Progress in Retinal and Eye Research xxx (2015) 1e23

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Adult-onset foveomacular vitelliform dystrophy: A fresh perspective Itay Chowers a, *, 1, Liran Tiosano a, 1, Isabelle Audo c, d, e, f, 1, Michelle Grunin a, 1, Camiel J.F. Boon b, 1 a

Department of Ophthalmology, Hadassah e Hebrew University Medical Center, Jerusalem, Israel Department of Ophthalmology, Leiden University Medical Center, Albinusdreef 2, 2333 ZA Leiden, The Netherlands c INSERM, U968, Paris, F-75012, France d Sorbonne Universit es, UPMC Univ Paris 06, UMR_S 968, Institut de la Vision, Paris, F-75012, France e CNRS, UMR_7210, Paris, F-75012, France f Centre Hospitalier National d'Ophtalmologie des Quinze-Vingts, DHU ViewMaintain, INSERM-DHOS CIC 1423, Paris, F-75012, France b

a r t i c l e i n f o

a b s t r a c t

Article history: Received 8 November 2014 Received in revised form 1 February 2015 Accepted 4 February 2015 Available online xxx

Adult-onset foveomacular vitelliform dystrophy (AFVD) was first described by Gass four decades ago. AFVD is characterized by subretinal vitelliform macular lesions and is usually diagnosed after the age of 40. The lesions gradually increase and then decrease in size over the years, leaving an area of atrophic outer retina and retinal pigment epithelium. This process is accompanied by a loss of visual acuity. Vitelliform lesions are hyperautofluorescent and initially have a dome-shaped appearance on optical coherence tomography. The electro-oculogram and full-field electroretinogram are typically normal, indicating localized retinal pathology. Phenocopies are also associated with other ocular disorders, such as vitreomacular traction, age-related macular degeneration, pseudodrusen, and central serous chorioretinopathy. A minority of AFVD patients have a mutation in the PRPH2, BEST1, IMPG1, or IMPG2 genes. A single-nucleotide polymorphism in the HTRA1 gene has also been associated with this phenotype. Accordingly, the phenotype can arise from alterations in the photoreceptors, retinal pigment epithelium, and/or interphotoreceptor matrix depending on the underlying gene defect. Excess photoreceptor outer segment production and/or impaired outer segment uptake due to impaired phagocytosis are likely underlying mechanisms. At present, no cure is available for AFVD. Thus, the current challenges in the field include identifying the underlying cause in the majority of AFVD cases and the development of effective therapeutic approaches. © 2015 Elsevier Ltd. All rights reserved.

Keywords: Pattern dystrophy Vitelliform lesion Adult-onset foveomacular vitelliform dystrophy

Contents 1. 2.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Clinical characteristics of adult-onset foveomacular vitelliform dystrophy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1. The adult-onset foveomacular vitelliform dystrophy phenotype . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2. Additional tests in adult-onset foveomacular vitelliform dystrophy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2.1. Imaging . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2.2. Electrophysiology and psychophysical analysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.3. Differential diagnosis of AFVD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.3.1. Vitelliform lesions accompanied by drusen and age-related macular degeneration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.3.2. Vitelliform lesions associated with separation of the retinal pigment epithelium and photoreceptors . . . . . . . . . . . . . . . . . . . . . . . . . . 2.3.3. Best disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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* Corresponding author. Department of Ophthalmology, Hadassah e Hebrew University Medical Center, PO Box 12000, Jerusalem 91120, Israel. Tel.: þ972 50 8573361; fax: þ972 2 6777228. E-mail address: [email protected] (I. Chowers). 1 Percentage of work contributed by each author in the production of the manuscript is as follows: Itay Chowers: 50%; Liran Tiosano: 15%; Isabelle Audo: 5%; Michelle Grunin: 5%; Camiel Boon: 25%. http://dx.doi.org/10.1016/j.preteyeres.2015.02.001 1350-9462/© 2015 Elsevier Ltd. All rights reserved.

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I. Chowers et al. / Progress in Retinal and Eye Research xxx (2015) 1e23

3. 4.

5.

6. 7.

2.3.4. Vitelliform lesions associated with systemic disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.3.5. Butterfly-shaped pigment dystrophy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Histopathology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Genetic associations in adult-onset foveomacular vitelliform dystrophy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.1. The PRPH2 gene . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.2. The BEST1 gene . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.3. The IMPG1 and IMPG2 genes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.4. The overall contribution of known monogenic mutations to adult-onset foveomacular vitelliform dystrophy . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.5. Single-nucleotide polymorphisms (SNPs) and the risk of developing adult-onset foveomacular vitelliform dystrophy . . . . . . . . . . . . . . . . . . . . Treatment options . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.1. Treatment of the degenerative process in adult-onset foveomacular vitelliform dystrophy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.2. Treatment of choroidal neovascularization associated with adult-onset foveomacular vitelliform dystrophy . . . . . . . . . . . . . . . . . . . . . . . . . . . . Integration of current knowledge . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1. Introduction Adult-onset foveomacular vitelliform dystrophy (AFVD) is one of the most prevalent forms of macular degeneration. When first described by Gass in 1974, this phenotype was initially called “peculiar foveomacular dystrophy” (Gass, 1974). It was later renamed adult-onset foveomacular vitelliform dystrophy (AFVD), and has since been classified as one of several forms of pattern dystrophy (PD) (Gass, 1997). Following Gass' initial description, several groups have reported patients with a similar phenotype. Thus, the nature of the underlying pathology, the potential role of genetics in the etiology, and the composition and location of the vitelliform lesion has become the subject of intense interest and debate. AFVD has traditionally been included in the heterogeneous group of PDs which also includes the phenotypes of butterflyshaped pigment dystrophy (BPD), reticular dystrophy of the retinal pigment epithelium, pseudo-Stargardt pattern dystrophy (multifocal pattern dystrophy simulating Stargardt disease/fundus flavimaculatus), and fundus pulverulentus. The term PD itself was suggested by Marmor and by Hsieh to describe dystrophies affecting the retinal pigment epithelium (RPE) (Marmor and Byers, 1977; Hsieh et al., 1977). However, some of the aforementioned PDs, including AFVD, pseudo-Stargardt pattern dystrophy, and butterfly-shaped pigment dystrophy have been associated with mutations in the same gene, PRPH2, which encodes the photoreceptor (and not RPE) protein peripherin-2, which has an important structural role in the photoreceptor outer segments (Boon et al., 2007b, 2008a). Typically, eyes affected by PDs show various patterns of progressive RPE alterations often accompanied by deposition of yellow-dark subretinal material involving the macula and posterior pole. The age at onset in PDs is highly variable, but, patients tend to remain asymptomatic until the 5th decade, or may even remain asymptomatic throughout life. The course of PDs is relatively benign, although severe vision loss occurs in up to 50% of the affected individuals after the age of 70, as a result of chorioretinal atrophy and/or the development of choroidal neovascularization (Yang et al., 2003; Francis et al., 2005). Patients may show different subtypes of PD in each eye, or PD forms which do not fit one specific subtype, suggesting clinical and pathogenetic overlap of the PDs, in particular by AFVD and BPD (Sections 2.3 and 4). Unfortunately, several different terms have been used over the years when describing AFVD. These terms include adult macular vitelliform degeneration (Glacet-Bernard et al., 1990), adult vitelliform macular degeneration (Epstein and Rabb, 1980; Greaves et al., 1990; Theischen et al., 1997), pseudovitelliform macular

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degeneration (Sabates et al., 1982), adult-onset foveomacular pigment epithelial dystrophy (Vine and Schatz, 1980), adult foveomacular vitelliform dystrophy (Burgess et al., 1987; Benhamou et al., 2003), and adult vitelliform macular dystrophy (Brecher and Bird, 1990; Renner et al., 2004). The generic term adult vitelliform lesion was also used to describe vitelliform lesions in adults that do not necessarily have genetic origin. This wide diversity in nomenclature has led to considerable confusion among clinicians, researchers, and patients, and it might accountdat least in partdfor this condition's high misdiagnosis rate (Renner et al., 2004). This variable terminology reflects the lack of consensus with respect to the diagnostic criteria and pathogenesis of AFVD. In this review, Gass' term adult-onset foveomacular vitelliform dystrophy will be used exclusively to describe the phenotype, regardless of the underlying specific genetic cause, family history, and/or age of onset (provided the onset occurred in adulthood). This original term, AFVD, describes the phenotype appropriately with regard to its age at onset, clinical aspect, and its genetic component. For phenocopies which are assumed not to be with a genetic cause (central serous chorioretinopathy, vitreomacular traction, etc.; Section 2.3) the term “acquired vitelliform lesion” may be more appropriate as it does not commit to genetic predisposition (Freund et al., 2011). However, while Gass' terminology suggests that AFVD is a dystrophy, a significant fraction of cases may in fact not be monogenic and could thus be better described with the term degeneration which will be discussed further in Section 6. Furthermore, any precise definition of the AFVD phenotype should take into consideration the fact that vitelliform lesions can be associated with a wide variety of underlying diseases. Because these associations were not recognized fully by Gass when AFVD was originally described, the definition of AFVD should be revisited (see Section 6). The review summarizes the knowledge and insights regarding AFVD obtained in the 40 years since its original description. We will discuss the clinical, histological, genetic, imaging, and functional characteristics of AFVD, and we will conclude with a comprehensive overview of our current understanding of AFVD and its putative causes. 2. Clinical characteristics of adult-onset foveomacular vitelliform dystrophy 2.1. The adult-onset foveomacular vitelliform dystrophy phenotype In his original description of nine cases, Gass suggested that AFVD typically manifests between 30 and 50 years of age, presenting with bilateral subfoveal yellowish deposits covering

Please cite this article in press as: Chowers, I., et al., Adult-onset foveomacular vitelliform dystrophy: A fresh perspective, Progress in Retinal and Eye Research (2015), http://dx.doi.org/10.1016/j.preteyeres.2015.02.001

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approximately one-third of the disc area, with a central pigmented spot (Fig. 1). Over time, the lesion's pigmentation may become more intense, the yellow discoloration can diminish, and the RPE may develop atrophic regions (see Sections 2.2.1.3 and 4, and Fig. 2). AFVD was described as being either asymptomatic or associated with a variety of visual symptoms, including reduced visual acuity and/or metamorphopsia, with a slow course of visual deterioration. Some of the nine patients in the initial report presented with drusen in the vicinity of the lesion. Electrophysiology and color vision studies were generally normal, except for a slightly subnormal electro-oculogram (EOG) in a few cases. Based on this initial description, and based on a suggestive family history in some cases, the disease was hypothesized to have an autosomal dominant inheritance pattern. While much of this initial description is still valid, we now recognize that AFVD often manifests at an older age compared with Gass' described cases, and that it is usually not associated with autosomal-dominant trait. It is worth noting that of the original nine cases described by Gass, two of the patients were 60 and 66 years of age and experienced a recent decrease in visual acuity. Both of these patients had a negative family history of maculopathy, and one patient presented with drusen in addition to the foveal lesions (Gass, 1974). These two cases underscore the heterogeneity of the phenotype commonly called AFVD, and they reflect the difficulty often encountered by clinicians and researchers when attempting to differentiate AFVD from the full spectrum of age-related macular degeneration (AMD). Following the initial description, several groups of patients with a similar phenotype have been reported, providing additional information regarding the spectrum and characteristics of this disorder (Epstein and Rabb, 1980; Vine and Schatz, 1980; Sabates et al., 1982; Burgess et al., 1987; Brecher and Bird, 1990; Glacet-Bernard et al., 1990; Greaves et al., 1990; Theischen et al., 1997; Pierro et al., 2002; Benhamou et al., 2003; Renner et al., 2004; Parodi et al., 2008; Puche et al., 2010; Freund et al., 2011; Querques et al., 2011a). Many of the initial observations were validated and several new findings were reported. In addition to the vitelliform lesion,

