Progress in Retinal and Eye Research 39 (2014) 23e57

Contents lists available at ScienceDirect

Progress in Retinal and Eye Research

journal homepage: www.elsevier.com/locate/prer

Macular dystrophies mimicking age-related macular degeneration

Nicole T.M. Saksens a,1, 2, 7, Monika Fleckenstein b,1, 3, 7, Steffen Schmitz-Valckenberg b, 4, 7,
Frank G. Holz b, 3, 7, Anneke I. den Hollander a, 5, 7, Jan E.E. Keunen a, 5, 7,
Camiel J.F. Boon a, c, d, 5, 6, 7, Carel B. Hoyng a, *, 7
a
Department of Ophthalmology, Radboud University Medical Centre, Philips van Leydenlaan 15, 6525 EX Nijmegen, The Netherlands
b
Department of Ophthalmology, University of Bonn, Ernst-Abbe-Str. 2, Bonn, Germany
c
Oxford Eye Hospital and Nuffield Laboratory of Ophthalmology, John Radcliffe Hospital, University of Oxford, West Wing, Headley Way, Oxford OX3 9DU,
United Kingdom
d
Department of Ophthalmology, Leiden University Medical Centre, Albinusdreef 2, 2333 ZA Leiden, The Netherlands

a r t i c l e i n f o a b s t r a c t

Article history: Age-related macular degeneration (AMD) is the leading cause of irreversible blindness in the elderly
Available online 28 November 2013 population in the Western world. AMD is a clinically heterogeneous disease presenting with drusen,
pigmentary changes, geographic atrophy and/or choroidal neovascularization. Due to its heterogeneous
Keywords: presentation, it can be challenging to distinguish AMD from several macular diseases that can mimic the
Age-related macular degeneration features of AMD. This clinical overlap may potentially lead to misdiagnosis. In this review, we discuss the
AMD
characteristics of AMD and the macular dystrophies that can mimic AMD. The appropriate use of clinical
Macular dystrophy
and genetic analysis can aid the clinician to establish the correct diagnosis, and to provide the patient
Differential diagnosis
Retina
with the appropriate prognostic information. An overview is presented of overlapping and distinguishing
Clinical characteristics clinical features.
Ó 2013 Elsevier Ltd. All rights reserved.

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .24
1.1. AMD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24
1.2. Differentiating macular dystrophies from AMD: difficulties and relevance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . 25
2. Fundoscopic findings in AMD and macular dystrophies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25
2.1. Drusen and ‘drusen-like lesions’ . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25
2.2. Pigmentary changes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29
2.3. Geographic atrophy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29
2.4. Choroidal neovascularization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29
3. Differential diagnostic tools . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .31
3.1. Symptoms and fundoscopy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 31
3.2. Fundus autofluorescence . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 31
3.3. Fluorescein angiography . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 32

* Corresponding author. Tel.: þ31 24 36 144 48; fax: þ31 24 35 405 22.
E-mail addresses: Nicole.Saksens@radboudumc.nl (N.T.M. Saksens), Monika.Fleckenstein@ukb.uni-bonn.de (M. Fleckenstein), Steffen.Schmitz-Valckenberg@ukb.uni-
bonn.de (S. Schmitz-Valckenberg), frank.holz@ukb.uni-bonn.de (F.G. Holz), Anneke.denHollander@radboudumc.nl (A.I. den Hollander), Jan.Keunen@radboudumc.nl (J.E.
E. Keunen), Camiel.Boon@radboudumc.nl (C.J.F. Boon), Carel.Hoyng@radboudumc.nl (C.B. Hoyng).
1
Shared first authors.
2
Tel.: þ31 24 36 102 41; fax: þ31 24 35 405 22.
3
Tel.: þ49 228 287 15647; fax: þ49 228 287 15603.
4
Tel.: þ49 228 287 16826; fax: þ49 228 287 11470.
5
Tel.: þ31 24 36 144 48; fax: þ31 24 35 405 22.
6
Camiel J.F. Boon was supported by a Niels Stensen Fellowship Award.
7
Percentage of work contributed by each author in the production of the manuscript is as follows: Nicole Saksens, 35%; Monika Fleckenstein 25%; Steffen Schmitz-
Valkenberg 5%; Camiel Boon 15%; Anneke den Hollander 5%; Holz 5%; Keunen 5%; Hoyng 5%.

1350-9462/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.preteyeres.2013.11.001
24 N.T.M. Saksens et al. / Progress in Retinal and Eye Research 39 (2014) 23e57

3.4. Optical coherence tomography . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 32

3.5. Psychophysical and electrophysiological testing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 33
3.6. Genetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 33
4. Macular dystrophies mimicking AMD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .35
4.1. Drusen and ‘drusen-like deposits’ . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 35
4.1.1. Malattia leventinese . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 35
4.1.2. Sorsby fundus Dystrophy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 36
4.1.3. North Carolina macular dystrophy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 37
4.1.4. Late-onset retinal degeneration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 38
4.2. Irregular yellowish flecks . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 39
4.2.1. Late-onset Stargardt disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 39
4.2.2. Pattern dystrophies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 40
4.3. Vitelliform lesions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 41
4.3.1. Adult-onset foveomacular vitelliform dystrophy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 41
4.3.2. Best vitelliform macular dystrophy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 41
4.4. Miscellaneous . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 42
4.4.1. Central areolar choroidal dystrophy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 42
4.4.2. Late-onset cone dystrophy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 43
4.4.3. Central serous chorioretinopathy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 44
4.4.4. Macular telangiectasia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 44
4.5. Dystrophies associated with a syndrome or systemic disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 47
4.5.1. Mitochondrial retinal dystrophy associated with the m.3243A > G mutation (maternally inherited diabetes and deafness and MELAS
syndrome) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 47
4.5.2. Dystrophies with angioid streaks . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 48
4.5.3. Cuticular drusen in membranoproliferative glomerulonephritis II . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . 49
4.5.4. Maculopathy in myotonic dystrophy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 50
5. Conclusions and future directions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 50
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 51

1. Introduction visual acuity from AMD is caused by these advanced forms of the
disease. In addition, psychophysical studies have demonstrated that
1.1. AMD several parameters of visual function, in particular contrast sensi-
tivity, visual adaptation, central visual field, and colour discrimina-
Age-related macular degeneration (AMD) is a progressive chronic tion, deteriorate already in the early stages of AMD (Neelam et al.,
disease of the central retina and the leading cause of irreversible 2009). Since the disturbance in psychophysical function in AMD is
blindness in the elderly population in industrialized countries (Lim not limited to the macular region, but extends well into the retinal
et al., 2012). Based on a meta-analysis of studies in white people periphery, it appears that there is a global impairment of retinal
aged 40 years and older, the prevalence of early AMD is estimated to function (Ronan et al., 2006; Walter et al., 1999).
be 6.8% and the late stages to be 1.5% (Smith et al., 2001). The prev- The pathogenesis of AMD is incompletely understood. As a
alence of AMD increases exponentially with age (Rudnicka et al., complex, multifactorial disease, it is thought to involve variations in
2012). In the Beaver Dam Eye Study that includes predominantly a number of genetic, systemic and environmental factors. Ageing
white participants, individuals of age 75 years and older, the fifteen itself appears to be the major risk factor that renders the retina
year cumulative incidence of early AMD was 24.4% and of late AMD more susceptible to environmental effects (Boulton, 2013).
was 7.6% (Klein et al., 2007). The prevalence of AMD, however, differs Biochemical, histological and genetic studies have indicated
in ethnic groups. The Baltimore Eye Study has shown that late stage several pathways in AMD pathogenesis, including excessive accu-
AMD was nine to ten times more prevalent in the white as compared mulation of lipofuscin, oxidative damage, malfunctioning of the
to the black participants (Friedman et al., 1999). In the Asian popu- complement system, and chronic low-grade inflammation and
lation, the prevalence of late stage AMD appears to be largely similar possible sequences of events have been proposed.
to that in white people (Kawasaki et al., 2010). Lipofuscin accumulates in postmitotic RPE cells with age
Different cell layers are involved in the disease process: the apparently due to incomplete lysosomal degradation of photore-
photoreceptors, the retinal pigment epithelium (RPE), Bruch’s ceptor outer segments (reviewed by Boulton (2013)). Lipofuscin
membrane and the choriocapillaris. consists of a multitude of molecules including the dominant fluo-
Different stages and phenotypic manifestations of AMD have been rophore N-retinyl-N-retinylidene ethanolamine (A2E), a by-
categorized (Ferris et al., 2013): The early stages (early and inter- product of the visual cycle (Suter et al., 2000) (Palczewska et al.,
mediate AMD) are characterized by pigmentary alterations and/or 2010). Exposure of lipofuscin containing RPE cells to blue light
the formation of so called ‘drusen’, extracellular material located (390e520 nm) results in a lipofuscin-dependent lipid peroxidation,
between the RPE and the Bruch’s membrane. Patients with early protein oxidation, loss of lysosomal integrity, mitochondrial DNA
AMD are usually asymptomatic. AMD may progress to exudative damage, and RPE cell death (reviewed by Boulton (2013)). It has
(neovascular) AMD and non-exudative (atrophic) AMD, both result- further been suggested that products of the photooxidation of A2E
ing in vision loss. Typically, patients with neovascular AMD describe in RPE cells could serve as a trigger for complement activation
sudden worsening of central vision with distortion of straight lines or (Zhou et al., 2006). An aberrant complement regulation - that is
a dark patch in their central vision. In atrophic AMD progressive loss implicated by the association of the risk for AMD with DNA
of vision develops over many years. Neovascular AMD and atrophic sequence variants in genes encoding for complement factors (see
AMD may also occur in combination. The most severe decline of below) e appears to contribute to chronic inflammation. Herein,
 N.T.M. Saksens et al. / Progress in Retinal and Eye Research 39 (2014) 23e57 25

Abbreviations PXE pseudoxanthoma elasticum

MIDD maternally inherited diabetes and deafness
AMD age-related macular degeneration MPGN II Membranoproliferative glomerulonephritis type II
RPE retinal pigment epithelium ML Malattia leventinese
GA geographic atrophy ERG electroretinography
CNV choroidal neovascularization EOG electro-oculography
CFH complement factor H TIMP3 Tissue Inhibitor of Metalloproteinase 3
C3 complement component 3 VEGF vascular endothelial growth factor
FA fluorescein angiography A2E N-retinylidene-N-retinylethanolamine
FAF fundus autofluorescence CACD central areolar choroidal dystrophy
SD-OCT spectral-domain optical coherence tomography CSC Central serous chorioretinopathy
cSLO confocal scanning laser ophthalmoscopy MacTel Macular Telangiectasia
ICGA indocyanine green angiography MELASmitochondrial encephalopathy mitochondrial
AFVD Adult-onset foveomacular vitelliform dystrophy encephalopathylactic
BVMD Best vitelliform macular dystrophy acidosis and stroke-like
NCMD North Carolina macular dystrophy episodes
LORD Late-onset retinal degeneration DMPK myotonic dystrophy protein kinase
SFD Sorsby fundus dystrophy CNBP CCHC-type zinc finger, nucleic acid-binding protein.

drusen are thought to form as a product of those local inflammatory spectrum of AMD. Due to this clinical variability of AMD, there is a
processes (Donoso et al., 2006; Hageman et al., 2001). considerable overlap with a number of macular dystrophies that
In recent years, major progress was made in elucidating the ge- are often monogenic with specific inheritance patterns. Also, AMD
netic basis of AMD through the identification of two common var- and the macular dystrophies show a considerable variation in their
iants on chromosome 1 and 10, together likely accounting for clinical presentation and severity. Flecks that may resemble drusen
approximately 50% of cases. On chromosome 1, a strong association can be present in several hereditary macular conditions. Many
was identified with variants in the complement factor H (CFH) gene, macular dystrophies may show chorioretinal atrophy comparable
suggesting an involvement of the complement cascade in AMD to geographic atrophy (GA) in AMD. Choroidal neovascularisation
pathogenesis (Edwards et al., 2005; Hageman et al., 2005; Haines (CNV) can also occur in macular dystrophies, although it is rare and
et al., 2005; Klein et al., 2005). Subsequently, AMD risk variants in appears to have a relatively favourable prognosis as compared to
other genes involved in the complement cascade were identified, for CNV in AMD (Marano et al., 2000).
example in the complement component 2/factor B (Gold et al., A differentiation between AMD and other macular disorders is
2006), component 3 (C3) (Maller et al., 2007), and complement important as the exact diagnosis can have implications for the
factor I genes (Maller et al., 2007). The second major AMD risk locus prognosis and genetic counselling as well as for preventive and
was identified on chromosome 10. Disease associated variants therapeutic strategies.
support a region harbouring two genes in strong linkage disequi- This review aims to give an overview of macular dystrophies
librium, named the age-related maculopathy susceptibility 2 gene that may mimic AMD. For every disease we describe the symptoms,
and the high temperature requirement factor A1 gene (Jakobsdottir multimodal imaging and psychophysical and electrophysiological
et al., 2005; Rivera et al., 2005). However, the functional implica- testing. In addition, we also summarize the genetic background and
tions of the chromosome 10 locus on AMD pathology are still un- the pathophysiology of each disease. Based on these specific clinical
clear. A genomic wide association study recently performed by the and genetic characteristics, we provide a practical differential
AMD Gene Consortium found in total 19 loci associated with AMD, diagnostic guideline.
including seven new loci (Fritsche et al., 2013). Recently, rare, highly
penetrant mutations in the CFH and Complement Factor I genes have
been identified besides the common genetic variants, conferring a 2. Fundoscopic findings in AMD and macular dystrophies
high risk of AMD (Boon et al., 2008c; Raychaudhuri et al., 2011; van
de Ven et al., 2012a; van de Ven et al., 2013). Rare variants may play 2.1. Drusen and ‘drusen-like lesions’
an important role in the pathogenesis of AMD particularly in case of
densely affected families. Drusen are considered as the phenotypic hallmark of AMD, but
Recently, a predictive model for late stage AMD based on data they are not pathognomonic of AMD (Wang et al., 2010). Drusen are
from population-based studies (the Rotterdam Study, the Beaver focal deposits of extracellular debris located between the basal
Dam Eye Study, and the Blue Mountains Eye Study) has been re- lamina of the RPE and the inner collagenous layer of Bruch’s
ported. It has been shown that best prediction for late AMD was membrane (Green and Enger, 1993; Sarks, 1980). Drusen are known
based on age, sex, 26 genetic variants, 2 environmental variables, to contain carbohydrates, zinc, and at least 129 different proteins,
and early AMD phenotype (Buitendijk et al., 2013). including apolipoproteins and excluding extracellular matrix
(Anderson et al., 2001; Crabb et al., 2002; Lengyel et al., 2007; Li
et al., 2005; Malek et al., 2003; Mullins and Hageman, 1999;
1.2. Differentiating macular dystrophies from AMD: difficulties and Mullins et al., 2000).
relevance Fundoscopically, drusen are yellowish nodular lesions located
at the posterior pole. Previous classifications of AMD have
There are no pathognomonic clinical characteristics for AMD, included the following qualities of drusen: drusen size (e.g., large
despite the fact that drusen are a hallmark feature. Different clinical vs. small), character (e.g., soft vs. hard), location, number, and area
manifestations may be present, leading to a broad phenotypic (Bird et al., 1995; Ferris et al., 2005; Seddon et al., 2006). The
26 N.T.M. Saksens et al. / Progress in Retinal and Eye Research 39 (2014) 23e57
 N.T.M. Saksens et al. / Progress in Retinal and Eye Research 39 (2014) 23e57 27

recently reported AMD classification by Ferris et al. again stresses thickening of RPE/Bruch’s membrane complex or as a ‘sawtooth’
the importance of drusen size in AMD patients, particularly with RPE elevation on SD-OCT scans (Fig. 1H) (Querques et al., 2011b).
regards to the prognostic relevance for late-stage disease devel- A higher allele frequency of the CFH Y402H risk allele in patients
opment. Hereby, small drusen (63 mm) are considered to repre- with cuticular drusen suggests that activation of the alternative
sent normal ageing changes and should be differentiated from pathway of the complement system may play a larger role in the
early AMD (Ferris et al., 2013). Medium sized drusen (>63 mm and pathogenesis of the cuticular drusen phenotype than in the
125 mm) without associated pigment abnormalities represent remainder of the AMD phenotypes (Reynolds et al., 2009; Scholl
early while large drusen (<125 mm) and/or any AMD-related et al., 2008; van de Ven et al., 2012b). This is supported by previ-
pigmentary abnormality (i.e. any definite hyper- or hypopig- ous studies that identified rare pathogenic CFH mutations in a
mentary abnormalities associated with medium or large drusen) subset of families with cuticular drusen (Boon et al., 2008c; van de
represent intermediate AMD (Fig. 1A) (Ferris et al., 2013). Drusen Ven et al., 2012a).
may present as clusters and become confluent (‘confluent dru- In addition, reticular (pseudo-)drusen have been described.
sen’). Large confluent drusen may form clinically evident pigment Initially reported by Mimoun et al. (1990) as ‘pseudodrusen visible
epithelial detachments without underlying CNV (‘drusenoid en lumière bleu’ [‘the pseudo-drusen visible in blue light’]. It has
pigment epithelium detachment’) (Sarks et al., 1994). On fluores- been described by others using different terms, including ‘reticular
cein angiography (FA), small drusen may show a focal hyper- drusen’ (Klein et al., 1991). There is still an ongoing debate whether
fluorescence in the late-stage, whereas larger drusen usually show reticular drusen are located anterior or posterior to the RPE.
a hypofluorescence due to the blockage of choroidal background Reticular drusen are subtle, fundoscopically hardly detectable in-
fluorescence. Fundus autofluorescence (FAF) does not allow clear dividual lesions showing an interlacing network of round or oval
distinction of most AMD-related drusen because drusen exhibit a shaped multiple, yellowish irregularities with an approximately
similar signal compared to the background (Fig. 1B). One exception size between 50 and 250 mm (Fig. 1I). Several studies, for instance
is large, confluent drusen that show a mildly increased signal. the Beaver Dam Eye study, identified reticular drusen as a risk
Compared to fundus photography, the area involved by soft drusen factor for the development of late-stage AMD (Klein et al., 2008;
appears to be better detectable by FAF imaging. On spectral- Knudtson et al., 2004). On FA reticular drusen may show a
domain optical coherence tomography (SD-OCT) imaging, drusen discrete hypofluorescence towards the later phases. The reticular
typically present as ‘dome-shaped’ elevations of variable size of pattern is typical for reticular drusen by FAF imaging showing
the outer retinal layers and the RPE (Fig. 1D). SD-OCT herein en- multiple spots with decreased intensity surrounded by mildly
ables to reveal differential reflectivity of the drusen material by increased intensity (Fig. 1J). The reticular drusen pattern in cSLO
itself (Khanifar et al., 2008). This may point to differences in the (confocal scanning laser ophthalmoscopy) images correlates with
biochemical composition of drusen. marked changes at a level anterior to the RPE/Bruch’s membrane
Cuticular drusen, formerly known as ‘basal laminar drusen’ that complex (Fleckenstein et al., 2008; Schmitz-Valckenberg et al.,
have been firstly described by Gass in 1977 (Agarwal, 2012). It has 2010; Zweifel et al., 2010). By scanning precisely through a row of
been estimated that the cuticular drusen phenotype comprises reticular lesions by SD-OCT, accumulation of material between the
approximately 10% of the AMD spectrum (van de Ven et al., 2012a). ellipsoid zone of the photoreceptors and the RPE/Bruch’s mem-
Cuticular drusen are usually 25e75 mm in size and are discretely brane complex is visible (Fig. 1K) (Fleckenstein et al., 2008;
round, slightly raised, yellow, subretinal pigment epithelium nod- Schmitz-Valckenberg et al., 2010; Zweifel et al., 2010) (anatomical
ules that initially may be randomly scattered in the macular area in correlations of SD-OCT bands are according to the nomenclature
young adults, but later often become more numerous and in some proposed by the ‘International Nomenclature for Optical Coherence
patients are grouped in clusters of 15e20 drusen (Fig. 1E) (Agarwal, Tomography Panel’).
2012). These clusters, in turn, may be closely arranged in a knit Large colloid drusen are large (200e300 mm) lesions associated
pattern giving the entire macula and the paramacula an orange- with an early age at onset and a relatively good vision (Guigui et al.,
peel appearance (Agarwal, 2012). FA is particularly helpful for the 2011). The lesions show increased autofluorescence on FAF and are
visualization of cuticular drusen. They fluoresce discretely during mildly hyperfluorescent in the early phases of FA, with a progres-
the early arterio-venous phase and in many patients they give the sive staining in late phases (Guigui et al., 2011). On indocyanine
fundus a ‘stars-in-the-sky’ picture (Fig. 1G) (Agarwal, 2012). FAF green angiography (ICGA), large colloid drusen are hypofluorescent
shows cuticular drusen as areas of ill-defined autofluorescence in the early phase, and in later phases the hypofluorescent centre is
centered by punctate hypo-autofluorescent lesions (Fig. 1F) surrounded by a hyperfluorescent halo bordered by a thin hypo-
(Meyerle et al., 2007; Querques et al., 2011b; Spaide and Curcio, fluorescent ring (Guigui et al., 2011).
2010). Besides correlating with ‘dome-shaped’ elevations, cutic- Irregular flecks: Fundus flavimaculatus is characterized by the
ular drusen have been reported to further appear as irregular slight presence of irregular yellowish flecks in the deeper retinal layers of

Fig. 1. (AeD) Drusen and hyperpigmentation in a 67-year-old patient with intermediate Age related macular degeneration (AMD). The colour fundus image (A) shows medium and
large sized drusen associated with hyperpigmentation. Fundus autofluorescence (FAF) imaging (B) shows an increased signal that is mainly associated with the hyperpigmentary
changes. Drusen are associated with increased, decreased or normal FAF. Note the “reticular drusen” FAF pattern pronounced superior-temporally. Optical coherence tomography
(OCT) imaging reveals hyperreflective foci that correspond to the hyperpigmentary changes (C) or shows the characteristic dome-shaped appearance of drusen (D). The images (Ee
H) show cuticular drusen in a 38-year-old patient. (E) Colour fundus photograph showing small yellow cuticular drusen in the macula and peripheral retina. (F) FAF image showing
increased autofluorescence of the deposits in the posterior pole (black arrows). (G) Fluorescein angiography (FA) image showing the hyperfluorescent deposits as a typical ‘stars-in-
the-sky’ picture in the early phase. (H) Horizontal OCT scan showing the cuticular drusen corresponding to hyperreflective elevations of the retinal pigment epithelium (RPE). The
images (IeK) show reticular drusen in an 80-year-old patient associated with intermediate AMD. The colour fundus image (I) shows the superior central area with drusen and
hyperpigmentation in an interlacing network of round and oval shaped yellowish irregularities. FAF imaging (J) shows multiple spots with decreased intensity surrounded by mildly
increased intensity. SD-OCT imaging (K) reveals a wavy pattern of the ellipsoid zone (black arrow) with accumulation of highly reflective material between the ellipsoid zone and
the RPE/Bruch’s membrane complex (white arrow) corresponding to the reticular pattern in the IR image. The images (LeN) show a multifocal geographic atrophy (GA) secondary to
AMD, in a 77-year-old patient. Fundoscopically (L), the GA appears as a sharply demarcated area with depigmentation and typically enhanced visualisation of deep choroidal vessels.
On FAF imaging (M) there is a well-demarcated area with decreased FAF corresponding to the GA lesion. On SD-OCT imaging (N), GA is characterized by loss of the outer retinal
layers and a signal enhancement within the choroid. (OeR) Choroidal neovascularisation (CNV) in a 68-year-old patient with occult CNV secondary to AMD. In the fundus image (O),
there is a PED and drusen. In the FAF image (P), the lesion extends beyond the edge of the lesion defined by FA (Q). On SD-OCT imaging (R), there is a PED visible with subretinal
fluid in the inferior part of the lesion.
28 N.T.M. Saksens et al. / Progress in Retinal and Eye Research 39 (2014) 23e57

Table 1
Summary of distinguishing features of macular dystrophies in comparison with AMD.

Clinical characteristics Diagnosis Distinguishing features Gene/locus

Drusen and drusen-like deposits ML - Earlier age at onset (30e40 y) EFEMP1

- Positive family history (AD inheritance pattern)
- Presence of typical radially oriented macular drusen,
sometimes with nodular peripapillary drusen, which
evolve to large densely packed and confluent drusen
SFD - Earlier age at onset (30e50 y) TIMP3
- Positive family history (AD inheritance pattern)
- Delayed choroidal filling on FA
- Extramacular chorioretinal disease
NCMD - Early age at onset (in childhood or possibly congenital) (MCDR1 locus on chr 6q16)
- Positive family history (AD inheritance pattern and Irish-
American ancestry)
- Relatively stationary course, except in rare cases of CNV
- Absence of sub-RPE deposits on SD-OCT
- Relatively preserved visual acuity despite sometimes
marked atrophy
LORD - Onset of night vision problems before the age of 50 C1QTNF5
- Positive family history (AD inheritance pattern)
- Extensive scalloped areas of chorioretinal atrophy
- Long anteriorly inserted lens zonules and peripupillary
iris transillumination
- Evidence of widespread retinal disease on dark adapta-
tion and full-field ERG in advanced LORD.
Yellowish flecks Irregular Late-onset - Flecks are more irregularly shaped and do not cluster in ABCA4
Stargardt the central macula
- Intense autofluorescence of flecks on FAF images
- Dark choroid on FA
Pseudo-Stargardt - Early age at onset (<55 y) PRPH2/RDS
pattern dystrophy - Positive family history (AD inheritance pattern)
- Flecks show intense autofluorescence on FAF images and
hyperfluorescence with a central hypofluorescent spot on
FA.
- Constriction of peripheral visual field
Pattern dystrophy - Earlier age at onset (20e50 y) PRPH2/5q21.2-q33.2
- Positive family history (AD inheritance pattern may be
masked)
- Absence of typical soft drusen
- Specific AF and FAF patterns
Vitelliform AFVD - Central vitelliform lesion without surrounding drusen PRPH2/BEST1
- Marked autofluorescence changes within AFVD lesions
- Lesion corresponding to hyperreflective accumulation
above the RPE on SD-OCT
BVMD - Age at onset before the age of 50 BEST1
- Positive family history (AD inheritance pattern)
- Central vitelliform lesion without surrounding drusen
- Marked autofluorescence changes within BVMD lesion
- Lesion corresponding to hyperreflective accumulation
above the RPE on SD-OCT
- Markedly abnormal EOG
Atrophy without Miscella-neous CACD - Relatively early age at onset (30e50 y) PRPH2
drusen or - Positive family history (AD inheritance pattern)
flecks - Absence of genuine drusen on ophthalmoscopy and SD-
OCT
- More pronounced FAF changes than in atrophic AMD
Late-onset cone - Earlier age at onset (30e60 y)
dystrophy - No drusen
- Temporal optic disc pallor
- ERG findings typical for cone dystrophy
CSC - Relatively early age at onset
- History of serous neuroretinal detachment without dru-
sen on ophthalmoscopy and SD-OCT
- Gravitational tracks on FA and FAF
MacTel - Earlier age at onset (>40 y)
- Absence of drusen
- Capillary dilatation on FA, particular temporally to the
fovea
- Parafoveal hyperreflectivity in blue reflectance
- Retinal thinning and cavities on SD-OCT
Dystrophy associated MIDD/MELAS - Positive family history (maternal inheritance pattern) m.3243A > G
with syndrome associated macular - Speckled hypo- and hyperautofluorescence that may
or systemic disease dystrophy spread along the temporal retinal vascular arcades and
surround the optic disc
- Concomitant symptoms such as hearing loss and diabetes
- Earlier age at onset (in adolescents) ABCC6
 N.T.M. Saksens et al. / Progress in Retinal and Eye Research 39 (2014) 23e57 29

Table 1 (continued )

Clinical characteristics Diagnosis Distinguishing features Gene/locus

Angioid streaks - Angioid streaks on near infrared-, FA-, FAF-, and SD-OCT-
related dystrophy imaging.
- Accompanied ocular findings such as peau d’ orange and
comet tail lesions
- Accompanied systemic symptoms such as skin abnor-
malities, cardiovascular disease, gastro-intestinal
bleeding
MPGN II - Earlier age at onset (in childhood) C3 þ CFH
- Stars in the sky appearance on FA
- Accompanied renal disease
Maculopathy in - Positive family history for myotonic dystrophy DMPK þ CNBP
Myotonic dystrophy - Associated ocular symptoms such as posterior subcapsu-
lar cataracts, ptosis, ophthalmoplegia, and low intraocular
pressure
- Generalized muscle weakness and myotonia

Abbreviations: ML, Malattia Leventinese; AD, autosomal-dominant; SFD, Sorsby Fundus Dystrophy; FA, fluorescein angiography; NCMD, North Carolina Macular Dystrophy;
CNV, choroidal neovascularization; RPE, retinal pigment epithelium; SD-OCT, spectral-domain optical coherence tomography; LORD, Late Onset Retinal Macular Dystrophy;
ERG, electroretinography; FAF, fundus autofluorescence; AFVD, Adult-onset Foveo Macular dystrophy; BVMD, Best Vitelliform Macular Dystrophy; EOG, electro-oculography;
CACD, Central Areolar Choroidal Dystrophy; AMD, Age-related Macular Degeneration; CSC; Central Serous Chorioretinopathy; MacTel, Macular Telangiectasia; MIDD,
Maternally Inherited Diabetes and Deafness; MELAS, Mitochondrial Encephalopathy, Lactic Acidosis and Stroke-like episodes.

