749553.