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consistent findings among these reports were various degrees of visual acuity, RPE atrophy or hyperpigmentation, and the presence of drusen in a subset of patients (Vine and Schatz, 1980; Sabates et al., 1982; Burgess et al., 1987; Brecher and Bird, 1990; GlacetBernard et al., 1990; Greaves et al., 1990; Theischen et al., 1997; Benhamou et al., 2003; Renner et al., 2004). Additional findings of interest include choroidal neovascularization (CNV) (Vine and Schatz, 1980; Glacet-Bernard et al., 1990; Battaglia Parodi et al., 2000; Da Pozzo et al., 2001; Francis et al., 2005; Mimoun et al., 2013; Tiosano et al., 2014) and RPE detachment (Battaglia Parodi et al., 2000; Puche et al., 2010; Querques et al., 2011a). A major difficulty in the interpretation of the results of these previous studies is the lack of strict diagnostic criteria for AFVD, potentially leading to inclusion of adults with vitelliform lesions secondary to other diseases which are different from AFVD in these reports (Section 2.3). The association of vitelliform lesions with many of these diseases was unknown at the time, also due to a lack of appropriate imaging possibilities such as spectral domain optical coherence tomography (SD-OCT) and fundus autofluorescence (FAF). Yet, despite these limitations, a critical evaluation of these previous reports provides significant insights to AFVD. The role of an autosomal-dominant inheritance pattern, demographics, visual function and outcome of AFVD, and its distinction from AMD were at the focus of such studies. Vine and Schatz described 33 patients who presented with findings similar to the ones described by Gass, and they reported possible autosomaldominant inheritance (Vine and Schatz, 1980). Similarly, Hodes and colleagues reported three cases with a positive family history with progression and visual deterioration in one patient, suggesting that the visual prognosis of AFVD may be guarded with advanced age (Hodes et al., 1984). On the other hand, an autosomal-dominant inheritance pattern was not identified in several other studies. Sabates and colleagues described 42 cases with an AFVD phenotype; their patient cohort had a median age at presentation of 51 years and normal EOG findings (Sabates et al., 1982). Ten of their cases had a follow-up period that exceeded five years, and vision in at least one eye was

Fig. 1. Multimodal imaging of adult-onset foveomacular vitelliform dystrophy. (A) Color fundus photograph showing a typical yellowish vitelliform foveal lesion; the size of the lesion is approximately one-fourth of the disc diameter. (B) Fluorescein angiogram showing blocked fluorescence in the foveal center surrounded by a transmission defect in the early phase of the angiogram. Several small drusen are also visible in the color (A) and early-phase fluorescein angiogram (B). (C) In the late phase of the angiogram, the lesion exhibits staining. (DeE) Fundus autofluorescence imaging reveals hyper-autofluorescence at the site of the vitelliform lesion (D), whereas optical coherence tomography reveals a corresponding dome-shaped hyperreflective subretinal lesion (E).

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Fig. 2. Stages of adult-onset foveomacular vitelliform dystrophy. (A) Spectral-domain optical coherence tomography (SD-OCT), showing a dome-shaped subretinal lesion in the vitelliform stage. The content of the lesion is homogenously hyper-reflective. (B) In the pseudohypopyon stage, a hyporeflective area is visible (presumably corresponding to an area of partial liquefaction of the lesion) in combination with a hyperreflective homogenous area containing the remaining vitelliform material. This hyporeflective material can accumulate in the upper part of the lesion or on the temporal or nasal sides (B). Note the irregular retinal undersurface thickening of the outer segment layer overlying the liquefied area, presumably representing deposits of non-phagocytized shed photoreceptor outer segment material. (C) In the vitelliruptive stage, the lesion flattens, much of the fluid is absorbed, and atrophy of the outer retina and retinal pigment epithelium is evident. (D) The atrophic stage marks the complete absorption of the vitelliform material, atrophy of the photoreceptor outer and inner segments, and atrophy of the outer nuclear layer and retinal pigment epithelium.

preserved at 20/50 or better, suggesting preservation of functional vision at least in the mid-term. Unlike previous reports of AFVD phenotype, no clear inheritance pattern was seen in this patient cohort. The same phenotype together with a negative family history and normal EOG findings was also described in two patients by Skalka (1981). A larger cohort of 81 patients was reported by Greaves et al. (1990). These patients presented with either yellow foveal lesions or foveal pigmented clumps surrounded by a hypopigmented halo, both of these manifestations are compatible with a clinical diagnosis of AFVD. The mean age at the time of their evaluation was 67

years, considerably older than Gass' original cohort and unlike Gass' only one patient had a positive family history. Thirty-four of their patients (42%) also had lesions that were compatible with AMD (in particular, small drusen). Of the 17 patients for whom follow-up data were available (with a median follow-up period of three years), nine had stable vision, whereas the vision of the other eight deteriorated by at least one line of acuity. Based on the age at diagnosis and the presence of clinical features compatible with AMD, Greaves and colleagues concluded that this phenotype is degenerative in nature and is part of the spectrum of AMD. High prevalence of drusen (60%) among patients with vitelliform lesions

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was also detected among another group of 53 eyes (in 31 patients over the age of 50 years) (Burgess et al., 1987). Family history was negative in this cohort, and the authors noted that 53% of the study eyes lost at least two lines of vision (in a median follow-up period of three years). The eyes that presented with yellowish lesions in that study had an increased tendency for vision loss compared to eyes that presented with the pigmented spot subtype. Another relatively large group of 85 cases with putative AFVD had median age of onset of 61 years, and 31 cases had follow-up data ranging from one to ten years (Glacet-Bernard et al., 1990). Only one patient had a positive family history of AFVD. Although 43% of the eyes had visual acuity that was better than or equal to 0.6 at the time of presentation, only 20% of the eyes that were followed for four years maintained this level of acuity, and 15% of eyes developed CNV. The authors commented that based on the late onset of the disease, the lack of consistent familial involvement, and the similarity with other retinal degenerative disorders, this entity may represent a distinct subgroup of AMD with a possible genetic predisposition (see Section 6 for discussion regarding this issue). Finally, 120 eyes in 61 patients that were classified as adult vitelliform macular dystrophy (AVMD) were reported (Renner et al., 2004). The primary inclusion criterion for their study was the presence of a central yellow subretinal lesion smaller than one disc diameter in one or both eyes. The mean age at diagnosis was 55 years, and visual acuity varied among the patients. Fifty-six cases (92%) had a negative family history of AVMD, whereas the other five patients had a first-degree relative with similar pathology. Of the 120 eyes in the study, 25 had follow-up data ranging from 0.9 to 5.3 years. Approximately half of these eyes had disease progression manifesting as reduced visual acuity (in the majority of cases), as well as other visual symptoms such as metamorphopsia, central scotoma, and visual disturbances. These relatively large series as well as more recent AFVD series (Querques et al., 2011a; Jaouni et al., 2012) suggested that the average age at diagnosis of AFVD (6the8th decade of life) is considerably higher compared with Gass' original description. These studies also underscored the fact that most patients have no family history of macular disease. Yet, genetic defects were still suspected to be associated with some AFVD cases, as autosomal-dominant inheritance was described in some of the series as discussed previously, and since AFVD has also been described in identical twins (Cohen et al., 1993). The conclusions based on these studies must be interpreted with caution. In retrospect, it is likely that a subset of AMD patients with acquired vitelliform lesions, typical AFVD cases, and potentially, acquired vitelliform lesions secondary to other diseases (especially when monocular cases were enrolled) were included in the studies. The difficulty in differentiating AFVD from AMD complicates research in AFVD, and is subject to an ongoing discussion (Section 6). The identification of drusen is an important but not sufficient criterion to differentiate AMD from AFVD. AFVD patients can be asymptomatic and AFVD is a late-onset disease. Thus, it is possible that patients remain unaware of the existence of additional affected family members. In support of this hypothesis, Brecher and Bird (1990) identified affected relatives in 10 of the 12 AFVD patients who were evaluated. The majority of these individuals were not aware that they had an affected relative. These authors also suggested that the term “adult vitelliform macular dystrophy” should be reserved for individuals who present with a small vitelliform foveal lesion (as described by Gass) together with an autosomal-dominant inheritance pattern. Brecher and Bird suggested that phenocopies that contain only some of the features should be given a different name. In particular, a subgroup of AMD patients may comprise one such phenocopy (Bloom et al., 1981; Brecher and Bird, 1990).

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New information on additional genetic factors predisposing to AFVD including risk single nucleotide polymorphisms (SNPs) (Jaouni et al., 2012) and mutations transmitted in autosomalrecessive inheritance mode (Bandah-Rozenfeld et al., 2010; Manes et al., 2013) was obtained recently. These data suggest that Brecher and Bird's definition of AFVD should be extended to each AFVD case in which a genetic cause is likely even in patients who do not show autosomal-dominant inheritance pattern. It is worth noting that while AFVD cases associated with monogenic inheritance may be labeled as dystrophies, the majority of AFVD cases are not associated with monogenic mutations and are more compatible with the definition of degeneration. Multifocal vitelliform lesions can also be seen in AFVD (Fig. 3). Such lesions have OCT and fundus autofluorescence (FAF) features that are similar to the classic foveal vitelliform lesion in AFVD (see Section 2.2.1), although the number, location, and/or size of these non-foveal lesions can vary among patients (Boon et al., 2007a). 2.2. Additional tests in adult-onset foveomacular vitelliform dystrophy 2.2.1. Imaging 2.2.1.1. Fluorescein angiography and indocyanine green angiography. A variety of imaging tools and functional analyses have been used to diagnose and study AFVD. In his original report of the phenotype, Gass provided a description of the pathology on fluorescein angiography (FA), and since his original description, many others have repeated his findings. In the early stages of the disease, the vitelliform lesions can have blocked fluorescence due to the presence of vitelliform material and pigment in the foveal area, and this can be surrounded by a ring of defective transmission corresponding to an area of atrophied RPE. In the recirculation phase, staining of the vitelliform material by the fluorescein dye is often evident, and the staining pattern can be mistaken as occult CNV (Gass, 1974; Freund et al., 2011). Indeed, CNV can develop in eyes with AFVD; in such cases, a combination of clinical assessment and multimodal imaging such as indocyanine green angiography (ICGA) may be required in order to confirm or exclude the presence of CNV in addition to the vitelliform lesion (Battaglia Parodi et al., 2000; Menchini et al., 2002; Battaglia Parodi et al., 2003; Francis et al., 2005; Freund et al., 2011; Gallego-Pinazo et al., 2011; Mimoun et al., 2013; Querques et al., 2013; Tiosano et al., 2014). 2.2.1.2. Fundus autofluorescence. An additional feature of vitelliform lesionsdbut not specific to AFVDdis an increased fundus autofluorescence (FAF) signal (Figs. 1 and 3). Several patterns of increased autofluorescence have been described in the literature; however, whether these patterns are relevant in terms of prognostic and/or diagnostic value is not clear (Renner et al., 2004; Furino et al., 2008; Parodi et al., 2008). FAF of 18 eyes in 15 AFVD patients (mean age: 74 years) demonstrated patchy, ring-like focal and linear patterns of fluorescence. However, no correlation between these patterns and visual acuity was identified (Furino et al., 2008). Parodi and colleagues compared 15 AFVD patients with 10 control subjects using blue-light autofluorescence analysis, nearinfrared autofluorescence analysis, and microperimetry (Parodi et al., 2008); they found that blue-light autofluorescence revealed normal, patchy, and focal patterns of fluorescence, whereas nearinfrared autofluorescence revealed patchy and focal patterns of fluorescence. Based on their findings, the authors suggested that the presence of a patchy pattern in both wavelengths is associated with the least favorable outcome (Parodi et al., 2008). As the disease progresses and atrophy develops, most cases develop regions of hypo-autofluorescence, presumably reflecting atrophied or lost RPE, although central hypo-autofluorescence can also be present in