the posterior pole. The flecks are variable in size, shape and dis- choroidal vessels (Fig. 1L). GA may occur as uni-focal or multi-focal
tribution. In the midperipheral retina, these yellowish flecks can be lesion. The configuration of atrophy may vary from round or oval to
interconnected to form a reticular pattern (Wabbels et al., 2006a). lobular. Histologically, areas of GA in AMD are characterized by loss
Vitelliform lesions: The term ‘vitelliform’ is aspecific, referring of the RPE, of outer layers of the neurosensory retina and the
to a round, yellowish lesion that looks like an egg yolk. Vitelliform choriocapillaris (Green and Key, 1977; Sarks et al., 1988).
lesions show intense hyperautofluorescence on FAF and hypo- On FA, GA typically presents with late well-defined hyper-
fluorescence on FA, due to the accumulation of hyperreflective fluorescence. Due to the loss of the RPE, the hyperfluorescent signal
material between the neuroretina and RPE, which is visible on SD- derives from the staining of the exposed deep choroid and sclera
OCT (Boon et al., 2009c; Spaide et al., 2006). Vitelliform lesions can (‘window defect’).
be seen in a broad range of macular conditions, such as adult-onset Due to RPE atrophy and thus loss of intrinsic fluorophores, GA in
foveomacular vitelliform dystrophy (AFVD), Best vitelliform mac- AMD presents as well-demarcated lesion with decreased FAF signal
ular dystrophy (BVMD), drusenoid vitelliform RPE detachments, (Fig. 1M). FAF imaging allows for more precise delineation of the
mitochondrial retinal dystrophy associated with the m.3243A > G atrophy process as compared to fundus photography. Furthermore,
mutation, vitreofoveal traction, acute vitelliform polymorphous in the area surrounding the GA, different patterns of abnormal FAF
exudative maculopathy, and paraneoplastic vitelliform retinopathy may be differentiated (Bindewald et al., 2005; Holz et al., 2007).
(Boon et al., 2009b; Freund et al., 2011). This allows for phenotypic sub-classification of GA. Herein, the
‘banded’ and the ‘diffuse’ GA sub-types have been shown to be
2.2. Pigmentary changes associated with a significantly faster progression of the GA lesions
as compared to the ‘none’ and ‘focal’ sub-types (Holz et al., 2007).
Pigmentary changes appear on clinical examination either as On SD-OCT imaging, GA is characterized by loss of the outer
hypopigmentary changes, which are seen as depigmented areas of retinal layers, including the outer nuclear layer, the external
the RPE or hyperpigmentary changes, which are deposits of grey or limiting membrane, ellipsoid zone, myoid zone, and interdigitation
black pigment within the retina or at the level of the RPE (Ferris zone, respectively, and by loss of the inner part of the RPE/Bruch’s
et al., 2005; Wang et al., 2003). Hyperpigmentation in AMD is membrane complex (assumed RPE-layer) (Fig. 1N) (Fleckenstein
presumed to result from RPE displacement, migration, or degen- et al., 2008). The GA border in AMD usually shows marked alter-
eration (Ferris et al., 2005; Wang et al., 2003). Any hyper- or ations of the outer retinal SD-OCT layers. In the area surrounding
hypopigmentary abnormality associated with medium or large GA, SD-OCT imaging may reveal various microstructural alterations
drusen is a defining feature of intermediate AMD (Ferris et al., that may also be found in eyes with only drusen and hyperpig-
2013). mentation (Fleckenstein et al., 2008).
On FA, hyperpigmentations usually appear hypofluorescent due
to blocked background fluorescence, while on FAF, there is 2.4. Choroidal neovascularization
frequently a correlating increased signal (Fig. 1B). On SD-OCT,
hyperpigmentary alterations usually correlate with hyper- CNV is the in-growth of pathologic new blood vessels through
reflective foci (Fig. 1C). These foci may be located at the level of the Bruch’s membrane into the sub-RPE and/or the subretinal space
RPE or in more inner retinal layers (Fleckenstein et al., 2008; Folgar originating from the choriocapillaris. Leakage of plasma or blood
et al., 2012). Serial examinations in vivo by high-resolution OCT into the surrounding tissue is characteristic of CNV lesion. The
imaging have shown migration of these hyperreflective foci into natural course of CNV is evolution to fibrovascular scar formation.
more inner retinal layers with time (Fleckenstein et al., 2010; Ho Retinal Angiomatous Proliferation (RAP) has recently been recog-
et al., 2011). nized as a variant of neovascular AMD that is characterized by the
formation of pathologic new vessels within the retina that may
2.3. Geographic atrophy secondarily invade into the subretinal space or into the choroid
(Yannuzzi et al., 2001). Polypoidal choroidal vasculopathy (PCV) is
Fundoscopically, GA appears as a sharply demarcated area with characterized by branching vascular networks terminating in pol-
depigmentation and typically enhanced visualisation of deep ypoidal dilations that appear as reddish-orange structures beneath
30 N.T.M. Saksens et al. / Progress in Retinal and Eye Research 39 (2014) 23e57
 N.T.M. Saksens et al. / Progress in Retinal and Eye Research 39 (2014) 23e57 31

the RPE (Yannuzzi et al., 1999). It is still debated if PCV is a sub-form normal (Jackson et al., 1999). Furthermore, distinct drusen may
of AMD or if it is a separate clinical entity. CNV may present fun- cause metamorphopsia. Progression of the disease generally results
doscopically as greyish subretinal lesion (Fig. 1O). Other fundo- in vision loss, increased metamorphopsia and/or a dark patch in
scopic changes that suggest CNV include macular edema, subretinal central vision. The course of visual symptoms and the age of onset
fluid, hard exudates, haemorrhage, and RPE detachment. may help to discriminate AMD from macular dystrophies.
It has been shown that CNV may be associated with normal, North Carolina macular dystrophy (NCMD) patient for instance,
increased, or decreased focal RPE autofluorescence (Dandekar et al., typically present with visual complaints during their childhood and
2005; Framme et al., 2006; McBain et al., 2011; Suzuki et al., 2013; complaints and fundoscopic features have a stable course. The visual
Yamagishi et al., 2012). Abnormal FAF intensities visible in eyes acuity is relatively good and stable, like in patients with late-onset
with CNV often extend beyond the edge of a lesion defined by FA, Stargardt and pseudo-Stargardt pattern dystrophy. Patients with
which indicates a more widespread disease process, over and above late-onset retinal degeneration (LORD), Sorsby fundus dystrophy
that witnessed on conventional angiograms (Fig. 1P). It has been (SFD) and pseudo-Stargardt pattern dystrophy may also present
speculated that this observation may reflect the proliferation of RPE with night vision problems or loss of peripheral vision. Some mac-
cells around the CNV (McBain et al., 2007). ular diseases discussed in this review are multisystemic disorders
Fluorescence angiography is the gold standard for visualization presenting with additional multisystemic symptoms. Patients with
of CNV and differentiation of CNV variants. According to its maculopathy in myotonic dystrophy often present with muscle
appearance during FA, CNV can be classified into classic or occult weakness and myotonia and patients with pseudoxanthoma elas-
lesion types. The classic type shows well-defined margins and ticum (PXE) may suffer from cardiovascular disease, gastro-
homogeneous leakage of dye within the entire lesion, whereas intestinal bleeding and skin papules. Hearing loss and diabetes in
occult lesions demonstrate irregular margins with heterogeneous maternally inherited diabetes and deafness (MIDD) patients and
leakage of fluorescein within the lesion (1991) (Fig. 1Q). Originally, renal disease in membranoproliferative glomerulonephritis type II
the differences in leakage pattern were assumed to be explained by (MPGN II) patients are also systemic symptoms, which may help to
the anatomic location e subretinal or sub-RPE - of the CNV. How- come to the correct diagnosis.
ever, clinico-pathological correlations indicated a lack of strong In AMD, fundoscopic features are present mainly in the macular
correlation between fluorescein angiography pattern and anatomic area. In contrast, deposits in SFD patients are present in the entire
localization of the CNV (Grossniklaus et al., 2005). posterior pole, extending to the equator. The presence of comet tail
For the diagnosis and visualization of PCV and RAP, indocyanine lesions, angioid streaks and peau d’orange point to PXE-related
green (ICG) angiography is superior to other imaging modalities. dystrophy. In addition, the aspect of the optic disc and the peri-
High-resolution OCT imaging allows for precise visualization of papillary region may provide distinguishing information like dru-
subretinal and intraretinal fluid and other CNV-associated charac- sen of the optic disc in PXE dystrophies, and juxtapapillary
teristics (Fig. 1R). Furthermore, detection of changes in retinal drusenoid lesions in Malattia Leventinese (ML).
thickness by OCT imaging has become an important indicator in the
monitoring of therapeutic effects in CNV. 3.2. Fundus autofluorescence

3. Differential diagnostic tools Besides fundoscopy, FAF is probably the most valuable differ-
entiating tool to distinguish the different macular dystrophies from
The most important differential diagnostic findings and genetic each other and from AMD. Abnormalities on FAF are often more
associations of each macular dystrophy are summarized in Table 1. extensive than the abnormalities seen on fundoscopy or FA. FAF
With the advancements in multimodal retinal imaging and genetic gives an indirect reflection of metabolic changes and lipofuscin
testing, a spectrum of diagnostic tools is currently available to accumulation at the level of the RPE and allows topographical
establish the correct diagnosis. An overview of important differ- mapping of lipofuscin distribution in the RPE. Lesions with
entiating findings with the available differential diagnostic tools is increased FAF often corresponds to fundoscopically visible yellow
given below. lesions that contain lipofuscin, either due to accumulation of
abnormally increased amounts of lipofuscin in the RPE (such as the
3.1. Symptoms and fundoscopy flecks seen in Stargardt disease), and/or accumulation of auto-
fluorescent material between the neuroretina and RPE that con-
Patients with early AMD usually present with normal central tains lipofuscin precursors (such as in BVMD) (Spaide et al., 2006;
visual acuity. Impaired dark adaptation upon moving from brightly Westeneng-van Haaften et al., 2012). Decreased FAF is observed
lit to dim environments, however, is commonly reported by pa- for instance in areas of RPE atrophy (Figs. 1M, 2I and 5F). Lesions in
tients with early AMD, although central visual acuity remains AMD show increased, decreased or normal autofluorescence, but

Fig. 2. (AeE) Malattia Leventinese in a 51-year-old patient who carried an EFEMP1 mutation. (A) Colour fundus photograph showing small radiating drusen (white arrow) and larger
confluent drusen in the macular area (black arrow) and around the optic disc. Centrally located large drusen confluence to a yellow-white plaque. (B) Fundus autofluorescence (FAF)
image showing that large drusen located in the macula (black arrow) and drusenoid lesions nasally in the optic disc correspond to increased FAF, whereas the small radial drusen
(white arrow) are faintly visible. (C) Fluorescein angiography (FA) image showing blockage of background fluorescence caused by the central large drusen and small hyper-
fluorescent radially oriented drusen. (D) Horizontal optical coherence tomography (OCT) scan showing the sawtooth elevations of the retinal pigment epithelium (RPE) corre-
sponding to the small radial drusen. (E) Horizontal OCT scan (scan in the plane indicated by black arrowhead in A), showing diffuse deposition of hyperreflective material between
the RPE and Bruch’s membrane, corresponding to large round drusen. (FeG) Sorsby fundus dystrophy (Courtesy of SM Downes). (F) Colour fundus photograph showing typical
drusen along the arcade with a central choroidal neovascular complex. (G) Colour fundus photograph showing poor response to previous photodynamic therapy. (HeJ) North
Carolina macular dystrophy stage 3 in a 19-year-old patient (Courtesy of Alessandro Iannaccone, MD, MS, Retinal Degeneration & Ophthalmic Genetics Service, Hamilton Eye
Institute, University of Tennessee Health Science Center, Memphis, TN, USA). (H) Colour fundus photograph showing a large circumscribed area of chorioretinal atrophy in the
macula, with surrounding drusen-like lesions. (I) FAF image showing decreased autofluorescent in the atrophic lesion with a hyperautofluorescent surrounding edge of the lesion.
(J) OCT scan (scan in the plane indicated by black arrowhead in H) showing atrophy of the neurosensory retina, RPE, and choroid, but intact photoreceptors adjacent to the lesion.
(KeM) Late onset retinal dystrophy in an 82-year-old patient who carried the p.Ser163Arg mutation in the C1QTNF5 gene (Courtesy of Moorfields Eye Hospital). (K) Slit lamp ex-
amination showing long anteriorly inserted lens zonules and peripupillary atrophy. (L) An enlarged view of slit lamp examination image K clearly showing long anteriorly inserted
lens zonules. (M) Colour fundus photograph showing small drusenoid deposits in the posterior pole with some pigmentary changes.
32 N.T.M. Saksens et al. / Progress in Retinal and Eye Research 39 (2014) 23e57

Fig. 3. (AeD) Late-onset Stargardt in a 58-year-old patient. (A) Colour fundus photograph showing irregular, pisciform, flavimaculatus flecks in the posterior pole and central ir-
regularities of the retinal pigment epithelium. (B) Fundus autofluorescence (FAF) image showing increased autofluorescence of the flecks. (C) Fluorescein angiography (FA) image
showing decreased choroidal background fluorescence causing a “dark choroid” aspect and hyperfluorescent flecks. (D) Horizontal optical coherence tomography (OCT) scan (scan
in the plane indicated by black arrowhead in A) showing hyperreflective thickening of the retinal pigment epithelium (RPE) corresponding to the flecks. The RPE thickening is
associated with thinning of the photoreceptor layer. (EeH) Pseudo-Stargardt pattern dystrophy in a 57-year-old patient. (E) Colour fundus photograph showing irregular yellowish
flecks in the posterior pole and around the vascular arcades. (F) FAF image showing increased autofluorescence of the flecks with an adjacent hypofluorescent zone, showing the
“dot and halo” feature with enlargement of the macular hypoautofluorescent zone. (G) FA image showing hyperfluorescent flecks. (H) Horizontal OCT scan showing some
hyperreflective focal thickening of the photoreceptor-RPE complex, but without sub-RPE deposits. (IeK) Pattern dystrophy in a 63-year-old patient who carried a mutation in the
PRPH2 gene (Courtesy of J.R.M. Cruysberg, UMC St. Radboud). (I) FAF image showing increased autofluorescence of the hyperpigmentation. (J) FA image showing hyperfluorescence
that outlines the hypofluorescent figures. (K) Horizontal OCT scan (scan in the plane indicated by black arrowhead in I) showing hyperreflective material between the RPE and
Bruch’s membrane.

generally to a more modest degree than in macular dystrophy sometimes still be useful in the diagnosis and follow-up of specific
(Figs. 1M, F and 5B, F). In contrast, macular dystrophies often have macular dystrophies. Although CNV is rare present in most macular
very marked FAF abnormalities because of the higher and earlier- dystrophies, it is a prominent and early-onset feature for instance
onset overload of autofluorescent lipofuscin due to the underly- in SFD (Isashiki et al., 1999).
ing effects of the genetic defect. As will be discussed below in the FA can also show a typical pattern of flecks, such as a ‘stars in the
disease-specific sections, FAF imaging is able to identify fairly sky’ appearance in cuticular drusen and MPGN II, and a ‘dot-and-
disease-specific distributions of FAF that strongly point to specific halo’ or ‘solar eclipse’ lesion in AFVD. Moreover, FA can show other
macular dystrophies. In a way, FAF can show a certain ‘genetic hallmark features such as an absence of choroidal background
fingerprint’. For instance, markedly autofluorescent irregular flecks fluorescence (‘dark choroid’) in Stargardt disease and delayed
in the posterior pole are very suggestive of either autosomal- choroidal filling in SFD (Peters et al., 2006; Westeneng-van Haaften
recessive Stargardt macular dystrophy or autosomal-dominant et al., 2012).
pseudo-Stargardt pattern dystrophy (Boon et al., 2007b).
3.4. Optical coherence tomography
3.3. Fluorescein angiography
Spectral-domain optical coherence tomography (SD-OCT) al-
Fluorescein angiography (FA) permits the study of the retinal lows a high-resolution analysis of the anatomical location of de-
and choroidal circulation by administration of fluorescein dye. posits and/or flecks in or under the retina/RPE. Deposits located
Although FA is used less frequently in the era of FAF and OCT, it can under the RPE, like drusen in AMD, can be found in several macular
 N.T.M. Saksens et al. / Progress in Retinal and Eye Research 39 (2014) 23e57 33

Fig. 4. (AeD) Adult onset foveomacular vitelliform dystrophy in a 49-year-old patient who did not carry a mutation in the PRPH2 or BEST1 gene. (A) Colour fundus photograph
showing a round yellow lesion in the fovea with some small yellow lesions temporally in the fovea. (B) Fundus autofluorescence (FAF) image showing increased autofluorescence of
the foveal round lesion and hyperautofluorescence of the smaller lesions temporally in the fovea. (C) Fluorescein angiography (FA) image showing late staining of the central lesion,
as well as hyperfluorescence of some temporal small spots. (D) Horizontal optical coherence tomography (OCT) scan showing the foveal yellow lesion corresponding to accu-
mulation of material between the neuroretina and the retinal pigment epithelium (RPE). (EeL) Best vitelliform macular dystrophy in a 15-year-old (EeH) and 13-year-old patient (Ie
L). (E) Colour fundus photograph showing a scrambled-egg appearance with a fibrotic scar. (F) FAF image showing irregularly hyperautofluorescence of the yellow lesion in the
macula. (G) FA image showing hyperfluorescence due to RPE window defects, as well as hypofluorescence caused by blocking of background fluorescence. (H) Horizontal OCT scan
(scan in the plane indicated by black arrowhead in E) showing subretinal fibrous scar tissue associated with subretinal fluid. (I) Colour fundus photograph showing a vitelliform/
vitelliruptive lesion in the macular area. (J) FAF image showing intense hyperfluorescence of the subretinal material. (K) Two years later, the vitelliform/vitelliruptive stage has been
evolved into the pseudohypopyon stage. FA image clearly shows hyperfluorescent material of the partly scrambled vitelliform lesion. (L) Vertical OCT scan showing hyperreflective
material between the neuroretina and the RPE.

dystrophies such as, LORD, ML and cuticular drusen (Querques become progressively abnormal in some diseases, such as in
et al., 2012). Deposits in ML and cuticular drusen appear as pseudo-Stargardt pattern dystrophy. Multifocal ERG and pattern
sawtooth RPE elevations or dome-shaped elevations and may also ERG can become abnormal early in the course of the disease,
present as thickening of the RPE/Bruch’s membrane complex. although these examinations are of limited differential diagnostic
Thickening of the RPE may also be found on SD-OCT in patients value. The electro-oculography (EOG), which reflects panretinal
with SFD, NCMD, and MIDD. In contrast to AMD drusen, the sub- function of the RPE, can be performed to distinguish between
retinal deposits in pattern dystrophy, AFVD, BVMD and reticular BVMD and AFVD, as the EOG response is markedly abnormal in
pseudodrusen are located anterior to the RPE (Boon et al., 2009c; BVMD in contrast to AFVD (Boon et al., 2009b; Renner et al., 2004).
Puche et al., 2010). In addition to the localizing value of OCT in These examples illustrate that the so-called ‘macular’ dystrophies
the analysis of deposits, SD-OCT will also show the location of can actually affect photoreceptor and/or RPE function of the entire
atrophic lesions. Finally, SD-OCT is able to visualize evidence of retina in selected entities.
intraretinal and subretinal fluid accumulation, such as in CNV.
3.6. Genetics
3.5. Psychophysical and electrophysiological testing
AMD is a multifactorial disease in which several genetic as well as
Despite the fact that most of the discussed dystrophies pre- environmental factors play a role. Although the majority of AMD
dominantly affect the macula, the full-field electroretinography cases are sporadic, the disease may also run in the family (Seddon
(ERG) e which reflects panretinal cone and rod function e can et al., 1997). Some families are very densely affected, and it has
34 N.T.M. Saksens et al. / Progress in Retinal and Eye Research 39 (2014) 23e57
 N.T.M. Saksens et al. / Progress in Retinal and Eye Research 39 (2014) 23e57 35

Table 2 clinically suspected diagnosis can aid in providing a clinical prog-

Summary of macular dystrophies associated with identified genes and loci. nosis for the patient, and the identification of a causative gene will
Gene or locus Associated diseases facilitate genetic counselling. Table 2 provides an overview of
5q21.2-q33.2 Pattern dystrophy
identified genes and loci and the associated macular dystrophies
ABCA4 Late-onset Stargardt that are discussed in this review.
ABCC6 Angioid streaks related dystrophy
BEST1 Adult-onset foveomacular vitelliform dystrophy 4. Macular dystrophies mimicking AMD
Best-vitelliform macular dystrophy
C1QTNF5 Late-onset retinal degeneration
C3 Cuticular drusen 4.1. Drusen and ‘drusen-like deposits’
Membranoproliferative glomerulonephritis type II
CFH Cuticular drusen 4.1.1. Malattia leventinese
Membranoproliferative glomerulonephritis type II
4.1.1.1. Introduction. Malattia leventinese (ML), also known as
CNBP Maculopathy in Myotonic dystrophy
DMPK Maculopathy in Myotonic dystrophy Doyne honeycomb retinal dystrophy, is an autosomal-dominantly
EFEMP1 Malattia leventinese inherited macular dystrophy. Some authors refer to this entity as
m.3243A > G MIDD/MELAS associated macular dystrophy ‘dominant drusen’, although this term is not specific as there are
MCDR1 locus North Carolina macular dystrophy more forms of dominantly inherited drusen, such as cuticular
PRPH2/RDS Central areolar choroidal dystrophy
drusen (Doyne, 1899; Evans et al., 1997; Piguet et al., 1995; van de
Pseudo-Stargardt pattern dystrophy
Pattern dystrophy Ven et al., 2012a).
Adult-onset foveomacular vitelliform dystrophy
TIMP3 Sorsby fundus dystrophy 4.1.1.2. Clinical characteristics. The onset of ML is generally in the
Abbreviations: MIDD, Maternally Inherited Diabetes and Deafness; MELAS, Mito- third to fourth decade of life, but shows a wide variation (Evans
chondrial Encephalopathy, Lactic Acidosis and Stroke-like episodes. et al., 1997; Guigui et al., 2011; Querques et al., 2012; Souied
et al., 2006b). Most patients are asymptomatic until the age of
been suggested that such families may carry rare genetic variants 30e40 years, when they may start to experience a variety of early
that confer a large risk on developing AMD (Sobrin et al., 2010). Most visual symptoms, including central vision loss, paracentral scoto-
disease discussed in this review are monogenic diseases caused by a mata, photophobia, colour vision problems, and metamorphopsia
known genetic mutation or locus, which may help in the diagnostic (Haimovici et al., 2002; Michaelides et al., 2006). A more rapid,
procedure. progressive central vision loss generally starts around the mid-40s
A thorough family history and drawing of a pedigree can be as a result of extensive pigmentary changes, GA, and/or CNV (Evans
pivotal in the identification of an inheritance pattern in a specific et al., 1997). The evolution of the disease and its impact on visual
macular disorder. Patients with an autosomal-dominant macular function are highly variable between families and between in-
dystrophies, like Central areolar choroidal dystrophy, ML, NCMD, dividuals of the same family (Evans et al., 1997; Michaelides et al.,
LORD, AFVD and butterfly-shaped pattern dystrophy, frequently 2006; Takeuchi et al., 2010).
have family members with a history of macular disease. However,
incomplete penetrance and variable expression can complicate the 4.1.1.3. Ophthalmoscopic features. The first ophthalmoscopic signs
recognition of inheritance patterns. of ML appear by the age of 20 years, through the appearance of
Some genes and their defects are associated with a certain de- typical small, radially oriented drusen in the macular area (Fig. 2A)
gree of genotypeephenotype correlation, such as the ABCA4 gene (Evans et al., 1997; Marmorstein, 2004; Piguet et al., 1995). In this
and its associated phenotypes, (Klevering et al., 2005), although the early stage, visual acuity is relatively preserved. With time, large
spectrum of clinically defined ABCA4 disease is notably broad round drusen appear in the macula, extending in the nasal area and
(Allikmets, 2007; Burke and Tsang, 2011). Mutations in other genes, around the optic disc. Centrally in the macula the drusen usually
such as the PRPH2 and BEST1 gene, are associated with marked become a confluent yellow-white subretinal plaque with pigmen-
phenotypic heterogeneity and show relatively limited genotypee tary changes. ML may progress to central chorioretinal atrophy in
phenotype correlation (Boon et al., 2008a, 2009b). 26e69% of patients older than 45 years and may be complicated by
Genetic testing may play an important role in the diagnostic CNV in 6e24% of these patients (Evans et al., 1997; Marmorstein,
procedure, as the identification of the causative gene in many cases 2004; Michaelides et al., 2006).
can be the definitive confirmation of a specific macular dystrophy.
This is especially helpful in patients with early and end-stage dis- 4.1.1.4. Fundus autofluorescence. FAF reveals an intense auto-
ease, with less specific, ophthalmoscopic abnormalities, as it may fluorescence of large round drusen located around the macular area
be difficult to discern macular diseases. Genetic confirmation of a and optic disc area, whereas smaller radial drusen are faintly visible

Fig. 5. (AeG) Central areolar choroidal dystrophy stage 2 in a 48-year-old patient (AeD) and stage 3 in a 54-year-old patient (EeG), both carrying a PRPH2 mutation. (A) Colour
fundus photograph showing parafoveal pigmentary changes. (B) Fundus autofluorescence (FAF) image showing hyperautofluorescent parafoveal changes corresponding to the
pigmentary changes in A. (C) Fluorescein angiography (FA) image showing hyperfluorescence corresponding with hypopigmentation and hypofluorescence corresponding with
hyperpigmentations on A. (D) Horizontal optical coherence tomography (OCT) scan (scan in the plane indicated by black arrowhead in A) showing a disruption of the photore-
ceptors corresponding to hypopigmentary changes and hyperreflective elevations of the retinal pigment epithelium (RPE) corresponding to hyperpigmentation in A. (E) Colour
fundus photograph showing hypopigmentation of the macula with two parafoveal, oval-to-round, atrophic areas. (F) Chorioretinal atrophy corresponding with severely decreased
to absent FAF, bordered by speckled changes of increased and decreased FAF. (G) Horizontal OCT scan (scan in the plane indicated by black arrowhead in E) showing well-
circumscribed chorioretinal atrophy. (HeJ) Late onset cone dystrophy in a 49-year-old patient. (H) Colour fundus photograph showing central pigmentary changes and pallor of
the optic disc. (I) FAF image showing hyperautofluorescent foveal changes corresponding to the pigmentary changes in H. (J) Horizontal OCT scan (scan in the plane indicated by
black arrowhead in H) showing thinning of the outer retinal layers in the fovea. (KeN) Central serous chorioretinopathy in a 49-year-old patient. (K) Colour fundus photograph
showing serous detachment of the retina and RPE changes. (L) FAF image showing speckled FAF signals of increased and decreased autofluorescence. (M) FA image showing a
characteristic descending atrophic tract and several “hotspots” of active subretinal leakage. (N) Horizontal OCT scan (scan in the plane indicated by black arrowhead in K) showing a
shallow subretinal detachment combined with pigment epithelial detachment. (OeR) Macular telangiectasia in a 70-year-old patient. (O) Colour fundus photograph showing
greying of the perifoveolar retina. Right-angle venules extend into the depth of the temporal fovea with a lesion of black hyperplastic RPE beneath the venules. (P) FAF image
showing decreased FAF corresponding with hyperpigmentation in O. (Q) FA image showing hyperfluorescenc of the capillary dilatations, predominantly temporal to the fovea
located. Hyperpigmentations are hypofluorescent due to blockage. (R) Horizontal OCT scan (scan in the plane indicated by black arrowhead in O) showing intraretinal cysotid spaces
without foveal thickening and disruption of the photoreceptor layers in the parafoveal macula.
36 N.T.M. Saksens et al. / Progress in Retinal and Eye Research 39 (2014) 23e57

(Fig. 2B) (Guigui et al., 2011; Querques et al., 2012; Souied et al., 4.1.1.10. Differential diagnosis with age-related macular degenera-
2006b). The association of increased autofluorescence with large tion. ML may be confused with AMD because of:
drusen may be stronger in ML patients than in AMD patients
(Querques et al., 2012; Schmitz-Valckenberg et al., 2009a; von - the presence of drusen and possible evolution to GA and CNV
Ruckmann et al., 1998). (Evans et al., 1997; Marmorstein, 2004).

