Macular dystrophies mimicking age-related macular degeneration
Introduction
Age-related macular degeneration (AMD) is a progressive chronic disease of the central retina and the leading cause of irreversible blindness in the elderly population in industrialized countries (Lim et al., 2012). Based on a meta-analysis of studies in white people aged 40 years and older, the prevalence of early AMD is estimated to be 6.8% and the late stages to be 1.5% (Smith et al., 2001). The prevalence of AMD increases exponentially with age (Rudnicka et al., 2012). In the Beaver Dam Eye Study that includes predominantly white participants, individuals of age 75 years and older, the fifteen year cumulative incidence of early AMD was 24.4% and of late AMD was 7.6% (Klein et al., 2007). The prevalence of AMD, however, differs in ethnic groups. The Baltimore Eye Study has shown that late stage AMD was nine to ten times more prevalent in the white as compared to the black participants (Friedman et al., 1999). In the Asian population, the prevalence of late stage AMD appears to be largely similar to that in white people (Kawasaki et al., 2010).
Different cell layers are involved in the disease process: the photoreceptors, the retinal pigment epithelium (RPE), Bruch's membrane and the choriocapillaris.
Different stages and phenotypic manifestations of AMD have been categorized (Ferris et al., 2013): The early stages (early and intermediate AMD) are characterized by pigmentary alterations and/or the formation of so called ‘drusen’, extracellular material located between the RPE and the Bruch's membrane. Patients with early AMD are usually asymptomatic. AMD may progress to exudative (neovascular) AMD and non-exudative (atrophic) AMD, both resulting in vision loss. Typically, patients with neovascular AMD describe sudden worsening of central vision with distortion of straight lines or a dark patch in their central vision. In atrophic AMD progressive loss of vision develops over many years. Neovascular AMD and atrophic AMD may also occur in combination. The most severe decline of visual acuity from AMD is caused by these advanced forms of the disease. In addition, psychophysical studies have demonstrated that several parameters of visual function, in particular contrast sensitivity, visual adaptation, central visual field, and colour discrimination, deteriorate already in the early stages of AMD (Neelam et al., 2009). Since the disturbance in psychophysical function in AMD is not limited to the macular region, but extends well into the retinal periphery, it appears that there is a global impairment of retinal function (Ronan et al., 2006, Walter et al., 1999).
The pathogenesis of AMD is incompletely understood. As a complex, multifactorial disease, it is thought to involve variations in a number of genetic, systemic and environmental factors. Ageing itself appears to be the major risk factor that renders the retina more susceptible to environmental effects (Boulton, 2013).
Biochemical, histological and genetic studies have indicated several pathways in AMD pathogenesis, including excessive accumulation of lipofuscin, oxidative damage, malfunctioning of the complement system, and chronic low-grade inflammation and possible sequences of events have been proposed.
Lipofuscin accumulates in postmitotic RPE cells with age apparently due to incomplete lysosomal degradation of photoreceptor outer segments (reviewed by Boulton (2013)). Lipofuscin consists of a multitude of molecules including the dominant fluorophore N-retinyl-N-retinylidene ethanolamine (A2E), a by-product of the visual cycle (Suter et al., 2000) (Palczewska et al., 2010). Exposure of lipofuscin containing RPE cells to blue light (390–520 nm) results in a lipofuscin-dependent lipid peroxidation, protein oxidation, loss of lysosomal integrity, mitochondrial DNA damage, and RPE cell death (reviewed by Boulton (2013)). It has further been suggested that products of the photooxidation of A2E in RPE cells could serve as a trigger for complement activation (Zhou et al., 2006). An aberrant complement regulation - that is implicated by the association of the risk for AMD with DNA sequence variants in genes encoding for complement factors (see below) – appears to contribute to chronic inflammation. Herein, drusen are thought to form as a product of those local inflammatory processes (Donoso et al., 2006, Hageman et al., 2001).
In recent years, major progress was made in elucidating the genetic basis of AMD through the identification of two common variants on chromosome 1 and 10, together likely accounting for approximately 50% of cases. On chromosome 1, a strong association was identified with variants in the complement factor H (CFH) gene, suggesting an involvement of the complement cascade in AMD pathogenesis (Edwards et al., 2005, Hageman et al., 2005, Haines et al., 2005, Klein et al., 2005). Subsequently, AMD risk variants in other genes involved in the complement cascade were identified, for example in the complement component 2/factor B (Gold et al., 2006), component 3 (C3) (Maller et al., 2007), and complement factor I genes (Maller et al., 2007). The second major AMD risk locus was identified on chromosome 10. Disease associated variants support a region harbouring two genes in strong linkage disequilibrium, named the age-related maculopathy susceptibility 2 gene and the high temperature requirement factor A1 gene (Jakobsdottir et al., 2005, Rivera et al., 2005). However, the functional implications of the chromosome 10 locus on AMD pathology are still unclear. A genomic wide association study recently performed by the AMD Gene Consortium found in total 19 loci associated with AMD, including seven new loci (Fritsche et al., 2013). Recently, rare, highly penetrant mutations in the CFH and Complement Factor I genes have been identified besides the common genetic variants, conferring a high risk of AMD (Boon et al., 2008c, Raychaudhuri et al., 2011, van de Ven et al., 2012a, van de Ven et al., 2013). Rare variants may play an important role in the pathogenesis of AMD particularly in case of densely affected families.