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Fig. 3. Multimodal images of multifocal adult-onset foveomacular vitelliform dystrophy. (AeE) Pseudo-color imaging and en-face OCT of the right eye of a 78 year-old man with multifocal AFVD. Images were acquired using Heidelberg Spectralis OCT. (A) Multicolor imaging shows a small bright red foveal lesion bordered by pseudo-dark coloring at the superior edge. Additional smaller lesions are visible at the temporal edge of the optic disc and superotemporal to the fovea. (B) Fundus autofluorescence image showing an increased autofluorescence signal from the vitelliform foveal and extrafoveal lesions. (C) SD-OCT showing the vitelliform lesion with hyper-reflective material in the inner foveal layers overlying the lesion. This material may represent pigment migration to the inner retinal layers during the course of absorption of the vitelliform lesion. (DeE) En-face OCT showing transverse sections of the lesion. (D) A homogenous hyper-reflective area of the lesion is visible above the level of the RPE. (E) A smaller irregular hyper-reflective signal corresponds to the area of the inner retinal lesion at the level of the outer nuclear layer. (FeG) Color fundus photograph (F) and autofluorescence image (G) of a 39-year-old patient, showing multifocal vitelliform lesions. The patient was negative for mutations in the BEST1 gene, and the patient's electro-oculogram was normal. The color photograph shows a yellowish foveal lesion and a smaller lesion adjacent to the superior arcade. The autofluorescence image reveals more multifocal hyperautofluorescent lesions. Both the foveal lesion and the largest extrafoveal lesions show a pseudohypopyon aspect of the hyperautofluorescent material that has gravitated inferiorly in the lesions.

the vitelliform stage of AFVD (Parodi et al., 2008; Freund et al., 2011; Querques et al., 2011a). 2.2.1.3. Optical coherence tomography. The advent of optical coherence tomography (OCT) facilitated in vivo delineation of vitelliform lesions and the adjacent retina (Figs. 1e3) (Pierro et al., 2002; Benhamou et al., 2003; Saito et al., 2003; Schatz et al., 2003;

Furino et al., 2008; Petropoulos et al., 2008; Querques et al., 2008; Lee et al., 2009; Finger et al., 2010; Puche et al., 2010; Freund et al., 2011; Gallego-Pinazo et al., 2011; Querques et al., 2011a; Rodman and Duchnowski, 2011). Pierro and colleagues evaluated 72 eyes in 43 patients with AFVD using time-domain OCT, ICGA, and FA (Pierro et al., 2002). On ICGA and FA, most of their patients had a central area of hypofluorescence surrounded by an area of

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increased fluorescence. All 72 eyes had a thickened region in the reflective band of the RPE on OCT, and a correlation was found between neuroretinal thickness on OCT and visual acuity, a finding also validated by others (Pierro et al., 2002; Benhamou et al., 2003). The subretinal location of the vitelliform lesion was also confirmed by time-domain OCT and OCT was suggested as a valuable tool to confirm the diagnosis of AFVD (Benhamou et al., 2003). Accordingly, Querques and colleagues reported a correlation between visual acuity, thickness of the neuroretina, and the stage of the lesion (determined using time-domain OCT) in 20 AFVD patients with a mean age of 58 years (Querques et al., 2008). Spectral domain OCT (SD-OCT) provides considerably higher resolution than time-domain OCT and thus facilitates a more detailed assessment of the vitelliform lesions. Puche and colleagues evaluated 60 eyes in 49 consecutive AFVD patients using this technique (Puche et al., 2010). Approximately half of the 60 eyes contained hyper-reflective clumps within the outer plexiform and outer nuclear layers, potentially representing pigment migration originating in the vitelliform lesion area. An altered ellipsoid zone was also observed in approximately half of the cases. In the majority of cases, the vitelliform lesion was in a subretinal location and appeared heterogeneous and hyper-reflective on SD-OCT. Interestingly, the RPE was irregular in appearance in 40 of the 60 eyes, and approximately half of the eyes had RPE detachment. Thus, pathological changes in AFVD are present beyond the boundaries of the subretinal vitelliform lesion, and both the neuroretina and the RPE can be involved in the disease. SD-OCT also facilitates quantification of lesion spatial and temporal characteristics. For example, Querques et al. used SD-OCT to follow the natural course of the disease in 46 eyes from 31 patients with a mean age of 75 years and a mean follow-up period of 16 months (Querques et al., 2011a). In this patient cohort, the mean maximum lesion diameter at baseline was 1605 mm. Using the OCT findings, the authors classified the lesions into vitelliform, pseudohypopyon, vitelliruptive, and atrophic stages. At follow-up, mean visual acuity had decreased from 0.32 logMAR to 0.39 logMAR, and the authors concluded that progression of the vitelliform lesion stage (based on OCT analysis) was accompanied by disruption of the ellipsoid zone and visual loss. Overall, 61% of the lesions were vitelliform-shaped at the start of the study and remained so throughout the follow-up. Eleven percent of the lesions initially presenting as vitelliform-shaped developed atrophic lesions during the follow-up period. In the eyes that progressed to a subsequent lesion stage during the study (as determined by the OCT findings), the lesion's dimensions also changed. Specifically, the mean maximal lesion height from the RPE to the photoreceptor decreased from 277 mm to 105 mm, while the mean maximal width of the lesion decreased from 2324 mm to 1751 mm. Additional findings included hyperreflective nodules at the level of the RPE, and RPE elevation, each of which occurred in approximately 40% of the eyes examined. Two patients also had reticular drusen. Pseudohypopyon-shaped lesions were larger in diameter than vitelliform lesions, and the lesions followed a course of decreasing size as they progressed to the vitelliruptive and atrophic stages. It is worth noting that the RPE-like nodules reported by Querques et al. (2011a) were also reported by both Finger et al. (2010) and Freund et al. (2011). These RPE-like nodules were described in patients with vitelliform lesions both with and without cuticular drusen; however, the precise significance and nature of these nodules is unclear. Potentially, it reflects altered RPE function as part of AFVD (Section 6). It is also possible to utilize SD-OCT to assess AFVD compared with other pathologies associated with vitelliform lesions. Freund and colleagues evaluated 90 eyes in 67 patients (mean age: 72 years) who developed vitelliform lesions secondary to a variety of

7

disorders (Freund et al., 2011). The authors noted that the vitelliform material was hyperfluorescent, and vision was correlated with ellipsoid zone integrity (based on OCT image analysis). Of their 67 patients, 28 had isolated vitelliform lesions (the mean age of these 28 patients was 73 years), and 14 patients also had cuticular drusen, usually accompanied by other features of AMD. In these two categories of lesions, the vitelliform lesions were bilateral in 43% of the eyes. Sixteen eyes had dry AMD (the mean age of these patients was 79 years); only three of these 16 eyes (19%) had bilateral vitelliform lesions, and two eyes also had reticular drusen. In addition to a vitelliform lesion, seven patients presented with RPE detachment. The mean lesion diameter was 975 mm at baseline and 747 mm at the last follow-up exam, and lesion size was inversely correlated with visual acuity. Similarly, mean lesion height was 185 mm and decreased to 152 mm at the last follow-up exam and was also inversely correlated with visual acuity. The outer nuclear layer over the lesion also became thinner; however, this change was not correlated with visual acuity. On the other hand, the presence of an ellipsoid zone on OCT was correlated with visual acuity. Twenty-six of the 67 patients (39%) had a stable visual acuity during their follow-up period (which ranged from 6 to 22 months, with a mean of 11 months). Among the eyes that were followed for >6 months, the lesion resolved in 13% of cases; these eyes had atrophic retinal changes in the vicinity of the absorbed material, but they did not develop a significant loss of vision. Freund et al. postulated that a vitelliform lesion can be absorbed when substantial photoreceptor loss occurs, resulting in fewer outer segments being produced, and the remaining RPE can then clear the subretinal material. They further postulated that the thinning of the outer nuclear layer observed in their study was the result of photoreceptor loss. Finally, their finding that the thinning of the outer nuclear layer was over the lesion that was absorbed supports their hypothesis that photoreceptor loss leads to absorption of the vitelliform lesion (Section 6). En-face OCT provides another imaging dimension to assess AFVD (Fig. 3). Using this modality, the vitelliform lesions appear as concentric rings, each ring being characterized by reflectivity intensity which corresponds to the reflectivity level observed in the B-section of the OCT. The typical hyperreflective vitelliform material is observed in the center of the lesion in the vitelliform stage whereas hyporeflective content is observed in the pseudohypopyon elevations which also appear hyperreflective in infrared reflectance (Puche et al., 2014). Another interesting observation was obtained using macular choroidal thickness measurements with enhanced depth imaging OCT (EDI-OCT). It was suggested that AFVD eyes are characterized by subfoveal choroidal thickening compared with both normal eyes and eyes of AMD patients (Coscas et al., 2014). The known genetic mutations associated with AFVD (Section 4) were identified in genes that are not expressed in the choroid and that are not directly related to its physiology. Thus, further studies should confirm this possible role for the choroid in AFVD. 2.2.2. Electrophysiology and psychophysical analysis 2.2.2.1. Electro-oculography. Electrophysiological studies, including electro-oculography (EOG), electroretinography (ERG), and multifocal ERG, have also been performed in patients with AFVD to assess retinal and RPE function. In his original description of the phenotype, Gass reported that the EOG was normal in most cases, but can be subnormal (Gass, 1974); other groups have reproduced these findings (Vine and Schatz, 1980; Burgess et al., 1987; Theischen et al., 1997; Renner et al., 2004). For example, Theischen and colleagues reported that 98 eyes in 49 patients with AFVD had normal EOG findings (Theischen et al., 1997). Moreover, in AFVD, the EOG Arden ratio can be either normal or subnormal in association with mutations in the PRPH2 and BEST1 genes. Thus, some PRPH2