4.1.1.5. Fluorescein and indocyanine green angiography (ICGA). Features that help to distinguish ML from AMD:
In the early phase of FA, the large central drusen are indistinct and
hypofluorescent, whereas the small radial drusen are well demar- - an earlier age at onset
cated and highly hyperfluorescent (Fig. 2C) (Guigui et al., 2011; - a positive family history with an autosomal-dominant inheri-
Querques et al., 2012; Souied et al., 2006b). In the late phase of tance pattern
FA, the large round central drusen are intensely hyperfluorescent - the presence of drusen localized nasal of the disc and the
due to staining and the fluorescence of small drusen decrease presence of typical radially oriented macular drusen, which can
(Guigui et al., 2011; Querques et al., 2012; Souied et al., 2006b). The evolve to large densely packed and confluent drusen in later
fluorescence pattern on ICGA is comparable to that in FA, but the stages, often with nodular juxtapapillary drusenoid lesions.
hyperfluorescent large drusen are surrounded by a hypofluorescent - genetic analysis revealing a mutation in the EFEMP1gene
halo in the late phase of ICGA (Guigui et al., 2011; Querques et al.,
2012; Souied et al., 2006b). Possible CNV on ophthalmoscopy and 4.1.2. Sorsby fundus Dystrophy
SD-OCT may be confirmed on FA and ICGA. 4.1.2.1. Introduction. Sorsby fundus dystrophy (SFD) is an
autosomal-dominantly inherited retinal dystrophy, leading to
4.1.1.6. Optical coherence tomography. The small radial drusen on bilateral loss of central vision secondary to CNV, pigment epithelial
SD-OCT correspond to irregular slight thickening of the RPE/Bruch’s atrophy, or both at the macula (Hoskin et al., 1981; Saihan et al.,
membrane complex and/or ‘sawtooth RPE elevation’ (Fig. 2D) 2009; Sivaprasad et al., 2008; Szental et al., 2009). Also, the pe-
(Querques et al., 2012). The large round drusen correspond to focal ripheral vision may be severely affected (Hoskin et al., 1981). SFD is
dome-shaped or more diffuse deposition of hyperreflective mate- exceptional among the inherited retinal dystrophies mimicking
rial between the RPE and Bruch’s membrane within the macular AMD in that subretinal neovascularization is characteristic of the
and peripapillary area (Fig. 2E) (Querques et al., 2012). SD-OCT also disease, whereas CNV only occurs rarely in other macular dystro-
shows confluence of large focal drusen over time (Querques et al., phies (Isashiki et al., 1999).
2012). Large drusen may be associated with a relative preserva-
tion of the overlying neurosensory retina and may be compatible 4.1.2.2. Clinical characteristics. The majority of SFD cases present
with relatively spared visual acuity (Souied et al., 2006a). during the fourth to fifth decades of life, but with a broad range of
age at onset up to the eight decade (Lin et al., 2006; Polkinghorne
4.1.1.7. Psychophysical and electrophysiological testing. The EOG is et al., 1989; Sivaprasad et al., 2008). A large clinical variability is
normal in ML, suggesting that the disease does not lead to a possible both within and between affected families, with regard to
diffusely dysfunctional RPE (Evans et al., 1997; Takeuchi et al., age at onset, disease progression and fundus appearance (Felbor
2010). Multifocal ERG abnormalities localized to the macular re- et al., 1997; Saihan et al., 2009; Sivaprasad et al., 2008). In their
gion may be recorded only in patients with advanced disease early 40s, more than half of the patients have difficulties with dark
(Evans et al., 1997; Gerber and Niemeyer, 2002; Takeuchi et al., adaptation as an early symptom without other visual symptoms
2010). The full-field ERG is generally normal, but the 30-Hz (Capon et al., 1989; Peters et al., 2006). Nyctalopia is the result of
flicker responses may be reduced (Evans et al., 1997; Haimovici peripheral retinal dysfunction (Capon et al., 1988; Saihan et al., 2009;
et al., 2002; Takeuchi et al., 2010). Visual fields are normal or Sivaprasad et al., 2008), which can eventually lead to progressive
show loss of sensitivity of the central visual field (Evans et al., 1997; loss of peripheral vision (Schoenberger and Agarwal, 2013). Some
Gerber and Niemeyer, 2002; Michaelides et al., 2006). patients remain asymptomatic until the onset of central vision loss,
often in the 4the6th decade of life, because of CNV or GA of the
4.1.1.8. Genetic association. ML and Doyne honeycomb retinal macula (Peters et al., 2006; Polkinghorne et al., 1989; Sivaprasad
dystrophy were considered separate entities until a single et al., 2008). In approximately 60% of patients, a CNV with rapid
autosomal-dominantly inherited mutation (p.Arg345Trp) in the vision loss develops in at least one eye in the fifth decade of life, and
EFEMP1 gene, also known as fibulin-3, was identified in both con- 50% of the patients develop CNV in the second eye within a few years
ditions (Doyne, 1899; Evans et al., 1997; Stone et al., 1999). after the onset of CNV in the first eye (Sivaprasad et al., 2008). SFD
usually leads to legal blindness in the 5the7th decade because of
4.1.1.9. Pathophysiology. Histopathological studies of ML demon- marked central and peripheral vision loss (Capon et al., 1988; Isashiki
strate drusenoid deposits between the RPE and Bruch’s membrane et al., 1999; Polkinghorne et al., 1989; Szental et al., 2009).
with thickening of Bruch’s membrane, atrophy of the RPE and
structural damage to rod and cone photoreceptors (Collins, 1913; 4.1.2.3. Ophthalmoscopic features. The first ophthalmoscopic find-
Dusek et al., 1982). The EFEMP1 gene encodes fibulin-3, an extracel- ings are subretinal, fine, yellow drusen-like deposits, located in the
lular matrix protein (Marmorstein, 2004; Zhang and Marmorstein, entire posterior pole with extension to the equator (Fig. 2F)
2010). Efemp1 Arg345Trp mutation knock-in mice studies have (Polkinghorne et al., 1989; Sivaprasad et al., 2008). These deposits
shown aberrant EFEMP1/fibulin-3 and Tissue Inhibitor of Metal- often appear after the age of twenty, with preservation of visual
loproteinase 3 (TIMP3) protein accumulation within RPE cells and acuity (Polkinghorne et al., 1989; Sivaprasad et al., 2008). Within a
between the RPE and Bruch’s membrane (Fu et al., 2007; few years after the first symptoms, pigmentary changes, chorior-
Marmorstein et al., 2002). In this mouse model of ML, sub-RPE dru- etinal atrophy, and CNV can appear in the macula (Fig. 2F), resulting
sen-like deposits, RPE abnormalities, and complement activation in in a more rapid loss of central vision (Capon et al., 1988; Peters et al.,
the RPE and Bruch’s membrane are seen (Fu et al., 2007; Marmorstein 2006; Polkinghorne et al., 1989; Schoenberger and Agarwal, 2013).
et al., 2007). These findings in ML show that there is not only a clinical Patients can also develop extensive and extrafoveal CNV in the
overlap, but also a pathophysiological overlap with AMD. macula (Sivaprasad et al., 2008). After the age of 60, extensive and
 N.T.M. Saksens et al. / Progress in Retinal and Eye Research 39 (2014) 23e57 37

peripheral chorioretinal atrophy can develop, together with a various functions: it regulates extracellular matrix remodelling by
central disciform scar and atrophy that is indistinguishable from modulating matrix metalloproteinase activity, it inhibits angio-
AMD (Agarwal, 2012; Capon et al., 1988; Hoskin et al., 1981; genesis by blocking vascular endothelial growth factor (VEGF) re-
Polkinghorne et al., 1989; Sivaprasad et al., 2008). ceptors, and it regulates inflammation (Della et al., 1996; Qi et al.,
2003). SFD is thought to be caused by an accumulation of
4.1.2.4. Fundus autofluorescence. The yellow deposits on ophthal- abnormal TIMP3 protein, leading to a thickened and dysfunctional
moscopy correspond to reduced FAF, unlike drusen in AMD and Bruch’s membrane (Langton et al., 2000, 2005). This TIMP3 accu-
yellowish deposits in most other macular dystrophies (Boon et al., mulation inhibits transport across Bruch’s membrane, either by
2008b; Saihan et al., 2009; Schmitz-Valckenberg et al., 2009a). inhibiting normal turnover of the extracellular matrix or by
Areas of stippled increased and decreased autofluorescence extend creating a direct physical barrier (Langton et al., 2005; Stohr and
toward and sometimes beyond the vascular arcades corresponding Anand-Apte, 2012). Such a barrier would impair retinal nutrition,
to the areas of subretinal fluid (Saihan et al., 2009). In the late stage, leading to atrophy of the RPE and photoreceptor death. Neo-
FAF shows bilateral areas of central confluent decreased auto- vascularization may be a secondary response to retinal malnutri-
fluorescence corresponding to the areas of RPE atrophy, with tion, hypoxia, and VEGF upregulation (Langton et al., 2005; Qi et al.,
hyperautofluorescent borders surrounding these atrophic areas 2003; Schoenberger and Agarwal, 2013). The clinically observed
(Saihan et al., 2009). yellowish deposits in SFD are localized between the basement
membrane of the RPE and the inner collagenous layer of Bruch’s
4.1.2.5. Fluorescein and indocyanine green angiography. The earliest membrane (Capon et al., 1989; Fariss et al., 1998) and are strongly
phenotypic marker of SFD is a delayed filling of the choriocapillaris positive for TIMP3 protein (Fariss et al., 1998).
on FA (Peters et al., 2006; Polkinghorne et al., 1989). This patchy
hypofluorescence may be a typical finding before the onset of CNV 4.1.2.10. Differential diagnosis with age-related macular degenera-
and becomes more profound and extend centrifugally with time tion. SFD may be confused with AMD because of:
(Polkinghorne et al., 1989; Sivaprasad et al., 2008). The deposits in
SFD are not markedly hyperfluorescent in contrast to AMD and - the overlap in age at onset
cuticular drusen. In SFD, hyperfluorescent CNV can develop mul- - the presence of drusen-like deposits, pigmentary changes, GA
tifocally with multiple recurrences, and classic CNV is more and CNV.
frequent than in AMD (Schoenberger and Agarwal, 2013;
Sivaprasad et al., 2008). ICGA can show early mottling and late Features that help to distinguish SFD from AMD:
hyperfluorescence in the peripheral retina (Lip et al., 1999).
- a positive family history with an autosomal-dominant inheri-
4.1.2.6. Optical coherence tomography. SD-OCT images demonstrate tance pattern
focal hyperreflectivity of the ellipsoid zone to the choroid layer - the earlier age at the onset of complaints and fundoscopic
which may represent the thickened Bruch’s membrane (Saihan et al., findings
2009). In early stages, SD-OCT can show evidence of retinal atrophy, - delayed choroidal filling on FA
specifically loss of the outer nuclear layer in the perifoveal region - extramacular chorioretinal atrophy and CNV
(Saihan et al., 2009). This finding may represent early morphological - genetic analysis revealing a mutation in the TIMP3 gene
changes related to the symptoms of night blindness (Saihan et al.,
2009). In cases with CNV, SD-OCT can show subretinal and/or 4.1.3. North Carolina macular dystrophy
intraretinal fluid before clinical or angiographic evidence of CNV 4.1.3.1. Introduction. North Carolina macular dystrophy (NCMD) is
(Peters et al., 2006; Saihan et al., 2009; Sivaprasad et al., 2008). an autosomal-dominantly inherited macular dystrophy which was
initially described in 1971 in a large family in North Carolina, USA
4.1.2.7. Psychophysical and electrophysiological testing. Even early (Lefler et al., 1971).
in the course of the disease, EOG results show an abnormally low
light rise in most SFD cases, (Assink et al., 2000; Capon et al., 1988) 4.1.3.2. Clinical characteristics. The onset of NCMD is in early
indicating a generalized RPE dysfunction. Full-field ERG results childhood and it has a stable course (Schworm et al., 1998; Small
remain normal until extensive and peripheral chorioretinal atrophy et al., 1991). In most cases, there are only minor changes in clinical
become apparent (Assink et al., 2000; Capon et al., 1988; Isashiki appearance or visual acuity over time (Kiernan et al., 2011; Small,
et al., 1999; Lip et al., 1999). In the early stage of SFD, a tritanano- 1989; Szlyk et al., 2005). The visual acuity is often better than ex-
maly may be present (Capon et al., 1988; Felbor et al., 1997; Lip pected from the clinical examination and does not correlate signif-
et al., 1999) with prolonged dark adaptation times in patients icantly to the grade of the disease or to the age of the patient
with nyctalopia (Capon et al., 1988). Visual field testing may show (Rosenberg et al., 2010; Schworm et al., 1998; Small, 1998). Patients
(para)central scotoma and moderate peripheral constriction may be largely asymptomatic unless they develop CNV (Agarwal,
(Capon et al., 1988; Isashiki et al., 1999; Lip et al., 1999). 2012), which is rare. Atrophic lesions can result in vision loss, but
even in those cases the visual acuity may be relatively preserved as a
4.1.2.8. Genetic association. SFD is an autosomal-dominantly result of eccentric fixation (Kiernan et al., 2011; Reichel et al., 1998).
inherited fundus dystrophy with full penetrance and variable
expression (Hamilton et al., 1989; Saihan et al., 2009). Several 4.1.3.3. Ophthalmoscopic features. The phenotype is highly variable
mutations in the TIMP3 gene are associated with SFD, of which and can be subdivided in 3 grades (Small, 1989; Small et al., 1991).
p.Ser181Cys is the most common mutation (Stohr and Anand-Apte, In grade 1, fine small yellow drusen-like lesions and pigmentary
2012; Weber et al., 1994). The onset and severity of SFD appears to changes may be observed in the central macula with relatively
depend roughly on the specific TIMP3 mutation (Stohr and Anand- preserved visual acuity (Agarwal, 2012). The yellow lesions that
Apte, 2012). seem to be located at the level of the RPE, can have a radial pattern,
and can also be present in the peripheral retina (Agarwal, 2012;
4.1.2.9. Pathophysiology. TIMP3 protein is secreted by the RPE and Kiernan et al., 2011; Small, 1989; Small et al., 1991). In grade 2,
deposited into Bruch’s membrane (Della et al., 1996). TIMP3 has patients show larger, confluent macular lesions with or without
38 N.T.M. Saksens et al. / Progress in Retinal and Eye Research 39 (2014) 23e57

RPE atrophy, which can be associated with some visual impairment. 4.1.4. Late-onset retinal degeneration
Grade 3 NCMD is characterized by larger areas of profound cho- 4.1.4.1. Introduction. Late-onset retinal degeneration (LORD) is an
rioretinal atrophy in the macula that may even resemble a colo- autosomal-dominantly inherited macular dystrophy, first described
boma or staphyloma, with hyperpigmentation and drusen-like in patients with Scottish ancestry (Borooah et al., 2009; Kuntz et al.,
lesions surrounding this atrophic lesion (Fig. 2H). Occasionally, 1996).
NCMD is complicated by CNV resulting in a markedly central vision
loss (Kiernan et al., 2011; Small et al., 1991).
4.1.4.2. Symptoms. Patients with LORD usually present with night
blindness in the fifth to sixth decade of life (Borooah et al., 2009;
4.1.3.4. Fundus autofluorescence. The small drusen-like yellowish
Milam et al., 2000; Soumplis et al., 2013), followed by progressive
lesions in NCMD patients are hyperautofluorescent (Rosenberg
central and peripheral vision loss in the following decades
et al., 2010). Markedly atrophic areas on ophthalmoscopy corre-
(Borooah et al., 2009; Milam et al., 2000; Soumplis et al., 2013).
spond to absent autofluorescence with a hyperautofluorescent
surrounding border of the lesion (Fig. 2I) (Kiernan et al., 2011).
4.1.4.3. Clinical features. Patients with LORD typically have long
4.1.3.5. Fluorescein angiography. In grade 1 and 2 NCMD, FA shows anteriorly inserted lens zonules and peripupillary iris atrophy
transmission defects with hyperfluorescence of the drusen-like (Fig. 2K and L) (Borooah et al., 2009; Vincent et al., 2012). Fundo-
lesions both in the early and late phases of FA (Agarwal, 2012). In scopic changes become visible from the fifth decade onwards,
grade 3 disease, the FA highlights the remaining choroidal vessels together with the onset of night blindness, with drusenoid deposits
in the atrophic area due to the RPE window defect. in the mid-peripheral retina often being the first visible retinal
manifestations (Fig. 2M) (Borooah et al., 2009; Vincent et al., 2012).
4.1.3.6. Optical coherence tomography. On SD-OCT, a thickening of In the following decades, scalloped areas of chorioretinal atrophy in
the ellipsoid zone to the RPE layer can be present (Rosenberg et al., the posterior pole and beyond the vascular arcades develop (Milam
2010), but no clear accumulation of material between the RPE and et al., 2000; Soumplis et al., 2013). When this atrophy affects the
Bruch’s membrane is present, in contrast to drusen in AMD (Khurana fovea, this results in marked central vision loss. In the late stages of
et al., 2009; Rosenberg et al., 2010). In grade 3 disease, SD-OCT shows the disease, peripheral bone-spicule hyperpigmentation as well as
a marked thinning and atrophy of the neurosensory retina, RPE, and central or peripheral CNV may develop (Borooah et al., 2009; Milam
choroid, but intact photoreceptors adjacent to the lesion (Fig. 2J) et al., 2000; Soumplis et al., 2013).
(Khurana et al., 2009; Kiernan et al., 2011; Szlyk et al., 2005).
4.1.4.4. Fundus autofluorescence. The early drusenoid yellow dots
4.1.3.7. Psychophysical and electrophysiological testing. The EOG in the retina may show increased FAF (Borooah et al., 2009). FAF
and full-field ERG are normal in all stages, indicating that there is highlights marked autofluorescence changes in macular atrophy by
both no generalised retinal or RPE dysfunction (Reichel et al., 1998). decreased autofluorescence with scalloped borders (Soumplis et al.,
The multifocal ERG can show decreased amplitudes within fun- 2013; Vincent et al., 2012).
doscopically visible lesions in the macular area (Szlyk et al., 2005).
Colour vision is relatively well-preserved (Reichel et al., 1998; 4.1.4.5. Fluorescein angiography. The fine structure and staining
Rosenberg et al., 2010). characteristics of the sub-RPE deposits in early LORD may resemble
those in AMD, and in advanced disease FA shows RPE window
4.1.3.8. Genetic association. NCMD is an autosomal-dominantly defects of the scalloped atrophic lesions (Agarwal, 2012; Milam
inherited disorder (Lefler et al., 1971), linked to the MCDR1 locus et al., 2000).
on chromosome 6q16 (Small et al., 1992; Yang et al., 2008), but the
exact gene and its function are currently unknown.
4.1.4.6. Optical coherence tomography. Midreflective deposits
An early-onset autosomal-dominant macular dystrophy
located between the RPE and Bruch’s membrane may be seen on
(MCDR3) resembling NCMD has been mapped to chromosome 5
SD-OCT (Milam et al., 2000; Soumplis et al., 2013; Vincent et al.,
(Michaelides et al., 2003; Rosenberg et al., 2010).
2012). In advanced cases, SD-OCT shows chorioretinal atrophy
with also outer retinal abnormalities (Borooah et al., 2009;
4.1.3.9. Pathophysiology. The pathogenesis of NCMD is unknown.
Soumplis et al., 2013; Vincent et al., 2012).
Histopathological studies in eyes with markedly atrophic NCMD
lesions have shown a complete loss of photoreceptors and RPE,
attenuation of Bruch’s membrane, and choroidal atrophy (Small 4.1.4.7. Psychophysical and electrophysiological testing.
et al., 2001; Voo et al., 2001). Adjacent to the central lesion, lip- Abnormal dark adaptation is the first manifestation of LORD, pre-
ofuscin accumulation has been identified in the RPE (Small et al., ceding subjective night blindness and fundus changes (Borooah
2001; Voo et al., 2001). et al., 2009; Milam et al., 2000). The full-field ERG may become
abnormal in advanced disease (Milam et al., 2000; Vincent et al.,
4.1.3.10. Differential diagnosis with age-related macular degenera- 2012), revealing a generalized rod-cone dysfunction (Kuntz et al.,
tion. NCMD can be confused with AMD because of: 1996; Soumplis et al., 2013). In advanced LORD, the peripheral vi-
sual field also becomes constricted (Agarwal, 2012; Borooah et al.,
- the association with yellow drusen-like lesions, GA and CNV. 2009; Milam et al., 2000).

Features that help to distinguish NCMD from AMD include: 4.1.4.8. Genetic association. LORD is a genetically heterogeneous
disease with an autosomal-dominant inheritance pattern
- an early age at the onset (in childhood or possibly congenital) (Hayward et al., 2003; Kuntz et al., 1996) caused by a heterozygous
- a positive family history with an autosomal-dominant inheri- p.Ser163Arg founder mutation in the C1QTNF5 gene on chromo-
tance pattern, and Irish - American ancestry some 11 (Hayward et al., 2003). This mutation presumably origi-
- a relatively stationary course, except in rare cases of CNV nates from a single ancestor from south-east Scotland (Borooah
- no sub-RPE deposits visible on SD-OCT et al., 2009).
 N.T.M. Saksens et al. / Progress in Retinal and Eye Research 39 (2014) 23e57 39

4.1.4.9. Pathophysiology. Histopathological studies reveal loss of halo of reduced autofluorescence. In up to 50% of the cases, a
photoreceptors and extensive sub-RPE deposits, resembling AMD relatively preserved autofluorescence signal of the fovea is seen,
drusen in structure and lipid composition (Kuntz et al., 1996; Milam indicating foveal spare. This difference in autofluorescence signal
et al., 2000). Although a C1qtnf5 knock-in mouse model closely and degree of foveal sparing corresponded with structural findings
mimics the phenotypic features of LORD (Chavali et al., 2011), the on SD-OCT.
exact function of the C1QTNF5 gene is unknown. The C1QTNF5 is
highly expressed in the RPE, lens and ciliary body epithelium 4.2.1.5. Fluorescein angiography. A decreased choroidal background
(Hayward et al., 2003). Deposits may be caused by misfolded fluorescence (‘dark choroid’) on FA is present in about 80% of the
C1QTNF5 protein accumulating in the endoplasmic reticulum of the patients (Fig. 3C) (Westeneng-van Haaften et al., 2012). In rare
RPE, compromising the function of the RPE and resulting in sub- cases, CNV is visible by focal staining and leakage of dye in
RPE deposits as well as impaired RPE adhesion to Bruch’s mem- respectively the early and late phase (Souied et al., 2005).
brane (Hayward et al., 2003; Shu et al., 2006).
4.2.1.6. Optical coherence tomography. SD-OCT shows hyper-
4.1.4.10. Differential diagnosis with age-related macular degenera- reflective thickening of the RPE layer in Stargardt disease, which is
tion. LORD may be confused with AMD because of: distinguishing from sub-RPE drusen in AMD (Fig. 3D). The accu-
mulation in Stargardt disease is usually associated with photore-
- the presence of drusenoid deposits, chorioretinal atrophy and ceptor thinning (Westeneng-van Haaften et al., 2012). In cases of
sometimes CNV foveal sparing, a near normal photoreceptor layer in the fovea may
be observed explaining the late onset of visual complaints.
Features that help to distinguish LORD from AMD include:
4.2.1.7. Psychophysical and electrophysiological testing.
- an autosomal-dominant inheritance pattern Photopic and scotopic full-field ERG recordings are normal in the
- onset of night vision problems before the age of 60 majority of cases (Westeneng-van Haaften et al., 2012). In contrast,
- extensive ‘scalloped’ areas of chorioretinal atrophy multifocal ERG is in the majority of cases outside normal limits.
- long anteriorly inserted lens zonules and peripupillary iris Patients with foveal sparing have normal multifocal ERG ampli-
transillumination tudes in the foveal area. Central visual field examinations show
- evidence of widespread retinal disease on dark adaptation and paracentral scotomata and central scotoma of varying extensions.
full-field ERG in advanced LORD
- mutation in the C1QTNF5 gene 4.2.1.8. Genetic association. Homozygous or compound heterozy-
gous mutations in the ABCA4 gene encoding the photoreceptor-
4.2. Irregular yellowish flecks specific, ATP-binding cassette transporter A4 are responsible for
STGD (Allikmets et al., 1997). In half of the late-onset Stargardt
4.2.1. Late-onset Stargardt disease disease patients, only one heterozygous mutation in the ABCA4 gene
4.2.1.1. Introduction. Autosomal-recessive Stargardt disease is a may be found (Holz et al., 2001; Westeneng-van Haaften et al.,
hereditary retinal dystrophy, usually diagnosed within the first two 2012). It is possible that the latter patients carry a second mild
decades of life (Stargardt, 1909). A later age at onset (50 years) has mutation in one of the introns or they may carry variants in modifier
been reported in a small number of patients. Late-onset Stargardt genes or a variant in a promoter or enhancer region near the ABCA4
disease belongs to the spectrum of retinal dystrophies caused by gene, which causes lower expression of the intact ABCA4 allele.
mutations in the ABCA4 gene (Westeneng-van Haaften et al., 2012).
The estimated carrier frequency of mild ABCA4 mutations in pop- 4.2.1.9. Pathophysiology. ABCA4 defects lead to the intracellular
ulation studies is 1/25 individuals (Jaakson et al., 2003; Maugeri accumulation of N-retinylidene-N-retinylethanolamine (A2E) in
et al., 1999). Over 600 disease-causing mutations in the ABCA4 RPE cells (Quazi et al., 2012; Radu et al., 2004). A2E is cytotoxic to
gene have been identified and some ABCA4 mutations have been the RPE in high concentrations (Sparrow et al., 2003) and may be
associated with STGD1, cone-rod dystrophy, retinitis pigmentosa visualized in living eyes using FAF. In heterozygous abca4 () mice,
and AMD (Burke and Tsang, 2011). a light-dependent fourfold increase in lipofuscin compounds has
been observed (Mata et al., 2001). These findings in animal studies
4.2.1.2. Clinical characteristics. Usually at the age of 55 patients may indicate that heterozygous ABCA4 mutations in humans
present with progressive central vision loss and may be accompa- eventually also lead to increased lipofuscin accumulation and
nied by metamorphopsia or oscillopsia (Westeneng-van Haaften possibly even retinal pathology. A study in the Abca4 knockout
et al., 2012). The fundus abnormalities, however, may be coinci- mouse model for Stargardt disease has identified oxidative stress,
dentally found in asymptomatic patients at ophthalmologic complement activation, and down-regulation of protective com-
screening for glaucoma, diabetes or thyroid eye disease. plement regulatory proteins as potential mechanism of retinal
dystrophy (Radu et al., 2011). These animal data and the association
4.2.1.3. Ophthalmoscopic features. Fundus examination shows of ABCA4 variants with AMD could indicate that there is a patho-
irregular, pisciform, flavimaculatus flecks scattered throughout the physiologic overlap between late-onset Stargardt disease and AMD.
posterior pole or spread to the midperipheral retina (Fig. 3A).
Yellowish flecks or dots may be limited to the centre of the macula, 4.2.1.10. Differential diagnosis with age-related macular degenera-
whereas sometimes no flecks, but small yellowish spots are present tion. It is important to distinguish late-onset Stargardt disease from
in the macula. Extensive chorioretinal atrophy may be present and AMD because some AMD patients use nutritional supplements,
it is rarely complicated by CNV (Armstrong et al., 1998; Pawlak containing the vitamin A-derivative beta-carotene, to prevent pro-
et al., 2006; Souied et al., 2005). gression to advanced disease (Age-Related Eye Disease Study
Research, 2001). However, studies in Abca4 knockout mice, an ani-
4.2.1.4. Fundus autofluorescence. The yellowish flecks correspond mal model for Stargardt disease, have shown that vitamin A sup-
to intense autofluorescence on FAF imaging (Fig. 3B) (Westeneng- plementation can cause an increase of lipofuscin accumulation in the
van Haaften et al., 2012). Some flecks may be surrounded by a RPE (Radu et al., 2008). Therefore, beta-carotene or vitamin A
40 N.T.M. Saksens et al. / Progress in Retinal and Eye Research 39 (2014) 23e57

supplementation should be discouraged in Stargardt disease patients abnormal autofluorescence. In pseudo-Stargardt pattern dystrophy
as it may accelerate lipofuscin accumulation and retinal the flecks show highly increased autofluorescence (Fig. 3F). With
degeneration. time, the flecks tend to evolve toward a confluent atrophic area
Late-onset Stargardt disease may be confused with AMD which shows larger zones of decreased FAF signal.
because of:
4.2.2.5. Fluorescein angiography. The pigmented areas in the
- the late age at onset (>50 years) pattern dystrophies usually show early hypofluorescence on FA,
- the presence of yellowish flecks, chorioretinal atrophy and surrounded by hyperfluorescence, with some degree of late stain-
rarely CNV ing (Boon et al., 2008a; Tuppurainen and Mantyjarvi, 1994). In
pseudo-Stargardt pattern dystrophy the flecks are hyper-
Features that help to distinguish late-onset Stargardt disease fluorescent, sometimes with a central hypofluorescent spot
from AMD include: (Fig. 3G) (Boon et al., 2007b; Vaclavik et al., 2012). A dark choroid,
as seen in Stargardt disease, is typically absent.
- ‘flavimaculatus’ flecks are more irregularly shaped than drusen
- intense autofluorescence of flecks on FAF imaging with a sur- 4.2.2.6. Optical coherence tomography. SD-OCT imaging reveals
rounding halo of decreased FAF. relatively consistent features among the different subtypes of
- ‘dark choroid’ on FA pattern dystrophies (Hannan et al., 2013): hyperreflectivity be-
- mutations in the ABCA4 gene tween the RPE/Bruch’s membrane complex and more inner retinal
layers (Fig. 3H); further, disruptions of the ellipsoid zone are
4.2.2. Pattern dystrophies common findings (Hannan et al., 2013).
4.2.2.1. Introduction. The heterogeneous group of ‘pattern dystro-
phies’ encompass a broad spectrum of inherited diseases that are
4.2.2.7. Psychophysical and electrophysiological testing.
characterized by various patterns of pigment distribution at the
Full-field ERG shows normal cone and rod amplitudes and implicit
posterior pole. These include butterfly-shaped pigment dystrophy,
times in most patients with pattern dystrophies, except in pseudo-
adult-onset foveomacular vitelliform dystrophy (AFVD) (see chapter
Stargardt pattern dystrophy. Herein, the full-field photopic and
4.3.1.), reticular dystrophy of the RPE, fundus pulverulentus and
scotopic ERG results can vary from normal in mild cases to non-
pseudo-Stargardt pattern dystrophy. However, the value of this
recordable in advanced disease, and the EOG is abnormal in half
clinical classification is subject of debate (Alkuraya and Zhang, 2010)
of the patients (Boon et al., 2007b).
because different types of pattern dystrophy are known to occur in
The EOG in pattern dystrophies is usually normal or only
different members of the same family carrying an identical muta-
moderately reduced (Fishman et al., 2001).
tion. Furthermore, one form of pattern dystrophy can evolve into
another within a single patient, and the type of pattern dystrophy
can even be different between the two eyes of a patient (Agarwal, 4.2.2.8. Genetic association. Mutations in the PRPH2 gene are the
2012; Boon et al., 2008a, 2007b; Kim et al., 1995; Yang et al., 2004). most common cause of the different pattern dystrophies. Recently,
an association of AFVD and butterfly-shaped pigment dystrophy
4.2.2.2. Clinical characteristics. Pattern dystrophies present in phenotypes has been suggested with a high temperature require-
midlife with mild central visual disturbances in one or both eyes. In ment factor A1 risk SNP in individuals who did not carry PRPH2 gene
advanced cases, patients can develop CNV and/or GA. However, mutations (Jaouni et al., 2012).
many patients will retain driving vision in at least one eye well into
their seventh decade of life (Sohn et al., 2013). 4.2.2.9. Pathophysiology. The PRPH2 gene encodes a
photoreceptor-specific glycoprotein that plays a role in the devel-
4.2.2.3. Ophthalmoscopic features. Butterfly-shaped pigment dys- opment and maintenance of photoreceptor outer segment discs
trophy has first been described by Deutman and co-workers in a (Arikawa et al., 1992; Boon et al., 2008a; Connell et al., 1991; Travis
family with autosomal-dominant inherited pigmentation in a et al., 1991). Mutation in PRPH2 could mediate pattern dystrophy
pattern that showed resemblance to the wings of a butterfly disease pathogenesis by interfering with the integrity of the
(Deutman et al., 1970). The pigmentation can be yellow-white or photoreceptor membrane (Zhang et al., 2002).
dark. The central lesion can be surrounded by depigmentation. Further, secondary atrophic changes where observed (Arnold
Reticular dystrophy of the RPE was first reported in 1950 by et al., 2003). In a patient with butterfly-shaped pigment dystro-
Sjogren (1950) as a clearly defined network of pigmented lines that phy due to mutation in the PRPH2 gene, there was an abrupt
resemble a fishnet with knots. transition between healthy and degenerated retina and RPE with
Fundus pulverulentus is characterized by coarse, punctiform massively lipofuscin-laden RPE cells at the transition (Zhang et al.,
mottling of the RPE in the macular area (Slezak and Hommer, 1969). 2002). Surgical specimens from a patient with a PRPH2 mutation
This rare entity is seen mostly in patients with macular dystrophy exhibited ultra-structural alterations in outer-segment disc struc-
associated with PXE (for pseudoxanthoma elasticum see chapter ture (Wickham et al., 2009). Based on these genetic and histo-
4.5.2.) (Agarwal et al., 2005). pathologic findings, the primary defect in pattern dystrophies may
Patients with pseudo-Stargardt pattern dystrophy show irreg- be assumed to be localized in the photoreceptors with subsequent
ular yellowish flecks in the posterior pole and around the retinal changes in the RPE and choriocapillaris.
vascular arcades, resembling the flecks seen in fundus flavimacu-
latus phenotype of Stargardt disease (Fig. 3E). The yellowish flecks 4.2.2.10. Differential diagnosis with age-related macular degenera-
are preceded by typical macular pattern dystrophy or by non- tion. Patients with pattern dystrophies may be misdiagnosed as
specific pigmentary changes in the fovea (Boon et al., 2007b; having AMD because:
Vaclavik et al., 2012).
- clinically visible signs commonly present in midlife and visual
4.2.2.4. Fundus autofluorescence. Like in most macular dystrophies, complains may manifest later in life
the pattern dystrophies have variable patterns of markedly - secondary changes such as CNV or GA may be present
 N.T.M. Saksens et al. / Progress in Retinal and Eye Research 39 (2014) 23e57 41

Features that help to distinguish pattern dystrophies from AMD 4.3.1.8. Genetic association. A genetic cause may be identified in a
include: minority of cases (Zhuk and Edwards, 2006). Autosomal-dominant
inheritance has been described, and mutations in the PRPH2 gene
- a relatively early age at onset account for 2e18% of the cases, whereas mutations in the BEST1
- positive family history gene cause up to 25% of cases (Brecher and Bird, 1990; Kramer et al.,
- absence of typical sub-RPE drusen 2000; Seddon et al., 2001).
- more pronounced autofluorescence changes than in AMD
(pseudo-Stargardt pattern dystrophy) 4.3.1.9. Pathophysiology. Histopathologic evaluation of patients
- specific patterns on fluorescein angiography and fundus with AFVD revealed an accumulation of vitelliform material be-
autofluorescence tween the neuroretina and RPE beneath the fovea, consisting of
- peripheral retinal abnormalities with corresponding abnormal photoreceptor outer segment-derived material and lipofuscin
full-field ERG (pseudo-Stargardt pattern dystrophy) loaded pigmented cells, accounting for the vitelliform appearance
- genetic analysis revealing a mutation in the PRPH2 gene (Boon et al., 2009b; Dubovy et al., 2000; Gass, 1974). Lipofuscin
accumulation was also seen in the RPE, with focal atrophy of the
4.3. Vitelliform lesions RPE bordered by hypertrophic RPE (Patrinely et al., 1985).