Recently, a predictive model for late stage AMD based on data from population-based studies (the Rotterdam Study, the Beaver Dam Eye Study, and the Blue Mountains Eye Study) has been reported. It has been shown that best prediction for late AMD was based on age, sex, 26 genetic variants, 2 environmental variables, and early AMD phenotype (Buitendijk et al., 2013).
There are no pathognomonic clinical characteristics for AMD, despite the fact that drusen are a hallmark feature. Different clinical manifestations may be present, leading to a broad phenotypic spectrum of AMD. Due to this clinical variability of AMD, there is a considerable overlap with a number of macular dystrophies that are often monogenic with specific inheritance patterns. Also, AMD and the macular dystrophies show a considerable variation in their clinical presentation and severity. Flecks that may resemble drusen can be present in several hereditary macular conditions. Many macular dystrophies may show chorioretinal atrophy comparable to geographic atrophy (GA) in AMD. Choroidal neovascularisation (CNV) can also occur in macular dystrophies, although it is rare and appears to have a relatively favourable prognosis as compared to CNV in AMD (Marano et al., 2000).
A differentiation between AMD and other macular disorders is important as the exact diagnosis can have implications for the prognosis and genetic counselling as well as for preventive and therapeutic strategies.
This review aims to give an overview of macular dystrophies that may mimic AMD. For every disease we describe the symptoms, multimodal imaging and psychophysical and electrophysiological testing. In addition, we also summarize the genetic background and the pathophysiology of each disease. Based on these specific clinical and genetic characteristics, we provide a practical differential diagnostic guideline.
Section snippets
Drusen and ‘drusen-like lesions’
Drusen are considered as the phenotypic hallmark of AMD, but they are not pathognomonic of AMD (Wang et al., 2010). Drusen are focal deposits of extracellular debris located between the basal lamina of the RPE and the inner collagenous layer of Bruch's membrane (Green and Enger, 1993, Sarks, 1980). Drusen are known to contain carbohydrates, zinc, and at least 129 different proteins, including apolipoproteins and excluding extracellular matrix (Anderson et al., 2001, Crabb et al., 2002, Lengyel
Differential diagnostic tools
The most important differential diagnostic findings and genetic associations of each macular dystrophy are summarized in Table 1. With the advancements in multimodal retinal imaging and genetic testing, a spectrum of diagnostic tools is currently available to establish the correct diagnosis. An overview of important differentiating findings with the available differential diagnostic tools is given below.
Clinical characteristics
The onset of ML is generally in the third to fourth decade of life, but shows a wide variation (Evans et al., 1997
Conclusions and future directions
A broad range of dystrophic macular disorders share clinical characteristics with AMD, which can make a differential diagnosis challenging. Although macular dystrophies and AMD show broad genetic and phenotypic heterogeneity, with overlapping features that may complicate a comprehensive clinical classification, there are often characteristic phenotypic features that can help in the differential diagnosis in a practical clinical setting. We propose a diagnostic flow chart in Fig. 7. This flow
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Cited by (65)
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2023, Ophthalmology ScienceWeakly-supervised detection of AMD-related lesions in color fundus images using explainable deep learning
2023, Computer Methods and Programs in BiomedicineCitation Excerpt :Despite their convenience, implementing screening programs for AMD on a large scale is usually unfeasible, since the population at risk is large and the analysis of color fundus images is highly challenging. The inherent difficulty of the diagnosis is compounded by the fact that AMD is characterized by many different lesions that, in many cases, coincide with (or resemble) those of other macular diseases [12]. This forces such analyses to be performed by expert clinicians.
The Natural History of Leber Congenital Amaurosis and Cone–Rod Dystrophy Associated with Variants in the GUCY2D Gene
2022, Ophthalmology RetinaCitation Excerpt :The chorioretinal atrophy in advanced cases of GUCY2D-associated CORD can also resemble end-stage central areolar choroidal dystrophy associated with the PRPH2 gene or geographic atrophy found in end-stage atrophic age-related macular degeneration.24–26 The resemblance with age-related macular degeneration has also been described in other IRDs, but the absence of drusen and, in most cases, the early onset around the second decade of life of GUCY2D-associated CORD are helpful in differentiating the condition from age-related macular degeneration26; however, 1 patient displayed drusenoid, hyperautofluorescent dots on FAF and later developed atrophy (Fig 3D–H), which could complicate differentiation. It is noteworthy that 3 patients who were screened for CORD at young ages because of known affected family members had isolated tritan color vision disturbances without other clear abnormalities or symptoms.15
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Camiel J.F. Boon was supported by a Niels Stensen Fellowship Award.
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Percentage of work contributed by each author in the production of the manuscript is as follows: Nicole Saksens, 35%; Monika Fleckenstein 25%; Steffen Schmitz-Valkenberg 5%; Camiel Boon 15%; Anneke den Hollander 5%; Holz 5%; Keunen 5%; Hoyng 5%.