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mutations that are potentially associated with AFVD can bedbut are not alwaysdaccompanied by reduced EOG findings, whereas other PRPH2 mutations that can cause AFVD are associated with normal EOG findings; the underlying factor responsible for this association is unclear (Meunier et al., 2011). While EOG suggests that RPE function in AFVD is overall normal, it does not preclude local dysfunction of the RPE in the fovea. 2.2.2.2. Electroretinography. In his original AFVD patient cohort, Gass reported that full-field ERG findings were normal (Gass, 1974). However, Renner and colleagues recorded full-field ERGs from 43 eyes and reported that the b-wave amplitude of the mixed rodcone response was reduced slightly in 12 eyes, and the singleflash cone response was reduced in 18 eyes. On the other hand, both the cone-evoked flicker response of the full-field ERG and the central P1 amplitude of the multifocal ERG were subnormal in 72% and 63% of patients, respectively (Renner et al., 2004). Multifocal ERG was also reported to be suppressed in 12 eyes from six patients both in the macular area and in the outermost tested ring (i.e., 20e30 ) (Saito et al., 2003). Thus, these ERG findings suggest that macular function is affected in AFVD, whereas panretinal photoreceptor function is normal. These findings are in agreement with the OCT studies (Section 2.2.1.3) reporting foveal photoreceptor loss over vitelliform lesions in AFVD, as well as with the largely unaffected EOG in AFVD suggesting normal RPE function outside the macula. 2.2.2.3. Psychophysical testing. The results of psychophysical tests such as color vision evaluation and visual field testing are often unremarkable in AFVD (Gass, 1974). Nonspecific color vision errors of various degrees of severity, with no typical axis of color confusion, were reported in 37 (47%) of 79 eyes with AFVD (Renner et al., 2004). No major changes in color vision performance were noted in ten eyes during a follow-up period ranging from 1.2 years to 6.4 years. Renner and colleagues also reported an intact visual field in

approximately half of the 53 eyes that were tested; the remaining eyes had a relative central scotoma, and only two eyes had absolute scotoma. Yet, AFVD is associated with decreased retinal sensitivity measured with microperimetry testing. Of 25 eyes with AFVD tested with microperimetry and blue FAF and near-infrared FAF stable fixation was detected in 68% (Parodi et al., 2008) (Fig. 4). Decreased fixation showed correlation with increased abnormal blue channel autofluorescence findings. Furthermore, each eye tested had a relative or absolute scotoma in conjunction with the yellowish lesion observed on ophthalmoscopy. Scotomata outside of the yellowish lesion were detected in 24 out of 25 eyes, suggesting that retinal regions that appear normal on ophthalmoscopy can actually have abnormal function. Querques and colleagues correlated visual acuity and time-domain OCT findings with microperimetry findings in 20 AFVD patients (Querques et al., 2008). Reduced thickness of the foveal neurosensory retina correlated with visual acuity and disease progression, as well as with the development of absolute scotoma, and eccentric or unstable fixation. Thus, despite the presence of a vitelliform lesion at the initial stages of the disease, both anatomical and functional characteristics of the retina in the foveal region are often relatively preserved. Marked functional declined correlates with morphological progression to the advanced atrophic stage of the disease, which is also accompanied by photoreceptor and RPE loss in the retina area bordering the lesion. 2.3. Differential diagnosis of AFVD 2.3.1. Vitelliform lesions accompanied by drusen and age-related macular degeneration The realization that AFVD-like lesions can be associated with several additional phenotypes and pathologies (Table 1 and Figs. 5 and 6) has fueled the debate regarding whether AFVD is a bona fide dystrophy (as its name implies) transmitted as an autosomal

Fig. 4. Retinal sensitivity changes in adult-onset foveomacular vitelliform dystrophy. Color (A, D), red-free (B, E), and microperimetry (C, F) imaged from the right (AeC) and left (DeE) eyes of an 84-year-old man with AFVD in the vitelliform stage. Patient was negative for mutations in PRPH2, BEST1, and IMPG1/2. Central retinal sensitivity is decreased (indicated by the red and orange colored circles) in the retinal areas overlying the vitelliform lesion. The right fovea has a larger area of reduced sensitivity compared to the left fovea (compare C with F) in accordance with the larger lesion size in the right eye observed on the color and red-free images (compare A and B with D and E, respectively).

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Disease

Age at diagnosis

Inheritance pattern

Typical fundoscopic findings

Autofluorescence of central vitelliform lesion

Fluorescein angiography of lesion

Additional diagnostic and clinical characteristics

Associated gene(s)

References

Typical adult-onset foveomacular vitelliform dystrophy

>40 years

Sporadic, AD, AR

Central round yellow lesion (60

Unknown, increased risk in first degree relatives

Central yellowish lesion surrounded by drusen; drusen/AMD in other eye (Fig. 5)

Drusen-associated serous vitelliform lesion

>60

Sporadic, increased risk in first degree relatives

Moderate e high hyperautofluorescence

Early hypofluorescence, late staining; hyperfluorescent drusen (if sub-RPE)

Subretinal hyperreflective exudation in Neovascular AMD Mitochondrial retinal dystrophy

>60

Sporadic, increased risk in first degree relatives Maternal transmission

Yellow-white lesion surrounded by sub-RPE drusen, cuticular drusen, or reticular pseudodrusen (subretinal drusenoid deposits); drusen/AMD in other eye (Fig. 5) Yellow-white subretinal lesion ± PED and hemorrhage(s)

- EOG markedly abnormal - Hyperopia, increased risk of angle-closure glaucoma - EOG normal - Large central drusenoid PED with surrounding drusen on OCT. May have small vitelliform lesion on top of PED. - EOG normal - Drusen on OCT

BEST1

Drusenoid RPE detachment

More diffuse abnormalities, highly hyperautofluorescent components Iso-autofluorescent to moderately hyperautofluorescent often ring pattern at circumference of lesion

(Gass, 1974; Renner et al., 2004; Boon et al., 2008a; Boon et al., 2009b; Meunier et al., 2014) (Spaide et al., 2006; Spaide, 2008; Boon et al., 2009b; Boon et al., 2009c) (Burgess et al., 2008; Boon et al., 2013)

Variable autofluorescence, no markedly increased autofluorescence

Iso- or blocked fluorescence from lesion, leakage from adjacent neovascularization Early mild hyperfluorescence, late staining, surrounding granular RPE window defects Mottled hyperfluorescence around the macula, early blocked fluorescence and late staining of vitelliform lesion Hypofluorescent lesions

Moderately hyperreflective in OCT. Associated with active neovascular AMD - EOG normal - Maternally inherited diabetes and deafness and other systemic abnormalities Chronic progressive external ophthalmoplegia, ptosis, tapeto-retinal degeneration, complete heart block - ERG and EOG can be abnormal - Anti-RPE antibodies

Diffuse leakage

- Acute onset followed by resolution of lesions within weeks - EOG may be abnormal

Childhood

Foveal sparing (except in rare vitelliform cases), perifoveal irregular RPE alterations

Moderately hyperautofluorescent

Kearns-Sayre Syndrome (KSS)

Childhood (maculaopathy may develop at adulthood)

Maternal Transmission

Salt and pepper retinopathy, yellowish foveal lesion

Hyperautofluorescent

Paraneoplastic vitelliform retinopathy

Adults

Central or multifocal yellowish lesions

Mildly, moderately, or highly hyperautofluorescent

Acute exudative polymorphous vitelliform maculopathy

Adults

Sporadic, associate with ocular and skin melanoma Sporadic, may be associated with cancer or

Multifocal, oval, or curvilinear subretinal yellowish lesions

Moderately e highly hyperautofluorescent

Early hypofluorescence, late pooling in PED and drusen

MF

(Hartnett et al., 1992; Spaide and Curcio, 2010; Saito et al., 2014)

MF

(Finger et al., 2010; Lima et al., 2012)

MF

(Shah et al., 2014)

m.3243A > G mutation in MTTL1 gene

(De Laat et al., 2013)

mtDNA deletions

(Ascaso et al., 2010)

e

(Eksandh et al., 2008; Aronow et al., 2012)

e

(Gass et al., 1988; Vaclavik et al., 2007;

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Table 1 Differential diagnostic considerations in adult-onset foveomacular vitelliform dystrophy. Abbreviations: AD, autosomal dominant; AR, autosomal recessive; AMD, age-related macular degeneration; CSC, central serous choroidopathy; EOG, electro-oculogram; MF, multifactorial; OCT, optical coherence tomography; PED, pigment epithelial detachment; RPE, retinal pigment epithelium.

(continued on next page) 9

Disease

10

Age at diagnosis

Inheritance pattern

Pseudoxanthoma elasticum

Variable

inflammatory conditions AR

MEK inhibitor related vitelliform lesions

Variable

Sporadic

Desferrioxamine related vitelliform lesions

Variable

Sporadic

Central Serous Chorioretinopathy (CSC)

Adults

Persistent subretinal fluid following retinal detachment

Vitreomacular traction (VMT) and epiretinal membrane (ERM)

Typical fundoscopic findings

Autofluorescence of central vitelliform lesion

Fluorescein angiography of lesion

Mildly e moderately hyperautofluorescent

Irregular fluorescence abnormalities, late fluorescence of angioid streaks Hypofluorescent lesions, neovascularization

Hyperautofluorescence

Staining of lesion

Irregular RPE alterations, often in both eyes. Small central yellowish lesion

Hyperautofluorescent

Possible leaks associated with CSC

Sporadic

Small yellowish lesion

Variable autofluorescent

Early hypofluorescence, late leakage

Sporadic

Small central round yellow lesion (G mutation (De Laat et al., 2013), Kearns-Sayre syndrome (Ascaso et al., 2010), and toxic conditions including desferrioxamine-related retinopathy (Gonzales et al., 2004; Genead et al., 2010; Viola et al., 2014), binimetinib treatment‒related transient retinopathy (Urner-Bloch et al., 2014) (Fig. 5F), anddpossiblydtopiramaterelated toxicity (Tsui et al., 2008). Presumably, altered RPE function underlies the development of acquired vitelliform lesions in such conditions. In line with this hypothesis is the fact that additional RPE insults are associated with many of the above mentioned pathologies (Table 1). Vitelliform lesions can also be both multifocal and acute in acute exudative polymorphous vitelliform maculopathy (Gass et al., 1988) were they may be preceded by accumulation of subretinal fluid. This is a putative paraneoplastic manifestation in which the immune system produces anti-RPE antibodies (Sotodeh et al., 2005; Eksandh et al., 2008; Khan et al., 2010; Grunwald et al., 2011; Koreen et al., 2011; Al-Dahmash et al., 2012). Interestingly, as mentioned above with respect to drusen (see Section 2.2.1), vitelliform lesions can present with classic morphology and characteristics on multimodal imaging, regardless of the presence or absence of an associated retinal or systemic pathology (Eksandh

Fig. 7. Butterfly-shaped pigment dystrophy (BPD) and adult-onset foveomacular vitelliform dystrophy (AFVD) in fellow eyes. Multimodal imaging of the right (AeC) and left (DeF) eyes of a 74 year-old male. Best corrected visual acuity was 0.8 in each eye. Color photograph and infrared reflectance demonstrates a pigmented foveal lesion in the right eye accompanied by RPE atrophy temporal to the lesion (AeB), while in the left eye there were branching lines of RPE atrophy with hyperpigmentation at the edge of the atrophic lines (DeE). OCT of the right eye shows a typical vitelliform lesion (C), while in the left eye (F) OCT demonstrates RPE atrophy nasal to the fovea and flat vitelliform material temporal to the fovea center. Thus, findings in the right eye are more compatible with AFVD whereas in the left eye the description BPD is more appropriate.