4.3.1. Adult-onset foveomacular vitelliform dystrophy 4.3.1.10. Differential diagnosis with age-related macular degenera-
4.3.1.1. Introduction. Adult-onset foveomacular vitelliform dystro- tion. AFVD can be confused with AMD because of:
phy (AFVD) was first described by Gass in 1974. According to the
classification of Gass, AFVD is considered one of the pattern dys- - the presence of small, round yellow-white macular lesions that
trophies (Agarwal, 2012). may be complicated by CNV

Features that help to distinguish AFVD from AMD include:

4.3.1.2. Clinical characteristics. Patients experience mild loss of vi-
sual acuity and/or metamorphopsia in one or both eyes, usually
- central vitelliform lesion without surrounding drusen
after the age of 35, but may also remain asymptomatic.
- marked autofluorescence changes within AFVD lesions
- lesion corresponding to hyperreflective accumulation above the
4.3.1.3. Ophthalmoscopic features. In typical AFVD, bilateral small RPE on SD-OCT
round yellow-white lesions of less than 1/3 disc diameter are seen
in the fovea, without surrounding drusen (Fig. 4A) (Renner et al.,
4.3.2. Best vitelliform macular dystrophy
2004). The central part of the lesion can be mildly pigmented. Le-
sions in AFVD can go through stages that are similar to BVMD (see 4.3.2.1. Introduction. Best vitelliform macular dystrophy (BVMD)
Chapter 4.3.2.) (Querques et al., 2011a), and can be multifocal (Boon was first described by Friedrich Best in 1905, and is an autosomal-
et al., 2007a). Some cases can be complicated by CNV, which can dominantly inherited macular dystrophy with incomplete pene-
respond to anti-VEGF treatment (Mimoun et al., 2013). trance and variable expression (Boon et al., 2009b).

4.3.2.2. Clinical characteristics. The age at the onset of central

4.3.1.4. Fundus autofluorescence. Lesions in AFVD are hyper-
vision loss is highly variable, ranging from the first to the sixth
autofluorescent, especially when the lesions have a yellowish
decade (Boon et al., 2007a, 2009c; Clemett, 1991; Mohler and Fine,
fundoscopic aspect without significant RPE atrophy (Fig. 4B) (Boon
1981; Wabbels et al., 2006b). Most patients become symptomatic
et al., 2008b; Renner et al., 2004).
before the age of 40. A commonly associated finding is mild to
moderate hyperopia (Boon et al., 2009b).
4.3.1.5. Fluorescein angiography. FA typically shows a hypofluor-
escent centre of the lesion, surrounded by a small hyperfluorescent
4.3.2.3. Ophthalmoscopic features. In most classifications of BVMD,
ring (‘dot-and-halo’ or ‘solar eclipse’ aspect). Some larger, less
the first stage is the asymptomatic carrier (‘previtelliform’) stage
pigmented lesions may show a central, patchy hyperfluorescence
(Boon et al., 2009b; Clemett, 1991; Deutman, 1971). In this stage, no
with late staining (Fig. 4C).
or very mild RPE abnormalities are visible in the fundus, although
the EOG is already markedly abnormal. This stage may evolve into a
4.3.1.6. Optical coherence tomography. On SD-OCT, lesions are typical yellowish, slightly elevated, round-to-oval vitelliform lesion
located between the neuroretina and RPE, with a variable amount in the fovea, usually with a size of at least a disc diameter (as
of hyperreflective material accumulated in the space between these mentioned in chapter 2 in drusenoid vitelliform lesions). When the
layers (Fig. 4D) (Puche et al., 2010). This material corresponds to the vitelliform material gradually shows inhomogeneous clumping,
yellowish material seen on fundoscopy. Based on their high- this is referred to as the vitelliruptive or ‘scrambled-egg’ stage
definition OCT findings in patients with different stages of AFVD, (Figs. 4E and I). The vitelliform material may also gravitate to the
Querques and co-workers hypothesized that early changes involve inferior part of the lesion, which corresponds to the pseudohy-
the layer between the RPE and the ellipsoid zone, first with accu- popyon stage. With time, a variable degree of chorioretinal atrophy
mulation of material beneath the sensory retina. In advanced dis- and subretinal scarring may develop, to form the atrophic and
ease, the photoreceptors and RPE layer eventually become cicatricial stage, respectively. Many patients show a different stage
disrupted and attenuated (Querques et al., 2008). in each eye, characteristics of different stages within a single lesion,
and sometimes even multifocal vitelliform lesions (Boon et al.,
4.3.1.7. Psychophysical and electrophysiological testing. A charac- 2007a, 2009c; Clemett, 1991). CNV occurs in 2e9% of patients
teristic differential diagnostic feature to distinguish AFVD from with BVMD, which tends to show a relatively benign and self-
BVMD is the presence of a normal or only slightly subnormal light limiting course (Chung et al., 2001; Clemett, 1991; Mohler and
rise on the EOG (Renner et al., 2004), whereas this light rise on EOG Fine, 1981), although CNV in these cases also responds to intra-
is often virtually absent in Best disease. The full-field ERG is normal. vitreal anti-VEGF treatment (Leu et al., 2007).
42 N.T.M. Saksens et al. / Progress in Retinal and Eye Research 39 (2014) 23e57

4.3.2.4. Fundus autofluorescence. BVMD lesions show variably- 4.4. Miscellaneous

sized areas of intense hyperautofluorescence, corresponding to
the vitelliform material (Figs. 4F and J) (Boon et al., 2009b, 2009c; 4.4.1. Central areolar choroidal dystrophy
Spaide et al., 2006) (as mentioned in chapter 2 in drusenoid vitel- 4.4.1.1. Introduction. Central areolar choroidal dystrophy (CACD) is
liform lesions). Areas of scarring and/or RPE atrophy within a lesion an autosomal-dominantly inherited macular dystrophy that be-
show decreased autofluorescence. longs to the wide spectrum of retinal dystrophies caused by mu-
tations in the PRPH2 gene (Boon et al., 2008a). Other PRPH2-
4.3.2.5. Fluorescein angiography. On FA, the early phases show associated retinal dystrophies include multifocal pattern dystrophy
blocking of background fluorescence in lesions with large amounts simulating Stargardt disease/fundus flavimaculatus (‘pseudo-Star-
of vitelliform material (Fig. 4K), but in other cases the BVMD lesions gardt pattern dystrophy’) (Boon et al., 2007b), pattern dystrophies
show mild hyperfluorescence due to an RPE window defect and/or such as butterfly-shaped pigment dystrophy and AFVD, as well as
staining (Fig. 4G) (Boon et al., 2009c; Spaide et al., 2006). autosomal-dominant retinitis pigmentosa (Boon et al., 2008a).

4.4.1.2. Clinical characteristics. The visual acuity in CACD generally

4.3.2.6. Optical coherence tomography. Like in AFVD, early lesions
deteriorates in the fourth to fifth decade of life (Boon et al., 2009a;
in BVMD are located between the neuroretina and RPE on SD-OCT,
Hoyng and Deutman, 1996; Piguet et al., 1996), which is earlier than
with a variable amount of hyperreflective material accumulated in
in patients with AMD (Smailhodzic et al., 2011). However, a later
the space between these layers (Fig. 4L) (Boon et al., 2009c; Spaide
onset (after the age of 55) or even an absence of visual symptoms
et al., 2006). In more advanced lesions, hyperreflective subretinal
may be seen in up to a third of CACD patients, depending on the
scars and intraretinal edema may be seen (Fig. 4H).
type of PRPH2 mutation (Boon et al., 2008a, 2009a). Therefore, late-
onset CACD may be confused with atrophic AMD (Boon et al.,
4.3.2.7. Psychophysical and electrophysiological testing. A virtually 2009a; Renner et al., 2009). Visual disturbances are mainly asso-
pathognomonic feature for BVMD and other BEST1-gene related ciated with the development of GA, and marked central vision loss
diseases is the absence of a normal light rise on the EOG, reflected will eventually develop when the chorioretinal atrophy affects the
in a markedly diminished Arden ratio (Boon et al., 2009b). This fovea (Boon et al., 2009a). Besides loss of visual acuity and meta-
abnormal EOG also allows to detect asymptomatic carriers of a morphopsia, some CACD patients may experience mild photo-
BEST1 mutation (Deutman, 1969). The full-field ERG is normal. phobia (Boon et al., 2008a, 2009a; Michaelides et al., 2005).
Nyctalopia is reported only rarely in CACD and seems to be asso-
ciated with pigmentary changes of the peripheral retina (Boon
4.3.2.8. Genetic association. BVMD, a member of the group of
et al., 2009a; Michaelides et al., 2005). A positive family history
‘bestrophinopathies’, is caused by autosomal-dominantly inherited
for vision loss is more common in CACD than in AMD (Boon et al.,
mutations in the BEST1 gene (Boon et al., 2009b; Petrukhin et al.,
2009a; Smailhodzic et al., 2011).
1998). The BEST1 gene encodes the bestrophin-1 protein, a
calcium-activated chloride channel that also influences voltage-
gated calcium channels within the RPE (Boon et al., 2009b). Pa- 4.4.1.3. Ophthalmoscopic features. Four clinical stages of CACD have
tients with autosomal-recessive bestrophinopathy have more been described (Boon et al., 2008a; Hoyng and Deutman, 1996;
extensive retinal abnormalities and carry a BEST1 mutation on both Piguet et al., 1996). In stage 1, fine parafoveal pigmentary RPE
alleles (Boon et al., 2013). changes may be observed, usually under the age of 50 (Fig. 5A)
(Boon et al., 2009a; Nakazawa et al., 1995). In stage 2, an oval-to-
round, mildly atrophic, hypopigmented area may be observed.
4.3.2.9. Pathophysiology. The accumulation of subretinal fluid and Stage 3 is characterized by one or more patches of well-
vitelliform material e which supposedly originates from outer circumscribed RPE atrophy outside the fovea (Fig. 5E). The areas
photoreceptor debris - has been postulated to be the result of RPE of GA tend to enlarge concentrically and become confluent (Ferry
dysfunction due to abnormal RPE ionic transport (Boon et al., et al., 1972; Hoyng and Deutman, 1996; Klevering et al., 2002). In
2009b). The prolonged neuroretinal detachment and lipofuscin stage 4, the area of profound chorioretinal atrophy affects the fovea,
overload of the RPE may eventually lead to photoreceptor and RPE resulting in a markedly decreased visual acuity. Patients with CACD
dysfunction. usually do not have any flecks or drusen, but in some cases it is
associated with drusen-like deposits (Deutman and Jansen, 1970;
4.3.2.10. Differential diagnosis with age-related macular degenera- Klevering et al., 2002; Piguet et al., 1996), making the differential
tion. BVMD may be confused with AMD because of: diagnosis with AMD more difficult.

- the presence of yellowish lesion(s) with chorioretinal atrophy 4.4.1.4. Fundus autofluorescence. Like in most other macular dys-
and CNV trophies, marked FAF changes are a hallmark feature of CACD that
distinguishes this disease entity from the more moderate FAF ab-
Features that help to distinguish BVMD from AMD include: normalities in most cases of early AMD and GA in AMD (Boon et al.,
2009a; Schmitz-Valckenberg et al., 2009a; Smailhodzic et al., 2011).
- an age at the onset before the age of 50 FAF abnormalities are more sharply demarcated, regularly oval-
- a positive family history with an autosomal-dominant inheri- shaped and are confined to the central macular region, in
tance pattern contrast to AMD FAF abnormalities, which frequently covers the
- central vitelliform lesions without surrounding drusen entire posterior fundus. In early CACD, a speckled pattern of
- marked autofluorescence changes within BVMD lesion increased and decreased FAF signal predominates (Fig. 5B) (Boon
- lesions corresponding to hyperreflective accumulation above et al., 2008a; Renner et al., 2009; Smailhodzic et al., 2011). Areas
the RPE on SD-OCT of markedly decreased to absent FAF appear in stages 3 and 4
- a markedly abnormal EOG (Fig. 5F) (Boon et al., 2008a, 2009a; Renner et al., 2009; Smailhodzic
- identification of a mutation in the BEST1 gene et al., 2011).
 N.T.M. Saksens et al. / Progress in Retinal and Eye Research 39 (2014) 23e57 43

4.4.1.5. Fluorescein angiography. FA is helpful in detecting the - the decreased penetrance and variable expression, that com-
earliest stage 1 abnormalities, showing pigmentary changes and plicates recognition of the mode of inheritance (Michaelides
small parafoveal window defects (Fig. 5C) (Boon et al., 2009a; et al., 2005)
Hoyng and Deutman, 1996). In stage 2e4, hyperfluorescent win- - the association with drusen-like lesions, RPE changes, chorior-
dow defects become more prominent (Boon et al., 2009a; Piguet etinal atrophy
et al., 1996).
Features that help to distinguish CACD from AMD:
4.4.1.6. Optical coherence tomography. SD-OCT reveals reduced
- a relatively early onset
retinal thickness in CACD with a disruption of the ellipsoid zone of
- a positive family history with an autosomal-dominant inheri-
the photoreceptors, proportional to the degree of chorioretinal at-
tance pattern
rophy (Fig. 5D) (Boon et al., 2009a; Renner et al., 2009; Smailhodzic
- absence of genuine drusen on ophthalmoscopy and SD-OCT
et al., 2011). In contrast to AMD, sub-RPE deposits (drusen) are
- more pronounced autofluorescence changes than in atrophic
generally absent and rosette-like structures are more often present
AMD
(Smailhodzic et al., 2011). In eyes with atrophic lesions due to
- genetic analysis revealing a mutation in the PRPH2 gene
CACD, the remaining retinal layers have a relatively homogeneous
aspect (Fig. 5G), whereas eyes with GA due to AMD frequently have
4.4.2. Late-onset cone dystrophy
an irregular structure of the remaining retinal layers within the
4.4.2.1. Introduction. Clinical signs of cone dystrophies may
atrophic lesion on SD-OCT (Smailhodzic et al., 2011).
develop progressively during all decades of life (Krill et al., 1973a).
Late onset, in the fourth (Francois et al., 1974; Rowe et al., 1990) or
4.4.1.7. Psychophysical and electrophysiological testing. Tests of the even after the sixth decade (Krill et al., 1973a; Rowe et al., 1990),
macular function, such as the pattern ERG and multifocal ERG, as however, is rare. Therefore, the diagnosis of cone dystrophy is not
well as results from colour vision testing usually become abnormal often considered in older patients (Ladewig et al., 2003). In addi-
early in the course of CACD (Hoyng and Deutman, 1996; tion, age-related morphological changes, such as pigment irregu-
Michaelides et al., 2005; Renner et al., 2009). The full-field ERG is larities and drusen, may mask the correct diagnosis (Ladewig et al.,
generally normal, but may display generalized cone or cone-rod 2003).
dysfunction in advanced CACD, depending on the associated
PRPH2 mutation (Boon et al., 2008a; Hoyng and Deutman, 1996; 4.4.2.2. Clinical characteristics. In cone dystrophy, patients suffer
Michaelides et al., 2005; Nakazawa et al., 1995). The EOG is from progressive visual loss, central visual field defects, colour
normal or slightly subnormal (Boon et al., 2009a; Hoyng and vision impairment and photophobia (Krill et al., 1973a). In cases
Deutman, 1996; Piguet et al., 1996). Early in the course visual with cone dystrophy with late onset, symptoms and signs may be
fields are normal, but with disease progression a relative and mild to moderate and often non-specific, leading to misdiagnosis
eventually absolute paracentral scotoma may be demonstrated, (Langwinska-Wosko et al., 2010). Patients with late onset cone
corresponding to the area of advanced atrophy (Gundogan et al., dystrophy develop slowly progressive loss of central or paracentral
2010; Hoyng and Deutman, 1996; Piguet et al., 1996; Renner vision usually in the absence of any fundoscopic abnormalities
et al., 2009). The peripheral visual field is normal (Gundogan (Agarwal, 2012).
et al., 2010; Nakazawa et al., 1995; Piguet et al., 1996).
4.4.2.3. Ophthalmoscopic features. Ophthalmoscopic findings in
4.4.1.8. Genetic association. In most cases, CACD has an autosomal- late-onset cone dystrophy range from normal or unspecific retinal
dominant inheritance pattern, caused by mutations in the PRPH2 pigment irregularities to bull’s eye maculopathy and atrophy
gene, although autosomal-recessive and sporadic cases have also (Fig. 5H). Furthermore, pallor of the optic disc has been described
been reported (Boon et al., 2008a, 2009a). (Krill et al., 1973a; Ladewig et al., 2003).

4.4.2.4. Fundus autofluorescence (cone dystrophy in general).

4.4.1.9. Pathophysiology. Several histopathological studies on non-
Fundus and near-infrared autofluorescence allow detection of
genotyped CACD patients have shown an absence of photorecep-
retinal structural abnormalities even when findings from
tors, RPE, and choriocapillaris in the area of atrophy (Ashton, 1953;
ophthalmoscopy are normal (Kellner and Kellner, 2009). However,
Ferry et al., 1972). Boon and co-workers have suggested that the
in about 8.5% of patients, FAF and near-infrared autofluorescence
abnormal peripherin/rds protein structure results in a dysmorphic
also do not show pathological findings (Kellner and Kellner, 2009).
cone and possibly rod outer segment structure (Boon et al., 2009a).
Similar to the variability in the fundoscopic appearance of cone
These structural abnormalities hinder normal photoreceptor
dystrophy, FAF and near-infrared autofluorescence may show a
function and lead to alterations in the normal photoreceptor outer
high heterogeneity ranging from normal signals to widespread RPE
segment-RPE interaction. These changes may raise the level of
atrophy (Fig. 5I).
lipofuscin and toxic byproducts in the RPE cells, resulting in RPE
and photoreceptor cell death through apoptosis. Atrophy of the RPE
4.4.2.5. Fluorescein angiography (cone dystrophy in general).
and choriocapillaris eventually lead to the typical ‘punched-out’
FA may show a dark choroid in patients with ABCA4 associated cone
CACD lesions (Boon et al., 2009a). The term ‘central areolar
dystrophy. Otherwise, FA imaging in patients with cone dystrophy
choroidal dystrophy’ may, therefore, be a misnomer, as it suggests
does not add significant information (Kellner and Kellner, 2009).
that the primary dystrophic focus is the choroid instead of the
retina.
4.4.2.6. Optical coherence tomography (cone dystrophy in general).
High-resolution OCT imaging frequently reveals thinning of the
4.4.1.10. Differential diagnosis with age-related macular degenera- retina (Fig. 5J) (Kellner and Kellner, 2009). In the outer retinal layers
tion. CACD may be confused with atrophic AMD because of: and at the RPE-level, unspecific alterations may be visible even
when findings from ophthalmoscopy are normal (Kellner and
- the overlap in age at the onset (in late-onset CACD), Kellner, 2009).
44 N.T.M. Saksens et al. / Progress in Retinal and Eye Research 39 (2014) 23e57

4.4.2.7. Psychophysical and electrophysiological testing. (Agarwal, 2012; Spaide and Klancnik, 2005). These hyper-
Initially, full-field ERG findings may be normal. In advanced stages, autofluorescent areas may be explained by the accumulation of
full-field ERG reveals decreased or absent photopic responses lipofuscin in the RPE, and/or from autofluorescent A2E-precursors
implying severe cone function impairment with normal to slightly in the subretinal space, derived from the shed outer segments of
depressed rod responses (Langwinska-Wosko et al., 2010). photoreceptors (Spaide and Klancnik, 2005).

4.4.2.8. Genetic association. There are only a few reports of patients 4.4.3.5. Fluorescein angiography. On FA, chronic CSC typically
with late-onset cone dystrophy. Possible familial inheritance has shows granular areas of hyperfluorescence, often with one or more
been reported in some of these patients (Ladewig et al., 2003; Rowe ‘hot spots’ of active subretinal fluid leakage (Fig. 5M) (Nicholson
et al., 1990). et al., 2013). With more extensive disease, larger hyperfluorescent
RPE window defects may be seen due to RPE atrophy, sometimes
4.4.2.9. Pathophysiology. The exact pathogenesis of late-onset cone with characteristic descending atrophic tracts (Fig. 5M) (Agarwal,
dystrophy remains unclear. The cones appear to be primarily 2012; Oosterhuis, 1996). ICGA in active disease shows multiple
affected with subsequent photoreceptor loss in the cone-rich cen- areas of choroidal hyperfluorescence due to choroidal vascular
tral retina. The pathological changes in the underlying RPE appear dilation and hyperpermeability (Giovannini et al., 1997).
to be secondary.
4.4.3.6. Optical coherence tomography. A shallow subretinal
4.4.2.10. Differential diagnosis with age-related macular degenera- detachment, often combined with one or more small pigment
tion. Late-onset cone dystrophy may be confused with atrophic epithelial detachments may be seen on SD-OCT in chronic CSC
AMD because of: patients (Fig. 5N) (Song et al., 2012; Spaide and Klancnik, 2005), but
e in contrast to AMD e there are no drusen (Inhoffen et al., 2012).
- the age at onset (>50 y) In severe cases, atrophy of the outer retinal layers and RPE remains
- presence of pigmentary abnormalities after the serous fluid has disappeared (Song et al., 2012; Spaide and
Klancnik, 2005; Wang et al., 2002). Enhanced depth imaging OCT
Features that help to distinguish late-onset cone dystrophy from may demonstrate a thickened choroid (Nicholson et al., 2013).
AMD are:
4.4.3.7. Psychophysical and electrophysiological testing. EOG is
- absence of drusen generally normal, but mfERG reveals abnormalities even in patients
- temporal optic disc pallor with a mild course (Nicholson et al., 2013). Visual field testing and
- full-field and/or multifocal ERG findings typical for cone microperimetry may show loss of sensitivity with progression to
dystrophy (paracentral) scotoma (Castro-Correia et al., 1992; Chen et al.,
2006), and colour vision testing is often abnormal (Agarwal, 2012).
4.4.3. Central serous chorioretinopathy
4.4.3.1. Introduction. Central serous chorioretinopathy (CSC) is a 4.4.3.8. Genetic association. Familial occurrence of CSC has been
relatively common cause of maculopathy characterized by serous described, indicating that genetic factors may play a role in the
fluid leakage under the neuroretina. CSC is usually sporadic, pathogenesis of this disease (Oosterhuis, 1996; Weenink et al.,
although familial cases have been described. Acute CSC often re- 2001). So far, no genetic variants involved in CSC have yet been
solves spontaneously but sometimes recurs or becomes chronic reported.
(Gilbert et al., 1984). Risk factors for developing CSC include corti-
costeroid use, male sex, and type A personality (Nicholson et al., 4.4.3.9. Pathophysiology. The pathophysiology of CSC remains
2013). poorly understood. There is strong evidence for a choroidal vas-
culopathy and hyperpermeability in CSC, leading to secondary RPE
4.4.3.2. Symptoms. Although the chronic form of CSC may be pre- dysfunction and subretinal fluid leakage (Giovannini et al., 1997;
ceded by acute CSC episodes, it is most often observed as a primary Nicholson et al., 2013). The underlying mechanism of the
lesion (Oosterhuis, 1996; Yannuzzi et al., 1984). Generally, chronic choroidal dysfunction remains to be determined, but it may be
CSC becomes manifest before the sixth decade and may cause related to inappropriate activation of the mineralocorticoid recep-
bilateral vision loss (Agarwal, 2012; Nicholson et al., 2013; tor (Zhao et al., 2012).
Oosterhuis, 1996; Yannuzzi et al., 1984). In bilateral chronic cases
of CSC in which the serous subretinal fluid has eventually resorbed, 4.4.3.10. Differential diagnosis with age-related macular degenera-
the remaining central atrophic lesions may mimic AMD and atro- tion. CSC may be confused with AMD because of:
phic macular dystrophies. Chronic CSC is more often bilateral and
may be complicated by CNV, further complicating the differential - late central atrophic lesions and it may be accompanied by
diagnosis with AMD (Wang et al., 2008). yellowish subretinal deposits and complicated by CNV.

4.4.3.3. Clinical features. In chronic CSC, persistent serous detach- Features that help to distinguish CSC from AMD include:
ment or recurrent multifocal detachments of the retina and/or RPE
may lead to atrophy of the RPE and the outer retina (Fig. 5K) - a relatively early age at onset
(Agarwal, 2012; Wang et al., 2002). Some patients develop - (history of) serous neuroretinal detachment without drusen on
yellowish subretinal deposits, intraretinal cystoid edema, fibrinous ophthalmoscopy and SD-OCT
greyewhite subretinal material, and/or CNV (Agarwal, 2012; - gravitational tracks on FA and FAF
Nicholson et al., 2013).
4.4.4. Macular telangiectasia
4.4.3.4. Fundus autofluorescence. Areas of RPE atrophy in chronic 4.4.4.1. Introduction. The spectrum of idiopathic juxtafoveal retinal
CSC correspond to hypoautofluorescence and most long-standing telangiectasia has been classified by Gass and Blodi (1993). Type 2a,
CSC lesions also have speckled areas of increased FAF (Fig. 5L) also called macular telangiectasia type 2 or ‘MacTel’, is the most
 N.T.M. Saksens et al. / Progress in Retinal and Eye Research 39 (2014) 23e57 45

common type and may show several morphological similarities to full thickness macular holes may be visualized. These alterations
AMD. In recent years, there has been tremendous research into are limited to the parafoveal macula and most prominent to the
MacTel (Issa et al., 2013). While the underlying cause is still not foveal centre. Gillies and co-workers have reported that the
clear, clinical features, the natural history and the correlation to earliest subtle changes on SD-OCT imaging may be a temporal
retinal dysfunction have been extensively studied. enlargement of the foveal pit that results in an asymmetry of the
foveal contour with its thinnest sector temporally (Gillies et al.,
4.4.4.2. Clinical characteristics. MacTel is a bilateral disease in per- 2009).
sons 40 years and older causing progressive visual loss. It usually
presents with a slow decrease in vision, metamorphopsia, positive
scotoma and reading difficulties. Symptoms may occur prior to 4.4.4.7. Psychophysical and electrophysiological testing.
fundoscopically visible changes. Paracentral scotomata at the site of pigment hypertrophy and
outer retinal cavities may be clearly confirmed by microperimetry
4.4.4.3. Ophthalmoscopic features. Based on fundus photographs (Issa et al., 2007; Schmitz-Valckenberg et al., 2009b). Retinal
and FA findings, Gass and Blodi divided MacTel into five clinical cavities limited to the inner retina typically show preserved
stages according to the disease development (Gass and Blodi, 1993). function. Visible disruption of the inner segment-outer segment
In stage 1, no abnormalities on biomicroscopy may be appreciated. borders as shown by SD-OCT imaging is spatially confined to
FA may show minimal capillary dilatation and mild staining in the reduced retinal sensitivity. Fine matrix mapping findings suggest
late-phase in the area temporal to the foveola. that rod function may be more severely affected as compared to
Biomicroscopy shows in stage 2 slight greying and loss of cone function and occurs earlier in the disease. By contrast,
transparency of the perifoveolar retina and no or minimal telan- routine examinations with visual acuity testing might not be
giectatic vessel with similar FA findings as in stage 1. The occur- sufficient to estimate the abilities of the patient to cope with daily
rence of blunted, right-angle venules that extend into the depth of visual tasks particularly reading.
the parafoveolar retina, typically in the temporal fovea, charac- Standard visual field testing or ERG is usually normal or sub-
terize stage 3. Stage 4 manifests with one or several foci of black normal in MacTel. It would be well conceivable that the affected
hyperplastic RPE within the retina, often beneath the blunted tips retinal area in MacTel is relatively small compared to the sensitivity
of the right angle venules and extending in some cases into the of these modalities.
inner retina (Fig. 5O). The development of subretinal neo-
vascularization is defined as stage 5.
4.4.4.8. Genetic association. No causal mutation has been identi-
fied, but a genetic association of the ATM gene and a locus have
4.4.4.4. Fundus autofluorescence. In early disease stage, a key
been reported (Barbazetto et al., 2008; Parmalee et al., 2012).
finding is the depletion of macular pigment in MacTel that may
MacTel may occur in monozygotic twin, other siblings and also in
even occur before visible capillary dilatation in FA (Helb et al., 2008;
families with vertical transmission, suggestive of a dominant in-
Schmitz-Valckenberg et al., 2009b). This finding has been
heritance mode (Gillies et al., 2009).
confirmed by FAF imaging. In later stages, localized fundoscopically
visible hyperpigmentations show a well-defined area of severely
decreased FAF intensity (Fig. 5P). This has been explained by RPE 4.4.4.9. Pathophysiology. The cause of MacTel is unknown. While
atrophy with loss of intrinsic fluorophores. Hyporeflective cavities the name ‘macular telangiectasia’ suggest a disease of the retinal
in the neurosensory retina may show an increased signal, partic- vasculature, recent findings have provided increasing evidence
ularly following bleaching of the retina with blue light (Theelen that MacTel is not limited to the retinal vasculature and that
et al., 2008). early neuronal involvement may be implicated in the patho-
Blue confocal reflectance imaging is usually largely neglected in genesis of disease. Furthermore, affection of Müller cells has
the clinical setting although it is available by standard cSLO. In been discussed recently (Baumuller et al., 2010; Cherepanoff
MacTel, blue confocal reflectance is particularly helpful as it shows et al.; Powner et al., 2010, 2013; Sallo et al., 2011; Zhu et al.,
a distinctive parafoveal hyperreflectivity, already in the early stages 2013).
of the disease (Charbel Issa et al., 2008). This characteristic signal
may be caused by alterations in macular pigment and/or Müller cell
loss (Powner et al., 2013). 4.4.4.10. Differential diagnosis with age-related macular degenera-
tion. MacTel may be confused with AMD because of:
4.4.4.5. Fluorescein angiography. FA has traditionally been the
gold-standard for the diagnosis of MacTel as it clearly demon- - similar symptoms; bilateral slow progressive loss of central
strates the capillary dilatations in the early phase with diffuse vision, metamorphopsia, positive scotoma and reading
hyperfluorescence in the late stages (Fig. 5Q). These telangiec- difficulties
tatic vessels predominantly occur temporally to the fovea. Using - presence of pigmentary changes and CNV may develop
stereoscopic images, these vascular alterations appear to be
located in the deeper capillary plexus (Gass and Oyakawa, Features that help to distinguish MacTel from AMD are:
1982). Further typical findings with FA are the hypofluor-
escence at the site of hyperpigmentations due to blockage - an earlier age at onset
(Fig. 5Q) and the occurrence of leakage by retinal neo- - no drusen
vascularization in stage 5. - affection of abnormalities limited to the parafovea and pre-
dominantly temporal to the foveal centre
4.4.4.6. Optical coherence tomography. SD-OCT imaging shows - Parafoveal hyperreflectivity in confocal blue reflectance
intraretinal cystoid spaces or cavities without foveal thickening - Presence of telangiectatic vessels
(Fig. 5R) (Issa et al., 2013). Furthermore, disruption of the ellip- - Depletion of macular pigment by fundus autofluorescence
soid zone, increased reflectivity of the inner neurosensory layers, - Retinal thinning (usual no thickening) and cavities by SD-OCT
outer neurosensory atrophy, foveal detachment and laminar or imaging
46 N.T.M. Saksens et al. / Progress in Retinal and Eye Research 39 (2014) 23e57
 N.T.M. Saksens et al. / Progress in Retinal and Eye Research 39 (2014) 23e57 47

4.5. Dystrophies associated with a syndrome or systemic disease significantly larger than would be expected from the fundoscopic
appearance (Boon et al., 2008b; Michaelides et al., 2008; Rath et al.,
4.5.1. Mitochondrial retinal dystrophy associated with the 2008).
m.3243A > G mutation (maternally inherited diabetes and deafness
and MELAS syndrome) 4.5.1.5. Fluorescein angiography. The FA signal may vary from small
4.5.1.1. Introduction. The m.3243A > G mutation was first hyper and hypofluorescent spots to extensive RPE window defect
described in association with mitochondrial myopathy, encepha- with visibility of the underlying larger choroidal vasculature and
lopathy, lactic acidosis and stroke-like episodes (MELAS) (Goto atrophy of the choriocapillaris depending of the disease grade
et al., 1990; Kobayashi et al., 1990). Up to 86% of patients with the (Fig. 6C) (de Laat et al., 2013b).
m.3243A > G mutation have evidence of retinal dystrophy (de Laat
et al., 2013b; Massin et al., 1999). Over time, more phenotypic 4.5.1.6. Optical coherence tomography. Irregular thickening or
variations of the m.3243A > G mutation have been reported, the attenuation of the line corresponding to the ellipsoid zone and of
most frequent being maternally inherited diabetes and deafness the underlying RPE layer may be visualized in affected retinal area
(MIDD) (de Laat et al., 2012; van den Ouweland et al., 1992). Other (Fig. 6D). The atrophic areas correspond to a loss of the outer retinal
systemic associations include cardiac, renal, and gastro-intestinal layers on OCT imaging (de Laat et al., 2013b).
involvement (Chinnery et al., 1999; Goto et al., 1990; Kobayashi
et al., 1990; Manouvrier et al., 1995; Reardon et al., 1992; van den 4.5.1.7. Psychophysical and electrophysiological testing. The full-
Ouweland et al., 1992). field ERG and EOG are normal (de Laat et al., 2013b). Multifocal
ERG in mitochondrial retinal dystrophy can show reduced peak
4.5.1.2. Clinical characteristics. Most patients have a relatively amplitudes with normal implicit times in the mfERG suggesting
preserved central visual function because of the frequent occur- localized loss of function and indicating damage to the cone
rence of structural and functional sparing of the fovea (de Laat et al., photoreceptor outer segments or cone photoreceptor loss in MIDD
2013b). Up to 80% of patients maintain a visual acuity of 20/25 or (Bellmann et al., 2004).
better in at least one eye (de Laat et al., 2013b; Massin et al., 1999).
However, even if the fovea is spared, considerable visual impair- 4.5.1.8. Genetic association and pathophysiology. The m.3243A > G
ment may be present as a result of paracentral scotomata in cases of mutation is by far the most common cause of mitochondrial retinal
progressive atrophy around the fovea (de Laat et al., 2013b). dystrophy in adults (de Laat et al., 2013b). The percentage of cells
with the affected mitochondrial DNA in a specific tissue is referred
4.5.1.3. Ophthalmoscopic features. The spectrum of retinal abnor- to as ‘heteroplasmy’, and within a single individual, the degree of
malities ranges from barely discernible pigmentary abnormalities heteroplasmy may vary widely between tissues (de Laat et al.,
in the outer retinal layers of the macula to profound chorioretinal 2013a; de Laat et al., 2013b). Therefore, mitochondrial disease
atrophy in the macula (de Laat et al., 2013b). Patients with the may present at any age, with virtually any symptom or sign, and by
m.3243A > G mutation have retinal lesions that are localized at the any apparent mode of inheritance (Koopman et al., 2012). This
posterior pole but tend to spare the fovea and often include the marked intra-individual and inter-individual variation in mito-
retina surrounding the optic disc (Fig. 6A). Recently, Boon has chondrial heteroplasmy explains the wide spectrum of clinical
proposed a classification system into 4 grades based on findings on symptoms and disease severity observed between family members
ophthalmoscopy, FAF, and SD-OCT (de Laat et al., 2013b). This who share a given mitochondrial mutation (Koopman et al., 2012).
classification correlates both with age and visual acuity. There is no clear correlation of the grade of mitochondrial retinal
dystrophy with systemic heteroplasmy levels or overall systemic
4.5.1.4. Fundus autofluorescence. The retinal abnormalities in disease involvement (de Laat et al., 2013b)
m.3243A > G mutation associated macular dystrophy are clearly
visible on FAF imaging (de Laat et al., 2013b; Michaelides et al., 4.5.1.9. Differential diagnosis with age-related macular degeneration.
2008; Rath et al., 2008). Mild hypofluorescent mottling correlates m.3243A > G associated macular dystrophy may be confused with
with the mild pigmentary abnormalities in the central fundus in AMD because of:
grade 1 mitochondrial retinal dystrophy. In grade 2, fundoscopi-
cally visible yellow-white spots/flecks correspond to mostly - The pigmentary abnormalities and chorioretinal atrophy that
increased FAF, while a decreased FAF signal is present in mildly can mimic drusen and GA in AMD.
atrophic areas (Fig. 6B). In grade 3, there are one or more areas of - The maternal inheritance pattern may be masked and the sys-
well delineated areas of chorioretinal atrophy that present with a temic disease associations may be variable or even absent
well-defined area of decreased FAF. Unlike grade 4 disease, these
atrophic zones may encircle the fovea but do not involve the central Features that help to distinguish m.3243A > G associated mac-
fovea. A diffuse speckled FAF pattern may be present that is ular dystrophy from AMD include:

Fig. 6. (AeD) m.3243A > G Macular dystrophy associated with MIDD in a 26-year-old patient with diabetes mellitus who carried an m.3243A > G mutation. (A) Colour fundus
photograph showing hyperpigmented irregular spots in the macula and an oval area of mottled hypopigmentation that involved the macula and surrounded the optic disc. (B)
Fundus autofluorescence (FAF) image showing that the hyperpigmented spots in the macula correspond to mainly increased FAF, whereas the hypopigmented spots and zones
mainly correspond to a decreased FAF signal. (C) Fluorescein angiography (FA) image showing blockage of background fluorescence in the area of hyperpigmentation and
hyperfluorescence due to a retinal pigment epithelium (RPE) window defect in the retinal areas that were hypopigmented and mildly atrophic on the fundus image A. (D) Hor-
izontal optical coherence tomography (OCT) scan (scan in the plane indicated by black arrowhead in A) showing the hyperpigmented spot corresponding to a hyperreflective dome-
shaped lesion that seemed to originate from the RPE. (EeK) Choroidal neovascularization (CNV) associated with angioid streaks in a 45-year-old patient with pseudoxanthoma
elasticum. On fundoscopy (E) the identification of angioid streaks is challenging. Infra-red (F) or FAF (G) imaging might be more reliable to detect angioid streaks. FA (H) shows a
classic CNV originating from an angioid streak. On SD-OCT image (I) fibrovascular invasion with subretinal fluid is visible. The OCT image (J) reveals a break in Bruch‘s membrane
associated with an angioid streak. (K) Magnification of image J highlighting the break in Bruch’s membrane (white arrow). (LeM) Membranoproliferative glomerulonephritis II in a 58-
year-old patient who carried compound heterozygous mutations in the Complement Factor H gene. (L) Colour fundus photograph showing widespread drusenoid lesions with
irregular RPE alterations. (M) FA image showing stars-in-the-sky appearance with small, hyperfluorescent drusen scattered in the posterior pole. (NeO) Maculopathy in a 53-year-
old patient with myotonic dystrophy (Courtesy of J.R.M. Cruysberg, Radboud University Nijmegen Medical Centre). (N) Colour fundus photograph showing pigmentary changes in the
macula. (O) FA image showing window defects and hypofluorescence corresponding with the pigmentary changes due to blockage of background fluorescence.
48 N.T.M. Saksens et al. / Progress in Retinal and Eye Research 39 (2014) 23e57

- A typical speckled FAF pattern that may spread along the tem- which are often more extensive than fundoscopy or FA would
poral retinal vascular arcades and surround the optic disc (Boon suggest (Finger et al., 2009).
et al., 2008b; Rath et al., 2008)
- Systemic associations such as hearing loss and early-onset
4.5.2.5. Fluorescein angiography. Angioid streaks may show
diabetes
increased fluorescence if there is thinning of the RPE overlying an
- maternal inheritance of disease (no male-to-male transmission)
intact choriocapillaris. In this situation, there would be gradual
- genetic analysis revealing the m.3243A > G mutation
fading of an early choroidal blush in the later phases of the
angiogram (Clarkson and Altman, 1982). If there is actual separa-
4.5.2. Dystrophies with angioid streaks tion of the choriocapillaris at the time of the separation of Bruch’s
4.5.2.1. Introduction. Angioid streaks are irregular and radiating membrane, one may see only hyperfluorescence along the margin
lines extending from the disc to the peripheral retina caused by of the streak with the central portion of the streak showing very
breaks in the Bruch’s membrane (Klein, 1947). Angioid streaks little or no fluorescence (Clarkson and Altman, 1982). CNVs usually
frequently occur in patients with systemic diseases, including originate from the rim of angioid streaks and show similar angio-
pseudoxanthoma elasticum (PXE), osteitis deformans, sickle cell graphic pattern to that described in AMD (Fig. 6H) (Lafaut et al.,
anaemia, acromegalie, Marfan syndrome, fibrodysplasia hyper- 1998; Pece et al., 1997; Quaranta et al., 1995).
elastica, thalassemia, and spherocytosis (Lam, 2013).
PXE is the most commonly associated systemic disorder: 59e
4.5.2.6. Optical coherence tomography. On SD-OCT scans the pa-
87% of cases with angioid streaks are due to PXE (Conner and
thology of angioid streaks is localized to the Bruch’s membrane-
Juergens, 1961). It is associated with accumulation of mineralized
RPE complex (Charbel Issa et al., 2009). The RPE overlying breaks
and fragmented elastic fibers in the skin, vascular walls, and Bruch’s
in Bruch’s membrane may seem unaffected, but often appears
membrane in the eye (Finger et al., 2009), manifested in soft, ivory-
altered, focally detached, or absent. In many advanced cases,
coloured papules in a reticular pattern that predominantly affect
fibrovascular tissue extends from the choroidal into the sub-
the neck and large flexor surfaces, peripheral and coronary arterial
occlusive disease and gastrointestinal bleedings (Finger et al., neurosensory space (Fig. 6I) through the gaps in Bruch’s membrane
(Fig. 6J). Simultaneous SD-OCT and cSLO imaging reveals the most
2009).
reliable detection of angioid streaks in the near-infrared mode
(Fig. 6F) (Charbel Issa et al., 2009).
4.5.2.2. Clinical characteristics. Patients with angioid streaks usu-
ally remain asymptomatic. However, complications such as atrophy
of outer retinal layers, choroidal rupture, or CNV, with or without 4.5.2.7. Psychophysical and electrophysiological testing.
haemorrhage and subretinal fibrosis may be associated with severe Full-field ERG may reveal mild to significant amplitude reduction of
visual impairment when affecting the macula (Clarkson and cone and rod responses (Audo et al., 2007; Francois and de Rouck,
Altman, 1982; Georgalas et al., 2009). This has been reported in 1980).
73e86% of PXE cases (Conner and Juergens, 1961; Groenblad, 1958;
Mansour et al., 1993), frequently leading to severe reduction of
4.5.2.8. Genetic association. PXE is an autosomal-recessive disorder
visual acuity as early as age 14 (Mansour et al., 1993). By the age of
and in the majority of cases, homozygosity or compound hetero-
50, the majority of PXE patients have bilaterally impaired visual
zygosity is found for mutations in the ABCC6 gene, a member of the
acuity of 20/200 or less (Finger et al., 2009; Groenblad, 1958).
large ATP-dependent transmembrane transporter family. Since the
ABCC6 gene is expressed primarily, if not exclusively, in the liver
4.5.2.3. Ophthalmoscopic features. Typically, there is a peripapillary and kidneys, it has been suggested that PXE is a primary metabolic
ring from which irregularly radiating linear streaks extend in all disorder with secondary involvement of elastic fibres (Chassaing
directions (Fig. 6E). Fibrovascular ingrowth into the angioid streaks et al., 2005; Ringpfeil et al., 2001).
may result in serous and/or hemorrhagic detachment of the over-
lying retina. In advanced stages, detachment and atrophy of the RPE
and may also occur (Clarkson and Altman, 1982). 4.5.2.9. Pathophysiology. Angioid streaks represent breaks of the
In PXE, first visible changes on fundoscopy are pigmentary calcified and thickened Bruch’s membrane, which are not associ-
regularities called peau d’orange, which are most prominently ated with morphological changes in the overlying layers of the
visible temporal to the fovea (Hu et al., 2003; Krill et al., 1973b). retina and the underlying choriocapillaris in early stages (Dreyer
These pigment irregularities have a fine, yellow, drusen-like and Green, 1978).
appearance and are assumed to be localized at the level of the
RPE (Agarwal, 2012; Mansour et al., 1993). Peau d’orange typically 4.5.2.10. Differential diagnosis with age-related macular degenera-
precedes angioid streaks on average by 1e8 years (Mansour et al., tion. Angioid streaks related dystrophies may be confused with
1993). Additional ocular findings in PXE are multiple small cho- AMD because of: -atrophy and/or CNV may occur secondary to the
rioretinal atrophic lesions, so called comet tail lesions, as well as angioid streaks.
drusen of the optic disc (Gass, 2003). Features that help to distinguish between angioid streaks
related diseases and AMD include:
4.5.2.4. Fundus autofluorescence. On FAF, angioid streaks may show
areas of increased as well as decreased FAF (Fig. 6G) (Sawa et al., - visualization of angioid streaks by angiography, near-infrared-,
2006; Shiraki et al., 2001). Focal spots of increased FAF alongside AF-, and SD-OCT-imaging.
angioid streaks, consisting of pigmentations on fundoscopy, - An earlier age at onset
constitute a parastreak phenomenon. - accompanied ocular findings such as peau d’ orange and comet
Macular FAF patterns in PXE patients are often similar to those tail lesions in PXE
observed in pattern dystrophies (Shiraki et al., 2001). Comet tail - accompanied systemic symptoms
lesions in the midperiphery typically show an increased FAF signal - genetic analysis (mutations in ABCC6).
and appear hyperfluorescent on FA. FAF depicts RPE atrophies, - skin biopsy in patients with PXE
 N.T.M. Saksens et al. / Progress in Retinal and Eye Research 39 (2014) 23e57 49

Psychophysical Genetic
Ophthalmoscopy FAF FA Additional features OCT Anamnestic findings
testing testing
Long anterior lens
+ atrophy with DA and ffERG Night vision problems,
zonules and iris C1QTNF5 LORD
scalloped borders transillumination disturbance AD Fam+
+ speckled m.3243 MIDD/
Foveal sparing Hearing loss, diabetes
autofluorescence A>G MELAS

Yes MPGN II
Stars in the sky Renal disease
appearance
Cuticular
Hyperautofluorescent No
drusen
deposits
Radial, peripapillary
and large confluent AD Fam+ EFEMP1 ML
Hypo-/
drusen
Drusen and hyperfluorescence of
Hypoautofluorescent drusen, GA / CNV
Drusen-like Genuine drusen AMD
deposits
deposits
Extramacular location Night vision problems,
Delayed choroidal of deposits / CNV / peripheral vision loss, TIMP3 SFD
filling / multifocal CNV chorioretinal atrophy AD Fam+
Small radial drusen- Onset in childhood,
No sub-RPE MCDR1 NCMD
like lesions and larger Relatively preserved VA,
deposits locus
confluent lesions stable course, AD Fam+

Relatively good and Late onset

Yes stable VA ABCA4
Stargardt
Intense
Dark choroid Yes
Atrophic Irregular autofluorescent flecks Relatively good and PRPH2/ Pseudo-
yellowish No Foveal sparing No
maculopathy stable VA, AD Fam+ RDS Stargardt
flecks
Hypofluorescent lesion
Hyperautofluorescent PRPH2/ Pattern
with hyperfluorescent AD Fam+
pattern with RDS dystrophy
outline
hypofluorescence in-
between Normal /
Vitelliform AFVD
Subnormal EOG
lesion without Hyperautofluorescent Hyperreflective
surrounding lesions material above RPE
drusen Abnormal EOG AD Fam+ BEST1 BVMD

Granular Serous neuroretinal

Speckled
hyperfluorescence, detachement CSC
autofluorescence
gravitational tracks
No flecks +pronounced FAF Remaining retinal PRPH2/
AD Fam+ CACD
changes in atrophy layers intact, no RDS
genuine drusen
Photopic ERG Late onset
No speckled Temporal optic disc decreased cone
autofluorescence pallor response dystrophy
Maculopathy
PSC, ptosis, low IOP, Muscle weakness,
in myotonic
ophthalmoplegia myotonia
dystrophy
No drusen,
Paracentral
Capillary dilatation intraretinal cystoid MacTel
scotomata
spaces or cavities

+Angioid streaks and Peau d’orange and Skin papules, CVD, PXE related
ABCC6
comet tail lesions comet tail lesions GI-bleeding dystrophy

Fig. 7. Diagnostic flowchart of atrophic macular dystrophies based on anamnestic, ophthalmoscopic, electrophysiologic and genetic findings. The flowchart indicates the most likely
diagnosis, but does not exclude other diagnoses. Only most typical features and findings are included in this figure, and therefore, the absence of a finding does not exclude the
diagnosis. The starting point of the flowchart is atrophic maculopathy, since atrophy can occur in all macular diseases.

4.5.3. Cuticular drusen in membranoproliferative correspond with focal hypoautofluorescent lesions on FAF image,
glomerulonephritis II even when the lesions are not advanced enough to show the classic
4.5.3.1. Introduction. Membranoproliferative glomerulonephritis stars-in-the-sky appearance on FA (Meyerle et al., 2007).
type II (MPGN II), also termed ‘dense deposit disease’, is a rare
condition characterized by the deposition of abnormal electron- 4.5.3.5. Fluorescein angiography. Drusen in MPGNII are identified
dense material within the glomerular basement membrane of the most readily by FA. Typically, the small drusen show hyper-
kidney and often within Bruch’s membrane in the eye (Appel et al., fluorescence in the early phase of the angiogram (Fig. 6M).
2005).
4.5.3.6. Psychophysical and electrophysiological testing. In long-
4.5.3.2. Clinical characteristics. The diagnosis is made in most pa- standing cases, EOG may become abnormal due to widespread
tients between the ages of 5 and 15 years of life. Within 10 years RPE atrophy (Kim et al., 1997; O’Brien et al., 1993). In these
after diagnosis, approximately half of patients progress to end- advanced stages, colour vision, dark adaption, as well as dark
stage renal disease, occasionally with the late co-morbidity of vi- adapted ERG may also become mildly abnormal (Kim et al., 1997).
sual impairment (Appel et al., 2005).
4.5.3.7. Genetic association. The pathophysiologic basis of MPGN II
4.5.3.3. Ophthalmoscopic features. The majority of patients with is associated with the uncontrolled systemic activation of the
MPGN II develop deposits at the posterior pole with the clinical alternative pathway of the complement cascade. In most patients,
appearance of cuticular drusen (Fig. 6L) (McAvoy and Silvestri, loss of complement regulation is caused by C3 nephritic factor, an
2005). Visual acuity tends to be preserved until GA or CNV autoantibody directed against the C3 convertase of the alternative
complicate the disease (Leys et al., 1991a, 1991b; Sohn et al., 2013; pathway, but in some patients, mutations in the CFH gene have
Ulbig et al., 1993). been identified (Appel et al., 2005; Boon et al., 2009d).

4.5.3.4. Fundus autofluorescence. To the best of our knowledge, no 4.5.3.8. Pathophysiology. The pathophysiologic basis for MPGN II
descriptions of FAF imaging in patients with cuticular drusen and seems to be the uncontrolled systemic activation of the alternative
MPGN II have been published thus far. Cuticular drusen in general pathway of the complement cascade (Berger and Daha, 2007;
50 N.T.M. Saksens et al. / Progress in Retinal and Eye Research 39 (2014) 23e57

Williams, 1997). In most patients, loss of complement regulation is 4.5.4.5. Fluorescein angiography. FA shows window defects and
caused by the C3 nephritic factor, an immunoglobulin (Ig)G auto- blocked fluorescence by focal pigment clumps (Fig. 6O) (Kim et al.,
antibody that binds and prevents the inactivation of C3 convertase 2009).
of the alternative pathway, thereby resulting in the perpetual
breakdown of C3 (Alchi and Jayne, 2010). The characteristic finding 4.5.4.6. Psychophysical and electrophysiological testing.
in MPGN II is an intense deposition of C3 cleavage products along Decreased b-wave and subnormal a-wave amplitudes in the ERG
the glomerula capillary walls together with electro-dense deposits and delayed dark adaption have been reported in patients with
in the central part of the glomerula basal membrane (Appel et al., myotonic dystrophy (Burian and Burns, 1967). The EOG remains
2005). Histopathological studies on drusen in MPGN II showed normal in patients with myotonic dystrophy (Kimizuka et al., 1993).
both linear and focal depositions throughout the extent of the inner
collagenous layer of Bruch’s membrane (Duvall-Young et al., 1989; 4.5.4.7. Genetic association. Myotonic dystrophy type 1 is caused
Mullins et al., 2001). This draws attention to the fact that the by the expansion of an unstable CTG trinucleotide repeat in the 30
choriocapillaris-Bruch’s membrane-RPE complex shows a remark- untranslated region of the myotonic dystrophy protein kinase
able resemblance to the capillary tuft-glomerula basal membrane- (DMPK) gene (Brook et al., 1992; Harper, 2001). The myotonic
glomerular epithelial interface (Appel et al., 2005; Duvall-Young dystrophy type 2 mutation consists in the expansion of an unstable
et al., 1989). CCTG tetranucleotide within the first intron of the CCHC-type zinc
finger, nucleic acid-binding protein (CNBP) gene (previously named
4.5.3.9. Differential diagnosis with age-related macular degeneration. myotonia) (Liquori et al., 2001).
PMGNII may be confused with AMD because:
4.5.4.8. Pathophysiology. Experimental evidence supports an RNA
- patients may develop cuticular drusen, GA and CNV gain-of-function mechanism of expanded transcripts in myotonic
dystrophy type 1 and 2 (Gomes-Pereira et al., 2011; Lueck et al.,
Features that help to distinguish MPGNII from AMD include: 2007; Ranum and Cooper, 2006; Ranum and Day, 2004; Sicot
et al., 2011). These ‘toxic’ RNA transcripts accumulate in nuclear
- renal dysfunction inclusions, interfering with the activity, localization and/or steady-
- retinal changes present at an early age and are often detectable state levels of RNA-interacting proteins. The exact mechanisms
in the first or second decade of life. Therefore, in patients with leading to the fundoscopic features of the disease are still unknown.
early onset or extensive cuticular drusen screening for renal
dysfunction is reasonable (van de Ven et al., 2012a). 4.5.4.9. Differential diagnosis with age-related macular degeneration.
Maculopathy in myotonic dystrophy may be confused with AMD
because of: -The pattern dystrophy-like features may resemble
4.5.4. Maculopathy in myotonic dystrophy drusen and AMD-related hyperpigmentary changes.
4.5.4.1. Introduction. Steinert (1909) (Steinert, 1909) and Batten Features that help to distinguish between myotonic dystrophy
and Gibb (1909) (Batten and Gibb, 1909) identified myotonic dys- associated macular dystrophy and AMD include:
trophy as a multisystemic disorder that is now recognized as one of
the most common forms of muscular dystrophy in adults (Ranum - posterior subcapsular cataracts that are present in almost all
and Day, 2004). This inherited disorder is accompanied by pro- patients with myotonic dystrophy
gressive weakness of the distal muscles and myotonia. Cases of - other associated ocular symptoms such as ptosis, oph-
myotonic dystrophy are generally classified as one of two types thalmoplegia, and low intraocular pressure
based on the genetic background (Schara and Schoser, 2006). - absence of typical sub-RPE or reticular drusen on SD-OCT
- generalized muscle weakness and myotonia and a positive
4.5.4.2. Clinical characteristics. In addition to muscular dystrophy family history
and myotonia, which also may cause ptosis and weakness of the - genetic testing (DMPK and CNBP)
ocular muscles, myotonic dystrophy causes a consistent constella-
tion of seemingly unrelated and rare clinical features, including 5. Conclusions and future directions
cardiac conduction defects, a peculiar and specific set of endocrine
changes, and posterior subcapsular iridescent cataracts (Harper, A broad range of dystrophic macular disorders share clinical
2001). Further ophthalmic features include low intraocular pres- characteristics with AMD, which can make a differential diagnosis
sure and in at least 20%e25% of patients with myotonic dystrophy challenging. Although macular dystrophies and AMD show broad
there is some evidence of retinal degeneration (Agarwal, 2012; genetic and phenotypic heterogeneity, with overlapping features
Burian and Burns, 1967). Most of the patients have minimal loss that may complicate a comprehensive clinical classification, there
of visual acuity (Agarwal, 2012). are often characteristic phenotypic features that can help in the
differential diagnosis in a practical clinical setting. We propose a
diagnostic flow chart in Fig. 7. This flow chart inevitably is an
4.5.4.3. Ophthalmoscopic features. A variety of fundoscopic pictures oversimplification, and many classifications have been proposed,
has been described. Besides peripheral pigmentary changes, dark some based on ophthalmoscopic features, others are based on
and yellow spots in the macular that are configured in stellae, electrophysiologic findings or underlying molecular genetic
butterfly, and reticular shape resembling pattern dystrophies may defect(s).
occur (Fig. 6N) (Agarwal, 2012; Burian and Burns, 1967). Long-term It is clinically relevant to distinguish AMD from macular dys-
follow-up of patients with myotonic dystrophy suggested that trophies, not only because of the prognostic implications and ge-
these pigmentary retinal changes progress slowly over time netic counselling, but also because of its consequences for present
(Kimizuka et al., 1993). and future preventive and therapeutic strategies.
A correct diagnosis can have significant implications for the
4.5.4.4. Fundus autofluorescence. To the best of our knowledge, prognosis. Atrophy in macular dystrophies, for example, may show
there are no descriptions published so far. a different rate of progression from that in atrophic AMD (Boon
 N.T.M. Saksens et al. / Progress in Retinal and Eye Research 39 (2014) 23e57 51