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et al., 2008). These characteristics can include a yellowish subretinal lesion on ophthalmoscopy, a dome-shaped appearance in OCT sections, and increased autofluorescence on FAF imaging. Patient demographics, ophthalmic history, medical history, and accompanying findings from ophthalmic examination and multimodal imaging can all point towards the underlying etiology of the vitelliform lesion (Table 1). The outcome of these conditions may be variable and does not necessarily follow the typical course of AFVD. 2.3.5. Butterfly-shaped pigment dystrophy Butterfly-shaped pigment dystrophy (BPD) was first described by Deutman and colleagues in a large Dutch family (Deutman et al., 1970). In this autosomal-dominantly inherited macular dystrophy, a spoke-like pigment pattern that may resemble the shape of a butterfly is observed in the macula. The typical BPD lesion appears yellowish in ophthalmoscopy, it is located at the level of the outer retina and RPE, and it has three or more branches (Fig. 7). On fluorescein angiography, the pigmented regions of the lesion are hypofluorescent, whereas surrounding depigmented zones and areas of chorioretinal atrophy are hyperfluorescent. Fundus autofluorescence shows variably increased and decreased signal, while in OCT the lesions correspond to hyperreflective granular material at the photoreceptor-RPE interface. The central visual field is normal or shows slightly decreased central sensitivity in cases without profound chorioretinal atrophy. The peripheral visual field is normal. Full-field electroretinography (ERG) is normal, and the electro-oculogram (EOG) in BPD is normal to slightly subnormal. Most patients with BPD have a good visual acuity in at least one eye for many decades. The development of CNV is very rare. However, marked central vision loss can develop after the seventh decade by progressive photoreceptor and RPE atrophy in the macula. Similar to other PD phenotypes including AFVD and pseudo-Stargardt pattern dystrophy, BPD may be caused by PRPH2 mutations (Boon et al., 2007b, 2008a). A locus on 5q21.2-q33.2 was also associated with autosomal-dominant BPD and other, yet unidentified, genetic alteration may be linked with this phenotype (Nichols et al., 1993a, 1993b; Van Lith-Verhoeven et al., 2003). The location of the BPD lesions between the RPE and photoreceptor outer segments is similar to AFVD lesions, and the clinical course in AFVD and BPD also appears similar. Furthermore, the butterfly-shaped lesions can evolve from typical vitelliform lesions characterizing AFVD and patients may manifest BPD in one eye and AFVD in the fellow eye at the same time (Fig. 7). Similar genetic defects can underlie both phenotypes. Thus, some cases of BPD and AFVD may be two manifestations of the same abnormality rather than two distinct entities. 3. Histopathology Histopathological studies provided important insights to the tissues and cells which are involved in AFVD (Gass, 1974; Patrinely et al., 1985; Jaffe and Schatz, 1988; Dubovy et al., 2000; Arnold et al., 2003). In his original description of the phenotype, Gass reported the histopathology findings from a 67-year-old woman with AFVD, describing a focal loss of photoreceptors and the migration of pigment towards the fovea. Additional findings included clumping of pigment-laden cells in the outer retina, chorioretinal adhesions in the fovea, paracentral attenuation of the RPE, and focal drusen. Vitelliform lesion was not present, and thus, this eye does not represent a “typical” AFVD case. Light microscopy and electron microscopy evaluation of another eye of a 61-year-old woman with AFVD revealed focal atrophy of the RPE in the foveal area and hypertrophic RPE cells at the edge of the atrophy (Patrinely et al., 1985). An eosinophilic collagenous plaque was noted between the RPE layer and Bruch's membrane.

The outer nuclear layer was atrophic, and the photoreceptor outer and inner segments appeared to be degenerated over the atrophic RPE. Pigment- and lipofuscin-laden macrophages were observed in the atrophic outer retina. Finally, increased lipofuscin accumulation was noted in the RPE cells. The lack of strict diagnostic criteria for AFVD also affects interpretation of histological studies. For example, although the suggested diagnosis was not AFVD, histopathological findings from six eyes of three patients (75e84 years of age) diagnosed with “adultonset foveomacular pigment epithelial dystrophy” may be partially extended to AFVD (Dubovy et al., 2000). Two of these patients also had fundoscopic features typical of AMD, including drusen and RPE alterations; one patient had a daughter with vitelliform lesions. Histology and electron microscopy revealed a loss of photoreceptor outer and inner segments anddin some eyesdthinning or loss of the outer nuclear layer overlying an attenuated RPE with areas of RPE apical villi loss. Subretinal periodic acid-Schiff‒positive material was also observed, as were basal laminar deposits and basal linear deposits. Subretinal and sub-RPE macrophages were present, as well as RPE cells containing lipofuscin and melanolipofuscin. The authors speculated that the presence of basal linear and laminar deposits suggests that the disease is part of the spectrum of AMD. As an alternative explanation for the presence of such deposits, they also suggested that the disease can accelerate the effects of aging, as these histological findings are typical of an aging retina. The authors also suggested that the yellowish color of the vitelliform lesion stems from an accumulation of lipofuscin in the RPE and macrophages. Autofluorescence of the vitelliform lesions also stems from the accumulation of lipofuscin (Figs. 1e3 and 7). While this study provided important information, it should be emphasized that two of the three patients reported had evidence of AMD on ophthalmoscopy. The findings of this histopathologic study can therefore not necessarily be generalized to AFVD, but, rather they provide insight to the alterations associated with vitelliform lesions. In that context, it should be noted that the findings by Dubovy et al. are in line with SD-OCT findings demonstrating thinning of the photoreceptor layer as well as hyperreflective dots in the inner retina (Section 2.2.1.3). Such dots may reflect migration of pigment-laden inflammatory or RPE cells to the inner retina as part of an absorption process of the vitelliform lesion. The largest histopathological study of AFVD included 14 eyes from patients 76e92 years of age (Arnold et al., 2003). Four of these eyes were diagnosed in the clinic as having AFVD, and the other ten cases were identified by reviewing the data obtained from 526 eyes that were initially diagnosed with AMD. Again, such cases may also potentially have vitelliform lesions associated with AMD and do not necessarily correspond to AFVD strictu sensu. Their study confirmed the subretinal location of the vitelliform deposits and demonstrated that the deposits were composed primarily of extracellular photoreceptor debris and RPE-derived material (Fig. 8). The authors hypothesized that their findings were consistent with an initial stage of RPE hypertrophy, which was followed by RPE attenuation, loss of apical RPE microvilli (in some cases), and the release of pigment as subretinal deposits. Unlike typical AMD, in which basal laminar deposits are an early finding, photoreceptors seem to be the first cells affected in AFVD. This notion is supported by the observation that photoreceptors can be disrupted at the edge of the vitelliform lesions. Photoreceptors overlying the center of the lesion were affected the most severely, with distorted nuclei, tubule formation in the inner segments, and markedly distorted outer segments. Basal laminar deposits were also present in the AFVD eyes; however, the authors suggested that their presence might have been related to the advanced age of the patients and did not necessarily represent the co-existence of AMD. Nevertheless, each eye had histopathological evidence of AMD, including drusen in

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Fig. 8. Schematic diagram depicting a typical vitelliform foveal lesion. Vitelliform material (shown in yellow) accumulates between the retinal pigment epithelium (RPE) and the outer segments of the photoreceptors. Depending on the size of the lesion, it may be covered either by cone photoreceptors only or by cone photoreceptors in the center surrounded by a combination of cone and rod photoreceptors. The outer nuclear layer shows focal nuclei loss, and the inner and outer segments overlying the lesion are disrupted (lower diagram). The vitelliform material is composed of photoreceptor outer segment debris as well as lipofuscin (yellow dots), melanin (brown dots), and melanolipofuscin‒loaded macrophages and RPE cells (large circles). The RPE at the base of the lesion is initially hypertrophic and followed by attenuation, loss of microvilli (lower diagram), and pigment released into the vitelliform lesion (light brown cells); RPE hyperpigmentation is evident at the circumference of the lesion. Basal laminar deposits and basal linear deposits (not depicted here) have also been reported underneath the RPE in adult-onset foveomacular vitelliform dystrophy eyes; however, their association with the pathology is uncertain (Dubovy et al., 2000; Arnold et al., 2003).

four of the eyes, as well as basal linear deposits and RPE alterations in the other ten eyes. These data underscore the fact that distinguishing between AFVD and AMD can be challenging, and the presence of drusen may not be sufficient to provide such a distinction. Interestingly, Arnold and colleagues observed a lower degree of inflammatory infiltration in the choroid in eyes with AFVD compared to eyes with AMD, and they speculated that this difference might be due to the subretinal location of the deposits in AFVD compared to the sub-RPE drusen in AMD. Since it is realized today that inflammation has a major role in the pathogenesis of AMD, and that it is not an epiphenomena in that respect, differential inflammatory reaction in AFVD compared with AMD may actually reflect an important difference in the pathogenesis of these two phenotypes. Indeed, such hypothesis is also supported by genetic studies of both conditions (Sections 4 and 6). 4. Genetic associations in adult-onset foveomacular vitelliform dystrophy 4.1. The PRPH2 gene Autosomal dominant mutations in the PRPH2 gene (previously called peripherin/RDS) were associated with a variety of retinal phenotypes, including AFVD in one family over two decades ago (Wells et al., 1993); this finding was later confirmed by several other groups (Nichols et al., 1993a, 1993b; Weleber et al., 1993; Feist et al., 1994; Keen et al., 1994; Gorin et al., 1995; Kim et al., 1995; Felbor et al., 1997; Yang et al., 2003; Francis et al., 2005; Testa et al., 2005; Zhuk and Edwards, 2006; Gamundi et al., 2007; Renner et al., 2009; Coco et al., 2010). The protein encoded by the

PRPH2 gene is a member of the tetraspanin family of proteins and plays a structural role in outer segment discs in rod and cone photoreceptors. Mutations in this gene are associated with a wide variety of phenotypes (Boon et al., 2008a), including other macular phenotypes such as central areolar choroidal dystrophy (Boon et al., 2009a), BPD, and pseudo-Stargardt pattern dystrophy (Boon et al., 2007b), but also including panretinal dystrophies such as conerod dystrophy and autosomal dominant and digenic (in combination with a ROM-1 mutation) retinitis pigmentosa (Nichols et al., 1993a; Weleber et al., 1993; Wells et al., 1993; Gorin et al., 1995; Kim et al., 1995; Fossarello et al., 1996; Felbor et al., 1997; Sears et al., 2001; Khani et al., 2003; Schatz et al., 2003; Yang et al., 2003; Testa et al., 2005; Gamundi et al., 2007; Leroy et al., 2007; Passerini et al., 2007; Renner et al., 2009; Coco et al., 2010). In their original report, Wells et al. (1993) hypothesized that the specific mutation associated with AFVD in their study (a Tyr258stop mutation) may cause a metabolic defect similar to the defect that underlie phenotype in heterozygous rds (rds/þ) mice, which have an insertion of a DNA fragment in the PRPH2 gene. These mice have increased outer segment shedding that can be differentially regulated by light and by the pigmentation level of the mice (Sanyal and Hawkins, 1988, 1989). This observation may be extrapolateddat least partiallydto AFVD, thereby explaining the formation of subretinal deposits due to excessive outer segment shedding, which overwhelms the phagocytic capacity of the RPE (Fig. 9). This finding also suggests that modifying factors (such as external light and/or pigmentation level) can modify the phenotype. Further supporting the notion of genetic modifiers in PRPH2associated dystrophies, a similar PRPH2 mutation has been reported to give rise to different phenotypes within members of the same family; moreover, several PRPH2 mutations have been