et al., 2009a; Mauschitz et al., 2012; McBain et al., 2012) and CNV in Leppert, M., 1997. Mutation of the Stargardt disease gene (ABCR) in age-related
macular degeneration. Science 277, 1805e1807.
macular dystrophies appears to have a relatively favourable prog-
Anderson, D.H., Ozaki, S., Nealon, M., Neitz, J., Mullins, R.F., Hageman, G.S.,
nosis as compared to CNV in AMD (Marano et al., 2000). Johnson, L.V., 2001. Local cellular sources of apolipoprotein E in the human
With regard to genetic counselling, it is very important to pro- retina and retinal pigmented epithelium: implications for the process of drusen
vide the patient with the correct information on the risk of affected formation. Am. J. Ophthalmol. 131, 767e781.
Appel, G.B., Cook, H.T., Hageman, G., Jennette, J.C., Kashgarian, M., Kirschfink, M.,
offspring, for instance in late-onset Stargardt disease versus Lambris, J.D., Lanning, L., Lutz, H.U., Meri, S., Rose, N.R., Salant, D.J., Sethi, S.,
pseudo-Stargardt pattern dystrophy. Although these retinal dys- Smith, R.J., Smoyer, W., Tully, H.F., Tully, S.P., Walker, P., Welsh, M., Wurzner, R.,
trophies can be clinically very similar, Stargardt disease is inherited Zipfel, P.F., 2005. Membranoproliferative glomerulonephritis type II (dense
deposit disease): an update. J. Am. Soc. Nephrol. 16, 1392e1403.
in an autosomal-recessive fashion, on contrast to autosomal- Arikawa, K., Molday, L.L., Molday, R.S., Williams, D.S., 1992. Localization of peripherin/
dominantly inherited pseudo-Stargardt. rds in the disk membranes of cone and rod photoreceptors: relationship to disk
An early recognition of syndrome-associated macular dystro- membrane morphogenesis and retinal degeneration. J. Cell Biol. 116, 659e667.
Armstrong, J.D., Meyer, D., Xu, S., Elfervig, J.L., 1998. Long-term follow-up of Star-
phies paves the way to a multidisciplinary approach, a timely gardt’s disease and fundus flavimaculatus. Ophthalmology 105, 448e457. Dis-
diagnosis, prevention and/or treatment of associated systemic cussion 457e448.
disease(s). For example, it is important to recognise macular dys- 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,
trophy in the constellation of pseudoxanthoma elasticum because 717e726.
this has implications for the prevention and treatment of cardio- Ashton, N., 1953. Central areolar choroidal sclerosis; a histo-pathological study. Br. J.
vascular disease. Mitochondrial retinal dystrophy associated can be Ophthalmol. 37, 140e147.
Assink, J.J., de Backer, E., ten Brink, J.B., Kohno, T., de Jong, P.T., Bergen, A.A., Meire, F.,
the first manifestation in carriers of the m.3243A > G mutation (de
2000. Sorsby fundus dystrophy without a mutation in the TIMP-3 gene. Br. J.
Laat et al., 2013b). These patients have a very high risk of other Ophthalmol. 84, 682e686.
systemic abnormalities, such as hearing loss and diabetes, for Audo, I., Vanakker, O.M., Smith, A., Leroy, B.P., Robson, A.G., Jenkins, S.A., Coucke, P.J.,
which they should be screened in a specialized centre for mito- Bird, A.C., De Paepe, A., Holder, G.E., Webster, A.R., 2007. Pseudoxanthoma
elasticum with generalized retinal dysfunction, a common finding? Invest.
chondrial disease. Ophthalmol. Vis. Sci. 48, 4250e4256.
Nutritional supplements are widely used by AMD patients. Balaskas, K., Hovan, M., Mahmood, S., Bishop, P., 2013. Ranibizumab for the man-
However, Stargardt patients might be advised to refrain from taking agement of Sorsby fundus dystrophy. Eye (London, England) 27, 101e102.
Barbazetto, I.A., Room, M., Yannuzzi, N.A., Barile, G.R., Merriam, J.E., Bardal, A.M.,
vitamin A supplements, as it may accelerate the disease course. A Freund, K.B., Yannuzzi, L.A., Allikmets, R., 2008. ATM gene variants in patients
misdiagnosis may therefore lead to recommendations which are with idiopathic perifoveal telangiectasia. Invest. Ophthalmol. Vis. Sci. 49, 3806e
potentially harmful (Radu et al., 2008). Misdiagnosis can lead to 3811.
Batten, F., Gibb, H., 1909. Myotonia atrophica. Brain 32, 187e205.
erroneous treatment of patients (Boon et al., 2013). Unlike in AMD, Baumuller, S., Charbel Issa, P., Scholl, H.P., Schmitz-Valckenberg, S., Holz, F.G., 2010.
argon laser and photodynamic therapy may not be effective in the Outer retinal hyperreflective spots on spectral-domain optical coherence to-
treatment of CNV in SFD patients (Fig. 2G) (Sivaprasad et al., 2008). mography in macular telangiectasia type 2. Ophthalmology 117, 2162e2168.
Bellmann, C., Neveu, M.M., Scholl, H.P., Hogg, C.R., Rath, P.P., Jenkins, S., Bird, A.C.,
On the other hand, anti-VEGF therapy may be a successful therapy Holder, G.E., 2004. Localized retinal electrophysiological and fundus auto-
(Balaskas et al., 2013; Sivaprasad et al., 2008), as in neovascular fluorescence imaging abnormalities in maternal inherited diabetes and deaf-
AMD. ness. Invest. Ophthalmol. Vis. Sci. 45, 2355e2360.
Berger, S.P., Daha, M.R., 2007. Complement in glomerular injury. Semin Immuno-
The development of gene therapy and stem cell based ap-
pathol. 29, 375e384.
proaches for patients with retinal dystrophies patients is advancing Bindewald, A., Schmitz-Valckenberg, S., Jorzik, J.J., Dolar-Szczasny, J., Sieber, H.,
at an accelerating pace, possibly leading to future therapeutic op- Keilhauer, C., Weinberger, A.W., Dithmar, S., Pauleikhoff, D., Mansmann, U.,
tions in patients with retinal dystrophies in whom the affected Wolf, S., Holz, F.G., 2005. Classification of abnormal fundus autofluorescence
patterns in the junctional zone of geographic atrophy in patients with age
gene has been identified. related macular degeneration. Br. J. Ophthalmol. 89, 874e878.
Therefore, a thorough differential diagnostic approach is Bird, A.C., Bressler, N.M., Bressler, S.B., Chisholm, I.H., Coscas, G., Davis, M.D., de
essential to establish the right clinical and genetic diagnosis. Jong, P.T., Klaver, C.C., Klein, B.E., Klein, R., et al., 1995. An international classi-
fication and grading system for age-related maculopathy and age-related
Rectangles: examinational findings. Oval: anamnestic findings. macular degeneration. The International ARM Epidemiological Study Group.
Abbreviations: FAF, fundus autofluorescence; FA, fluorescein angi- Surv. Ophthalmol. 39, 367e374.
ography; GA, geographic atrophy; CNV, choroidal neo- Boon, C.J., Klevering, B.J., den Hollander, A.I., Zonneveld, M.N., Theelen, T.,
Cremers, F.P., Hoyng, C.B., 2007a. Clinical and genetic heterogeneity in multi-
vascularization; PSC, posterior subcapsular cataracts; IOP, focal vitelliform dystrophy. Arch. Ophthalmol. 125, 1100e1106.
intraocular pressure; OCT, optical coherence tomography; DA, dark Boon, C.J., van Schooneveld, M.J., den Hollander, A.I., van Lith-Verhoeven, J.J., Zon-
adaptation; ffERG, full-field ERG; EOG, electro-oculography; AD neveld-Vrieling, M.N., Theelen, T., Cremers, F.P., Hoyng, C.B., Klevering, B.J.,
2007b. Mutations in the peripherin/RDS gene are an important cause of
Famþ, positive family history with autosomal-dominant inheri- multifocal pattern dystrophy simulating STGD1/fundus flavimaculatus. Br. J.
tance pattern; VA, visual acuity; CVD, cardiovascular disease; GI, Ophthalmol. 91, 1504e1511.
gastro-intestinal. Boon, C.J., den Hollander, A.I., Hoyng, C.B., Cremers, F.P., Klevering, B.J., Keunen, J.E.,
2008a. The spectrum of retinal dystrophies caused by mutations in the
peripherin/RDS gene. Prog. Ret. Eye Res. 27, 213e235.
Boon, C.J., Jeroen Klevering, B., Keunen, J.E., Hoyng, C.B., Theelen, T., 2008b. Fundus
References autofluorescence imaging of retinal dystrophies. Vis. Res. 48, 2569e2577.
Boon, C.J., Klevering, B.J., Hoyng, C.B., Zonneveld-Vrieling, M.N., Nabuurs, S.B.,
Agarwal, A., 2012. Gass’ Atlas of Macular Diseases, fifth ed. Elsevier, Nashville. Blokland, E., Cremers, F.P., den Hollander, A.I., 2008c. Basal laminar drusen
Agarwal, A., Patel, P., Adkins, T., Gass, J.D., 2005. Spectrum of pattern dystrophy in caused by compound heterozygous variants in the CFH gene. Am. J. Hum. Genet.
pseudoxanthoma elasticum. Arch. Ophthalmol. 123, 923e928. 82, 516e523.
Age-Related Eye Disease Study Research, G, 2001. A randomized, placebo- Boon, C.J., Klevering, B.J., Cremers, F.P., Zonneveld-Vrieling, M.N., Theelen, T., Den
controlled, clinical trial of high-dose supplementation with vitamins C and E, Hollander, A.I., Hoyng, C.B., 2009a. Central areolar choroidal dystrophy.
beta carotene, and zinc for age-related macular degeneration and vision loss: Ophthalmology 116, 771e782, 782 e771.
AREDS report no. 8. Arch. Ophthalmol. 119, 1417e1436. Boon, C.J., Klevering, B.J., Leroy, B.P., Hoyng, C.B., Keunen, J.E., den Hollander, A.I.,
Alchi, B., Jayne, D., 2010. Membranoproliferative glomerulonephritis. Pediatr. 2009b. The spectrum of ocular phenotypes caused by mutations in the BEST1
Nephrol. 25, 1409e1418. gene. Prog. Ret. Eye Res. 28, 187e205.
Alkuraya, H., Zhang, K., 2010. Pattern dystrophy of the retinal pigment epithelium. Boon, C.J., Theelen, T., Hoefsloot, E.H., van Schooneveld, M.J., Keunen, J.E.,
Ret. Phys.. Cremers, F.P., Klevering, B.J., Hoyng, C.B., 2009c. Clinical and molecular genetic
Allikmets, R., 2007. Stargardt disease: from gene discovery to therapy. In: Tombran- analysis of best vitelliform macular dystrophy. Retina (Philadelphia, Pa.) 29,
Tink, J., Barnstable., C.J. (Eds.), Retinal Degeneration: Biology, Diagnostics and 835e847.
Therapeutics. Humana Press, Totowa, NJ, pp. 105e118. Boon, C.J., van de Kar, N.C., Klevering, B.J., Keunen, J.E., Cremers, F.P., Klaver, C.C.,
Allikmets, R., Shroyer, N.F., Singh, N., Seddon, J.M., Lewis, R.A., Bernstein, P.S., Hoyng, C.B., Daha, M.R., den Hollander, A.I., 2009d. The spectrum of phenotypes
Peiffer, A., Zabriskie, N.A., Li, Y., Hutchinson, A., Dean, M., Lupski, J.R., caused by variants in the CFH gene. Mol. Immunol. 46, 1573e1594.
52 N.T.M. Saksens et al. / Progress in Retinal and Eye Research 39 (2014) 23e57

Boon, C.J., van den Born, L.I., Visser, L., Keunen, J.E., Bergen, A.A., Booij, J.C., Della, N.G., Campochiaro, P.A., Zack, D.J., 1996. Localization of TIMP-3 mRNA
Riemslag, F.C., Florijn, R.J., van Schooneveld, M.J., 2013. Autosomal recessive expression to the retinal pigment epithelium. Invest. Ophthalmol. Vis. Sci. 37,
bestrophinopathy: differential diagnosis and treatment options. Ophthal- 1921e1924.
mology 120, 809e820. Deutman, A.F., 1969. Electro-oculography in families with vitelliform dystrophy of
Borooah, S., Collins, C., Wright, A., Dhillon, B., 2009. Late-onset retinal macular the fovea. Detection of the carrier state. Arch. Ophthalmol. 81, 305e316.
degeneration: clinical insights into an inherited retinal degeneration. Br. J. Deutman, A.F., 1971. Vitelliform Dystrophy of the Fovea. The Hereditary Dystrophies
Ophthalmol. 93, 284e289. of the Posterior Pole of the Eye. Van gorcum & Comp. N.V, Assen.
Boulton, M., 2013. Ageing of the retina and retinal pigment epithelium. In: Deutman, A.F., Jansen, L.M., 1970. Dominantly inherited drusen of Bruch’s mem-
Holz, F.G., P., D., Spaide, R.F., Bird, A.C. (Eds.), Age-related Macular Degeneration. brane. Br. J. Ophthalmol. 54, 373e382.
Springer, Heidelberg, New York, Dordrecht, London, pp. 45e63. Deutman, A.F., van Blommestein, J.D., Henkes, H.E., Waardenburg, P.J., Solleveld-van
Brecher, R., Bird, A.C., 1990. Adult vitelliform macular dystrophy. Eye (London, En- Driest, E., 1970. Butterfly-shaped pigment dystrophy of the fovea. Arch. Oph-
gland) 4 (1), 210e215. thalmol. 83, 558e569.
Brook, J.D., McCurrach, M.E., Harley, H.G., Buckler, A.J., Church, D., Aburatani, H., Donoso, L.A., Kim, D., Frost, A., Callahan, A., Hageman, G., 2006. The role of
Hunter, K., Stanton, V.P., Thirion, J.P., Hudson, T., et al., 1992. Molecular basis of inflammation in the pathogenesis of age-related macular degeneration. Surv.
myotonic dystrophy: expansion of a trinucleotide (CTG) repeat at the 3’ end of a Ophthalmol. 51, 137e152.
transcript encoding a protein kinase family member. Cell 69, 385. Doyne, R., 1899. Peculiar condition of choroiditis occuring in several members of the
Buitendijk, G.H., Rochtchina, E., Myers, C., van Duijn, C.M., Lee, K.E., Klein, B.E., same family. Trans. Ophthalmol. Soc. UK 19, 71.
Meuer, S.M., de Jong, P.T., Holliday, E.G., Tan, A.G., Uitterlinden, A.G., Dreyer, R., Green, W.R., 1978. The pathology of angioid streaks: a study of twenty-
Sivakumaran, T.S., Attia, J., Hofman, A., Mitchell, P., Vingerling, J.R., Iyengar, S.K., one cases. Trans. Pa Acad. Ophthalmol. Otolaryngol. 31, 158e167.
Janssens, A.C., Wang, J.J., Klein, R., Klaver, C.C., 2013. Prediction of age-related Dubovy, S.R., Hairston, R.J., Schatz, H., Schachat, A.P., Bressler, N.M., Finkelstein, D.,
macular degeneration in the general population: the three Continent AMD Green, W.R., 2000. Adult-onset foveomacular pigment epithelial dystrophy: clin-
Consortium. Ophthalmology (published online ahead of print). icopathologic correlation of three cases. Retina (Philadelphia, Pa.) 20, 638e649.
Burian, H.M., Burns, C.A., 1967. Ocular changes in myotonic dystrophy. Am. J. Dusek, J., Streicher, T., Schmidt, K., 1982. Hereditary drusen of Bruch’s membrane. II:
Ophthalmol. 63, 22e34. studies of semi-thin sections and electron microscopy results. Klin. Monbl. fur
Burke, T.R., Tsang, S.H., 2011. Allelic and phenotypic heterogeneity in ABCA4 mu- Augenheilkd. 181, 79e83.
tations. Ophthal. Genetics 32, 165e174. Duvall-Young, J., MacDonald, M.K., McKechnie, N.M., 1989. Fundus changes in (type
Capon, M.R., Polkinghorne, P.J., Fitzke, F.W., Bird, A.C., 1988. Sorsby’s pseudoin- II) mesangiocapillary glomerulonephritis simulating drusen: a histopatholog-
flammatory macula dystrophyeSorsby’s fundus dystrophies. Eye (London, En- ical report. Br. J. Ophthalmol. 73, 297e302.
gland) 2 (Pt 1), 114e122. Edwards, A.O., Ritter 3rd, R., Abel, K.J., Manning, A., Panhuysen, C., Farrer, L.A., 2005.
Capon, M.R., Marshall, J., Krafft, J.I., Alexander, R.A., Hiscott, P.S., Bird, A.C., 1989. Complement factor H polymorphism and age-related macular degeneration.
Sorsby’s fundus dystrophy. A light and electron microscopic study. Ophthal- Science 308, 421e424.
mology 96, 1769e1777. Evans, K., Gregory, C.Y., Wijesuriya, S.D., Kermani, S., Jay, M.R., Plant, C., Bird, A.C.,
Castro-Correia, J., Coutinho, M.F., Rosas, V., Maia, J., 1992. Long-term follow-up of 1997. Assessment of the phenotypic range seen in Doyne honeycomb retinal
central serous retinopathy in 150 patients. Documenta Ophthalmologica. Adv. dystrophy. Arch. Ophthalmol. 115, 904e910.
Ophthalmol. 81, 379e386. Fariss, R.N., Apte, S.S., Luthert, P.J., Bird, A.C., Milam, A.H., 1998. Accumulation of
Charbel Issa, P., Berendschot, T.T., Staurenghi, G., Holz, F.G., Scholl, H.P., 2008. tissue inhibitor of metalloproteinases-3 in human eyes with Sorsby’s fundus
Confocal blue reflectance imaging in type 2 idiopathic macular telangiectasia. dystrophy or retinitis pigmentosa. Br. J. Ophthalmol. 82, 1329e1334.
Invest. Ophthalmol. Vis. Sci. 49, 1172e1177. Felbor, U., Benkwitz, C., Klein, M.L., Greenberg, J., Gregory, C.Y., Weber, B.H., 1997.
Charbel Issa, P., Finger, R.P., Holz, F.G., Scholl, H.P., 2009. Multimodal imaging Sorsby fundus dystrophy: reevaluation of variable expressivity in patients car-
including spectral domain OCT and confocal near infrared reflectance for rying a TIMP3 founder mutation. Arch. Ophthalmol. 115, 1569e1571.
characterization of outer retinal pathology in pseudoxanthoma elasticum. Ferris, F.L., Davis, M.D., Clemons, T.E., Lee, L.Y., Chew, E.Y., Lindblad, A.S., Milton, R.C.,
Invest. Ophthalmol. Vis. Sci. 50, 5913e5918. Bressler, S.B., Klein, R., 2005. A simplified severity scale for age-related macular
Chassaing, N., Martin, L., Calvas, P., Le Bert, M., Hovnanian, A., 2005. Pseudox- degeneration: AREDS Report No. 18. Arch. Ophthalmol. 123, 1570e1574.
anthoma elasticum: a clinical, pathophysiological and genetic update including Ferris 3rd, F.L., Wilkinson, C.P., Bird, A., Chakravarthy, U., Chew, E., Csaky, K.,
11 novel ABCC6 mutations. J. Med. Genet. 42, 881e892. Sadda, S.R., 2013. Clinical classification of age-related macular degeneration.
Chavali, V.R., Khan, N.W., Cukras, C.A., Bartsch, D.U., Jablonski, M.M., Ayyagari, R., Ophthalmology 120, 844e851.
2011. A CTRP5 gene S163R mutation knock-in mouse model for late-onset Ferry, A.P., Llovera, I., Shafer, D.M., 1972. Central areolar choroidal dystrophy. Arch.
retinal degeneration. Hum. Mol. Genet. 20, 2000e2014. Ophthalmol. 88, 39e43.
Chen, H., Wu, D., Huang, S., Guan, T., Liu, C., 2006. Microperimetry evaluation in Finger, R.P., Charbel Issa, P., Ladewig, M.S., Gotting, C., Szliska, C., Scholl, H.P.,
central serous chorioretinopathy. Yan Ke Xue Bao 22, 149e153. Holz, F.G., 2009. Pseudoxanthoma elasticum: genetics, clinical manifestations
Cherepanoff, S., Killingsworth, M.C., Zhu, M., Nolan, T., Hunyor, A.P., Young, S.H., and therapeutic approaches. Surv. Ophthalmol. 54, 272e285.
Hageman, G.S., Gillies, M.C., Ultrastructural and clinical evidence of subretinal Fishman, G.A., Birch, D.G., Holder, G.E., et al., 2001. Electrophysiologic Testing in
debris accumulation in type 2 macular telangiectasia. Br. J. Ophthalmol. 96, Disorders of the Retina, Optic Nerve, and Visual Pathway, Ophthalmology
1404e1409. Monograph, second ed. Foundation of the American Academy of Ophthal-
Chinnery, P.F., Howell, N., Andrews, R.M., Turnbull, D.M., 1999. Clinical mitochon- mology, San Francisco.
drial genetics. J. Med. Genet. 36, 425e436. Fleckenstein, M., Charbel Issa, P., Helb, H.M., Schmitz-Valckenberg, S., Finger, R.P.,
Chung, M.M., Oh, K.T., Streb, L.M., Kimura, A.E., Stone, E.M., 2001. Visual outcome Scholl, H.P., Loeffler, K.U., Holz, F.G., 2008. High-resolution spectral domain-OCT
following subretinal hemorrhage in Best disease. Retina (Philadelphia, Pa.) 21, imaging in geographic atrophy associated with age-related macular degenera-
575e580. tion. Invest. Ophthalmol. Vis. Sci. 49, 4137e4144.
Clarkson, J.G., Altman, R.D., 1982. Angioid streaks. Surv. Ophthalmol. 26, 235e246. Fleckenstein, M., Schmitz-Valckenberg, S., Adrion, C., Kramer, I., Eter, N., Helb, H.M.,
Clemett, R., 1991. Vitelliform dystrophy: long-term observations on New Zealand Brinkmann, C.K., Charbel Issa, P., Mansmann, U., Holz, F.G., 2010. Tracking
pedigrees. Austr. N. Z. J. Ophthalmol. 19, 221e227. progression with spectral-domain optical coherence tomography in geographic
Collins, E.T., 1913. A pathological report upon a case of Doyne’s chorioditis (’Hon- atrophy caused by age-related macular degeneration. Invest. Ophthalmol. Vis.
eycomb’or ’family’ choroiditis). Ophthalmocope 11, 2. Sci. 51, 3846e3852.
Connell, G., Bascom, R., Molday, L., Reid, D., McInnes, R.R., Molday, R.S., 1991. Folgar, F.A., Chow, J.H., Farsiu, S., Wong, W.T., Schuman, S.G., O’Connell, R.V.,
Photoreceptor peripherin is the normal product of the gene responsible for Winter, K.P., Chew, E.Y., Hwang, T.S., Srivastava, S.K., Harrington, M.W.,
retinal degeneration in the rds mouse. Proc. Natl. Acad. Sci. U. S. A. 88, 723e726. Clemons, T.E., Toth, C.A., 2012. Spatial correlation between hyperpigmentary
Conner, P.J., Juergens, J.L., 1961. Pseudoxanthoma elasticum and angioid streaks. A changes on color fundus photography and hyperreflective foci on SDOCT in
review of 106 cases. Am. J. Med. 30, 537e543. intermediate AMD. Invest. Ophthalmol. Vis. Sci. 53, 4626e4633.
Crabb, J.W., Miyagi, M., Gu, X., Shadrach, K., West, K.A., Sakaguchi, H., Kamei, M., Framme, C., Bunse, A., Sofroni, R., Thalhammer, T., Walter, A., Sachs, H.G., Gabel, V.P.,
Hasan, A., Yan, L., Rayborn, M.E., Salomon, R.G., Hollyfield, J.G., 2002. Drusen 2006. Fundus autofluorescence before and after photodynamic therapy for
proteome analysis: an approach to the etiology of age-related macular degen- choroidal neovascularization secondary to age-related macular degeneration.
eration. Proc. Natl. Acad. Sci. U. S. A. 99, 14682e14687. Ophthal. Surg. Lasers Imaging 37, 406e414.
Dandekar, S.S., Jenkins, S.A., Peto, T., Scholl, H.P., Sehmi, K.S., Fitzke, F.W., Bird, A.C., Francois, J., de Rouck, A., 1980. Electrophysiological studies in Groenblad-strandberg
Webster, A.R., 2005. Autofluorescence imaging of choroidal neovascularization syndrome. Doc. Ophthalmol. Proc. Ser 23, 19e25.
due to age-related macular degeneration. Arch. Ophthalmol. 123, 1507e1513. Francois, J., de Rouck, A., Verriest, G., de Laey, J.J., Cambie, E., 1974. Progressive
de Laat, P., Koene, S., van den Heuvel, L.P., Rodenburg, R.J., Janssen, M.C., generalized cone dysfunction. Ophthalmologica 169, 255e284.
Smeitink, J.A., 2012. Clinical features and heteroplasmy in blood, urine and Freund, K.B., Laud, K., Lima, L.H., Spaide, R.F., Zweifel, S., Yannuzzi, L.A., 2011. Ac-
saliva in 34 Dutch families carrying the m.3243A > G mutation. J. Inh. Metabol. quired Vitelliform lesions: correlation of clinical findings and multiple imaging
Dis. 35, 1059e1069. analyses. Retina (Philadelphia, Pa.) 31, 13e25.
de Laat, P., Koene, S., Heuvel, L.P., Rodenburg, R.J., Janssen, M.C., Smeitink, J.A., Friedman, D.S., Katz, J., Bressler, N.M., Rahmani, B., Tielsch, J.M., 1999. Racial dif-
2013a. Inheritance of the m.3243A>G mutation. JIMD Rep. 8, 47e50. ferences in the prevalence of age-related macular degeneration: the Baltimore
de Laat, P., Smeitink, J.A., Janssen, M.C., Keunen, J.E., Boon, C.J., 2013b. Mitochondrial Eye Survey. Ophthalmology 106, 1049e1055.
retinal dystrophy associated with the m.3243A>G mutation. Ophthalmology Fritsche, L.G., Chen, W., Schu, M., Yaspan, B.L., Yu, Y., Thorleifsson, G., Zack, D.J.,
(published online ahead of print). Arakawa, S., Cipriani, V., Ripke, S., Igo Jr., R.P., Buitendijk, G.H., Sim, X.,
 N.T.M. Saksens et al. / Progress in Retinal and Eye Research 39 (2014) 23e57 53

Weeks, D.E., Guymer, R.H., Merriam, J.E., Francis, P.J., Hannum, G., Agarwal, A., Hageman, G.S., Anderson, D.H., Johnson, L.V., Hancox, L.S., Taiber, A.J., Hardisty, L.I.,
Armbrecht, A.M., Audo, I., Aung, T., Barile, G.R., Benchaboune, M., Bird, A.C., Hageman, J.L., Stockman, H.A., Borchardt, J.D., Gehrs, K.M., Smith, R.J.,
Bishop, P.N., Branham, K.E., Brooks, M., Brucker, A.J., Cade, W.H., Cain, M.S., Silvestri, G., Russell, S.R., Klaver, C.C., Barbazetto, I., Chang, S., Yannuzzi, L.A.,
Campochiaro, P.A., Chan, C.C., Cheng, C.Y., Chew, E.Y., Chin, K.A., Chowers, I., Barile, G.R., Merriam, J.C., Smith, R.T., Olsh, A.K., Bergeron, J., Zernant, J.,
Clayton, D.G., Cojocaru, R., Conley, Y.P., Cornes, B.K., Daly, M.J., Dhillon, B., Merriam, J.E., Gold, B., Dean, M., Allikmets, R., 2005. A common haplotype in the
Edwards, A.O., Evangelou, E., Fagerness, J., Ferreyra, H.A., Friedman, J.S., complement regulatory gene factor H (HF1/CFH) predisposes individuals to
Geirsdottir, A., George, R.J., Gieger, C., Gupta, N., Hagstrom, S.A., Harding, S.P., age-related macular degeneration. Proc. Natl. Acad. Sci. U. S. A. 102, 7227e7232.
Haritoglou, C., Heckenlively, J.R., Holz, F.G., Hughes, G., Ioannidis, J.P., Haimovici, R., Wroblewski, J., Piguet, B., Fitzke, F.W., Holder, G.E., Arden, G.B.,
Ishibashi, T., Joseph, P., Jun, G., Kamatani, Y., Katsanis, N., Keilhauer, N.C., Bird, A.C., 2002. Symptomatic abnormalities of dark adaptation in patients with
Khan, J.C., Kim, I.K., Kiyohara, Y., Klein, B.E., Klein, R., Kovach, J.L., Kozak, I., EFEMP1 retinal dystrophy (Malattia Leventinese/Doyne honeycomb retinal
Lee, C.J., Lee, K.E., Lichtner, P., Lotery, A.J., Meitinger, T., Mitchell, P., Mohand- dystrophy). Eye (Lond) 16, 7e15.
Said, S., Moore, A.T., Morgan, D.J., Morrison, M.A., Myers, C.E., Naj, A.C., Haines, J.L., Hauser, M.A., Schmidt, S., Scott, W.K., Olson, L.M., Gallins, P., Spencer, K.L.,
Nakamura, Y., Okada, Y., Orlin, A., Ortube, M.C., Othman, M.I., Pappas, C., Kwan, S.Y., Noureddine, M., Gilbert, J.R., Schnetz-Boutaud, N., Agarwal, A.,
Park, K.H., Pauer, G.J., Peachey, N.S., Poch, O., Priya, R.R., Reynolds, R., Postel, E.A., Pericak-Vance, M.A., 2005. Complement factor H variant increases
Richardson, A.J., Ripp, R., Rudolph, G., Ryu, E., Sahel, J.A., Schaumberg, D.A., the risk of age-related macular degeneration. Science 308, 419e421.
Scholl, H.P., Schwartz, S.G., Scott, W.K., Shahid, H., Sigurdsson, H., Silvestri, G., Hamilton, W.K., Ewing, C.C., Ives, E.J., Carruthers, J.D., 1989. Sorsby’s fundus dys-
Sivakumaran, T.A., Smith, R.T., Sobrin, L., Souied, E.H., Stambolian, D.E., trophy. Ophthalmology 96, 1755e1762.
Stefansson, H., Sturgill-Short, G.M., Takahashi, A., Tosakulwong, N., Truitt, B.J., Hannan, S.R., de Salvo, G., Stinghe, A., Shawkat, F., Lotery, A.J., 2013. Common
Tsironi, E.E., Uitterlinden, A.G., van Duijn, C.M., Vijaya, L., Vingerling, J.R., spectral domain OCT and electrophysiological findings in different pattern
Vithana, E.N., Webster, A.R., Wichmann, H.E., Winkler, T.W., Wong, T.Y., dystrophies. Br. J. Ophthalmol. 97, 605e610.
Wright, A.F., Zelenika, D., Zhang, M., Zhao, L., Zhang, K., Klein, M.L., Harper, P.S., 2001. Myotonic Dystrophy. Saunders, London.
Hageman, G.S., Lathrop, G.M., Stefansson, K., Allikmets, R., Baird, P.N., Hayward, C., Shu, X., Cideciyan, A.V., Lennon, A., Barran, P., Zareparsi, S., Sawyer, L.,
Gorin, M.B., Wang, J.J., Klaver, C.C., Seddon, J.M., Pericak-Vance, M.A., Hendry, G., Dhillon, B., Milam, A.H., Luthert, P.J., Swaroop, A., Hastie, N.D.,
Iyengar, S.K., Yates, J.R., Swaroop, A., Weber, B.H., Kubo, M., Deangelis, M.M., Jacobson, S.G., Wright, A.F., 2003. Mutation in a short-chain collagen gene,
Leveillard, T., Thorsteinsdottir, U., Haines, J.L., Farrer, L.A., Heid, I.M., CTRP5, results in extracellular deposit formation in late-onset retinal degen-
Abecasis, G.R., Consortium, A.M.D.G., 2013. Seven new loci associated with age- eration: a genetic model for age-related macular degeneration. Hum. Mol.
related macular degeneration. Nat. Genet. 45, 433e439, 439e431-432. Genet. 12, 2657e2667.
Fu, L., Garland, D., Yang, Z., Shukla, D., Rajendran, A., Pearson, E., Stone, E.M., Helb, H.M., Charbel Issa, P., RL, V.D.V., Berendschot, T.T., Scholl, H.P., Holz, F.G., 2008.
Zhang, K., Pierce, E.A., 2007. The R345W mutation in EFEMP1 is pathogenic and Abnormal macular pigment distribution in type 2 idiopathic macular telangi-
causes AMD-like deposits in mice. Hum. Mol. Genet. 16, 2411e2422. ectasia. Retina 28, 808e816.
Gass, J.D., 1974. A clinicopathologic study of a peculiar foveomacular dystrophy. Ho, J., Witkin, A.J., Liu, J., Chen, Y., Fujimoto, J.G., Schuman, J.S., Duker, J.S., 2011.
Trans. Am. Ophthalmol. Soc. 72, 139e156. Documentation of intraretinal retinal pigment epithelium migration via high-
Gass, J.D., 2003. “Comet” lesion: an ocular sign of pseudoxanthoma elasticum. speed ultrahigh-resolution optical coherence tomography. Ophthalmology
Retina 23, 729e730. 118, 687e693.
Gass, J.D., Blodi, B.A., 1993. Idiopathic juxtafoveolar retinal telangiectasis. Update of Holz, F.G., Bellman, C., Staudt, S., Schutt, F., Volcker, H.E., 2001. Fundus auto-
classification and follow-up study. Ophthalmology 100, 1536e1546. fluorescence and development of geographic atrophy in age-related macular
Gass, J.D., Oyakawa, R.T., 1982. Idiopathic juxtafoveolar retinal telangiectasis. Arch. degeneration. Invest. Ophthalmol. Vis. Sci. 42, 1051e1056.
Ophthalmol. 100, 769e780. Holz, F.G., Bindewald-Wittich, A., Fleckenstein, M., Dreyhaupt, J., Scholl, H.P.,
Georgalas, I., Papaconstantinou, D., Koutsandrea, C., Kalantzis, G., Karagiannis, D., Schmitz-Valckenberg, S., 2007. Progression of geographic atrophy and impact of
Georgopoulos, G., Ladas, I., 2009. Angioid streaks, clinical course, complications, fundus autofluorescence patterns in age-related macular degeneration. Am. J.
and current therapeutic management. Ther. Clin. Risk Manag. 5, 81e89. Ophthalmol. 143, 463e472.
Gerber, D.M., Niemeyer, G., 2002. Ganzfeld and multifocal electroretinography in Hoskin, A., Sehmi, K., Bird, A.C., 1981. Sorsby’s pseudoinflammatory macular dys-
malattia leventinese and Zermatt macular dystrophy. Klin. Monbl. Augenheilkd. trophy. Br. J. Ophthalmol. 65, 859e865.
219, 206e210. Hoyng, C.B., Deutman, A.F., 1996. The development of central areolar choroidal
Gilbert, C.M., Owens, S.L., Smith, P.D., Fine, S.L., 1984. Long-term follow-up of central dystrophy. Graefe’s Arch. Clin. Exp. Ophthalmol. 234, 87e93.
serous chorioretinopathy. Br. J. Ophthalmol. 68, 815e820. Hu, X., Plomp, A.S., van Soest, S., Wijnholds, J., de Jong, P.T., Bergen, A.A., 2003.
Gillies, M.C., Zhu, M., Chew, E., Barthelmes, D., Hughes, E., Ali, H., Holz, F.G., Pseudoxanthoma elasticum: a clinical, histopathological, and molecular update.
Scholl, H.P., Charbel Issa, P., 2009. Familial asymptomatic macular telangiectasia Surv. Ophthalmol. 48, 424e438.
type 2. Ophthalmology 116, 2422e2429. Inhoffen, W., Ziemssen, F., Bartz-Schmidt, K.U., 2012. Chronic central serous cho-
Giovannini, A., Scassellati-Sforzolini, B., D’Altobrando, E., Mariotti, C., Rutili, T., rioretinopathy (cCSC): differential diagnosis to choroidal neovascularisation
Tittarelli, R., 1997. Choroidal findings in the course of idiopathic serous pigment (CNV) secondary to age-related macular degeneration (AMD). Klin. Monbl.
epithelium detachment detected by indocyanine green videoangiography. Augenheilkd. 229, 889e896.
Retina (Philadelphia, Pa.) 17, 286e293. Isashiki, Y., Tabata, Y., Kamimura, K., Ohba, N., 1999. Sorsby’s fundus dystrophy in
Gold, B., Merriam, J.E., Zernant, J., Hancox, L.S., Taiber, A.J., Gehrs, K., Cramer, K., two Japanese families with unusual clinical features. Jap. J. Ophthalmol. 43,
Neel, J., Bergeron, J., Barile, G.R., Smith, R.T., Hageman, G.S., Dean, M., 472e480.
Allikmets, R., 2006. Variation in factor B (BF) and complement component 2 Issa, P.C., Helb, H.M., Rohrschneider, K., Holz, F.G., Scholl, H.P., 2007. Microperimetric
(C2) genes is associated with age-related macular degeneration. Nat. Genet. 38, assessment of patients with type 2 idiopathic macular telangiectasia. Invest.
458e462. Ophthalmol. Vis. Sci. 48, 3788e3795.
Gomes-Pereira, M., Cooper, T.A., Gourdon, G., 2011. Myotonic dystrophy mouse Issa, P.C., Gillies, M.C., Chew, E.Y., Bird, A.C., Heeren, T.F., Peto, T., Holz, F.G.,
models: towards rational therapy development. Trends Mol. Med. 17, 506e517. Scholl, H.P., 2013. Macular telangiectasia type 2. Prog. Retin. Eye Res. 34, 49e77.
Goto, Y., Nonaka, I., Horai, S., 1990. A mutation in the tRNA(Leu)(UUR) gene asso- Jaakson, K., Zernant, J., Kulm, M., Hutchinson, A., Tonisson, N., Glavac, D., Ravnik-
ciated with the MELAS subgroup of mitochondrial encephalomyopathies. Na- Glavac, M., Hawlina, M., Meltzer, M.R., Caruso, R.C., Testa, F., Maugeri, A.,
ture 348, 651e653. Hoyng, C.B., Gouras, P., Simonelli, F., Lewis, R.A., Lupski, J.R., Cremers, F.P.,
Green, W.R., Enger, C., 1993. Age-related macular degeneration histopathologic Allikmets, R., 2003. Genotyping microarray (gene chip) for the ABCR (ABCA4)
studies. The 1992 Lorenz E. Zimmerman Lecture. Ophthalmology 100, 1519e gene. Hum. Mut. 22, 395e403.
1535. Jackson, G.R., Owsley, C., McGwin Jr., G., 1999. Aging and dark adaptation. Vis. Res.
Green, W.R., Key 3rd, S.N., 1977. Senile macular degeneration: a histopathologic 39, 3975e3982.
study. Trans. Am. Ophthalmol. Soc. 75, 180e254. Jakobsdottir, J., Conley, Y.P., Weeks, D.E., Mah, T.S., Ferrell, R.E., Gorin, M.B., 2005.
Groenblad, E., 1958. Color photographs of angioid streaks in the late stages. Acta. Susceptibility genes for age-related maculopathy on chromosome 10q26. Am. J.
Ophthalmol. 36, 472e474. Hum. Genet. 77, 389e407.
Grossniklaus, H.E., Miskala, P.H., Green, W.R., Bressler, S.B., Hawkins, B.S., Toth, C., Jaouni, T., Averbukh, E., Burstyn-Cohen, T., Grunin, M., Banin, E., Sharon, D.,
Wilson, D.J., Bressler, N.M., 2005. Histopathologic and ultrastructural features of Chowers, I., 2012. Association of pattern dystrophy with an HTRA1 single-
surgically excised subfoveal choroidal neovascular lesions: submacular surgery nucleotide polymorphism. Arch. Ophthalmol. 130, 987e991.
trials report no. 7. Arch. Ophthalmol. 123, 914e921. Kawasaki, R., Yasuda, M., Song, S.J., Chen, S.J., Jonas, J.B., Wang, J.J., Mitchell, P.,
Guigui, B., Leveziel, N., Martinet, V., Massamba, N., Sterkers, M., Coscas, G., Wong, T.Y., 2010. The prevalence of age-related macular degeneration in Asians:
Souied, E.H., 2011. Angiography features of early onset drusen. Br. J. Ophthalmol. a systematic review and meta-analysis. Ophthalmology 117, 921e927.
95, 238e244. Kellner, U., Kellner, S., 2009. Clinical findings and diagnostics of cone dystrophy.
Gundogan, F.C., Dinc, U.A., Erdem, U., Ozge, G., Sobaci, G., 2010. Multifocal elec- Ophthalmologe 106, 99e108.
troretinogram and central visual field testing in central areolar choroidal dys- Khanifar, A.A., Koreishi, A.F., Izatt, J.A., Toth, C.A., 2008. Drusen ultrastructure im-
trophy. Eur. J. Ophthalmol. 20, 919e924. aging with spectral domain optical coherence tomography in age-related
Hageman, G.S., Luthert, P.J., Victor Chong, N.H., Johnson, L.V., Anderson, D.H., macular degeneration. Ophthalmology 115, 1883e1890.
Mullins, R.F., 2001. An integrated hypothesis that considers drusen as biomarkers Khurana, R.N., Sun, X., Pearson, E., Yang, Z., Harmon, J., Goldberg, M.F., Zhang, K.,
of immune-mediated processes at the RPE-Bruch’s membrane interface in aging 2009. A reappraisal of the clinical spectrum of North Carolina macular dys-
and age-related macular degeneration. Prog. Retin Eye Res. 20, 705e732. trophy. Ophthalmology 116, 1976e1983.
54 N.T.M. Saksens et al. / Progress in Retinal and Eye Research 39 (2014) 23e57

Kiernan, D.F., Shah, R.J., Hariprasad, S.M., Grassi, M.A., Small, K.W., Kiernan, J.P., Leys, A., Vanrenterghem, Y., Van Damme, B., Snyers, B., Pirson, Y., Leys, M., 1991b.
Mieler, W.F., 2011. Thirty-Year follow-up of an African American family with Fundus changes in membranoproliferative glomerulonephritis type II. A fluo-
macular dystrophy of the retina, locus 1 (North Carolina macular dystrophy). rescein angiographic study of 23 patients. Graefes Arch. Clin. Exp. Ophthalmol.
Ophthalmology 118, 1435e1443. 229, 406e410.
Kim, R.Y., Dollfus, H., Keen, T.J., Fitzke, F.W., Arden, G.B., Bhattacharya, S.S., Bird, A.C., Li, C.M., Chung, B.H., Presley, J.B., Malek, G., Zhang, X., Dashti, N., Li, L., Chen, J.,
1995. Autosomal dominant pattern dystrophy of the retina associated with a 4- Bradley, K., Kruth, H.S., Curcio, C.A., 2005. Lipoprotein-like particles and cho-
base pair insertion at codon 140 in the peripherin/RDS gene. Arch. Ophthalmol. lesteryl esters in human Bruch’s membrane: initial characterization. Invest.
113, 451e455. Ophthalmol. Vis. Sci. 46, 2576e2586.
Kim, R.Y., Faktorovich, E.G., Kuo, C.Y., Olson, J.L., 1997. Retinal function abnormalities Lim, L.S., Mitchell, P., Seddon, J.M., Holz, F.G., Wong, T.Y., 2012. Age-related macular
in membranoproliferative glomerulonephritis type II. Am. J. Ophthalmol. 123, degeneration. Lancet 379, 1728e1738.
619e628. Lin, R.J., Blumenkranz, M.S., Binkley, J., Wu, K., Vollrath, D., 2006. A novel His158Arg
Kim, U.S., Kim, J.S., Hwang, J.M., 2009. A case of myotonic dystrophy with mutation in TIMP3 causes a late-onset form of Sorsby fundus dystrophy. Am. J.
pigmentary retinal changes. Kor. J. Ophthalmol. 23, 121e123. Ophthalmol. 142, 839e848.
Kimizuka, Y., Kiyosawa, M., Tamai, M., Takase, S., 1993. Retinal changes in myotonic Lip, P.L., Good, P.A., Gibson, J.M., 1999. Sorsby’s fundus dystrophy: a case report of 24
dystrophy. Clinical and follow-up evaluation. Retina 13, 129e135. years follow-up with electrodiagnostic tests and indocyanine green angiog-
Klein, B.A., 1947. Angioid streaks: a clinical and histopathologic study. Am. J. Oph- raphy. Eye (London, England) 13 (1), 16e25.
thalmol. 30, 955e968. Liquori, C.L., Ricker, K., Moseley, M.L., Jacobsen, J.F., Kress, W., Naylor, S.L., Day, J.W.,
Klein, R., Davis, M.D., Magli, Y.L., Segal, P., Klein, B.E., Hubbard, L., 1991. The Wisconsin Ranum, L.P., 2001. Myotonic dystrophy type 2 caused by a CCTG expansion in
age-related maculopathy grading system. Ophthalmology 98, 1128e1134. intron 1 of ZNF9. Science 293, 864e867.
Klein, R.J., Zeiss, C., Chew, E.Y., Tsai, J.Y., Sackler, R.S., Haynes, C., Henning, A.K., Lueck, J.D., Lungu, C., Mankodi, A., Osborne, R.J., Welle, S.L., Dirksen, R.T.,
SanGiovanni, J.P., Mane, S.M., Mayne, S.T., Bracken, M.B., Ferris, F.L., Ott, J., Thornton, C.A., 2007. Chloride channelopathy in myotonic dystrophy resulting
Barnstable, C., Hoh, J., 2005. Complement factor H polymorphism in age-related from loss of posttranscriptional regulation for CLCN1. Am. J. Physiol. Cell
macular degeneration. Science 308, 385e389. Physiol. 292, C1291eC1297.
Klein, R., Klein, B.E., Knudtson, M.D., Meuer, S.M., Swift, M., Gangnon, R.E., 2007. Malek, G., Li, C.M., Guidry, C., Medeiros, N.E., Curcio, C.A., 2003. Apolipoprotein B in
Fifteen-year cumulative incidence of age-related macular degeneration: the cholesterol-containing drusen and basal deposits of human eyes with age-
Beaver Dam Eye Study. Ophthalmology 114, 253e262. related maculopathy. Am. J. Pathol. 162, 413e425.
Klein, R., Meuer, S.M., Knudtson, M.D., Iyengar, S.K., Klein, B.E., 2008. The epide- Maller, J.B., Fagerness, J.A., Reynolds, R.C., Neale, B.M., Daly, M.J., Seddon, J.M., 2007.
miology of retinal reticular drusen. Am. J. Ophthalmol. 145, 317e326. Variation in complement factor 3 is associated with risk of age-related macular
Klevering, B.J., van Driel, M., van Hogerwou, A.J., van De Pol, D.J., Deutman, A.F., degeneration. Nat. Genet. 39, 1200e1201.
Pinckers, A.J., Cremers, F.P., Hoyng, C.B., 2002. Central areolar choroidal dystro- Manouvrier, S., Rotig, A., Hannebique, G., Gheerbrandt, J.D., Royer-Legrain, G.,
phy associated with dominantly inherited drusen. Br. J. Ophthalmol. 86, 91e96. Munnich, A., Parent, M., Grunfeld, J.P., Largilliere, C., Lombes, A., et al., 1995.
Klevering, B.J., Deutman, A.F., Maugeri, A., Cremers, F.P., Hoyng, C.B., 2005. The Point mutation of the mitochondrial tRNA(Leu) gene (A 3243 G) in maternally
spectrum of retinal phenotypes caused by mutations in the ABCA4 gene. inherited hypertrophic cardiomyopathy, diabetes mellitus, renal failure, and
Graefe’s Arch. Clin. Exp. Ophthalmol. 243, 90e100. sensorineural deafness. J. Med. Genet. 32, 654e656.
Knudtson, M.D., Klein, R., Klein, B.E., Lee, K.E., Meuer, S.M., Tomany, S.C., 2004. Mansour, A.M., Ansari, N.H., Shields, J.A., Annesley Jr., W.H., Cronin, C.M., Stock, E.L.,
Location of lesions associated with age-related maculopathy over a 10-year 1993. Evolution of angioid streaks. Ophthalmologica 207, 57e61.
period: the Beaver Dam Eye Study. Invest. Ophthalmol. Vis. Sci. 45, 2135e2142. Marano, F., Deutman, A.F., Leys, A., Aandekerk, A.L., 2000. Hereditary retinal dys-
Kobayashi, Y., Momoi, M.Y., Tominaga, K., Momoi, T., Nihei, K., Yanagisawa, M., trophies and choroidal neovascularization. Graefe’s Arch. Clin. Exp. Ophthalmol.
Kagawa, Y., Ohta, S., 1990. A point mutation in the mitochondrial tRNA(Leu)(UUR) 238, 760e764.
gene in MELAS (mitochondrial myopathy, encephalopathy, lactic acidosis and Marmorstein, L., 2004. Association of EFEMP1 with malattia leventinese and age-
stroke-like episodes). Biochem. Biophys. Res. Commun. 173, 816e822. related macular degeneration: a mini-review. Ophthal. Genet. 25, 219e226.
Koopman, W.J., Willems, P.H., Smeitink, J.A., 2012. Monogenic mitochondrial dis- Marmorstein, L.Y., Munier, F.L., Arsenijevic, Y., Schorderet, D.F., McLaughlin, P.J.,
orders. N. Engl. J. Med. 366, 1132e1141. Chung, D., Traboulsi, E., Marmorstein, A.D., 2002. Aberrant accumulation of
Kramer, F., White, K., Pauleikhoff, D., Gehrig, A., Passmore, L., Rivera, A., Rudolph, G., EFEMP1 underlies drusen formation in Malattia Leventinese and age-related
Kellner, U., Andrassi, M., Lorenz, B., Rohrschneider, K., Blankenagel, A., macular degeneration. Proc. Natl. Acad. Sci. U. S. A. 99, 13067e13072.
Jurklies, B., Schilling, H., Schutt, F., Holz, F.G., Weber, B.H., 2000. Mutations in the Marmorstein, L.Y., McLaughlin, P.J., Peachey, N.S., Sasaki, T., Marmorstein, A.D., 2007.
VMD2 gene are associated with juvenile-onset vitelliform macular dystrophy Formation and progression of sub-retinal pigment epithelium deposits in
(Best disease) and adult vitelliform macular dystrophy but not age-related Efemp1 mutation knock-in mice: a model for the early pathogenic course of
macular degeneration. Eur. J. Hum. Genet. 8, 286e292. macular degeneration. Hum. Mol. Genet. 16, 2423e2432.
Krill, A.E., Deutman, A.F., Fishman, M., 1973a. The cone degenerations. Doc. Oph- Massin, P., Virally-Monod, M., Vialettes, B., Paques, M., Gin, H., Porokhov, B., Caillat-
thalmol. 35, 1e80. Zucman, S., Froguel, P., Paquis-Fluckinger, V., Gaudric, A., Guillausseau, P.J., 1999.
Krill, A.E., Klien, B.A., Archer, D.B., 1973b. Precursors of angioid streaks. Am. J. Prevalence of macular pattern dystrophy in maternally inherited diabetes and
Ophthalmol. 76, 875e879. deafness. GEDIAM Group. Ophthalmology 106, 1821e1827.
Kuntz, C.A., Jacobson, S.G., Cideciyan, A.V., Li, Z.Y., Stone, E.M., Possin, D., Mata, N.L., Tzekov, R.T., Liu, X., Weng, J., Birch, D.G., Travis, G.H., 2001. Delayed dark-
Milam, A.H., 1996. Sub-retinal pigment epithelial deposits in a dominant late- adaptation and lipofuscin accumulation in abcr  mice: implications for
onset retinal degeneration. Invest. Ophthalmol. Vis. Sci. 37, 1772e1782. involvement of ABCR in age-related macular degeneration. Invest. Ophthalmol.
Ladewig, M., Kraus, H., Foerster, M.H., Kellner, U., 2003. Cone dysfunction in patients Vis. Sci. 42, 1685e1690.
with late-onset cone dystrophy and age-related macular degeneration. Arch. Maugeri, A., van Driel, M.A., van de Pol, D.J., Klevering, B.J., van Haren, F.J., Tijmes, N.,
Ophthalmol. 121, 1557e1561. Bergen, A.A., Rohrschneider, K., Blankenagel, A., Pinckers, A.J., Dahl, N.,
Lafaut, B.A., Leys, A.M., Scassellati-Sforzolini, B., Priem, H., De Laey, J.J., 1998. Com- Brunner, H.G., Deutman, A.F., Hoyng, C.B., Cremers, F.P., 1999. The 2588G–>C
parison of fluorescein and indocyanine green angiography in angioid streaks. mutation in the ABCR gene is a mild frequent founder mutation in the Western
Graefes Arch. Clin. Exp. Ophthalmol. 236, 346e353. European population and allows the classification of ABCR mutations in pa-
Lam, L.A., 2013. Angioid streaks. In: Ryan, J.R. (Ed.), Retina. Elsevier, London, New tients with Stargardt disease. Am. J. Hum. Genet. 64, 1024e1035.
York, Oxford, St. Louis, Sydney, Toronto, pp. 1267e1273. Mauschitz, M.M., Fonseca, S., Chang, P., Gobel, A.P., Fleckenstein, M., Jaffe, G.J.,
Langton, K.P., McKie, N., Curtis, A., Goodship, J.A., Bond, P.M., Barker, M.D., Holz, F.G., Schmitz-Valckenberg, S., 2012. Topography of geographic atrophy in
Clarke, M., 2000. A novel tissue inhibitor of metalloproteinases-3 mutation age-related macular degeneration. Invest. Ophthalmol. Vis. Sci. 53, 4932e4939.
reveals a common molecular phenotype in Sorsby’s fundus dystrophy. J. Biol. McAvoy, C.E., Silvestri, G., 2005. Retinal changes associated with type 2 glomeru-
Chem. 275, 27027e27031. lonephritis. Eye (Lond) 19, 985e989.
Langton, K.P., McKie, N., Smith, B.M., Brown, N.J., Barker, M.D., 2005. Sorsby’s fundus McBain, V.A., Townend, J., Lois, N., 2007. Fundus autofluorescence in exudative age-
dystrophy mutations impair turnover of TIMP-3 by retinal pigment epithelial related macular degeneration. Br. J. Ophthalmol. 91, 491e496.
cells. Hum. Mol. Genet. 14, 3579e3586. McBain, V.A., Kumari, R., Townend, J., Lois, N., 2011. Geographic atrophy in retinal
Langwinska-Wosko, E., Szulborski, K., Broniek-Kowalik, K., 2010. Late onset cone angiomatous proliferation. Retina 31, 1043e1052.
dystrophy. Doc. Ophthalmol. 120, 215e218. McBain, V.A., Townend, J., Lois, N., 2012. Progression of retinal pigment epithelial
Lefler, W.H., Wadsworth, J.A., Sidbury Jr., J.B., 1971. Hereditary macular degeneration atrophy in stargardt disease. Am. J. Ophthalmol. 154, 146e154.
and amino-aciduria. Am. J. Ophthalmol. 71, 224e230. Meyerle, C.B., Smith, R.T., Barbazetto, I.A., Yannuzzi, L.A., 2007. Autofluorescence of
Lengyel, I., Flinn, J.M., Peto, T., Linkous, D.H., Cano, K., Bird, A.C., Lanzirotti, A., basal laminar drusen. Retina 27, 1101e1106.
Frederickson, C.J., van Kuijk, F.J., 2007. High concentration of zinc in sub-retinal Michaelides, M., Johnson, S., Tekriwal, A.K., Holder, G.E., Bellmann, C., Kinning, E.,
pigment epithelial deposits. Exp. Eye Res. 84, 772e780. Woodruff, G., Trembath, R.C., Hunt, D.M., Moore, A.T., 2003. An early-onset auto-
Leu, J., Schrage, N.F., Degenring, R.F., 2007. Choroidal neovascularisation secondary somal dominant macular dystrophy (MCDR3) resembling North Carolina macular
to Best’s disease in a 13-year-old boy treated by intravitreal bevacizumab. dystrophy maps to chromosome 5. Invest. Ophthalmol. Vis. Sci. 44, 2178e2183.
Graefe’s Arch. Clin. Exp. Ophthalmol. 245, 1723e1725. Michaelides, M., Holder, G.E., Bradshaw, K., Hunt, D.M., Moore, A.T., 2005. Cone-rod
Leys, A., Proesmans, W., Van Damme-Lombaerts, R., Van Damme, B., 1991a. Specific dystrophy, intrafamilial variability, and incomplete penetrance associated with
eye fundus lesions in type II membranoproliferative glomerulonephritis. the R172W mutation in the peripherin/RDS gene. Ophthalmology 112, 1592e
Pediatr. Nephrol. 5, 189e192. 1598.
 N.T.M. Saksens et al. / Progress in Retinal and Eye Research 39 (2014) 23e57 55