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degeneration. Mutations that affect the cytoplasmic, intradisc, and disc membrane‒spanning regions of the protein have been associated with macular dystrophy. Although both dominant-negative and haploinsufficiency mechanisms may underlie PRPH2-associated retinal and macular degeneration (Boon et al., 2008a), haploinsufficiency may be associated with rod-dominated degenerations, whereas a dominant-negative mechanism may be associated with cone-dominated pathologies such as macular dystrophy (Stricker et al., 2005; Conley et al., 2014). Extensive clinical description of six families with PD associated with mutations in the PRPH2 gene provided important genotypephenotype insight (Francis et al., 2005). A total of 32 patients were included in that report and half of these patients developed poor central vision due to geographic atrophy or CNV. The risk of developing these complications appears to increase with age. Nine individuals (30e49 years of age) had yellowish lesions with no detectable atrophy, and only two patients had visual acuity worse than 20/40. Thirteen patients 50e69 years of age had various degrees of RPE atrophy; five of these patients had geographic atrophy, and CNV developed in two eyes. Sixteen patients were 70e91 years of age; four had geographic atrophy, and five had CNV. Only three of these 16 patients (18.7%) maintained visual acuity of 20/40 or better in both eyes, whereas seven of the 16 patients (43.7%) had visual acuity worse than 20/40 in both eyes. Francis and colleagues also reviewed previous reports regarding the PD phenotype (though not necessarily AFVD) of patients with PRPH2 mutations (Weleber et al., 1993; Kim et al., 1995; Fossarello et al., 1996; Sears et al., 2001; Khani et al., 2003; Yang et al., 2003). In total, the affected individuals in ten families had a visual outcome that was similar to the patients reported by Francis et al., including vision loss at an advanced age. Among 53 affected individuals in these ten families, 38% had advanced macular pathology defined as geographic atrophy (in 25% of cases) and/or CNV (in 15% of cases). Moreover, among the nine affected individuals >70 years of age, six had a decline in visual acuity to 20/200 or worse in at least one eye, including four individuals with visual acuity of 20/200 or worse in both eyes. Thus, Francis and colleagues concluded that PD (including AFVD) associated with a PRPH2 mutation is often associated with a significant loss of visual acuity in old age. Fig. 9. Putative mechanisms underlying vitelliform lesion formation in monogenic adult-onset foveomacular vitelliform dystrophy. (A) AFVD is occasionally associated with mutations in the BEST1 gene (Kramer et al., 2000; Seddon et al., 2001; Renner et al., 2005; Zhuk and Edwards, 2006; Meunier et al., 2011). In these cases, altered function of the calcium-activated chloride channel bestrophin expressed in the basal membrane of the retinal pigment epithelium (RPE) disrupts outer segment phagocytosis by the RPE (panel A, right side). Outer segments that are not processed by the RPE accumulate between the RPE and the photoreceptors (shown in green), eventually leading to the formation of a vitelliform lesion (shown in yellow). (B) Mutations in the PRPH2 gene have also been associated with AFVD (Nichols et al., 1993a; Nichols et al., 1993b; Weleber et al., 1993; Wells et al., 1993; Kramer et al., 2000; Seddon et al., 2001; Renner et al., 2005). The PRPH2 gene is expressed in rod and cone photoreceptor outer segments. Mutations in the protein can cause aberrant outer segments that are either shed at a faster rate or are processed less efficiently by the RPE; consequently, the RPE's capacity to take up the shed outer segments is impaired (panel B, right side). The excess outer segment material (shown in green) accumulates between the RPE and photoreceptors, forming a vitelliform lesion (shown in yellow). (C) The interphotoreceptor matrix proteoglycans (encoded by the IMPG1 and IMPG2 genes) are components of the interphotoreceptor matrix scaffold. Mutations in these genes have been associated with AFVD (Bandah-Rozenfeld et al., 2010; Manes et al., 2013; Meunier et al., 2014) and can reduce the uptake of outer photoreceptor discs (shown in green) by the RPE, leading to a buildup of subretinal vitelliform material (shown in yellow; left side of panel C).

associated with the AFVD phenotype (Weleber et al., 1993; Francis et al., 2005; Passerini et al., 2007; Renner et al., 2009). However, specific mutations have been associated with macular dystrophy (though not necessarily AFVD) rather than rod-dominated

4.2. The BEST1 gene A minority of AFVD cases may be associated with autosomal dominant mutations in the BEST1 gene (Fig. 9). Mutations in BEST1 were first associated with Best vitelliform macular dystrophy (Best disease) (Petrukhin et al., 1998). Kramer and colleagues later identified BEST1 mutations in eight out of 32 unrelated AFVD patients (25%) who were negative for mutations in the PRPH2 gene (Kramer et al., 2000). Two of these eight patients had a family history of AFVD. Interestingly, six unrelated patients (i.e., from six separate families) carried the same mutation, an alanine-to-valine mutation at amino acid 243 (A243V). A mildly to moderately subnormal EOG was measured in five of these six patients, and one patient had a strikingly low Arden ratio of approximately 1.15; the authors suggested that this patient may have actually had Best disease in which the EOG is not severely affected. Another study evaluated 259 patients with AMD, and 28 patients with maculopathy that differed from classic Best disease, including three patients with AFVD and five patients with bull's eye maculopathy (Seddon et al., 2001). Two of these 28 patients with maculopathy including one of the three patients with AFVD had a mutation in BEST1. The AFVD patient with a BEST1 mutation was a 60-year-old woman with visual symptoms that began at the age of 54. This patient had a unilateral vitelliform lesion, bilateral drusen, and a markedly subnormal EOG; this patient also had a deceased

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Mutations in the interphotoreceptor matrix proteoglycan 1 (IMPG1) gene were detected in 18 individuals from five separate families with autosomal dominant vitelliform macular dystrophy, autosomal recessive vitelliform macular dystrophy, and one simplex case. Mutations were found in 3 separate exons of IMPG1, as well as in two of the introns at splice site mutations specifically (Manes et al., 2013) (Fig. 9). Patient age at the time of diagnosis ranged from 21 to 45 years, and the patients presented with normal or mildly subnormal EOG findings. Some of the cases manifested as a typical AFVD phenotype with small isolated macular vitelliform lesions, whereas other cases had multifocal vitelliform lesions. The IMPG1 gene was also associated with an autosomal dominant form of benign concentric annular macular dystrophy (Van LithVerhoeven et al., 2004). This phenotypic variability was not associated with any specific IMPG1 mutation or inheritance pattern (i.e., autosomal dominant vs. autosomal recessive). IMPG1 encodes a sialoprotein associated with cones and rods (SPACR), a component of the interphotoreceptor matrix. This SPACR protein interacts with hyaluronan and is believed to comprise the macromolecular scaffold in the insoluble interphotoreceptor matrix (Acharya et al., 1998). Mutations in the IMPG2 gene, which also encodes an interphotoreceptor matrix protein, have been associated with early-onset retinitis pigmentosa, as well as one patient with an AFVD-like phenotype (Bandah-Rozenfeld et al., 2010). Recently, another family with an autosomal dominant form of IMPG2-associated AFVD was reported by Meunier et al. (2014). In their report, they identified four families comprising 13 AFVD patients with mutations in the IMPG1 or IMPG2 gene. The authors suggested that the AFVD phenotypes associated with IMPG1 and IMPG2 mutations are similar, and the autosomal dominant form is characterized by adult-age onset (mean age at onset was 42 years) and moderately affected visual acuity (mean visual acuity was 20/40) (Meunier et al., 2014).

the presence of a vitelliform lesion in at least one eye and disease onset over the age of 40 years. In their patient cohort, the mean age at onset of AFVD was 51.5 years, and the age at onset of nine patients was >50 years. Five of the 19 cases had a positive family history for maculopathy, and PRPH2 mutations were identified in two of these five patients, but not in the other 12 patients. None of the AFVD patients had a mutation in the BEST1 gene (Meunier et al., 2011). Based on their findings, the authors concluded that a patient with AFVD who has a negative family history and normal EOG findings has a considerably decreased likelihood of having a mutation in either PRPH2 or BEST1. The same group also examined the prevalence of IMPG1 and IMPG2 mutations among patients with vitelliform macular dystrophy in which BEST1 and PRPH2 gene mutations were excluded (Meunier et al., 2014). In 49 such families, four (8%) had mutations in either IMPG1 or IMPG2. Three families (with a total of 11 patients) had an IMPG1 mutation, and one family (with two patients) had an IMPG2 mutation. Three of these four families had autosomal dominant inheritance, and one case was a sporadic mutation. Another study reported PRPH2 gene mutations in five out of 28 (18%) unrelated patients with AVMD (Felbor et al., 1997). These patients had various phenotypes, including Best-like, multifocal, and pattern-like lesions. All of the patients with a PRPH2 mutation had a negative family history of AVMD and were between the ages of 51 and 67 years. Three of the five patients had multifocal vitelliform lesions. Renner and colleagues genotyped the BEST1 and PRPH2 genes in 12 and 10 AFVD patients, respectively. They identified a putative pathogenic mutation in PRPH2 in one case only (Renner et al., 2004). Zhuk and Edwards screened for PRPH2 and BEST1 mutations in 12 patients who had adult-onset macular dystrophy with vitelliform lesions with an age at onset of the dystrophy after their fourth decade. The average age of their patient cohort was 69.7 years (range: 48e86 years), and five patients (42%) had a positive family history of macular dystrophy or degeneration. Eight of the 12 patients also presented with hyperpigmentation, and five presented with drusen or flecks. Only one of the patients in this cohort had a pathogenic PRPH2 mutation (Zhuk and Edwards, 2006). It is important to note that exon 3 of PRPH2 is highly polymorphic, rendering at least 5 nucleotide changes that may potentially be connected to the disease. Such association was not yet excluded; larger genetic studies of AFVD are required to evaluate the association of such single nucleotide variants with AFVD. Jaouni and colleagues screened 35 cases of AFVD and BPD and found no PRPH2 or BEST1 mutations (Jaouni et al., 2012). Barbazetto et al. identified a PRPH2 mutation in one out of 28 cases presenting with both vitelliform macular detachment and cuticular drusen, and none of the 28 cases had a BEST1 mutation (Barbazetto et al., 2007). Taken together, these studies indicate that only a minority of AFVD cases are associated with mutations in the BEST1, PRPH2, IMPG1, or IMPG2 genes, and that the likelihood of carrying such mutations is higher in patients with a positive family history for the disease.