Michaelides, M., Jenkins, S.A., Brantley Jr., M.A., Andrews, R.M., Waseem, N., coherence tomography features in adult onset foveomacular vitelliform dys-
Luong, V., Gregory-Evans, K., Bhattacharya, S.S., Fitzke, F.W., Webster, A.R., 2006. trophy. Br. J. Ophthalmol. 94, 1190e1196.
Maculopathy due to the R345W substitution in fibulin-3: distinct clinical fea- Qi, J.H., Ebrahem, Q., Moore, N., Murphy, G., Claesson-Welsh, L., Bond, M., Baker, A.,
tures, disease variability, and extent of retinal dysfunction. Invest. Ophthalmol. Anand-Apte, B., 2003. A novel function for tissue inhibitor of
Vis. Sci. 47, 3085e3097. metalloproteinases-3 (TIMP3): inhibition of angiogenesis by blockage of VEGF
Michaelides, M., Jenkins, S.A., Bamiou, D.E., Sweeney, M.G., Davis, M.B., Luxon, L., binding to VEGF receptor-2. Nat. Med. 9, 407e415.
Bird, A.C., Rath, P.P., 2008. Macular dystrophy associated with the A3243G Quaranta, M., Cohen, S.Y., Krott, R., Sterkers, M., Soubrane, G., Coscas, G.J., 1995.
mitochondrial DNA mutation. Distinct retinal and associated features, disease Indocyanine green videoangiography of angioid streaks. Am. J. Ophthalmol. 119,
variability, and characterization of asymptomatic family members. Arch. Oph- 136e142.
thalmol. 126, 320e328. Quazi, F., Lenevich, S., Molday, R.S., 2012. ABCA4 is an N-retinylidene-phosphati-
Milam, A.H., Curcio, C.A., Cideciyan, A.V., Saxena, S., John, S.K., Kruth, H.S., Malek, G., dylethanolamine and phosphatidylethanolamine importer. Nat. Commun. 3,
Heckenlively, J.R., Weleber, R.G., Jacobson, S.G., 2000. Dominant late-onset 925.
retinal degeneration with regional variation of sub-retinal pigment epithe- Querques, G., Regenbogen, M., Quijano, C., Delphin, N., Soubrane, G., Souied, E.H.,
lium deposits, retinal function, and photoreceptor degeneration. Ophthal- 2008. High-definition optical coherence tomography features in vitelliform
mology 107, 2256e2266. macular dystrophy. Am. J. Ophthalmol. 146, 501e507.
Mimoun, G., Soubrane, G., Coscas, G., 1990. Macular drusen. J. Fr. Ophtalmol. 13, Querques, G., Forte, R., Querques, L., Massamba, N., Souied, E.H., 2011a. Natural
511e530. course of adult-onset foveomacular vitelliform dystrophy: a spectral-domain
Mimoun, G., Caillaux, V., Querques, G., Rothschild, P.R., Puche, N., Souied, E.H., 2013. optical coherence tomography analysis. Am. J. Ophthalmol. 152, 304e313.
Ranibizumab for choroidal neovascularization associated with adult-onset Querques, G., Guigui, B., Leveziel, N., Querques, L., Coscas, G., Soubrane, G.,
foveomacular vitelliform dystrophy: one-year results. Retina (Philadelphia, Souied, E.H., 2011b. Insights into pathology of cuticular drusen from integrated
Pa.) 33, 513e521. confocal scanning laser ophthalmoscopy imaging and corresponding spectral
Mohler, C.W., Fine, S.L., 1981. Long-term evaluation of patients with Best’s vitelli- domain optical coherence tomography. Graefes Arch. Clin. Exp. Ophthalmol.
form dystrophy. Ophthalmology 88, 688e692. 249, 1617e1625.
Mullins, R.F., Hageman, G.S., 1999. Human ocular drusen possess novel core do- Querques, G., Guigui, B., Leveziel, N., Querques, L., Bandello, F., Souied, E.H., 2012.
mains with a distinct carbohydrate composition. J. Histochem. Cytochem. 47, Multimodal morphological and functional characterization of Malattia Lev-
1533e1540. entinese. Graefes Arch. Clin. Exp. Ophthalmol. 251, 705e714.
Mullins, R.F., Russell, S.R., Anderson, D.H., Hageman, G.S., 2000. Drusen associated Radu, R.A., Mata, N.L., Bagla, A., Travis, G.H., 2004. Light exposure stimulates for-
with aging and age-related macular degeneration contain proteins common to mation of A2E oxiranes in a mouse model of Stargardt’s macular degeneration.
extracellular deposits associated with atherosclerosis, elastosis, amyloidosis, Proc. Natl. Acad. Sci. U. S. A. 101, 5928e5933.
and dense deposit disease. Faseb J. 14, 835e846. Radu, R.A., Yuan, Q., Hu, J., Peng, J.H., Lloyd, M., Nusinowitz, S., Bok, D., Travis, G.H.,
Mullins, R.F., Aptsiauri, N., Hageman, G.S., 2001. Structure and composition of 2008. Accelerated accumulation of lipofuscin pigments in the RPE of a mouse
drusen associated with glomerulonephritis: implications for the role of com- model for ABCA4-mediated retinal dystrophies following Vitamin A supple-
plement activation in drusen biogenesis. Eye (Lond) 15, 390e395. mentation. Invest. Ophthalmol. Vis. Sci. 49, 3821e3829.
Nakazawa, M., Wada, Y., Tamai, M., 1995. Macular dystrophy associated with Radu, R.A., Hu, J., Yuan, Q., Welch, D.L., Makshanoff, J., Lloyd, M., McMullen, S.,
monogenic Arg172Trp mutation of the peripherin/RDS gene in a Japanese Travis, G.H., Bok, D., 2011. Complement system dysregulation and inflammation
family. Retina (Philadelphia, Pa.) 15, 518e523. in the retinal pigment epithelium of a mouse model for Stargardt macular
Neelam, K., Nolan, J., Chakravarthy, U., Beatty, S., 2009. Psychophysical function in degeneration. J. Biol. Chem. 286, 18593e18601.
age-related maculopathy. Surv. Ophthalmol. 54, 167e210. Ranum, L.P., Cooper, T.A., 2006. RNA-mediated neuromuscular disorders. Annu. Rev.
Nicholson, B., Noble, J., Forooghian, F., Meyerle, C., 2013. Central serous chorior- Neurosci. 29, 259e277.
etinopathy: update on pathophysiology and treatment. Surv. Ophthalmol. 58, Ranum, L.P., Day, J.W., 2004. Myotonic dystrophy: RNA pathogenesis comes into
103e126. focus. Am. J. Hum. Genet. 74, 793e804.
O’Brien, C., Duvall-Young, J., Brown, M., Short, C., Bone, M., 1993. Electrophysiology Rath, P.P., Jenkins, S., Michaelides, M., Smith, A., Sweeney, M.G., Davis, M.B.,
of type II mesangiocapillary glomerulonephritis with associated fundus ab- Fitzke, F.W., Bird, A.C., 2008. Characterisation of the macular dystrophy in pa-
normalities. Br. J. Ophthalmol. 77, 778e780. tients with the A3243G mitochondrial DNA point mutation with fundus auto-
Oosterhuis, J.A., 1996. Familial central serous retinopathy. Graefe’s Arch. Clin. Exp. fluorescence. Br. J. Ophthalmol. 92, 623e629.
Ophthalmol. 234, 337e341. Raychaudhuri, S., Iartchouk, O., Chin, K., Tan, P.L., Tai, A.K., Ripke, S., Gowrisankar, S.,
Palczewska, G., Maeda, T., Imanishi, Y., Sun, W., Chen, Y., Williams, D.R., Piston, D.W., Vemuri, S., Montgomery, K., Yu, Y., Reynolds, R., Zack, D.J., Campochiaro, B.,
Maeda, A., Palczewski, K., 2010. Noninvasive multiphoton fluorescence micro- Campochiaro, P., Katsanis, N., Daly, M.J., Seddon, J.M., 2011. A rare penetrant
scopy resolves retinol and retinal condensation products in mouse eyes. Nat. mutation in CFH confers high risk of age-related macular degeneration. Nat.
Med. 16, 1444e1449. Genet. 43, 1232e1236.
Parmalee, N.L., Schubert, C., Figueroa, M., Bird, A.C., Peto, T., Gillies, M.C., Reardon, W., Ross, R.J., Sweeney, M.G., Luxon, L.M., Pembrey, M.E., Harding, A.E.,
Bernstein, P.S., Kiryluk, K., Terwilliger, J.D., Allikmets, R., MacTel, P., 2012. Trembath, R.C., 1992. Diabetes mellitus associated with a pathogenic point
Identification of a potential susceptibility locus for macular telangiectasia type mutation in mitochondrial DNA. Lancet 340, 1376e1379.
2. Plos One 7, e24268. Reichel, M.B., Kelsell, R.E., Fan, J., Gregory, C.Y., Evans, K., Moore, A.T., Hunt, D.M.,
Patrinely, J.R., Lewis, R.A., Font, R.L., 1985. Foveomacular vitelliform dystrophy, adult Fitzke, F.W., Bird, A.C., 1998. Phenotype of a British North Carolina macular
type. A clinicopathologic study including electron microscopic observations. dystrophy family linked to chromosome 6q. Br. J. Ophthalmol. 82, 1162e1168.
Ophthalmology 92, 1712e1718. Renner, A.B., Tillack, H., Kraus, H., Kohl, S., Wissinger, B., Mohr, N., Weber, B.H.,
Pawlak, D., Souied, E., Mimoun, G., Papp-Pawlak, M., Coscas, G., Soubrane, G., 2006. Kellner, U., Foerster, M.H., 2004. Morphology and functional characteristics in
Fundus flavimaculatus and choroidal neovascularization. J. Fr. Ophtalmol. 29, adult vitelliform macular dystrophy. Retina 24, 929e939.
188e194. Renner, A.B., Fiebig, B.S., Weber, B.H., Wissinger, B., Andreasson, S., Gal, A., Cropp, E.,
Pece, A., Avanza, P., Introini, U., Brancato, R., 1997. Indocyanine green angiography in Kohl, S., Kellner, U., 2009. Phenotypic variability and long-term follow-up of
angioid streaks. Acta Ophthalmol. Scand. 75, 261e265. patients with known and novel PRPH2/RDS gene mutations. Am. J. Ophthalmol.
Peters, A.L., Young, M.J., Miller, J.K., 2006. Optical coherence tomography for 147, 518e530 e511.
assessing disease progression in sorsby fundus dystrophy. Retina (Philadelphia, Reynolds, R., Hartnett, M.E., Atkinson, J.P., Giclas, P.C., Rosner, B., Seddon, J.M., 2009.
Pa.) 26, 1082e1084. Plasma complement components and activation fragments: associations with
Petrukhin, K., Koisti, M.J., Bakall, B., Li, W., Xie, G., Marknell, T., Sandgren, O., Forsman, K., age-related macular degeneration genotypes and phenotypes. Invest. Oph-
Holmgren, G., Andreasson, S., Vujic, M., Bergen, A.A., McGarty-Dugan, V., thalmol. Vis. Sci. 50, 5818e5827.
Figueroa, D., Austin, C.P., Metzker, M.L., Caskey, C.T., Wadelius, C., 1998. Identifica- Ringpfeil, F., Pulkkinen, L., Uitto, J., 2001. Molecular genetics of pseudoxanthoma
tion of the gene responsible for Best macular dystrophy. Nat. Gen. 19, 241e247. elasticum. Exp. Dermatol. 10, 221e228.
Piguet, B., Haimovici, R., Bird, A.C., 1995. Dominantly inherited drusen represent Rivera, A., Fisher, S.A., Fritsche, L.G., Keilhauer, C.N., Lichtner, P., Meitinger, T.,
more than one disorder: a historical review. Eye (Lond) 9 (Pt 1), 34e41. Weber, B.H., 2005. Hypothetical LOC387715 is a second major susceptibility
Piguet, B., Heon, E., Munier, F.L., Grounauer, P.A., Niemeyer, G., Butler, N., gene for age-related macular degeneration, contributing independently of
Schorderet, D.F., Sheffield, V.C., Stone, E.M., 1996. Full characterization of the complement factor H to disease risk. Hum. Mol. Genet. 14, 3227e3236.
maculopathy associated with an Arg-172-Trp mutation in the RDS/peripherin Ronan, S., Nusinowitz, S., Swaroop, A., Heckenlively, J.R., 2006. Senile panretinal
gene. Ophthal. Genet. 17, 175e186. cone dysfunction in age-related macular degeneration (AMD): a report of 52
Polkinghorne, P.J., Capon, M.R., Berninger, T., Lyness, A.L., Sehmi, K., Bird, A.C., 1989. amd patients compared to age-matched controls. Trans. Am. Ophthalmol. Soc.
Sorsby’s fundus dystrophy. A clinical study. Ophthalmology 96, 1763e1768. 104, 232e240.
Powner, M.B., Gillies, M.C., Tretiach, M., Scott, A., Guymer, R.H., Hageman, G.S., Rosenberg, T., Roos, B., Johnsen, T., Bech, N., Scheetz, T.E., Larsen, M., Stone, E.M.,
Fruttiger, M., 2010. Perifoveal muller cell depletion in a case of macular telan- Fingert, J.H., 2010. Clinical and genetic characterization of a Danish family with
giectasia type 2. Ophthalmology 117, 2407e2416. North Carolina macular dystrophy. Mol. Vis. 16, 2659e2668.
Powner, M.B., Gillies, M.C., Zhu, M., Vevis, K., Hunyor, A.P., Fruttiger, M., 2013. Loss of Rowe, S.E., Trobe, J.D., Sieving, P.A., 1990. Idiopathic photoreceptor dysfunction
Muller’s cells and photoreceptors in macular telangiectasia type 2. Ophthal- causes unexplained visual acuity loss in later adulthood. Ophthalmology 97,
mology (Epub ahead of print). 1632e1637.
Puche, N., Querques, G., Benhamou, N., Tick, S., Mimoun, G., Martinelli, D., Rudnicka, A.R., Jarrar, Z., Wormald, R., Cook, D.G., Fletcher, A., Owen, C.G., 2012. Age
Soubrane, G., Souied, E.H., 2010. High-resolution spectral domain optical and gender variations in age-related macular degeneration prevalence in
56 N.T.M. Saksens et al. / Progress in Retinal and Eye Research 39 (2014) 23e57

populations of European ancestry: a meta-analysis. Ophthalmology 119, 571e Sobrin, L., Maller, J.B., Neale, B.M., Reynolds, R.C., Fagerness, J.A., Daly, M.J.,
580. Seddon, J.M., 2010. Genetic profile for five common variants associated with
Saihan, Z., Li, Z., Rice, J., Rana, N.A., Ramsden, S., Schlottmann, P.G., Jenkins, S.A., age-related macular degeneration in densely affected families: a novel analytic
Blyth, C., Black, G.C., McKie, N., Webster, A.R., 2009. Clinical and biochemical approach. Eur. J. Hum. Genet. 18, 496e501.
effects of the E139K missense mutation in the TIMP3 gene, associated with Sohn, E.H., Mullins, R.F., Stone, E.M., 2013. Macular dystrophies. V. In: Ryan, J.R.
Sorsby fundus dystrophy. Mol. Vis. 15, 1218e1230. (Ed.), Retina. Elsevier, London, New York, Oxford, St. Louis, Sydney, Toronto.
Sallo, F.B., Leung, I., Chung, M., Wolf-Schnurrbusch, U.E., Dubra, A., Williams, D.R., Song, I.S., Shin, Y.U., Lee, B.R., 2012. Time-periodic characteristics in the morphology
Clemons, T., Pauleikhoff, D., Bird, A.C., Peto, T., 2011. Retinal crystals in type 2 of idiopathic central serous chorioretinopathy evaluated by volume scan using
idiopathic macular telangiectasia. Ophthalmology 118, 2461e2467. spectral-domain optical coherence tomography. Am. J. Ophthalmol. 154, 366e
Sarks, S.H., 1980. Council Lecture. Drusen and their relationship to senile macular 375 e364.
degeneration. Aust. J. Ophthalmol. 8, 117e130. Souied, E.H., Pawlak, D., Algan, M., Sayag, D., Coscas, G., Soubrane, G., 2005.
Sarks, J.P., Sarks, S.H., Killingsworth, M.C., 1988. Evolution of geographic atrophy of Photodynamic therapy for choroidal neovascularization on late-onset fundus
the retinal pigment epithelium. Eye (Lond) 2 (5), 552e577. flavimaculatus. Am. J. Ophthalmol. 140, 312e314.
Sarks, J.P., Sarks, S.H., Killingsworth, M.C., 1994. Evolution of soft drusen in age- Souied, E.H., Leveziel, N., Letien, V., Darmon, J., Coscas, G., Soubrane, G., 2006a.
related macular degeneration. Eye (Lond) 8 (Pt 3), 269e283. Optical coherent tomography features of malattia leventinese. Am. J. Oph-
Sawa, M., Ober, M.D., Freund, K.B., Spaide, R.F., 2006. Fundus autofluorescence in thalmol. 141, 404e407.
patients with pseudoxanthoma elasticum. Ophthalmology 113, 814e820 e812. Souied, E.H., Leveziel, N., Querques, G., Darmon, J., Coscas, G., Soubrane, G., 2006b.
Schara, U., Schoser, B.G., 2006. Myotonic dystrophies type 1 and 2: a summary on Indocyanine green angiography features of Malattia leventinese. Br. J. Oph-
current aspects. Semin. Pediatr. Neurol. 13, 71e79. thalmol. 90, 296e300.
Schmitz-Valckenberg, S., Fleckenstein, M., Scholl, H.P., Holz, F.G., 2009a. Fundus Soumplis, V., Sergouniotis, P.I., Robson, A.G., Michaelides, M., Moore, A.T.,
autofluorescence and progression of age-related macular degeneration. Surv. Holder, G.E., Webster, A.R., 2013. Phenotypic findings in C1QTNF5 retinopathy
Ophthalmol. 54, 96e117. (late-onset retinal degeneration). Acta Ophthalmol. 91, e191ee195.
Schmitz-Valckenberg, S., Ong, E.E., Rubin, G.S., Peto, T., Tufail, A., Egan, C.A., Spaide, R.F., Curcio, C.A., 2010. Drusen characterization with multimodal imaging.
Bird, A.C., Fitzke, F.W., 2009b. Structural and functional changes over time in Retina 30, 1441e1454.
MacTel patients. Retina 29, 1314e1320. Spaide, R.F., Klancnik Jr., J.M., 2005. Fundus autofluorescence and central serous
Schmitz-Valckenberg, S., Steinberg, J.S., Fleckenstein, M., Visvalingam, S., chorioretinopathy. Ophthalmology 112, 825e833.
Brinkmann, C.K., Holz, F.G., 2010. Combined confocal scanning laser ophthal- Spaide, R.F., Noble, K., Morgan, A., Freund, K.B., 2006. Vitelliform macular dystrophy.
moscopy and spectral-domain optical coherence tomography imaging of Ophthalmology 113, 1392e1400.
reticular drusen associated with age-related macular degeneration. Ophthal- Sparrow, J.R., Vollmer-Snarr, H.R., Zhou, J., Jang, Y.P., Jockusch, S., Itagaki, Y.,
mology 117, 1169e1176. Nakanishi, K., 2003. A2E-epoxides damage DNA in retinal pigment epithelial
Schoenberger, S.D., Agarwal, A., 2013. A novel mutation at the N-Terminal domain cells. Vitamin E and other antioxidants inhibit A2E-epoxide formation. J. Biol.
of the Timp3 gene in sorsby fundus dystrophy. Retina (Philadelphia, Pa.) 33, Chem. 278, 18207e18213.
429e435. Stargardt, K., 1909. Über familiäre, progressive Degeneration in der Maculagegend
Scholl, H.P., Charbel Issa, P., Walier, M., Janzer, S., Pollok-Kopp, B., Borncke, F., des Auges. Graefes Arch. Clin. Exp. Ophthalmol. 71, 534e550.
Fritsche, L.G., Chong, N.V., Fimmers, R., Wienker, T., Holz, F.G., Weber, B.H., Steinert, H., 1909. Myopathologische Beitrage 1: Uber das klinischeund anatomi-
Oppermann, M., 2008. Systemic complement activation in age-related macular sche Bild des Muskelschwunds der Myotoniker. Dtsch. Z. Nervenheilkd. 37, 58e
degeneration. PLoS One 3, e2593. 104.
Schworm, H.D., Ulbig, M.W., Hoops, J., Rudolph, G., Weber, B.H., Ehrt, O., Stohr, H., Anand-Apte, B., 2012. A review and update on the molecular basis of
Boergen, K.P., 1998. North Carolina macular dystrophy. Hereditary macular pathogenesis of Sorsby fundus dystrophy. Adv. Exp. Med. Biol. 723, 261e267.
disease with good functional prognosis. Der. Ophthal. 95, 13e18. Stone, E.M., Lotery, A.J., Munier, F.L., Heon, E., Piguet, B., Guymer, R.H.,
Seddon, J.M., Ajani, U.A., Mitchell, B.D., 1997. Familial aggregation of age-related Vandenburgh, K., Cousin, P., Nishimura, D., Swiderski, R.E., Silvestri, G.,
maculopathy. Am. J. Ophthalmol. 123, 199e206. Mackey, D.A., Hageman, G.S., Bird, A.C., Sheffield, V.C., Schorderet, D.F., 1999.
Seddon, J.M., Afshari, M.A., Sharma, S., Bernstein, P.S., Chong, S., Hutchinson, A., A single EFEMP1 mutation associated with both Malattia Leventinese and
Petrukhin, K., Allikmets, R., 2001. Assessment of mutations in the Best macular Doyne honeycomb retinal dystrophy. Nat. Genet. 22, 199e202.
dystrophy (VMD2) gene in patients with adult-onset foveomacular vitelliform Subfoveal neovascular lesions in age-related macular degeneration. Guidelines for
dystrophy, age-related maculopathy, and bull’s-eye maculopathy. Ophthal- evaluation and treatment in the macular photocoagulation study. Macular
mology 108, 2060e2067. Photocoagulation Study Group. Arch. Ophthalmol. 109, 1242e1257.
Seddon, J.M., Sharma, S., Adelman, R.A., 2006. Evaluation of the clinical age-related Suter, M., Reme, C., Grimm, C., Wenzel, A., Jaattela, M., Esser, P., Kociok, N., Leist, M.,
maculopathy staging system. Ophthalmology 113, 260e266. Richter, C., 2000. Age-related macular degeneration. The lipofusion component
Shiraki, K., Kohno, T., Moriwaki, M., Yanagihara, N., 2001. Fundus autofluorescence N-retinyl-N-retinylidene ethanolamine detaches proapoptotic proteins from
in patients with pseudoxanthoma elasticum. Int. Ophthalmol. 24, 243e248. mitochondria and induces apoptosis in mammalian retinal pigment epithelial
Shu, X., Tulloch, B., Lennon, A., Vlachantoni, D., Zhou, X., Hayward, C., Wright, A.F., cells. J. Biol. Chem. 275, 39625e39630.
2006. Disease mechanisms in late-onset retinal macular degeneration associ- Suzuki, M., Gomi, F., Sawa, M., Ueno, C., Nishida, K., 2013. Changes in fundus
ated with mutation in C1QTNF5. Hum. Mol. Genet. 15, 1680e1689. autofluorescence in polypoidal choroidal vasculopathy during 3 years of follow-
Sicot, G., Gourdon, G., Gomes-Pereira, M., 2011. Myotonic dystrophy, when simple up. Graefes Arch. Clin. Exp. Ophthalmol. (Epub ahead of print).
repeats reveal complex pathogenic entities: new findings and future challenges. Szental, J.A., Harper, C.A., Baird, P.N., Michalova, K., Guymer, R.H., 2009. Sorsby’s
Hum. Mol. Genet. 20, R116eR123. Fundus Dystrophy: a case report to raise awareness of the disease and potential
Sivaprasad, S., Webster, A.R., Egan, C.A., Bird, A.C., Tufail, A., 2008. Clinical course future treatments. Clin. Exp. Ophthalmol. 37, 325e327.
and treatment outcomes of Sorsby fundus dystrophy. Am. J. Ophthalmol. 146, Szlyk, J.P., Paliga, J., Seiple, W., Rabb, M.F., 2005. Comprehensive functional vision
228e234. assessment of patients with North Carolina macular dystrophy (MCDR1). Retina
Sjogren, H., 1950. Dystrophia reticularis laminae pigmentosae retinae, an earlier not (Philadelphia, Pa.) 25, 489e497.
described hereditary eye disease. Acta Ophthalmol. (Copenh) 28, 279e295. Takeuchi, T., Hayashi, T., Bedell, M., Zhang, K., Yamada, H., Tsuneoka, H., 2010.
Slezak, H., Hommer, K., 1969. Fundus pulverulentus. Albrecht Von Graefes Arch. A novel haplotype with the R345W mutation in the EFEMP1 gene associated
Klin. Exp. Ophthalmol. 178, 176e182. with autosomal dominant drusen in a Japanese family. Invest. Ophthalmol. Vis.
Smailhodzic, D., Fleckenstein, M., Theelen, T., Boon, C.J., van Huet, R.A., van de Sci. 51, 1643e1650.
Ven, J.P., Den Hollander, A.I., Schmitz-Valckenberg, S., Hoyng, C.B., Weber, B.H., Theelen, T., Berendschot, T.T., Boon, C.J., Hoyng, C.B., Klevering, B.J., 2008. Analysis of
Holz, F.G., Klevering, B.J., 2011. Central areolar choroidal dystrophy (CACD) and visual pigment by fundus autofluorescence. Exp. Eye Res. 86, 296e304.
age-related macular degeneration (AMD): differentiating characteristics in Travis, G.H., Sutcliffe, J.G., Bok, D., 1991. The retinal degeneration slow (rds) gene
multimodal imaging. Invest. Ophthalmol. Vis. Sci. 52, 8908e8918. product is a photoreceptor disc membrane-associated glycoprotein. Neuron 6,
Small, K.W., 1989. North Carolina macular dystrophy, revisited. Ophthalmology 96, 61e70.
1747e1754. Tuppurainen, K., Mantyjarvi, M., 1994. The importance of fluorescein angiography
Small, K.W., 1998. North Carolina macular dystrophy: clinical features, genealogy, in diagnosing pattern dystrophies of the retinal pigment epithelium. Doc.
and genetic linkage analysis. Trans. Am. Ophthalmol. Soc. 96, 925e961. Ophthalmol. 87, 233e243.
Small, K.W., Killian, J., McLean, W.C., 1991. North Carolina’s dominant progressive Ulbig, M.R., Riordan-Eva, P., Holz, F.G., Rees, H.C., Hamilton, P.A., 1993. Mem-
foveal dystrophy: how progressive is it? Br. J. Ophthalmol. 75, 401e406. branoproliferative glomerulonephritis type II associated with central serous
Small, K.W., Weber, J.L., Roses, A., Lennon, F., Vance, J.M., Pericak-Vance, M.A., 1992. retinopathy. Am. J. Ophthalmol. 116, 410e413.
North Carolina macular dystrophy is assigned to chromosome 6. Genomics 13, Vaclavik, V., Tran, H.V., Gaillard, M.C., Schorderet, D.F., Munier, F.L., 2012. Pattern
681e685. dystrophy with high intrafamilial variability associated with Y141C mutation in
Small, K.W., Voo, I., Flannery, J., Udar, N., Glasgow, B.J., 2001. North Carolina macular the peripherin/RDS gene and successful treatment of subfoveal CNV related to
dystrophy: clinicopathologic correlation. Trans. Am. Ophthalmol. Soc. 99, 233e multifocal pattern type with anti-VEGF (ranibizumab) intravitreal injections.
237. Discussion 237e238. Retina (Philadelphia, Pa.) 32, 1942e1949.
Smith, W., Assink, J., Klein, R., Mitchell, P., Klaver, C.C., Klein, B.E., Hofman, A., van de Ven, J.P., Boon, C.J., Fauser, S., Hoefsloot, L.H., Smailhodzic, D., Schoenmaker-
Jensen, S., Wang, J.J., de Jong, P.T., 2001. Risk factors for age-related macular Koller, F., Klevering, J., Klaver, C.C., den Hollander, A.I., Hoyng, C.B., 2012a.
degeneration: pooled findings from three continents. Ophthalmology 108, Clinical evaluation of 3 families with basal laminar drusen caused by novel
697e704. mutations in the complement factor H gene. Arch. Ophthalmol. 130, 1038e1047.
 N.T.M. Saksens et al. / Progress in Retinal and Eye Research 39 (2014) 23e57 57

van de Ven, J.P., Smailhodzic, D., Boon, C.J., Fauser, S., Groenewoud, J.M., Chong, N.V., Westeneng-van Haaften, S.C., Boon, C.J., Cremers, F.P., Hoefsloot, L.H., den
Hoyng, C.B., Klevering, B.J., den Hollander, A.I., 2012b. Association analysis of Hollander, A.I., Hoyng, C.B., 2012. Clinical and genetic characteristics of late-
genetic and environmental risk factors in the cuticular drusen subtype of age- onset Stargardt’s disease. Ophthalmology 119, 1199e1210.
related macular degeneration. Mol. Vis. 18, 2271e2278. Wickham, L., Chen, F.K., Lewis, G.P., Uppal, G.S., Neveu, M.M., Wright, G.A.,
van de Ven, J.P., Nilsson, S.C., Tan, P.L., Buitendijk, G.H., Ristau, T., Mohlin, F.C., Robson, A.G., Webster, A.R., Grierson, I., Hiscott, P., Coffey, P.J., Holder, G.E.,
Nabuurs, S.B., Schoenmaker-Koller, F.E., Smailhodzic, D., Campochiaro, P.A., Fisher, S.K., Da Cruz, L., 2009. Clinicopathological case series of four patients
Zack, D.J., Duvvari, M.R., Bakker, B., Paun, C.C., Boon, C.J., Uitterlinden, A.G., with inherited macular disease. Invest. Ophthalmol. Vis. Sci. 50, 3553e3561.
Liakopoulos, S., Klevering, B.J., Fauser, S., Daha, M.R., Katsanis, N., Klaver, C.C., Williams, D.G., 1997. C3 nephritic factor and mesangiocapillary glomerulonephritis.
Blom, A.M., Hoyng, C.B., den Hollander, A.I., 2013. A functional variant in the CFI Pediatr. Nephrol. 11, 96e98.
gene confers a high risk of age-related macular degeneration. Nat. Gen. 45, Yamagishi, T., Koizumi, H., Yamazaki, T., Kinoshita, S., 2012. Fundus auto-
813e817. fluorescence in polypoidal choroidal vasculopathy. Ophthalmology 119, 1650e
van den Ouweland, J.M., Lemkes, H.H., Ruitenbeek, W., Sandkuijl, L.A., de 1657.
Vijlder, M.F., Struyvenberg, P.A., van de Kamp, J.J., Maassen, J.A., 1992. Mutation Yang, Z., Li, Y., Jiang, L., Karan, G., Moshfeghi, D., O’Connor, S., Li, X., Yu, Z., Lewis, H.,
in mitochondrial tRNA(Leu)(UUR) gene in a large pedigree with maternally Zack, D., Jacobson, S., Zhang, K., 2004. A novel RDS/peripherin gene mutation
transmitted type II diabetes mellitus and deafness. Nat. Genet. 1, 368e371. associated with diverse macular phenotypes. Ophthal. Genet. 25, 133e145.
Vincent, A., Munier, F.L., Vandenhoven, C.C., Wright, T., Westall, C.A., Heon, E., 2012. Yang, Z., Tong, Z., Chorich, L.J., Pearson, E., Yang, X., Moore, A., Hunt, D.M., Zhang, K.,
The characterization of retinal phenotype in a family with C1QTNF5-related 2008. Clinical characterization and genetic mapping of North Carolina macular
late-onset retinal degeneration. Retina (Philadelphia, Pa.) 32, 1643e1651. dystrophy. Vis. Res. 48, 470e477.
von Ruckmann, A., Schmidt, K.G., Fitzke, F.W., Bird, A.C., Jacobi, K.W., 1998. Fundus Yannuzzi, L.A., Shakin, J.L., Fisher, Y.L., Altomonte, M.A., 1984. Peripheral retinal
autofluorescence in patients with hereditary macular dystrophies, malattia detachments and retinal pigment epithelial atrophic tracts secondary to central
leventinese, familial dominant and aged-related drusen. Klin. Monbl. Augen- serous pigment epitheliopathy. Ophthalmology 91, 1554e1572.
heilkd. 213, 81e86. Yannuzzi, L.A., Wong, D.W., Sforzolini, B.S., Goldbaum, M., Tang, K.C., Spaide, R.F.,
Voo, I., Glasgow, B.J., Flannery, J., Udar, N., Small, K.W., 2001. North Carolina macular Freund, K.B., Slakter, J.S., Guyer, D.R., Sorenson, J.A., Fisher, Y., Maberley, D.,
dystrophy: clinicopathologic correlation. Am. J. Ophthalmol. 132, 933e935. Orlock, D.A., 1999. Polypoidal choroidal vasculopathy and neovascularized age-
Wabbels, B., Demmler, A., Paunescu, K., Wegscheider, E., Preising, M.N., Lorenz, B., related macular degeneration. Arch. Ophthalmol. 117, 1503e1510.
2006a. Fundus autofluorescence in children and teenagers with hereditary Yannuzzi, L.A., Negrao, S., Iida, T., Carvalho, C., Rodriguez-Coleman, H., Slakter, J.,
retinal diseases. Graefes Arch. Clin. Exp. Ophthalmol. 244, 36e45. Freund, K.B., Sorenson, J., Orlock, D., Borodoker, N., 2001. Retinal angiomatous
Wabbels, B., Preising, M.N., Kretschmann, U., Demmler, A., Lorenz, B., 2006b. Ge- proliferation in age-related macular degeneration. Retina 21, 416e434.
notype-phenotype correlation and longitudinal course in ten families with best Zhang, Y., Marmorstein, L.Y., 2010. Focus on molecules: fibulin-3 (EFEMP1). Exp. Eye
vitelliform macular dystrophy. Graefe’s Arch. Clin. Exp. Ophthalmol. 244, 1453e Res. 90, 374e375.
1466. Zhang, K., Garibaldi, D.C., Li, Y., Green, W.R., Zack, D.J., 2002. Butterfly-shaped
Walter, P., Widder, R.A., Luke, C., Konigsfeld, P., Brunner, R., 1999. Electrophysio- pattern dystrophy: a genetic, clinical, and histopathological report. Arch. Oph-
logical abnormalities in age-related macular degeneration. Graefes Arch. Clin. thalmol. 120, 485e490.
Exp. Ophthalmol. 237, 962e968. Zhao, M., Celerier, I., Bousquet, E., Jeanny, J.C., Jonet, L., Savoldelli, M., Offret, O.,
Wang, M.S., Sander, B., Larsen, M., 2002. Retinal atrophy in idiopathic central serous Curan, A., Farman, N., Jaisser, F., Behar-Cohen, F., 2012. Mineralocorticoid re-
chorioretinopathy. Am. J. Ophthalmol. 133, 787e793. ceptor is involved in rat and human ocular chorioretinopathy. J. Clin. Invest. 122,
Wang, J.J., Foran, S., Smith, W., Mitchell, P., 2003. Risk of age-related macular 2672e2679.
degeneration in eyes with macular drusen or hyperpigmentation: the Blue Zhou, J., Jang, Y.P., Kim, S.R., Sparrow, J.R., 2006. Complement activation by photo-
Mountains Eye Study cohort. Arch. Ophthalmol. 121, 658e663. oxidation products of A2E, a lipofuscin constituent of the retinal pigment
Wang, M., Munch, I.C., Hasler, P.W., Prunte, C., Larsen, M., 2008. Central serous epithelium. Proc. Natl. Acad. Sci. U. S. A. 103, 16182e16187.
chorioretinopathy. Acta Ophthalmol. 86, 126e145. Zhu, M., Krilis, M., Gillies, M.C., 2013. The relationship between inner retinal cavi-
Wang, L., Clark, M.E., Crossman, D.K., Kojima, K., Messinger, J.D., Mobley, J.A., tation, photoreceptor disruption, and the integrity of the outer limiting mem-
Curcio, C.A., 2010. Abundant lipid and protein components of drusen. PLoS One brane in macular telangiectasia type 2. Retina 33, 1547e1550.
5, e10329. Zhuk, S.A., Edwards, A.O., 2006. Peripherin/RDS and VMD2 mutations in macular
Weber, B.H., Vogt, G., Pruett, R.C., Stohr, H., Felbor, U., 1994. Mutations in the tissue dystrophies with adult-onset vitelliform lesion. Mol. Vis. 12, 811e815.
inhibitor of metalloproteinases-3 (TIMP3) in patients with Sorsby’s fundus Zweifel, S.A., Spaide, R.F., Curcio, C.A., Malek, G., Imamura, Y., 2010. Reticular pseu-
dystrophy. Nat. Genet. 8, 352e356. dodrusen are subretinal drusenoid deposits. Ophthalmology 117, 303e312 e301.
Weenink, A.C., Borsje, R.A., Oosterhuis, J.A., 2001. Familial chronic central serous
chorioretinopathy. Ophthalmologica 215, 183e187.