4.4. The overall contribution of known monogenic mutations to adult-onset foveomacular vitelliform dystrophy

4.5. Single-nucleotide polymorphisms (SNPs) and the risk of developing adult-onset foveomacular vitelliform dystrophy

If AFVD is indeed an autosomal-dominant transmitted disease then one would expect that most patients would carry a monogenic mutation. Yet, several studies have suggested that most AFVD cases do not show an autosomal-dominant inheritance pattern, although variable expression and decreased penetrance could partially explain such a lack of a clear inheritance pattern. Moreover, most AFVD patients do not have a mutation in PRPH2, BEST1, or IMPG1/2. For example, Meunier and colleagues screened for PRPH2 and BEST1 mutations in 19 patients with AFVD. They defined the phenotype as

AFVD and AMD have several features in common, including an average age of onset in the sixth decade or later, the presence of drusen and changes in the RPE, and an increased risk of developing CNV. Little is known regarding the role of previously identified genetic risk factors for AMD in AFVD. Barbazetto and colleagues examined the prevalence of a common AMD-associated SNP in the complement factor H (CFH) gene (Y402H) in 21 patients with combined vitelliform macular detachment and cuticular drusen (Barbazetto et al., 2007). The prevalence of the Y402H variant in the

brother with the same phenotype (based upon a retrospective review of his medical records). The mother also had maculopathy. The age at onset for Best disease can vary widely, and onset in adulthood is relatively common (Renner et al., 2005). Renner and colleagues also suggested that the vitelliform lesion in BEST1associated maculopathy is generally larger than in BEST1 mutation‒ negative AFVD cases. Furthermore, in their study, Renner et al. reported that BEST1-associated AFVD is often familial and typically presents at an earlier age than BEST1 mutation‒negative cases. Interestingly, the nature of the specific BEST1 mutation is not associated with the age of onset of the disease or with its phenotype (Renner et al., 2005). Thus, BEST1 mutation positive individuals with a vitelliform lesion which manifest at adulthood with a variable degree of EOG suppression may fit the diagnosis of AFVD, Best disease, and in some cases both conditions. Yet, based on the available data, the majority of such cases would better fit the diagnosis of late-onset Best disease. 4.3. The IMPG1 and IMPG2 genes

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patient cohort was similar to the prevalence in unaffected individuals, indicating that this AMD-associated SNP does not likely play a major role in AFVD. Jaouni and colleagues examined the association of the major AMD-associated SNPs in the CFH, C3, and HTRA1 genes in patients with PD. They compared a group of 35 patients (11 with BPD and 24 with AFVD; the combined mean age was 75.3 years, range: 46e93 years) and a negative family history for their respective disease with 317 AMD patients and 159 controls. Consistent with the findings reported by Barbazetto and colleagues, Jaouni and colleagues found a similar frequency of the CFH risk SNP (rs1061170) and the C3 risk SNP (rs2231099) for AMD between the PD patients and controls. However, they found a significant association between an HTRA1 SNP (rs11200638) and the risk of developing AFVD and BPD (odds ratio: 1.72; 95% CI: 1.11e2.66; P ¼ 0.03) (Jaouni et al., 2012). Additional studies on larger cohorts of AFVD patients should evaluate for potential association among SNPs and the disease. Such associations may account for sporadic AFVD cases where no other factor was associated with the development of vitelliform lesions. 5. Treatment options 5.1. Treatment of the degenerative process in adult-onset foveomacular vitelliform dystrophy At present, no validated therapy is available for preventing the development of a vitelliform lesion or facilitating its safe absorption. Ergun and colleagues reported that photodynamic therapy for treating vitelliform lesions caused a significant decrease in visual acuity in four out of eight eyes (in seven patients), suggesting a severe adverse effect associated with this treatment (Ergun et al., 2004). On the other hand, Gallego-Pinazo reported that anti-VEGF therapy yielded a short-term improvement in visual acuity in six patients with AFVD without CNV (Gallego-Pinazo et al., 2011). Montero reported a favorable anatomic response to anti-VEGF treatment in a patient with similar pathology (Montero et al., 2007). In contrast, Kandula and colleagues found no such favorable response upon treating another case (Kandula et al., 2010), and currently the use of anti-VEGF therapy in AFVD (where CNV is not present) appears unjustifiable. Gene therapy is a promising future option for treating monogenic forms of AFVD. For example, experiments in rds/rds and rds/þ mice provided proof-of-concept for using gene therapy to correct haploinsufficiency due to a mutation in the PRPH2 gene. In the future, similar therapies might be useful for treating patients with AFVD and to prevent development of the vitelliform lesion (Conley and Naash, 2014). Preliminary experiments in the canine multifocal retinopathy model for bestrophinopathies (diseases associated with BEST1 mutations), suggested that viral vector-assisted delivery of the BEST1 to the RPE is feasible. Thus, gene therapy for BEST1associated AFVD may also be developed in the future (Guziewicz et al., 2013). 5.2. Treatment of choroidal neovascularization associated with adult-onset foveomacular vitelliform dystrophy The development of CNV in association with AFVD can induce vision loss in addition to the AFVD-related visual consequences. The prevalence of CNV in AFVD is not well documented. Once developed, the CNV can be treated using anti-VEGF compounds, following a treatment regimen similar to the protocol used for treating neovascular AMD. Mimoun and colleagues reported that ranibizumab treatment stabilized visual acuity and reduced macular thickness in 24 eyes with AFVD and CNV (Mimoun et al., 2013). The patients received three monthly intravitreal injections

of ranibizumab followed by additional treatments as needed for 12 months. During the follow-up period, 21 of the 24 treated eyes (87.5%) had a decline in visual acuity of fewer than three lines, and mean visual acuity was stable. Tiosano et al. retrospectively assessed 11 eyes with AFVD and CNV following treatment with injections of bevacizumab; treatment outcome was compared with 60 neovascular AMD eyes from patients with similar demographics as the AFVD þ CNV patients (Tiosano et al., 2014). The initial and final visual acuity levels, as well as the mean number of injections required, were similar between the AFVD þ CNV and AMD groups. However, in the final examination of the AFVD þ CNV group, visual acuity had improved in three eyes, stabilized in one eye, and was reduced in seven eyes (Tiosano et al., 2014). A similar beneficial effect of ranibizumab was reported in another AFVD case with CNV (Prieto-Calvo et al., 2012), as well as in a group of 12 PD patients (10 with reticular dystrophy and two AFVD cases) with CNV who were treated with ranibizumab (Parodi et al., 2010). Taken together, these data suggest that when AFVD is complicated by CNV, anti-VEGF therapy can control and even reverse the CNV, and that the visual outcome might be guarded due to the presence and progression of the vitelliform lesion. On the other hand, using photodynamic therapy to treat AFVD-associated CNV might result in RPE atrophy and a poor visual outcome and should therefore be avoided (Battaglia Parodi et al., 2003). 6. Integration of current knowledge In the four decades since Gass' original description of peculiar foveomacular dystrophy (Gass, 1974), much progress has been made towards understanding the pathology underlying this disease. Some long-standing debatesdin particular, the possible overlap between this disease entity and AMDdremain unsettled, and several new questions have arisen. It is now clear that adultonset vitelliform macular lesion is a phenotype that encompasses a heterogeneous spectrum of disorders. Some cases can be defined as AFVD and can be inherited as an autosomal dominant trait in a minority of instances. A similar phenotype can be explained by a variety of genetic, toxic, immune-mediated, degenerative, mechanical, and other as-yet unidentified mechanisms. However, there is currently no consensus regarding whether AFVDdor one of its synonymsdshould be reserved for diagnosing patients who present with a specific underlying cause. For example, should we use this term for patients with autosomal dominant AFVD, or can this term also be used for sporadic cases? The term “dystrophy”, while originally coined to describe conditions associated with defective or faulty nutrition, is widely utilized in ophthalmology to describe inherited, monogenic, degenerative retinal diseases (i.e.: cone-rod dystrophy, etc.). To that extent, monogenic AFVD would fit the term “dystrophy” as suggested by Gass. On the other hand, there is no clear formal distinction between the terms “dystrophy” and “degeneration”. Thus, some also use the term “degeneration” to describe monogenic AFVD. We suggest that the term “adult-onset foveomacular vitelliform dystrophy” should be used solely to describe cases in which a monogenic mutation has been associated with the phenotype. For sporadic AFVD cases without an identifiable underlying mutation, the term “degeneration” may be considered better. This term describes gradual loss of tissue and function of the tissue in an aged individual without committing to an identified inheritance pattern or monogenic cause. Finally, the term “acquired vitelliform lesions” can be used for vitelliform lesions associated with other causes such as toxic maculopathies, systemic disorders (e.g. pseudoxanthoma elasticum, Kearns-Sayre syndrome), and mechanical factors (e.g. vitreomacular traction, epiretinal membrane) (Freund et al., 2011).

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From a genetic perspective, mutations in at least four genes have been associated with AFVD to date; thus, AFVD is both a phenotypically and genetically heterogeneous disease (Weleber et al., 1993; Wells et al., 1993; Keen et al., 1994; Gorin et al., 1995; Kim et al., 1995; Felbor et al., 1997; Kramer et al., 2000; Sears et al., 2001; Seddon et al., 2001; Schatz et al., 2003; Yang et al., 2003; Renner et al., 2004; Francis et al., 2005; Renner et al., 2005; Zhuk and Edwards, 2006; Gamundi et al., 2007; Passerini et al., 2007; Boon et al., 2009b; Bandah-Rozenfeld et al., 2010; Coco et al., 2010; Meunier et al., 2011; Manes et al., 2013). In these genetic cases, the inheritance pattern is usually autosomal-dominant, although autosomal recessive inheritance has been described (for example, for mutations in the IMPG1 and IMPG2 genes) (BandahRozenfeld et al., 2010; Manes et al., 2013). Most patients with AFVD do not have a family history of AFVD nor mutations in the aforementioned genes. Although this does not necessarily exclude the possibility of autosomal inheritance, it suggests that other factors, including polygenic predisposition, may play a role in the pathogenesis of the disease (Jaouni et al., 2012). Moreover, defects in similar genes and/or processesdand occasionally even identical mutationsdcan lead to AFVD in some patients, or they can lead to more severe, earlier-onset maculopathy such as Best vitelliform macular dystrophy or even devastating early-onset retinitis pigmentosa in other patients (Weleber et al., 1993; Wells et al., 1993; Gorin et al., 1995; Kramer et al., 2000; Renner et al., 2005; Leroy et al., 2007; Passerini et al., 2007; Renner et al., 2009; Coco et al., 2010; Manes et al., 2013). Modifying factors that have yet to be identified clearly play a role in generating this phenotypic variability. The long-term visual prognosis of AFVD appears to be variable and depends to a large extent on the patient's age and/or the disease duration. Visual acuity is often preserved or only mildly affected despite the presence of significant amount of vitelliform material between the RPE and photoreceptors. Accordingly, OCT demonstrates a preserved outer nuclear layer and ellipsoid zone in early AFVD cases. Such relatively preserved visual function also characterizes other conditions with subretinal fluid accumulation and relatively normal overlying neuroretina, such as central serous chorioretinopathy. This may be explained for instance by the fact that cone photoreceptors can function relatively well despite the physical separation from the RPE because of mechanisms such as an alternative, intraretinal visual pigment regeneration route (Wang and Kefalov, 2011; Tang et al., 2013). Essential metabolites may diffuse between the photoreceptors and RPE through the vitelliform material. Macrophages present in the vitelliform lesion may also take, to some extent, functions normally fulfilled by the RPE such as phagocytosis of waste products. These mechanisms do not compensate indefinitely for the lost RPE-photoreceptor apposition in AFVD. Studies with sufficient follow-up periods have reported a slowly progressive loss of central vision, and over the age of 70, vision can be substantially affected due to macular atrophy and/or the development of CNV (Hodes et al., 1984; Burgess et al., 1987; Glacet-Bernard et al., 1990; Thomann et al., 1995; Marmor and McNamara, 1996; Francis et al., 2005). Moreover, OCT studies revealed that the lesion's morphology and dimensions are dynamic, and subretinal accumulation can be absorbed in some cases (Querques et al., 2008; Freund et al., 2011). Nevertheless, adequate longitudinal data regarding the correlation between clinical characteristics, imaging (particularly OCT), and genetics are needed. Studies have also provided insights into the mechanisms underlying AFVD. For example, histology and imaging studies have revealed that the vitelliform material accumulates in the subretinal space and is composed primarily of shed photoreceptor outer segments, pigment, lipofuscin-laden macrophages, and RPE cells

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(Dubovy et al., 2000; Arnold et al., 2003; Benhamou et al., 2003; Querques et al., 2008; Freund et al., 2011; Querques et al., 2011a). Spaide suggested that the accumulation of subretinal hyperfluorescent vitelliform material is the result of abnormal outer segment uptake by the RPE, which may be due to a physical separation between the photoreceptors and the RPE (for example, in central serous chorioretinopathy), or due to abnormal physiology of the photoreceptor-RPE complex (Spaide, 2008). Given that there is currently no evidence of a pre-existing physical separation between the RPE and the photoreceptors in AFVD, the latter mechanism likely underlies the development of vitelliform material in this phenotype. The increased turnover of photoreceptor outer segment discs can exceed the RPE's capacity to take up and clear the shed material. This imbalance can result in an accumulation of material in the subretinal space. Based on findings obtained using heterozygous rds/þ mice, this process was suggested as the mechanism of action for a PRPH2 mutation (Sanyal and Hawkins, 1988, 1989; Wells et al., 1993). Perturbations in the interphotoreceptor matrixdpresumably due to mutations in IMPG1 or IMPG2dmight also disrupt uptake, which is potentially reminiscent of the physical separation described by Spaide (2008). Finally, altered RPE homeostasis and/or phagocytosis (for example, due to mutations in BEST1, senescence, inflammation, or oxidative injury) can potentially give rise to a superficially similar phenotype (Fig. 9) (Arnold et al., 2003; Boon et al., 2009b). After the vitelliform lesion has formed, several mechanisms can play a role in its resolution. Based on multimodal imaging findings, Freund et al. (2011) suggested that following the formation of the vitelliform lesion, photoreceptors degenerate, shedding of outer segments is reduced, and RPE cells can clear the vitelliform deposits. However, because RPE cells are often atrophic in the vicinity of the resolved vitelliform lesion, an alternative mechanism is that RPE cell loss can occur in parallel withdor even prior todphotoreceptor loss. The functional and physical loss of the RPE may be due to primary RPE failure, or it may develop secondary to the overload induced by the accumulated vitelliform material. Such an overload may drastically increase the RPE's phagocytotic activity, which is associated with oxidative injury, ultimately leading to RPE cell loss. This RPE cell loss can in turn lead to photoreceptor loss, and the subretinal material can be cleared by macrophages and surviving adjacent RPE cells. Accordingly, lipofuscin- and pigment-laden cells were observed in a histological analysis of AFVD eyes (Gass, 1974; Dubovy et al., 2000; Arnold et al., 2003) and using OCT findings (showing hyperreflective intraretinal spots) (Puche et al., 2010; Querques et al., 2011a). However, whether the timing and consequences of vitelliform lesion resolution are dictated by its underlying process remains unclear. For example, whether the rate of progression of the vitelliform lesion is associated with specific gene mutations and/or modifying factors is not currently known. Furthermore, although vitelliform lesion resolution often leads to foveal atrophy and substantial visual loss, in some cases vision can improve following lesion absorption (Freund et al., 2011; Querques et al., 2011a). Some other macular diseasesdparticularly AMDdmay involve mechanisms similar to AFVD. The relative dynamics of RPE and photoreceptor degeneration may determine whether the patient develops AMD or AFVD. Arnold and colleagues proposed that altered RPE phagocytosis leads to a buildup of subretinal lesions in AFVD; moreover, they proposed that vitelliform lesions do not usually occur in AMD because the RPE and overlying photoreceptors degenerate too rapidly to accumulate (Arnold et al., 2003). However, there is insufficient data to conclude that atrophy proceeds more rapidly in AMD than in AFVD. Alternatively, altered phagocytosis may be the primary defect in AFVD, whereas other

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RPE defects might dominate the pathology of AMD, possibly leading either to early RPE cell death (which is followed by photoreceptor cell death) or to a more pronounced accumulation of drusen and basal linear deposits under the RPE cells. Inflammation may play a role in both modulating the pathology and differentiating between the development of AFVD versus AMD. Inflammation plays a major role in AMD, and Arnold et al. suggested that fewer immune cells are present in the choroid in AFVD as compared to AMD (Arnold et al., 2003). Consistent with this notion, the major risk SNP in the CFH gene is not associated with AFVD (Barbazetto et al., 2007; Jaouni et al., 2012). On the other hand, histopathology studies revealed subretinal macrophages in AFVD patients (Gass, 1974; Dubovy et al., 2000; Arnold et al., 2003). Thus, specific forms of inflammation may characterize these distinct yet related pathologies, leading to specific complement activation‒mediated damage in AMD but not AFVD. According to this hypothesis, complement activation may underlie the formation of drusen and the earlier loss of RPE cells in AMD in contrast to AFVD. Further studies are needed to test this hypothesis. A significant hurdle in the study of AFVD is the current lack of clear consensus with respect to the clinical parameters that are required to establish a diagnosis. Although the presence or history of vitelliform lesions is a diagnostic prerequisite, others parameters are less clear, including whether the lesions are bilateral, the age at onset, and OCT findings (such as a lack of significant epiretinal membrane and/or vitreomacular traction). Particularly important factors include the presence, extent, and type of drusen compatible with this diagnosis. Drusen were described in the initial report of this phenotype, and drusen or drusen-like lesions can also be present in AFVD patients with BEST1, IMPG1, or IMPG2 mutations. Nevertheless, the distinction between AMD with a vitelliform lesion versus AFVD with drusen is not clear. There is currently no consensus in the published literature regarding whether a patient with multiple drusen (regardless of type or size) and a vitelliform lesion should be classified as having AFVD, AMD, or both. Clearly, the lack of standardized diagnostic criteria for AFVD has resulted in studies of heterogeneous patient populations, hampering meaningful comparison between studies and/or patient cohorts (DolzMarco et al., 2012; Querques et al., 2011a). Recent improvements in imaging and genetic diagnostic techniques for AFVD further underscore the difficulties faced when comparing the results of previous case series that describe AFVD as a clinical phenotype without genetic and OCT findings. Thus, factors such as the age at onset, the relative prevalence of monogenic AFVD cases, the rate of progression, and visual outcome can differ widely among studies as a result of applying different diagnostic criteria. Furthermore, Zhuk and Edwards noted that AFVD patients may receive a different diagnosis depending on when in the disease course they are evaluated. For example, an elderly individual with bilateral atrophic macular lesions might be diagnosed with central geographic atrophy (a manifestation of AMD); on the other hand, this same individual may have had vitelliform lesions a few years earlier and would therefore have been diagnosed with AFVD (Zhuk and Edwards, 2006). Marmor and McNamara examined four family members with PD over a twenty-year period and found that advanced PD can be mistaken for AMD-associated geographic atrophy (Marmor and McNamara, 1996). Similarly, Thomann and colleagues addressed this issue in their study of a large family with autosomal-dominant PD. They observed a variety of phenotypes among the family members, and the phenotype was significantly associated with age (Thomann et al., 1995). This age-dependent factor may also contribute to the heterogeneity of patients included in studies of AFVD. A better distinction between AMD and AFVD may result from detailed clinical evaluation using multimodal imaging, in combination with genetic characterization of

AFVD cases that are negative for the already identified monogenic mutations associated with this phenotype, and comparison of the data with genetic findings from AMD patients. 7. Conclusions The term “adult-onset foveomacular vitelliform dystrophy” that is currently used in the literature likely applies to a group of disorders with overlapping phenotypes. Many of these disorders may be associated with genetic factors; however, to date genetic defects underlying only a minority of AFVD cases have been identified. Most AFVD cases are sporadic and would more appropriately be labeled as a degeneration rather than a dystrophy. A third group of adult-onset acquired vitelliform lesions is associated with a variety of underlying conditions, including vitreomacular interphase alterations, mechanical factors, toxic maculopathies, and systemic disorders. In all cases, the common mechanism leading to the vitelliform lesions is an abnormal RPE-photoreceptor complex function. As a result of this dysfunction, vitelliform material (which is composed primarily of shed outer segment discs, pigment, and lipofuscin-laden RPE cells and macrophages) accumulates in the subretinal space. Once this material accumulates, and possibly regardless of the primary insult, a common final pathway may drive the progression of the vitelliform lesion. The process is associated with the slow progressive loss of visual acuity due to atrophy of photoreceptors and RPE in most cases, and in some cases due to the development of CNV. Future studies are needed to identify additional putative genetic factors underlying AFVD, and the results should provide a more clear delineation of possible genotype-phenotype correlations. Using insights gained from these studies, the distinction between monogenic and sporadic AFVDdas well as the line between AFVD, AMD, and other phenotypes with vitelliform lesionsdcan be better defined, and consensus can be reached on the terminology used to describe this disorder. Acknowledgments This study was supported in part by grants from the Israel Science Found (1006/13) and by the Chief Scientist of the Israeli Ministry of Health (9184). These funding agencies had no role in the study design, the collection, analysis, or interpretation of the data, writing of the report, or the decision to submit this article for publication. References Acharya, S., Rodriguez, I.R., Moreira, E.F., Midura, R.J., Misono, K., Todres, E., Hollyfield, J.G., 1998. SPACR, a novel interphotoreceptor matrix glycoprotein in human retina that interacts with hyaluronan. J. Biol. Chem. 273, 31599e31606. Al-Dahmash, S.A., Shields, C.L., Bianciotto, C.G., Witkin, A.J., Witkin, S.R., Shields, J.A., 2012. Acute exudative paraneoplastic polymorphous vitelliform maculopathy in five cases. Ophthalmic Surg. Lasers Imaging 43, 366e373. Arnold, J.J., Sarks, J.P., Killingsworth, M.C., Kettle, E.K., Sarks, S.H., 2003. Adult vitelliform macular degeneration: a clinicopathological study. Eye (Lond.) 17, 717e726. Aronow, M.E., Adamus, G., Abu-Asab, M., Wang, Y., Chan, C.C., Zakov, Z.N., Singh, A.D., 2012. Paraneoplastic vitelliform retinopathy: clinicopathologic correlation and review of the literature. Surv. Ophthalmol. 57, 558e564. Ascaso, F.J., Lopez-Gallardo, E., Del Prado, E., Ruiz-Pesini, E., Montoya, J., 2010. Macular lesion resembling adult-onset vitelliform macular dystrophy in Kearns-Sayre syndrome with multiple mtDNA deletions. Clin. Exp. Ophthalmol. 38, 812e816. Bandah-Rozenfeld, D., Collin, R.W., Banin, E., van den Born, L.I., Coene, K.L., Siemiatkowska, A.M., Zelinger, L., Khan, M.I., Lefeber, D.J., Erdinest, I., Testa, F., Simonelli, F., Voesenek, K., Blokland, E.A., Strom, T.M., Klaver, C.C., Qamar, R., Banfi, S., Cremers, F.P., Sharon, D., den Hollander, A.I., 2010. Mutations in IMPG2, encoding interphotoreceptor matrix proteoglycan 2, cause autosomal-recessive retinitis pigmentosa. Am. J. Hum. Genet. 87, 199e208.

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BMJ Case Rep. 23 http://dx.doi.org/ 10.1136/bcr.05.2010.3049 pii: bcr0520103049.

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Adult-onset foveomacular vitelliform dystrophy: A fresh perspective.

Adult-onset foveomacular vitelliform dystrophy (AFVD) was first described by Gass four decades ago. AFVD is characterized by subretinal vitelliform ma...
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